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Horton WB, Love KM, Gregory JM, Liu Z, Barrett EJ. Metabolic and vascular insulin resistance: partners in the pathogenesis of cardiovascular disease in diabetes. Am J Physiol Heart Circ Physiol 2025; 328:H1218-H1236. [PMID: 40257392 DOI: 10.1152/ajpheart.00826.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 12/29/2024] [Accepted: 04/16/2025] [Indexed: 04/22/2025]
Abstract
Vascular insulin resistance has emerged as a pivotal factor in the genesis of cardiovascular disease (CVD) in people with diabetes. It forms a complex pathogenic partnership with metabolic insulin resistance to significantly amplify the CVD risk of diabetes and other affected populations. Metabolic insulin resistance (characterized by quantitatively diminished insulin action on glucose metabolism in skeletal muscle, liver, and adipose tissue) is a hallmark of diabetes, obesity, and related conditions. In contrast, vascular insulin resistance is a less appreciated and not well-quantified complication of these conditions. Importantly, an impaired vascular response to insulin contributes directly to vascular dysfunction and over 40 years of research has convincingly shown that vascular and metabolic insulin resistance synergize to create an environment that predisposes individuals to CVD. In this review, we examine the multifaceted vascular actions of insulin, including its roles in regulating blood pressure, blood flow, endothelial health, and arterial stiffness. We also examine how these processes become disrupted in the setting of vascular insulin resistance, which subsequently undermines endothelial function, compromises tissue microvascular perfusion, and promotes vascular rigidity and atherosclerosis. We then highlight potential therapeutic strategies with demonstrated efficacy to improve vascular insulin sensitivity in people with diabetes and suggest that targeting disordered vascular insulin signaling holds promise not only for refining the functional understanding of vascular insulin resistance but also for developing innovative treatments with potential to reduce CVD risk and improve cardiovascular outcomes in people with diabetes.
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Affiliation(s)
- William B Horton
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
| | - Kaitlin M Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
| | - Justin M Gregory
- Ian M. Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
| | - Eugene J Barrett
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, United States
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia, United States
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Apostolopoulou M, Lambadiari V, Roden M, Dimitriadis GD. Insulin Resistance in Type 1 Diabetes: Pathophysiological, Clinical, and Therapeutic Relevance. Endocr Rev 2025; 46:317-348. [PMID: 39998445 PMCID: PMC12063105 DOI: 10.1210/endrev/bnae032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Indexed: 02/26/2025]
Abstract
People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.
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Affiliation(s)
- Maria Apostolopoulou
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - Vaia Lambadiari
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - George D Dimitriadis
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
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Carobene A, Kilpatrick E, Bartlett WA, Fernández Calle P, Coşkun A, Díaz-Garzón J, Jonker N, Locatelli M, Sandberg S, Aarsand AK. The biological variation of insulin resistance markers: data from the European Biological Variation Study (EuBIVAS). Clin Chem Lab Med 2025; 63:110-117. [PMID: 38987271 DOI: 10.1515/cclm-2024-0672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 06/18/2024] [Indexed: 07/12/2024]
Abstract
OBJECTIVES An insulin resistant state is characteristic of patients with type 2 diabetes, polycystic ovary syndrome, and metabolic syndrome. Identification of insulin resistance (IR) is most readily achievable using formulae combining plasma insulin and glucose results. In this study, we have used data from the European Biological Variation Study (EuBIVAS) to examine the biological variability (BV) of IR using the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) and the Quantitative Insulin sensitivity Check Index (QUICKI). METHODS Ninety EuBIVAS non-diabetic subjects (52F, 38M) from five countries had fasting HOMA-IR and QUICKI calculated from plasma glucose and insulin samples collected concurrently on 10 weekly occasions. The within-subject (CVI) and between-subject (CVG) BV estimates with 95 % CIs were obtained by CV-ANOVA after analysis of trends, variance homogeneity and outlier removal. RESULTS The CVI of HOMA-IR was 26.7 % (95 % CI 25.5-28.3), driven largely by variability in plasma insulin and the CVI for QUICKI was 4.1 % (95 % CI 3.9-4.3), reflecting this formula's logarithmic transformation of glucose and insulin values. No differences in values or BV components were observed between subgroups of men or women below and above 50 years. CONCLUSIONS The EuBIVAS, by utilising a rigorous experimental protocol, has produced robust BV estimates for two of the most commonly used markers of insulin resistance in non-diabetic subjects. This has shown that HOMA-IR, in particular, is highly variable in the same individual which limits the value of single measurements.
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Affiliation(s)
- Anna Carobene
- Laboratory Medicine, 48455 IRCCS San Raffaele Scientific Institute , Milano, Italy
| | | | | | | | - Abdurrahman Coşkun
- School of Medicine, Acibadem Mehmet Ali Aydınlar University, Istanbul, Türkiye
| | - Jorge Díaz-Garzón
- Department of Laboratory Medicine, Hospital Universitario La Paz, Madrid, Spain
| | - Niels Jonker
- Certe, Wilhelmina Ziekenhuis Assen, Assen, The Netherlands
| | - Massimo Locatelli
- Laboratory Medicine, 48455 IRCCS San Raffaele Scientific Institute , Milano, Italy
| | - Sverre Sandberg
- Norwegian Porphyria Centre, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
- Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Haraldsplass Deaconess Hospital, Bergen, Norway
- Department of Global Health and Primary Care, Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Aasne K Aarsand
- Norwegian Porphyria Centre, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
- Norwegian Organization for Quality Improvement of Laboratory Examinations (Noklus), Haraldsplass Deaconess Hospital, Bergen, Norway
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Mertens J, Roosens L, Braspenning R, Vandebeeck J, Francque S, De Block C. The 13C Glucose Breath Test Accurately Identifies Insulin Resistance in People With Type 1 Diabetes. J Clin Endocrinol Metab 2025; 110:e432-e442. [PMID: 38487831 DOI: 10.1210/clinem/dgae175] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Indexed: 01/22/2025]
Abstract
OBJECTIVE This study investigated whether the delta-over-baseline of exhaled 13CO2 (Δ13CO2), generated from a 13C glucose breath test (13C-GBT), measured insulin resistance (IR) in people with type 1 diabetes, using the hyperinsulinemic-euglycemic clamp (HEC) as a reference method. The secondary objective was to compare the 13C-GBT with the estimated glucose disposal rate (eGDR). METHODS A 40 mU/m2/min HEC and 2 separate 13C-GBTs (euglycemic with insulin bolus and hyperglycemic without bolus) were consecutively performed in 44 adults with type 1 diabetes with varying body compositions. eGDR was calculated based on hemoglobin A1c (HbA1c), presence of hypertension, and waist circumference. RESULTS The mean glucose disposal rate (M-value) was 5.9 ± 3.1 mg/kg/min and mean euglycemic Δ13CO2 was 6.4 ± 2.1 δ‰, while median eGDR was 5.9 [4.3-9.8] mg/kg/min. The hyperglycemic Δ13CO2 did not correlate with the M-value, while the euglycemic Δ13CO2 and the M-value correlated strongly (r = 0.74, P < .001). The correlation between M-value and eGDR was more moderate (Spearman's rho = 0.63, P < .001). Linear regression showed an association between Δ13CO2 and M-value, adjusted for age, sex, and HbA1c ]adjusted R² = 0.52, B = 1.16, 95% confidence interval (CI) .80-1.52, P < .001]. The area under the receiver-operator characteristics curve for Δ13CO2 to identify subjects with IR (M-value < 4.9 mg/kg/min) was 0.81 (95% CI .68-.94, P < .001). The optimal cut-off for Δ13CO2 to identify subjects with IR was ≤ 5.8 δ‰. CONCLUSION Under euglycemic conditions, the 13C-GBT accurately identified individuals with type 1 diabetes and concurrent IR, suggesting its potential as a valuable noninvasive index. Clinical Trial Identifier: NCT04623320.
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Affiliation(s)
- Jonathan Mertens
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650 Edegem, Belgium
- Department of Gastroenterology & Hepatology, Antwerp University Hospital, 2650 Edegem, Belgium
- Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, 2610 Wilrijk, Belgium
| | - Laurence Roosens
- Laboratory of Clinical Chemistry, Antwerp University Hospital, 2650 Edegem, Belgium
| | - Rie Braspenning
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650 Edegem, Belgium
| | - Joeri Vandebeeck
- Laboratory of Clinical Chemistry, Antwerp University Hospital, 2650 Edegem, Belgium
| | - Sven Francque
- Department of Gastroenterology & Hepatology, Antwerp University Hospital, 2650 Edegem, Belgium
- Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, 2610 Wilrijk, Belgium
| | - Christophe De Block
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650 Edegem, Belgium
- Laboratory of Experimental Medicine and Paediatrics, University of Antwerp, 2610 Wilrijk, Belgium
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Zhang S, Yan H, Cao D, Sun W, Li J, Xu J, Song B, Wu X. Research hotspots and trends in diabetes and insulin resistance: a bibliometric analysis. Front Nutr 2024; 11:1480491. [PMID: 39737158 PMCID: PMC11684393 DOI: 10.3389/fnut.2024.1480491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 11/21/2024] [Indexed: 01/01/2025] Open
Abstract
Background Many previous studies explored the relationship between diabetes and insulin resistance (IR); however, addressing the research gap where no bibliometric analysis had been conducted to summarize and analyze these publications, we will undertake a comprehensive bibliometric analysis to investigate the current status and emerging trends in publications examining the association between diabetes and IR. Methods We retrieved publications related to the interaction between diabetes and IR from the Web of Science Core Collection (WoSCC). By utilizing software such as CiteSpace, VOSviewer, and Excel 2019, we analyzed and extracted relevant information from the literature to identify and delineate the research hotspots and directions in the study of diabetes and IR. Results From 1900 to 2024, a total of 2,698 publications were included in the bibliometric analysis, showing a steady annual increase in the number of publications. The USA led in this research field, with the Harvard University being a key research institution. The author Olefsky JM, published the most papers;Defronzo RA was the most cited author. DIABETES was the journal with the highest number of published papers and was also the most cited journal. The main discipline in the field of diabetes and IR research was Endocrinology and Metabolism. The most cited article was "Mechanisms linking obesity to insulin resistance and type 2 diabetes (2006)";"The IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045(2018)" was the most cited reference. "insulin resistance" was the most frequently occurring keyword. The main research hotspots and frontier areas in diabetes and IR research were as follows: (1) The association between IR, diabetes, and obesity was a popular research topic; (2) Cardiovascular diseases secondary to diabetes and IR were another hot topic among researchers; (3) As a core pathological change in diabetes, IR was a major therapeutic target for improving diabetes. Conclusion This study summarized the research trends and hotspots in the field of diabetes and IR, provided valuable information and insights for scholars who focused on diabetes and IR scientific research, and offered a reference for future research directions.
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Affiliation(s)
- Shaobo Zhang
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, China
| | - Huixin Yan
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, China
| | - Di Cao
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Weichen Sun
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, China
- Department of Traditional Chinese Medicine, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jingnan Li
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, China
| | - Jing Xu
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, China
| | - Bailin Song
- Department of Acupuncture and Tuina, Changchun University of Chinese Medicine, Changchun, China
| | - Xingquan Wu
- Department of Tuina, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China
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Clinck I, Mertens J, Wouters K, Dirinck E, De Block C. Insulin Resistance and CGM-Derived Parameters in People With Type 1 Diabetes: Are They Associated? J Clin Endocrinol Metab 2024; 109:e2131-e2140. [PMID: 38198792 DOI: 10.1210/clinem/dgae015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 01/04/2024] [Accepted: 01/08/2024] [Indexed: 01/12/2024]
Abstract
BACKGROUND Insulin resistance (IR) is increasingly more prevalent in people with type 1 diabetes (T1D). OBJECTIVE We investigated whether IR is associated with continuous glucose monitor (CGM)-derived parameters (glucometrics), such as time in range (TIR), time above range (TAR), time below range (TBR), and glycemic variability (CV). METHODS This is a retrospective analysis of 2 databases: IR was quantified according to the estimated glucose disposal rate (eGDR) (NCT04664036) and by performing a hyperinsulinemic-euglycemic clamp (HEC) (NCT04623320). All glucometrics were calculated over 28 days. RESULTS A total of 287 subjects were included. Mean age was 46 ± 17 years, 55% were male, TIR was 57% ± 14%, and eGDR was 7.6 (5.6-9.3) mg/kg/min. The tertile of people with the lowest eGDR (highest level of IR) had a higher TAR compared to the tertile with the highest eGDR (39% ± 15% vs 33% ± 14%, P = .043). Using logistic regression, a higher eGDR was associated with a higher chance to fall in a higher TIR-tertile (odds ratio [OR] 1.251, P < .001), a lower TAR-tertile (OR 1.281, P < .001), and a higher TBR-tertile (OR 0.893, P = .039), adjusted for age, sex, diabetes duration, smoking status, and alcohol intake. In the 48 people undergoing a HEC, no significant association between glucometrics and the HEC-determined glucose disposal rate (M-value) was observed. CONCLUSION In people with T1D, an association between IR, measured by eGDR, and worse CGM profiles was observed.
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Affiliation(s)
- Isabel Clinck
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650 Edegem, Belgium
| | - Jonathan Mertens
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650 Edegem, Belgium
- Laboratory of Experimental Medicine and Paediatrics and member of the Infla-Med Centre of Excellence, University of Antwerp, Faculty of Medicine & Health Sciences, 2000 Antwerp, Belgium
| | - Kristien Wouters
- Clinical Trial Centre (CTC), CRC Antwerp, Antwerp University Hospital, 2650 Edegem, Belgium
| | - Eveline Dirinck
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650 Edegem, Belgium
- Laboratory of Experimental Medicine and Paediatrics and member of the Infla-Med Centre of Excellence, University of Antwerp, Faculty of Medicine & Health Sciences, 2000 Antwerp, Belgium
| | - Christophe De Block
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, 2650 Edegem, Belgium
- Laboratory of Experimental Medicine and Paediatrics and member of the Infla-Med Centre of Excellence, University of Antwerp, Faculty of Medicine & Health Sciences, 2000 Antwerp, Belgium
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Belal MM, Khalefa BB, Rabea EM, Aly Yassin MN, Bashir MN, Abd El-Hameed MM, Elkoumi O, Saad SM, Saad LM, Elkasaby MH. Low dose insulin infusion versus the standard dose in children with diabetic ketoacidosis: a meta-analysis. Future Sci OA 2024; 10:FSO956. [PMID: 38827803 PMCID: PMC11140676 DOI: 10.2144/fsoa-2023-0137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 12/13/2023] [Indexed: 06/05/2024] Open
Abstract
Aim: This systematic review aims to consolidate findings from current clinical trials that compare the effectiveness of insulin infusion at 0.05 IU/kg/h versus 0.1 IU/kg/h in managing pediatric diabetic ketoacidosis. Methods: We searched several databases, including PubMed, Embase, Scopus, Cochrane Central and Web of Science. Our primary outcomes were time to reach blood glucose ≤250 mg/dl and time to resolution of acidosis. Secondary outcomes included rate of blood glucose decrease per hour, incidence of hypoglycemia, hypokalemia, treatment failure, and cerebral edema. Results & conclusion: The present study establishes that a low insulin dose exhibits comparable efficacy to the standard dosage for managing pediatric patients suffering from diabetic ketoacidosis, with a lower incidence of complications.
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Affiliation(s)
- Mohamed Mohamed Belal
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
| | - Basma Badrawy Khalefa
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
- Faculty of Medicine, Ain shams University, Cairo, Egypt
| | - Eslam Mohammed Rabea
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
| | - Mazen Negmeldin Aly Yassin
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
- Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Mohamed Nabih Bashir
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
| | - Malak Mohamed Abd El-Hameed
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
- Faculty of Medicine, Zagazig University, Ash Sharqia, Egypt
| | - Omar Elkoumi
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
- Faculty of Medicine, Suez University, Suez, Egypt
| | - Saad Mohamed Saad
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
| | - Loubna Mohamed Saad
- Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
| | - Mohamed Hamouda Elkasaby
- Medical Research Group of Egypt (MRGE), Cairo, Egypt
- Faculty of Medicine, Al-Azhar University, Cairo, Egypt
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Lin YB, Chang TJ. Age at onset of type 1 diabetes between puberty and 30 years old is associated with increased diabetic nephropathy risk. Sci Rep 2024; 14:3611. [PMID: 38351110 PMCID: PMC10864267 DOI: 10.1038/s41598-024-54137-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 02/08/2024] [Indexed: 02/16/2024] Open
Abstract
Diabetic nephropathy is a critical complication of patients with type 1 diabetes, while epidemiological studies were scarce among Asian countries. We conducted a cross-sectional study to identify factors associated with diabetic nephropathy by questionnaires, using student's t-test, chi-square test, and multivariable logistic regression. Among 898 participants, 16.7% had diabetic nephropathy. Compared with non-diabetic nephropathy patients, the patients with diabetic nephropathy had significantly higher percentage with onset age of type 1 diabetes between puberty and under 30 years old (female ≥ 12 or male ≥ 13 years old to 29 years old), longer diabetes duration, having family history of diabetes and diabetic nephropathy, accompanied with hypertension, hyperlipidemia, or coronary artery disease (CAD). Compared with patients with onset age before puberty, the odds of diabetic nephropathy occurrence increased to 1.61 times in patients with onset age between puberty and under 30 years old (p = 0.012) after adjusting diabetes duration. Age of diabetes onset between puberty and under 30 years old, diabetes duration, HbA1c, hospital admission within 3 years, diabetic retinopathy, hypertension, systolic blood pressure (SBP), triglyceride levels, and use of angiotensin converting enzyme inhibitor (ACEI) and/or angiotensin receptor blockers (ARB) were independent factors associated with diabetic nephropathy Screening for proteinuria is important in daily clinical practice and should be part of diabetes self-management education for patients with type 1 diabetes.
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Affiliation(s)
- Yen-Bo Lin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital Bei-Hu Branch, Taipei, Taiwan
| | - Tien-Jyun Chang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- National Taiwan University School of Medicine, Taipei, Taiwan.
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Rabbani N, Thornalley PJ. Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications. Front Endocrinol (Lausanne) 2024; 14:1268308. [PMID: 38292764 PMCID: PMC10824962 DOI: 10.3389/fendo.2023.1268308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/12/2023] [Indexed: 02/01/2024] Open
Abstract
Hyperglycemia is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes. We propose the hypothesis, hexokinase-linked glycolytic overload and unscheduled glycolysis, in explanation. Hexokinases (HKs) catalyze the first step of glucose metabolism. Increased flux of glucose metabolism through glycolysis gated by HKs, when occurring without concomitant increased activity of glycolytic enzymes-unscheduled glycolysis-produces increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis. HK1 is saturated with glucose in euglycemia and, where it is the major HK, provides for basal glycolytic flux without glycolytic overload. HK2 has similar saturation characteristics, except that, in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis. This drives the development of vascular complications of diabetes. Similar HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance. Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes. Downstream effector pathways of HK-linked unscheduled glycolysis are mitochondrial dysfunction and increased reactive oxygen species (ROS) formation; activation of hexosamine, protein kinase c, and dicarbonyl stress pathways; and increased Mlx/Mondo A signaling. Mitochondrial dysfunction and increased ROS was proposed as the initiator of metabolic dysfunction in hyperglycemia, but it is rather one of the multiple downstream effector pathways. Correction of HK2 dysregulation is proposed as a novel therapeutic target. Pharmacotherapy addressing it corrected insulin resistance in overweight and obese subjects in clinical trial. Overall, the damaging effects of hyperglycemia are a consequence of HK-gated increased flux of glucose metabolism without increased glycolytic enzyme activities to accommodate it.
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Affiliation(s)
| | - Paul J. Thornalley
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
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Xie Y, Shi M, Ji X, Huang F, Fan L, Li X, Zhou Z. Insulin resistance is more frequent in type 1 diabetes patients with long disease duration. Diabetes Metab Res Rev 2023; 39:e3640. [PMID: 36964977 DOI: 10.1002/dmrr.3640] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 03/10/2023] [Accepted: 03/21/2023] [Indexed: 03/27/2023]
Abstract
AIMS To investigate the clinical status of insulin resistance (IR) and its correlation with disease duration in patients with type 1 diabetes (T1D). MATERIALS AND METHODS Cross-sectional data from a T1D cohort were obtained (n = 923). IR-related metabolic disorders including hypertension, obesity, and dyslipidemia were used as outcome variables to explore the cut-off point for estimated glucose disposal rate (eGDR) by restricted cubic spline (RCS) curve. Regression models were used for multivariate analysis of the clinical factors associated with IR. The correlation between the status of IR and diabetes duration was depicted with the RCS curve. RESULTS IR-related metabolic disorders were observed in 39.4% of patients, with 9.1% meeting the criteria for metabolic syndrome. Specifically, patients with ≥10 years of T1D were more likely to have IR-related metabolic disorders (54.7% vs. 36.9%, p < 0.05). The presence of IR, defined as an eGDR ≤9.0 mg/kg/min, was observed in 42.2% of patients. Patients with IR had a longer diabetes duration (3.5 vs. 2.7, years, p = 0.003) and higher insulin dose (0.5 vs. 0.4, units per kg per day, p < 0.001). Moreover, the presence of IR showed a gradual increase during 10 years' disease duration and further analysis showed that diabetes duration ≥10 years was a key element behind the development of IR and IR-related metabolic disorders. CONCLUSIONS The status of IR is common in T1D patients, especially in those with ≥10 years of disease duration. Therapies targeting balancing glycaemic control and IR are needed to decrease the future risk of cardiovascular diseases in T1D. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT03610984 (cohort study of patients with type 1 diabetes).
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Affiliation(s)
- Yuting Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, Hunan, China
| | - Mei Shi
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, Hunan, China
| | - Xiaolin Ji
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, Hunan, China
| | - Fansu Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, Hunan, China
- Department of Nutrition, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Li Fan
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, Hunan, China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, Changsha, Hunan, China
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11
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Spoorthi Shetty S, Halagali P, Johnson AP, Spandana KMA, Gangadharappa HV. Oral insulin delivery: Barriers, strategies, and formulation approaches: A comprehensive review. Int J Biol Macromol 2023:125114. [PMID: 37263330 DOI: 10.1016/j.ijbiomac.2023.125114] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 06/03/2023]
Abstract
Diabetes Mellitus is characterized by a hyperglycemic condition which can either be caused by the destruction of the beta cells or by the resistance developed against insulin in the cells. Insulin is a peptide hormone that regulates the metabolism of carbohydrates, proteins, and fats. Type 1 Diabetes Mellitus needs the use of Insulin for efficient management. However invasive methods of administration may lead to reduced adherence by the patients. Hence there is a need for a non-invasive method of administration. Oral Insulin has several merits over the conventional method including patient compliance, and reduced cost, and it also mimics endogenous insulin and hence reaches the liver by the portal vein at a higher concentration and thereby showing improved efficiency. However oral Insulin must pass through several barriers in the gastrointestinal tract. Some strategies that could be utilized to bypass these barriers include the use of permeation enhancers, absorption enhancers, use of suitable polymers, use of suitable carriers, and other agents. Several formulation types have been explored for the oral delivery of Insulin like hydrogels, capsules, tablets, and patches which have been described briefly by the article. A lot of attempts have been made for developing oral insulin delivery however none of them have been commercialized due to numerous shortcomings. Currently, there are several formulations from the companies that are still in the clinical phase, the success or failure of some is yet to be seen in the future.
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Affiliation(s)
- S Spoorthi Shetty
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India
| | - Praveen Halagali
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India
| | - Asha P Johnson
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India
| | - K M Asha Spandana
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India
| | - H V Gangadharappa
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru 570015, Karnataka, India.
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12
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le Goff S, Godin JP, Albalat E, Nieves JMR, Balter V. Magnesium stable isotope composition, but not concentration, responds to obesity and early insulin-resistant conditions in minipig. Sci Rep 2022; 12:10941. [PMID: 35768618 PMCID: PMC9243132 DOI: 10.1038/s41598-022-14825-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 06/13/2022] [Indexed: 11/29/2022] Open
Abstract
Hypomagnesemia is frequently associated with type 2 diabetes and generally correlates with unfavorable disease progression, but the magnesium status in pre-diabetic conditions remains unclear. Here, the magnesium metabolism is scrutinized in a minipig model of obesity and insulin resistance by measuring variations of the metallome—the set of inorganic elements—and the magnesium stable isotope composition in six organs of lean and obese minipigs raised on normal and Western-type diet, respectively. We found that metallomic variations are most generally insensitive to lean or obese phenotypes. The magnesium stable isotope composition of plasma, liver, kidney, and heart in lean minipigs are significantly heavier than in obese minipigs. For both lean and obese minipigs, the magnesium isotope composition of plasma and liver were negatively correlated to clinical phenotypes and plasma lipoproteins concentration as well as positively correlated to hyperinsulinemic-euglycemic clamp output. Because the magnesium isotope composition was not associated to insulin secretion, our results suggest that it is rather sensitive to whole body insulin sensitivity, opening perspectives to better comprehend the onset of insulin-resistant diabetic conditions.
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Affiliation(s)
- Samuel le Goff
- Laboratoire de Géologie de Lyon, ENS de Lyon, Université de Lyon, CNRS, Lyon, France
| | - Jean-Philippe Godin
- Nestlé Research, Institute of Food Safety and Analytical Sciences, Lausanne, Switzerland
| | - Emmanuelle Albalat
- Laboratoire de Géologie de Lyon, ENS de Lyon, Université de Lyon, CNRS, Lyon, France
| | | | - Vincent Balter
- Laboratoire de Géologie de Lyon, ENS de Lyon, Université de Lyon, CNRS, Lyon, France.
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13
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Emerging Glycation-Based Therapeutics-Glyoxalase 1 Inducers and Glyoxalase 1 Inhibitors. Int J Mol Sci 2022; 23:ijms23052453. [PMID: 35269594 PMCID: PMC8910005 DOI: 10.3390/ijms23052453] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)-a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer-particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.
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Rabbani N, Xue M, Thornalley PJ. Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis-Driver of Insulin Resistance and Development of Vascular Complications of Diabetes. Int J Mol Sci 2022; 23:ijms23042165. [PMID: 35216280 PMCID: PMC8877341 DOI: 10.3390/ijms23042165] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/01/2022] [Accepted: 02/14/2022] [Indexed: 12/11/2022] Open
Abstract
The recent discovery of the glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis in cell dysfunction in model hyperglycemia has revealed a likely key initiating factor contributing to the development of insulin resistance and vascular complications in diabetes. Consequently, the increased flux of glucose metabolism without a change in the expression and activity of glycolytic enzymes produces a wave of increased glycolytic intermediates driving mitochondrial dysfunction and increased reactive oxygen species (ROS) formation, the activation of hexosamine and protein kinase C pathways, the increased formation of methylglyoxal-producing dicarbonyl stress, and the activation of the unfolded protein response. This is called HK2-linked glycolytic overload and unscheduled glycolysis. The conditions required to sustain this are GLUT1 and/or GLUT3 glucose uptake and the expression of HK2. A metabolic biomarker of its occurrence is the abnormally increased deposition of glycogen, which is produced by metabolic channeling when HK2 becomes detached from mitochondria. These conditions and metabolic consequences are found in the vasculature, kidneys, retina, peripheral nerves, and early-stage embryo development in diabetes and likely sustain the development of diabetic vascular complications and embryopathy. In insulin resistance, HK2-linked unscheduled glycolysis may also be established in skeletal muscle and adipose tissue. This may explain the increased glucose disposal by skeletal uptake in the fasting phase in patients with type 2 diabetes mellitus, compared to healthy controls, and the presence of insulin resistance in patients with type 1 diabetes mellitus. Importantly, glyoxalase 1 inducer—trans-resveratrol and hesperetin in combination (tRES-HESP)—corrected HK2-linked glycolytic overload and unscheduled glycolysis and reversed insulin resistance and improved vascular inflammation in overweight and obese subjects in clinical trial. Further studies are now required to evaluate tRES-HESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes.
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Affiliation(s)
- Naila Rabbani
- Department of Basic Medical Science, College of Medicine, Qatar University Health, Qatar University, Doha P.O. Box 2713, Qatar
- Correspondence: (N.R.); (P.J.T.); Tel.: +974-7479-5649 (N.R.); +974-7090-1635 (P.J.T.)
| | - Mingzhan Xue
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
| | - Paul J. Thornalley
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
- Correspondence: (N.R.); (P.J.T.); Tel.: +974-7479-5649 (N.R.); +974-7090-1635 (P.J.T.)
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15
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Jahn LA, Logan B, Love KM, Horton WB, Eichner NZ, Hartline LM, Weltman AL, Barrett EJ. Nitric oxide-dependent micro- and macrovascular dysfunction occurs early in adolescents with type 1 diabetes. Am J Physiol Endocrinol Metab 2022; 322:E101-E108. [PMID: 34894721 PMCID: PMC8799398 DOI: 10.1152/ajpendo.00267.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 11/16/2021] [Accepted: 12/05/2021] [Indexed: 11/22/2022]
Abstract
Arterial stiffness and endothelial dysfunction are both reported in children with type 1 diabetes (DM1) and may predict future cardiovascular events. In health, nitric oxide (NO) relaxes arteries and increases microvascular perfusion. The relationships between NO-dependent macro- and microvascular functional responses and arterial stiffness have not been studied in adolescents with DM1. Here, we assessed macro- and microvascular function in DM1 adolescents and age-matched controls at baseline and during an oral glucose challenge (OGTT). DM1 adolescents (n = 16) and controls (n = 14) were studied before and during an OGTT. At baseline, we measured: 1) large artery stiffness using both aortic augmentation index (AI) and carotid-femoral pulse wave velocity (cfPWV); 2) brachial flow-mediated dilation (FMD) and forearm endothelial function using postischemic flow velocity (PIFV); and 3) forearm muscle microvascular blood volume (MBV) using contrast-enhanced ultrasound. Following OGTT, AI, cfPWV, and MBV were reassessed at 60 min and MBV again at 120 min. Within individual and between-group, comparisons were made by paired and unpaired t tests or repeated measures ANOVA. Baseline FMD was lower (P = 0.02) in DM1. PWV at 0 and 60 min did not differ between groups. Baseline AI did not differ between groups but declined with OGTT only in controls (P = 0.02) and was lower than DM1 at 60 min (P < 0.03). Baseline MBV was comparable in DM1 and control groups, but declined in DM1 at 120 min (P = 0.01) and was lower than the control group (P < 0.03). There was an inverse correlation between plasma glucose and MBV at 120 min (r = -0.523, P < 0.01). No differences were noted between groups for V̇O2max (mL/min/kg), body fat (%), or body mass index (BMI). NO-dependent macro- and microvascular function, including FMD and AI, and microvascular perfusion, respectively, are impaired early in the course of DM1, precede increases of arterial stiffness, and may provide an early indicator of vascular risk.NEW & NOTEWORTHY This is the first study to show that type 1 diabetes impairs multiple nitric oxide-dependent vascular functions.
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Affiliation(s)
- Linda A Jahn
- Department of Medicine, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
| | - Brent Logan
- Department of Pediatrics, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
| | - Kaitlin M Love
- Department of Medicine, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
| | - William B Horton
- Department of Medicine, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
| | - Natalie Z Eichner
- Department of Kinesiology, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
| | - Lee M Hartline
- Department of Medicine, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
| | - Arthur L Weltman
- Department of Medicine, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
- Department of Kinesiology, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
| | - Eugene J Barrett
- Department of Medicine, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
- Department of Pediatrics, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
- Department of Pharmacology, School of Medicine, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia
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16
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17
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Mao Y, Zhong W. Changes of insulin resistance status and development of complications in type 1 diabetes mellitus: Analysis of DCCT/EDIC study. Diabetes Res Clin Pract 2022; 184:109211. [PMID: 35066056 DOI: 10.1016/j.diabres.2022.109211] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/06/2022] [Accepted: 01/18/2022] [Indexed: 12/25/2022]
Abstract
AIM There is no longitudinal study regarding the changes of insulin resistance (IR) status and the development of complications in type 1 diabetes (T1D). By analyzing data sets from DCCT/EDIC study, we investigated the associations of IR status changes and diabetic complications in T1D. MATERIALS AND METHODS Estimated glucose disposal rate (eGDR) was calculated at entry of DCCT and in EDIC year 12 (average 18.5 years later) to represent IR. The participants (n = 957) were divided into four groups based on IR changes from baseline: RR group (stayed resistant; n = 49), RS group (became sensitive; n = 42), SR group (became resistant; n = 197), and SS group (stayed sensitive; n = 669). The association of diabetic complications were analyzed by using multivariable logistic regression models. RESULTS The improved IR decreased the risk of peripheral neuropathy, whereas the deteriorated IR increased the risk of diabetic complications including hypertension, peripheral artery disease, coronary artery calcification, retinopathy, albuminuria, peripheral neuropathy, and cardiac autonomic neuropathy (P < 0.05). Moreover, RR group (HR = 3.59, 95% CI (2.05-6.32)), RS group (HR = 2.27, 95% CI (1.11-4.64)) and SR group (HR = 1.90, 95% CI (1.24-2.92)) had higher risk of cardiovascular events compared to SS group (P < 0.05). CONCLUSIONS This study highlights the importance of IR changes represented by eGDR in the development of diabetic complications. Patients with T1D and IR may require intensive therapy.
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Affiliation(s)
- Yuanjie Mao
- Diabetes Institute, Ohio University, Athens, OH 45701, USA; Endocrinology Clinic, OhioHealth Castrop Health Center, Athens, OH 45701, USA.
| | - Wenjun Zhong
- Merck Research Labs, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486, USA
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18
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McDonnell T, Cussen L, McIlroy M, O’Reilly MW. Characterizing skeletal muscle dysfunction in women with polycystic ovary syndrome. Ther Adv Endocrinol Metab 2022; 13:20420188221113140. [PMID: 35874313 PMCID: PMC9297442 DOI: 10.1177/20420188221113140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 06/24/2022] [Indexed: 11/18/2022] Open
Abstract
Polycystic ovary syndrome (PCOS) is the most common endocrine condition affecting women. It has traditionally been viewed as a primarily reproductive disorder; however, it is increasingly recognized as a lifelong metabolic disease. Women with PCOS are at increased risk of insulin resistance (IR), type 2 diabetes mellitus, non-alcoholic fatty liver disease and cardiovascular disease. Although not currently a diagnostic criterion, IR is a cardinal pathophysiological feature and highly prevalent in women with PCOS. Androgens play a bidirectional role in the pathogenesis of IR, and there is a complex interplay between IR and androgen excess in women with PCOS. Skeletal muscle has a key role in maintaining metabolic homeostasis and is also a metabolic target organ of androgen action. Skeletal muscle is the organ responsible for the majority of insulin-mediated glucose disposal. There is growing interest in the relationship between skeletal muscle, androgen excess and mitochondrial dysfunction in the pathogenesis of metabolic disease in PCOS. Molecular mechanisms underpinning defects in skeletal muscle dysfunction in PCOS remain to be elucidated, but may represent promising targets for future therapeutic intervention. In this review, we aim to explore the role of skeletal muscle in metabolism, focusing particularly on perturbations in skeletal muscle specific to PCOS as observed in recent molecular and in vivo human studies. We review the possible role of androgens in the pathophysiology of skeletal muscle abnormalities in PCOS, and identify knowledge gaps, areas for future research and potential therapeutic implications. Despite increasing interest in the area of skeletal muscle dysfunction in women with PCOS, significant challenges and unanswered questions remain, and going forward, novel innovative approaches will be required to dissect the underlying mechanisms.
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Affiliation(s)
- Tara McDonnell
- Department of Medicine, Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Republic of Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Republic of Ireland
| | - Leanne Cussen
- Department of Medicine, Royal College of Surgeons in Ireland (RCSI), University of Medicine and Health Sciences, Dublin, Republic of Ireland
- Department of Endocrinology, Beaumont Hospital, Dublin, Republic of Ireland
| | - Marie McIlroy
- Endocrine Oncology Research Group, Department of Surgery, RCSI University of Medicine and Health Sciences, Dublin, Republic of Ireland
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Love KM, Barrett EJ, Malin SK, Reusch JEB, Regensteiner JG, Liu Z. Diabetes pathogenesis and management: the endothelium comes of age. J Mol Cell Biol 2021; 13:500-512. [PMID: 33787922 PMCID: PMC8530521 DOI: 10.1093/jmcb/mjab024] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/10/2021] [Accepted: 02/25/2021] [Indexed: 12/03/2022] Open
Abstract
Endothelium, acting as a barrier, protects tissues against factors that provoke insulin resistance and type 2 diabetes and itself responds to the insult of insulin resistance inducers with altered function. Endothelial insulin resistance and vascular dysfunction occur early in the evolution of insulin resistance-related disease, can co-exist with and even contribute to the development of metabolic insulin resistance, and promote vascular complications in those affected. The impact of endothelial insulin resistance and vascular dysfunction varies depending on the blood vessel size and location, resulting in decreased arterial plasticity, increased atherosclerosis and vascular resistance, and decreased tissue perfusion. Women with insulin resistance and diabetes are disproportionately impacted by cardiovascular disease, likely related to differential sex-hormone endothelium effects. Thus, reducing endothelial insulin resistance and improving endothelial function in the conduit arteries may reduce atherosclerotic complications, in the resistance arteries lead to better blood pressure control, and in the microvasculature lead to less microvascular complications and more effective tissue perfusion. Multiple diabetes therapeutic modalities, including medications and exercise training, improve endothelial insulin action and vascular function. This action may delay the onset of type 2 diabetes and/or its complications, making the vascular endothelium an attractive therapeutic target for type 2 diabetes and potentially type 1 diabetes.
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MESH Headings
- Age Factors
- Cardiovascular Diseases/epidemiology
- Cardiovascular Diseases/ethnology
- Cardiovascular Diseases/metabolism
- Cardiovascular Diseases/physiopathology
- Comorbidity
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/physiopathology
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Exercise
- Female
- Humans
- Hypoglycemic Agents/pharmacology
- Hypoglycemic Agents/therapeutic use
- Insulin Resistance
- Male
- Racial Groups
- Risk Factors
- Sex Factors
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Affiliation(s)
- Kaitlin M Love
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Eugene J Barrett
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
| | - Steven K Malin
- Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ, USA
- Division of Endocrinology, Metabolism and Nutrition, Rutgers University, New Brunswick, NJ, USA
- New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, USA
- Institute of Translational Medicine and Research, Rutgers University, New Brunswick, NJ, USA
| | - Jane E B Reusch
- Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
- Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, USA
| | - Judith G Regensteiner
- Center for Women’s Health Research, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA
| | - Zhenqi Liu
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908, USA
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20
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Bolli GB, Porcellati F, Lucidi P, Fanelli CG. The physiological basis of insulin therapy in people with diabetes mellitus. Diabetes Res Clin Pract 2021; 175:108839. [PMID: 33930505 DOI: 10.1016/j.diabres.2021.108839] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 10/21/2022]
Abstract
Insulin therapy has been in use now for 100 years, but only recently insulin replacement has been based on physiology. The pancreas secretes insulin at continuously variable rates, finely regulated by sensitive arterial glucose sensing. Pancreatic insulin is delivered directlyin the portal blood to insulinize preferentially the liver. In the fasting state, insulin is secreted at a low rate to modulate hepatic glucose output. After liver extraction (50%), insulin concentrations in peripheral plasma are 2.4-4 times lower than in portal, but still efficacious to restrain lipolysis. In the prandial condition, insulin is secreted rapidly in large amounts to increase portal and peripheral concentrations to peaks 10-20 times greater vs the values of fasting within 30-40 min from meal ingestion. The prandial portal hyperinsulinemia fully suppresses hepatic glucose production while peripheral hyperinsulinemia increases glucose utilization, thus limitating the post-prandial plasma glucose elevation. Physiology of insulin indicates that insulin should be replaced in people with diabetes mimicking the pancreas, i.e. in a basal-bolus mode, for fasting and prandial state, respectively. Despite the presently ongoing limitations (subcutaneous and peripheral rather than portal and intravenous insulin delivery), basal-bolus insulin allows people with diabetes to achieve A1c in the range with minimal risk of hypoglycaemia, to prevent vascular complications and to ensure good quality of life.
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Affiliation(s)
- Geremia B Bolli
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, Perugia University School of Medicine, Perugia, Italy.
| | - Francesca Porcellati
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, Perugia University School of Medicine, Perugia, Italy
| | - Paola Lucidi
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, Perugia University School of Medicine, Perugia, Italy
| | - Carmine G Fanelli
- Section of Endocrinology and Metabolism, Department of Medicine and Surgery, Perugia University School of Medicine, Perugia, Italy
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21
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Hishida Y, Nakamura Y, Tsukiyama H, Nakagawa T, Sone M. A retrospective cohort study for the treatment of Asian diabetic ketoacidosis: optimizing initial doses of insulin. Acute Med Surg 2021; 8:e721. [PMID: 34976402 PMCID: PMC8705869 DOI: 10.1002/ams2.721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 10/25/2021] [Accepted: 11/29/2021] [Indexed: 11/10/2022] Open
Abstract
Aim An insulin dose of 0.1 U/kg/h recommended by Western guidelines occasionally induces a precipitous decreasing blood glucose in Asian diabetic ketoacidosis (DKA). It is known that clinical factors, such as insulin sensitivity, differ between Asians and Americans/Europeans. We investigated how treatment options affect the time to DKA resolution to determine the optimal treatment for Asian DKA patients. Methods This was a retrospective cohort study from a single institution in Japan. A total of 34 adult DKA patients were observed. Baseline characteristics and treatment‐related parameters were compared between patients whose DKA was resolved within 18 h and those in which it was not. Results Significant differences were observed in the initial insulin dose (mean [standard deviation]: 0.053 [0.021] versus 0.031 [0.014] U/kg/h; P = 0.003) and the baseline β‐hydroxybutyrate (7.2 [3.2] versus 9.9 [2.6] mmol/L; P = 0.024) and HCO3− levels (11.2 [4.1] versus 7.7 [3.1] mmol/L; P = 0.014). Multivariable logistic regression analysis revealed that the initial insulin dose was significantly associated with early resolution of DKA and was independent of basal conditions. Receiver operating characteristic curve analysis indicated that the optimal cut‐off point for the initial insulin dose was 0.051 U/kg/h. With an initial insulin dose of 0.051 U/kg/h or higher, early resolution of DKA was obtained in 92.9% of patients. Conclusion An initial insulin dose of more than 0.05 U/kg/h provides an early resolution of DKA in Asian patients. Lower insulin doses significantly delay resolution. These results provide practical information for acute phase treatment of Asian DKA.
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Affiliation(s)
- Yoshiaki Hishida
- Division of Metabolism and Endocrinology, Department of Internal Medicine St. Marianna University School of Medicine Kawasaki Japan
| | - Yuta Nakamura
- Division of Metabolism and Endocrinology, Department of Internal Medicine St. Marianna University School of Medicine Kawasaki Japan
| | - Hidekazu Tsukiyama
- Division of Metabolism and Endocrinology, Department of Internal Medicine St. Marianna University School of Medicine Kawasaki Japan
| | - Tomoko Nakagawa
- Division of Metabolism and Endocrinology, Department of Internal Medicine St. Marianna University School of Medicine Kawasaki Japan
| | - Masakatsu Sone
- Division of Metabolism and Endocrinology, Department of Internal Medicine St. Marianna University School of Medicine Kawasaki Japan
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22
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Buckner T, Shao B, Eckel RH, Heinecke JW, Bornfeldt KE, Snell-Bergeon J. Association of apolipoprotein C3 with insulin resistance and coronary artery calcium in patients with type 1 diabetes. J Clin Lipidol 2021; 15:235-242. [PMID: 33257283 PMCID: PMC7887020 DOI: 10.1016/j.jacl.2020.10.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 10/26/2020] [Accepted: 10/28/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Apolipoprotein C3 (APOC3) is a risk factor for incident coronary artery disease in people with type 1 diabetes (T1D). The pathways that link elevated APOC3 levels to an increased risk of incident cardiovascular disease in people with T1D are not understood. OBJECTIVE To explore potential mechanisms, we investigated the association of APOC3 with insulin resistance and coronary artery calcium (CAC). METHODS In a random subcohort of participants with T1D from Coronary Artery Calcification in Type 1 Diabetes (n = 134), serum APOC3, high-density lipoprotein (HDL)-associated APOC3, and retinol binding protein 4 (RBP4; a potential marker of insulin resistance) were measured by targeted mass spectrometry. We used linear regression to evaluate associations of serum APOC3 and HDL-APOC3 with APOB, non-HDL cholesterol, serum- and HDL-associated RBP4, and estimated insulin sensitivity and logistic regression to evaluate association with presence of CAC, adjusted for age, sex, and diabetes duration. RESULTS Serum APOC3 correlated positively with APOB and non-HDL cholesterol and was associated with increased odds of CAC (odds ratio: 1.68, P = .024). Estimated insulin sensitivity was not associated with serum- or HDL-RBP4 but was negatively associated with serum APOC3 in men (ß estimate: -0.318, P = .0040) and decreased odds of CAC (odds ratio: 0.434, P = .0023). CONCLUSIONS Serum APOC3 associates with increased insulin resistance and CAC in T1D.
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Affiliation(s)
- Teresa Buckner
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
| | - Baohai Shao
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, WA, USA
| | - Robert H Eckel
- Division of Endocrinology, Metabolism and Diabetes, and Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Jay W Heinecke
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, WA, USA
| | - Karin E Bornfeldt
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, WA, USA; Department of Laboratory Medicine and Pathology, University of Washington Medicine Diabetes Institute, University of Washington School of Medicine, Seattle, WA, USA
| | - Janet Snell-Bergeon
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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23
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Williams KV, Shay CM, Price JC, Goodpaster BH, Kelley CA, Kelley DE, Orchard TJ. Muscle insulin resistance in type 1 diabetes with coronary artery disease. Diabetologia 2020; 63:2665-2674. [PMID: 32926189 DOI: 10.1007/s00125-020-05270-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 07/15/2020] [Indexed: 10/23/2022]
Abstract
AIMS/HYPOTHESIS The risk for coronary artery disease (CAD) is substantially increased in type 1 diabetes and it has been postulated that insulin resistance may contribute to this risk. The current study measured insulin resistance in type 1 diabetes with vs without CAD and with a focus upon skeletal muscle, to test the hypothesis that insulin resistance is more severe in participants who have type 1 diabetes and CAD. Additionally, in type 1 diabetes, we examined the hypothesis that insulin resistance is more severe in soleus (an oxidative type muscle) vs tibialis anterior (a more glycolytic type of muscle). METHODS Insulin resistance was measured in participants with type 1 diabetes with (n = 9, CAD+) and without CAD (n = 10, CAD-) using euglycaemic insulin infusions combined with positron emission tomography (PET) imaging of [18F]fluorodeoxyglucose (FDG) uptake into soleus and tibialis anterior skeletal muscles. Coronary artery calcium (CAC) score was quantified by electron beam tomography. RESULTS CAD+ participants with type 1 diabetes had a >100-fold higher CAC score than did CAD- participants with type 1 diabetes but groups did not differ in HbA1c or insulin dose. During clamp studies, CAD+ and CAD- groups had similar glucose disposal but were insulin resistant compared with historical non-diabetic participants (n = 13). FDG uptake by soleus muscle was similarly reduced, overall, in individuals with type 1 diabetes with or without CAD compared with non-diabetic individuals. However, FDG uptake by tibialis anterior muscle was not reduced in CAD- participants with type 1 diabetes while in CAD+ participants with type 1 diabetes it was 75% greater (p < 0.01). Across all participants with type 1 diabetes, FDG uptake by tibialis anterior muscle correlated positively with CAC severity. CONCLUSIONS/INTERPRETATION Our study confirms that systemic and skeletal muscle-specific insulin resistance is seen in type 1 diabetes but found that it does not appear to be more severe in the presence of CAD. There were, however, sharp differences between soleus and tibialis anterior muscles in type 1 diabetes: while insulin resistance was clearly manifest in soleus muscle, and was of equal severity in CAD+ and CAD- participants, tibialis anterior did not suggest insulin resistance in participants with type 1 diabetes, as FDG uptake by tibialis anterior correlated positively with CAC severity and was significantly increased in participants with type 1 diabetes and clinical CAD. Graphical abstract.
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Affiliation(s)
- Katherine V Williams
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Department of Family Medicine, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Christina M Shay
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Impact and Health Metrics, American Heart Association, Dallas, TX, USA
| | - Julie C Price
- Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA
| | - Bret H Goodpaster
- Department of Medicine, Division of Endocrinology and Metabolism, Pittsburgh, PA, USA
- Advent Health Translational Research Institute for Metabolism and Diabetes, Orlando, FL, USA
| | - Carol A Kelley
- Department of Medicine, Division of Endocrinology and Metabolism, Pittsburgh, PA, USA
| | - David E Kelley
- Department of Medicine, Division of Endocrinology and Metabolism, Pittsburgh, PA, USA
| | - Trevor J Orchard
- Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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24
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de Mattos ACMT, Campos YS, Fiorini VO, Sab Y, Tavares BL, Velarde LGC, Lima GAB, da Cruz RA. Relationship between sleep disturbances, lipid profile and insulin sensitivity in type 1 diabetic patients: a cross-sectional study. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2020; 64:412-417. [PMID: 32267356 PMCID: PMC10522075 DOI: 10.20945/2359-3997000000228] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 11/04/2019] [Indexed: 11/23/2022]
Abstract
Objective The consequences of sleep deprivation in type 1 diabetes (T1D) patients are poorly understood. Our aim was to determine how sleep disorders influence lipid profile and insulin sensitivity in T1D patients. Materials and methods This was a cross-sectional study at a public university hospital. Demographic information and medical histories were obtained during regular scheduled visit of T1D patients to the outpatient clinic. Insulin sensitivity was obtained using the estimated glucose disposal rate (eGDR) formula. Sleep quality was assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Berlin Questionnaire. Results The adult participants (n = 66, 62% women) had a median age of 28.0 years (interquartile range 21.8-33.0). Six patients (9%) had metabolic syndrome according to the International Diabetes Federation criteria. Thirty patients (46%) were considered poor sleepers according to the Pittsburgh Sleep Quality Index. The LDL-c and total cholesterol levels of poor sleepers were higher than those of good sleepers (103 v. 81; p = 0.003 and 178.0 v. 159.5 mg/dL; p = 0.009, respectively). Three patients (4%) were at high risk of obstructive sleep apnea syndrome (OSAS) according to the Berlin Questionnaire. The eGDR was lower in the group of patients with high probability of having OSAS (6.0 v. 9.1 mg.kg-1.min-1;p = .03). Conclusions Poor subjective quality of sleep and higher risk of OSAS were correlated with a worsened lipid profile and decreased insulin sensitivity, respectively. Therefore, T1D patients with sleep disturbances might have an increased cardiovascular risk in the future.
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Affiliation(s)
- Ana Carolina Musser Tavares de Mattos
- Departamento de Medicina ClínicaUniversidade Federal FluminenseNiteróiRJBrasilDepartamento de Medicina Clínica, Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil
| | - Yuri Sofiati Campos
- Departamento de Medicina ClínicaUniversidade Federal FluminenseNiteróiRJBrasilDepartamento de Medicina Clínica, Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil
| | - Vitória Oliveira Fiorini
- Departamento de Medicina ClínicaUniversidade Federal FluminenseNiteróiRJBrasilDepartamento de Medicina Clínica, Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil
| | - Yasmin Sab
- Departamento de Medicina ClínicaUniversidade Federal FluminenseNiteróiRJBrasilDepartamento de Medicina Clínica, Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil
| | - Bruna Landeiro Tavares
- Departamento de Medicina ClínicaUniversidade Federal FluminenseNiteróiRJBrasilDepartamento de Medicina Clínica, Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil
| | - Luis Guillermo Coca Velarde
- Departamento de Medicina ClínicaUniversidade Federal FluminenseNiteróiRJBrasilCurso de Pós-Graduação em Ciências Médicas, Departamento de Medicina Clínica, Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil
| | - Giovanna Aparecida Balarini Lima
- Departamento de Medicina ClínicaUniversidade Federal FluminenseNiteróiRJBrasilDepartamento de Medicina Clínica, Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil
| | - Rubens Antunes da Cruz
- Departamento de Medicina ClínicaUniversidade Federal FluminenseNiteróiRJBrasilDepartamento de Medicina Clínica, Universidade Federal Fluminense (UFF), Niterói, RJ, Brasil
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25
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Gregory JM, Cherrington AD, Moore DJ. The Peripheral Peril: Injected Insulin Induces Insulin Insensitivity in Type 1 Diabetes. Diabetes 2020; 69:837-847. [PMID: 32312900 PMCID: PMC7171956 DOI: 10.2337/dbi19-0026] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 02/12/2020] [Indexed: 12/13/2022]
Abstract
Insulin resistance is an underappreciated facet of type 1 diabetes that occurs with remarkable consistency and considerable magnitude. Although therapeutic innovations are continuing to normalize dysglycemia, a sizable body of data suggests a second metabolic abnormality-iatrogenic hyperinsulinemia-principally drives insulin resistance and its consequences in this population and has not been addressed. We review this evidence to show that injecting insulin into the peripheral circulation bypasses first-pass hepatic insulin clearance, which leads to the unintended metabolic consequence of whole-body insulin resistance. We propose restructuring insulin therapy to restore the physiological insulin balance between the hepatic portal and peripheral circulations and thereby avoid the complications of life-long insulin resistance. As technology rapidly advances and our ability to ensure euglycemia improves, iatrogenic insulin resistance will become the final barrier to overcome to restore normal physiology, health, and life in type 1 diabetes.
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Affiliation(s)
- Justin M Gregory
- Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN
| | - Alan D Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Daniel J Moore
- Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN
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26
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Khneizer G, Rizvi S, Gawrieh S. Non-alcoholic Fatty Liver Disease and Diabetes Mellitus. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1307:417-440. [PMID: 32424494 DOI: 10.1007/5584_2020_532] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading liver disease globally. NAFLD patients can have a progressive phenotype, non-alcoholic steatohepatitis (NASH) that could lead to cirrhosis, liver failure and cancer. There is a close bi-directional relationship between NAFLD and type 2 diabetes mellitus (T2DM); NAFLD increases the risk for T2DM and its complications whereas T2DM increases the severity of NAFLD and its complications. The large global impact of NAFLD and T2DM on healthcare systems requires a paradigm shift from specialty care to early identification and risk stratification of NAFLD in primary care and diabetes clinics. Approach to diagnosis, risk stratification and management of NAFLD is discussed. In addition to optimizing the control of coexisting cardiometabolic comorbidities, early referral of NAFLD patients at high risk of having NASH or significant fibrosis to hepatology specialist care may improve management and allow access for clinical trials. Lifestyle modifications, vitamin E, pioglitazone and metformin are currently available options that may benefit patients with T2DM and NAFLD. The burst of clinical trials investigating newer therapeutic agents for NAFLD and NASH offer hope for new, effective and safe therapies in the near future.
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Affiliation(s)
- Gebran Khneizer
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Syed Rizvi
- A&M College of Medicine, Round Rock, Austin, TX, USA
| | - Samer Gawrieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
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27
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Shen SF, Zhu LF, Wu Z, Wang G, Ahmad Z, Chang MW. Production of triterpenoid compounds from Ganoderma lucidum spore powder using ultrasound-assisted extraction. Prep Biochem Biotechnol 2019; 50:302-315. [PMID: 31755817 DOI: 10.1080/10826068.2019.1692218] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
When ingested as a dietary supplement, Ganoderma lucidum spore powders (GLSP) provide various health benefits such as enhanced immunity, liver protection and anti-cancer effects. In this study, triterpenoid extraction from GLSP was achieved using an ultrasound-assisted process which was optimized using response surface methodology (RSM). Ultrasound-assisted extraction (UAE) was also compared to the most conventional chemical extraction method. For UAE, optimum extraction conditions were found to be ethanol concentration = 95% v/v; solvent to solid ratio = 50:1 mL/g; ultrasound time = 5.4 min; ultrasound power = 564.7 w, and ultrasound probe distance = 8.2 cm. At optimal UAE conditions, no significant differences were found between experimental (0.97 ± 0.04 %) and predicted values (99%); which indicates appreciable correlation at the 97% confidence interval. The findings show the application of Box-Behnken design (BBD) to predict and optimize triterpenoid yield for UAE of triterpenoid from GLSP. Furthermore, glucose consumption was 2.68 times that of control samples when tested with insulin-resistant HepG2 cell, showing potential use in type 2 diabetes. In addition, triterpenoid extracts show good biocompatibility and inhibition of antioxidant activity.
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Affiliation(s)
- Shuang-Fei Shen
- Key Laboratory for Biomedical Engineering of Education Ministry of China, Zhejiang University, Hangzhou, P. R. China.,Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, P. R. China
| | - Li-Fang Zhu
- Key Laboratory for Biomedical Engineering of Education Ministry of China, Zhejiang University, Hangzhou, P. R. China.,Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, P. R. China
| | - Zijing Wu
- Tianhe Agricultural Group, Longquan City, P. R. China
| | - Guangkun Wang
- Tianhe Agricultural Group, Longquan City, P. R. China
| | - Zeeshan Ahmad
- Leicester School of Pharmacy, De Montfort University, Leicester, UK
| | - Ming-Wei Chang
- Key Laboratory for Biomedical Engineering of Education Ministry of China, Zhejiang University, Hangzhou, P. R. China.,Nanotechnology and Integrated Bioengineering Centre, University of Ulster, Jordanstown Campus, Newtownabbey, UK
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28
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Rickels MR, Robertson RP. Pancreatic Islet Transplantation in Humans: Recent Progress and Future Directions. Endocr Rev 2019; 40:631-668. [PMID: 30541144 PMCID: PMC6424003 DOI: 10.1210/er.2018-00154] [Citation(s) in RCA: 192] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/26/2018] [Indexed: 12/11/2022]
Abstract
Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.
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Affiliation(s)
- Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - R Paul Robertson
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington School of Medicine, Seattle, Washington
- Division of Endocrinology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
- Pacific Northwest Diabetes Research Institute, Seattle, Washington
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29
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Hosogi S, Ohsawa M, Kato I, Kuwahara A, Inui T, Inui A, Marunaka Y. Improvement of Diabetes Mellitus Symptoms by Intake of Ninjin'yoeito. Front Nutr 2018; 5:112. [PMID: 30538991 PMCID: PMC6277701 DOI: 10.3389/fnut.2018.00112] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/07/2018] [Indexed: 12/18/2022] Open
Abstract
Diabetes mellitus is a well-known common disease and one of the most serious social problems in the worldwide. Although various types of drugs are developed, the number of patients suffering from diabetes mellitus is still increasing. Ninjin'yoeito (NYT) is one of formulas used in Japanese traditional herbal medicines for improving various types of metabolic disorders. However, the effect of NYT on diabetes mellitus has not yet been investigated. In the present study, we tried to clarify the action of NYT on the serum glucose level in streptozotocin (STZ)-induced diabetic mice. We found that intake of NYT decreased the serum glucose level and increased insulin sensitivity in STZ-induced diabetic mice. NYT treatment also improved acidification of the interstitial fluid around skeletal muscles found in STZ-induced diabetic mice, while the interstitial fluid acidification has been reported to cause insulin resistance. Furthermore, in the proximal colon of STZ-induced diabetic mice, NYT treatment showed a tendency to increase the expression of sodium-coupled monocarboxylate transporter 1 (SMCT1), which has ability to absorb weak organic acids (pH buffer molecules) resulting in improvement of the interstitial fluid acidification. Based on these observations, the present study suggests that NYT is a useful formula to improve hyperglycemia and insulin resistance via elevation of interstitial fluid pH in diabetes mellitus, which might be caused by increased absorption of pH buffer molecules (SMCT1 substrates, weak organic acids) mediated through possibly elevated SMCT1 expression in the proximal colon.
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Affiliation(s)
- Shigekuni Hosogi
- Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Masahiro Ohsawa
- Department of Neuropharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
| | - Ikuo Kato
- Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan
| | - Atsukazu Kuwahara
- Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan
| | - Toshio Inui
- Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan.,Saisei Mirai Clinics, Moriguchi, Japan
| | - Akio Inui
- Pharmacological Department of Herbal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Yoshinori Marunaka
- Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.,Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan.,Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan
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30
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Grandl G, Straub L, Rudigier C, Arnold M, Wueest S, Konrad D, Wolfrum C. Short-term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high-fat diet. J Physiol 2018; 596:4597-4609. [PMID: 30089335 PMCID: PMC6166091 DOI: 10.1113/jp275173] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 06/18/2018] [Indexed: 11/25/2022] Open
Abstract
KEY POINTS A ketogenic diet is known to lead to weight loss and is considered metabolically healthy; however there are conflicting reports on its effect on hepatic insulin sensitivity. KD fed animals appear metabolically healthy in the fasted state after 3 days of dietary challenge, whereas obesogenic high-fat diet (HFD) fed animals show elevated insulin levels. A glucose challenge reveals that both KD and HFD fed animals are glucose intolerant. Glucose intolerance correlates with increased lipid oxidation and lower respiratory exchange ratio (RER); however, all animals respond to glucose injection with an increase in RER. Hyperinsulinaemic-euglycaemic clamps with double tracer show that the effect of KD is a result of hepatic insulin resistance and increased glucose output but not impaired glucose clearance or tissue glucose uptake in other tissues. ABSTRACT Despite being a relevant healthcare issue and heavily investigated, the aetiology of type 2 diabetes (T2D) is still incompletely understood. It is well established that increased endogenous glucose production (EGP) leads to a progressive increase in glucose levels, causing insulin resistance and eventual loss of glucose homeostasis. The consumption of high carbohydrate, high-fat, western style diet (HFD) is linked to the development of T2D and obesity, whereas the consumption of a low carbohydrate, high-fat, ketogenic diet (KD) is considered healthy. However, several days of carbohydrate restriction are known to cause selective hepatic insulin resistance. In the present study, we compare the effects of short-term HFD and KD feeding on glucose homeostasis in mice. We show that, even though KD fed animals appear to be healthy in the fasted state, they exhibit decreased glucose tolerance to a greater extent than HFD fed animals. Furthermore, we show that this effect originates from blunted suppression of hepatic glucose production by insulin, rather than impaired glucose clearance and tissue glucose uptake. These data suggest that the early effects of HFD consumption on EGP may be part of a normal physiological response to increased lipid intake and oxidation, and that systemic insulin resistance results from the addition of dietary glucose to EGP-derived glucose.
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Affiliation(s)
| | | | | | - Myrtha Arnold
- Physiology and Behavior LaboratoryETH ZürichSchwerzenbachSwitzerland
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology
- Children's Research CenterUniversity Children's HospitalZurichSwitzerland
| | - Daniel Konrad
- Division of Pediatric Endocrinology and Diabetology
- Children's Research CenterUniversity Children's HospitalZurichSwitzerland
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31
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Monaco CMF, Hughes MC, Ramos SV, Varah NE, Lamberz C, Rahman FA, McGlory C, Tarnopolsky MA, Krause MP, Laham R, Hawke TJ, Perry CGR. Altered mitochondrial bioenergetics and ultrastructure in the skeletal muscle of young adults with type 1 diabetes. Diabetologia 2018; 61:1411-1423. [PMID: 29666899 DOI: 10.1007/s00125-018-4602-6] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 02/28/2018] [Indexed: 02/06/2023]
Abstract
AIMS/HYPOTHESIS A comprehensive assessment of skeletal muscle ultrastructure and mitochondrial bioenergetics has not been undertaken in individuals with type 1 diabetes. This study aimed to systematically assess skeletal muscle mitochondrial phenotype in young adults with type 1 diabetes. METHODS Physically active, young adults (men and women) with type 1 diabetes (HbA1c 63.0 ± 16.0 mmol/mol [7.9% ± 1.5%]) and without type 1 diabetes (control), matched for sex, age, BMI and level of physical activity, were recruited (n = 12/group) to undergo vastus lateralis muscle microbiopsies. Mitochondrial respiration (high-resolution respirometry), site-specific mitochondrial H2O2 emission and Ca2+ retention capacity (CRC) (spectrofluorometry) were assessed using permeabilised myofibre bundles. Electron microscopy and tomography were used to quantify mitochondrial content and investigate muscle ultrastructure. Skeletal muscle microvasculature was assessed by immunofluorescence. RESULTS Mitochondrial oxidative capacity was significantly lower in participants with type 1 diabetes vs the control group, specifically at Complex II of the electron transport chain, without differences in mitochondrial content between groups. Muscles of those with type 1 diabetes also exhibited increased mitochondrial H2O2 emission at Complex III and decreased CRC relative to control individuals. Electron tomography revealed an increase in the size and number of autophagic remnants in the muscles of participants with type 1 diabetes. Despite this, levels of the autophagic regulatory protein, phosphorylated AMP-activated protein kinase (p-AMPKαThr172), and its downstream targets, phosphorylated Unc-51 like autophagy activating kinase 1 (p-ULK1Ser555) and p62, was similar between groups. In addition, no differences in muscle capillary density or platelet aggregation were observed between the groups. CONCLUSIONS/INTERPRETATION Alterations in mitochondrial ultrastructure and bioenergetics are evident within the skeletal muscle of active young adults with type 1 diabetes. It is yet to be elucidated whether more rigorous exercise may help to prevent skeletal muscle metabolic deficiencies in both active and inactive individuals with type 1 diabetes.
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Affiliation(s)
- Cynthia M F Monaco
- Department of Pathology and Molecular Medicine, McMaster University, 4N65 Health Sciences Centre, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada
| | - Meghan C Hughes
- School of Kinesiology and Health Sciences, Muscle Health Research Centre, York University, Toronto, ON, Canada
| | - Sofhia V Ramos
- School of Kinesiology and Health Sciences, Muscle Health Research Centre, York University, Toronto, ON, Canada
| | - Nina E Varah
- Department of Pathology and Molecular Medicine, McMaster University, 4N65 Health Sciences Centre, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada
| | | | - Fasih A Rahman
- Department of Kinesiology, University of Windsor, Windsor, ON, Canada
| | - Chris McGlory
- Department of Kinesiology, McMaster University, Hamilton, ON, Canada
| | | | - Matthew P Krause
- Department of Kinesiology, University of Windsor, Windsor, ON, Canada
| | - Robert Laham
- School of Kinesiology and Health Sciences, Muscle Health Research Centre, York University, Toronto, ON, Canada
| | - Thomas J Hawke
- Department of Pathology and Molecular Medicine, McMaster University, 4N65 Health Sciences Centre, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada.
| | - Christopher G R Perry
- School of Kinesiology and Health Sciences, Muscle Health Research Centre, York University, Toronto, ON, Canada
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Rydzon B, Monson RS, Oberholzer J, Varady KA, Bellin MD, Danielson KK. Long term (4 years) improved insulin sensitivity following islet cell transplant in type 1 diabetes. Diabetes Metab Res Rev 2018; 34:10.1002/dmrr.2972. [PMID: 29230944 PMCID: PMC5873303 DOI: 10.1002/dmrr.2972] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/28/2017] [Accepted: 11/29/2017] [Indexed: 12/25/2022]
Abstract
BACKGROUND Impaired insulin sensitivity (IS) predicts complications and mortality in type 1 diabetes (T1D). Insulin sensitivity improves shortly after islet cell transplant for T1D, yet long-term changes in IS and associated factors such as patient characteristics, transplant factors, clinical management, and IS-related biomarkers are unknown. METHODS Up to 9 years (mean 4) of longitudinal data were available on 22 adults (18 female) with T1D who received 1 to 3 transplants in Phase 1/2 or 3 clinical trials (2004-2014). Metabolic testing posttransplant estimated IS by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR; 111 observations) and the Simple Index of Insulin Sensitivity (SIis ; 95 observations). RESULTS Simple Index of Insulin Sensitivity significantly increased the first year posttransplant (P = .02), then stabilized (P = .39); HOMA-IR remained stable posttransplant (P = .92). Adjusting for age and BMI, higher SIis was associated with lower HbA1c following transplant (P = .03). Greater IS as measured by lower HOMA-IR and higher SIis was associated with lower fasting C-peptide (both P ≤ .04) and also with higher exenatide dose (both P ≤ .01). More islets transplanted were associated with higher SIis (P < .0001). Lower leptin at transplant predicted lower HOMA-IR and higher SIis after transplant, and lower bone marker receptor activator of nuclear factor kappa-B ligand predicted lower HOMA-IR (all P ≤ .01). CONCLUSIONS Insulin sensitivity measured by SIis was improved several years following transplant, while IS measured by HOMA-IR did not worsen. Higher exenatide dose, more islets transplanted, and diet and exercise (lowering leptin and receptor activator of nuclear factor kappa-B ligand) may improve IS, which may enhance glycaemic control and lower metabolic demand on transplanted islets. Long-term clamp studies are needed to confirm these results.
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Affiliation(s)
- Brett Rydzon
- Division of Transplant Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
- Division of Epidemiology & Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
| | - Rebecca S. Monson
- Division of Transplant Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Jose Oberholzer
- Division of Transplant Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
| | - Krista A. Varady
- Department of Kinesiology & Nutrition, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA
| | - Melena D. Bellin
- Division of Pediatric Endocrinology, Medical School, University of Minnesota, Minneapolis, MN, USA
| | - Kirstie K. Danielson
- Division of Transplant Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA
- Division of Epidemiology & Biostatistics, School of Public Health, University of Illinois at Chicago, Chicago, IL, USA
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Priya G, Kalra S. A Review of Insulin Resistance in Type 1 Diabetes: Is There a Place for Adjunctive Metformin? Diabetes Ther 2018; 9:349-361. [PMID: 29139080 PMCID: PMC5801219 DOI: 10.1007/s13300-017-0333-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Indexed: 12/18/2022] Open
Abstract
There is a rising trend of overweight and obesity among individuals with type 1 diabetes. This is often associated with insulin resistance, increased insulin dose requirements and poor glycemic control. Insulin resistance is also seen during puberty and is strongly related to increased risk of cardiovascular disease. The role of metformin as an adjunct to ongoing intensive insulin therapy in type 1 diabetics has been evaluated in several randomized trials, including the recently concluded T1D Exchange Network trial in adolescents and the REMOVAL trial in adults. Metformin reduces the insulin dose requirement, insulin-induced weight gain, and total and LDL cholesterol, but results in an increased risk of gastrointestinal adverse effects and a minor increase in the risk of hypoglycemia. In addition, metformin has been shown to reduce maximal carotid intima media thickness and therefore may extend cardioprotective benefits in type 1 diabetes. The role of metformin as adjunctive therapy in type 1 diabetes needs to be explored further in outcome trials.
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Dayem SMAE, Battah AA, Bohy AEME, Yousef RN, Ahmed AM, Talaat AA. Apelin, Nitric Oxide and Vascular Affection in Adolescent Type 1 Diabetic Patients. Open Access Maced J Med Sci 2017; 5:934-939. [PMID: 29362622 PMCID: PMC5771298 DOI: 10.3889/oamjms.2017.204] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 11/26/2017] [Accepted: 11/27/2017] [Indexed: 01/22/2023] Open
Abstract
AIM To evaluate the relationship of apelin and nitric oxide (NO) to endothelial dysfunction in type 1 diabetics. PATIENTS AND METHODS Sixty two type 1 diabetics and 30 healthy age and sex matched controls were included. Blood samples for apelin, NO, glycosylated hemoglobin (HbA1c), and lipid profile were collected. Albumin/creatinine ratio was assessed in urine. Flow mediated dilatation (FMD) via ultrasound was done. RESULTS The mean age of diabetics were 16.3 ± 1.5 yrs (14.0 - 19.0 yrs), and duration of disease, were 9.4 ± 2.9 yrs (5.0 - 16.5 yrs). FMD and FMD/nitrate mediated dilatation (NMD) ratio were lower in diabetics. NO was decreased, while apelin and albumin/creatinine ratio were increased significantly in diabetics. There was a positive correlation between apelin and HbA1c. On the contrary, NO had a negative correlation with HbA1c, albumin/creatinine ratio, LDL-c and OxLDL. CONCLUSION Diabetic patients had endothelial dysfunction and high apelin level, with no related to each other. High level of apelin is associated with bad glycemic control. Obesity had no role to increase in apelin level. NO is related to diabetic nephropathy and atherosclerosis. We recommend a further large study to evaluate the relationship of apelin with endothelial dysfunction.
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Affiliation(s)
| | - Ahmed A Battah
- Critical Care Department, Cairo University, Cairo, Egypt
| | | | - Rash Nazih Yousef
- Clinical Pathology Department, National Research Centre, Cairo, Egypt
| | - Azza M Ahmed
- Pediatrics Department, National Research Centre, Cairo, Egypt
| | - Ahmed A Talaat
- Pediatrics Department, National Research Centre, Cairo, Egypt
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35
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Kelly CB, Hookham MB, Yu JY, Lockhart SM, Du M, Jenkins AJ, Nankervis A, Hanssen KF, Henriksen T, Garg SK, Hammad SM, Scardo JA, Aston CE, Patterson CC, Lyons TJ. Circulating adipokines are associated with pre-eclampsia in women with type 1 diabetes. Diabetologia 2017; 60:2514-2524. [PMID: 28875223 PMCID: PMC9597852 DOI: 10.1007/s00125-017-4415-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 07/13/2017] [Indexed: 12/16/2022]
Abstract
AIMS/HYPOTHESIS The incidence of pre-eclampsia, a multisystem disorder of pregnancy, is fourfold higher in type 1 diabetic than non-diabetic women; it is also increased in women with features of the metabolic syndrome and insulin resistance. In a prospective study of pregnant women with type 1 diabetes, we measured plasma levels of adipokines known to be associated with insulin resistance: leptin, fatty acid binding protein 4 (FABP4), adiponectin (total and high molecular weight [HMW]; also known as high molecular mass), retinol binding protein 4 (RBP4) and resistin and evaluated associations with the subsequent development of pre-eclampsia. METHODS From an established prospective cohort of pregnant type 1 diabetic women, we studied 23 who developed pre-eclampsia and 24 who remained normotensive; for reference values we included 19 healthy non-diabetic normotensive pregnant women. Plasma adipokines were measured (by ELISA) in stored samples from three study visits (Visit 1- Visit 3) at different gestational ages (mean ± SD): Visit 1, 12.4 ± 1.8 weeks; Visit 2, 21.7 ± 1.4 weeks; and Visit 3, 31.4 ± 1.5 weeks. All the women were free of microalbuminuria and hypertension at enrolment. All study visits preceded the clinical onset of pre-eclampsia. RESULTS In all groups, leptin, the ratio of leptin to total or HMW adiponectin, FABP4 concentration, ratio of FABP4 to total or HMW adiponectin and resistin level increased, while total and HMW adiponectin decreased, with gestational age. At Visit 1: (1) in diabetic women with vs without subsequent pre-eclampsia, leptin, ratio of leptin to total or HMW adiponectin, and ratio of FABP4 to total or HMW adiponectin, were increased (p < 0.05), while total adiponectin was decreased (p < 0.05); and (2) in normotensive diabetic vs non-diabetic women, total adiponectin was elevated (p < 0.05). At Visits 2 and 3: (1) the primary findings in the two diabetic groups persisted, and FABP4 also increased in women with subsequent pre-eclampsia (p < 0.05); and (2) there were no differences between the two normotensive groups. By logistic regression analyses after covariate adjustment (HbA1c, insulin kg-1 day-1 and gestational age), the best predictive models for pre-eclampsia were as follows: Visit 1, doubling of leptin, OR 9.0 (p < 0.01); Visit 2, doubling of the leptin:total adiponectin ratio, OR 3.7 (p < 0.05); and Visit 3, doubling of FABP4 concentration, OR 25.1 (p < 0.01). The associations were independent of BMI. CONCLUSIONS/INTERPRETATION As early as the first trimester in type 1 diabetic women, adipokine profiles that suggest insulin resistance are associated with subsequent pre-eclampsia, possibly reflecting maternal characteristics that precede pregnancy. These associations persist in the second and third trimesters, and are independent of BMI. Insulin resistance may predispose women with type 1 diabetes to pre-eclampsia.
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Affiliation(s)
- Clare B Kelly
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK
- Division of Endocrinology and Diabetes, CSB Suite 822, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Michelle B Hookham
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK
- The Department of Clinical Biochemistry, Royal Victoria Hospital, Belfast, Northern Ireland, UK
| | - Jeremy Y Yu
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK
- Division of Endocrinology and Diabetes, CSB Suite 822, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Samuel M Lockhart
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK
| | - Mei Du
- Section of Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Alicia J Jenkins
- Division of Endocrinology and Diabetes, CSB Suite 822, Medical University of South Carolina, Charleston, SC, 29425, USA
- University of Sydney, NHMRC Clinical Trials Centre, Camperdown, Sydney, NSW, Australia
| | | | - Kristian F Hanssen
- Department of Endocrinology, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Tore Henriksen
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Satish K Garg
- Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO, USA
| | - Samar M Hammad
- Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA
| | | | - Christopher E Aston
- Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | | | - Timothy J Lyons
- Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK.
- Division of Endocrinology and Diabetes, CSB Suite 822, Medical University of South Carolina, Charleston, SC, 29425, USA.
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Chan CL, Pyle L, Morehead R, Baumgartner A, Cree-Green M, Nadeau KJ. The role of glycemia in insulin resistance in youth with type 1 and type 2 diabetes. Pediatr Diabetes 2017; 18:470-477. [PMID: 27503277 PMCID: PMC5298947 DOI: 10.1111/pedi.12422] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Revised: 05/17/2016] [Accepted: 07/06/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Hyperglycemia has traditionally been considered a major contributor to insulin resistance (IR) in type 1 diabetes (T1D), yet studies examining the relationship between HbA1c and IR are conflicting. Glucose measures captured by continuous glucose monitoring (CGM) (eg, peak glucose, standard deviation, hypoglycemia) in youth have not been explored as predictors of insulin sensitivity (IS). OBJECTIVE Assess the relationship between IS and glycemia in youth with T1D and type 2 diabetes (T2D). METHODS Sedentary 12-19 year olds with diabetes had peripheral IS measured by hyperinsulinemic-euglycemic clamp. HbA1c and 3 days of CGM data were also collected. Spearman correlation coefficients were calculated to examine the association between variables. RESULTS Participants included 100 youth with T1D [46% male, median body mass index (BMI) 74 percentile, HbA1c 8.5%] and 42 with T2D (26% male, BMI 99 percentile, HbA1c 6.9%). Nineteen with T1D and 13 with T2D also wore CGM. In T2D youth, higher HbA1c, average sensor glucose, area under the CGM curve, and metabolic syndrome characteristics correlated with lower IS. In T1D youth, higher BMI percentile, waist circumference, triglycerides, and LDL cholesterol, but not HbA1c, correlated with lower IS. Moreover, higher CGM overnight means glucose correlated with greater IS, and CGM hypoglycemia correlated with lower IS. CONCLUSIONS Markers of metabolic syndrome and hyperglycemia predicted decreased IS in T2D youth. Paradoxically, hypoglycemia predicted decreased IS in T1D youth and hyperglycemia, particularly overnight, predicted improved IS. These preliminary results imply different mechanisms underlying IR in T1D vs T2D and suggest a role for non-insulin therapies in T1D to improve IR.
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Affiliation(s)
- Christine L. Chan
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Denver, Aurora, CO, USA, 80045,Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA, 80045
| | - Laura Pyle
- Department of Pediatrics, Administrative Division, University of Colorado Denver, Aurora, CO, USA, 80045
| | - Rose Morehead
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Denver, Aurora, CO, USA, 80045
| | - Amy Baumgartner
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Denver, Aurora, CO, USA, 80045
| | - Melanie Cree-Green
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Denver, Aurora, CO, USA, 80045,Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA, 80045
| | - Kristen J. Nadeau
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Denver, Aurora, CO, USA, 80045,Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO, USA, 80045
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Abstract
Insulin remains indispensable to the treatment of diabetes, but its availability in injectable form only has hampered its timely and broader use. The development of an oral insulin remains an ultimate goal to both enhance ease of use, and to provide therapeutic advantages rooted in its direct delivery to the portal vein and liver. By mimicking the physiological path taken by pancreatic insulin, oral insulin is expected to have a distinct effect on the hepatic aspect of carbohydrate metabolism, hepatic insulin resistance, and, at the same time, avoid hyperinsulinemia and minimize the risk of hypoglycemia. With oral insulin approaching late stages of development, the goal of this review is to examine oral insulin in a physiological context and report on recent progress in its development.
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Affiliation(s)
- Ehud Arbit
- Oramed Pharmaceuticals, Inc. Jerusalem, Israel
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38
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Insulin Resistance and Chronic Kidney Disease in Patients with Type 1 Diabetes Mellitus. J Nutr Metab 2017; 2017:6425359. [PMID: 28392941 PMCID: PMC5368392 DOI: 10.1155/2017/6425359] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Accepted: 02/16/2017] [Indexed: 11/17/2022] Open
Abstract
Background and Aims. Diabetes mellitus (DM) is a chronic disease which can evolve towards devastating micro- and macrovascular complications. DM is the most frequent cause of chronic kidney disease (CKD). Insulin resistance plays an important role in the natural history of type 1 diabetes. The purpose of the study was to determine the prevalence of CKD in T1DM and the correlation with insulin resistance (IR) in patients with CKD. Materials and Methods. The study was conducted over a period of three years (2010-2013) and included patients with DM registered in the Clinical Centre of Diabetes, Nutrition and Metabolic Diseases of Dolj county. The study design was an epidemiological, transversal, noninterventional type. Finally, the study group included 200 subjects with type 1 DM. Insulin resistance (IR) was estimated by eGDR. The subjects with eGDR ≤ 7.5 mg/kg/min were considered with insulin resistance. Results. CKD was found in 44% of the patients. Analyzing statistically the presence of CKD, we found highly significant differences between patients with CKD and those without CKD regarding age and sex of the patients, the duration of diabetes, glycosylated hemoglobin (HbA1c), the estimated glucose disposal rate (eGDR), and the presence of hypertension, dyslipidemia, and hyperuricaemia. In patients with CKD, age and diabetes duration are significantly higher than in those who do not have this complication. CKD is more frequent in males than in females (50.9% men versus 34.5% women, p = 0.022). From the elements of metabolic syndrome, high blood pressure, hyperuricemia, and dyslipidemia are significantly increased in diabetic patients with CKD. eGDR value (expressed as mg·kg-1·min-1) is lower in patients with CKD than in those without CKD (15.92 versus 6.42, p < 0.001) indicating the fact that patients with CKD show higher insulin resistance than those without CKD. Conclusions. This study has shown that insulin resistance is associated with an increased risk of CKD, but, due to the cross-sectional design, the causal relationship cannot be assessed. However, the existence of this causality and the treatment benefit of insulin resistance in type 1 diabetes are issues for further discussion.
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Laurens C, Moro C. Intramyocellular fat storage in metabolic diseases. Horm Mol Biol Clin Investig 2017; 26:43-52. [PMID: 26741351 DOI: 10.1515/hmbci-2015-0045] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 11/18/2015] [Indexed: 12/13/2022]
Abstract
Over the past decades, obesity and its metabolic co-morbidities such as type 2 diabetes (T2D) developed to reach an endemic scale. However, the mechanisms leading to the development of T2D are still poorly understood. One main predictor for T2D seems to be lipid accumulation in "non-adipose" tissues, best known as ectopic lipid storage. A growing body of data suggests that these lipids may play a role in impairing insulin action in metabolic tissues, such as liver and skeletal muscle. This review aims to discuss recent literature linking ectopic lipid storage and insulin resistance, with emphasis on lipid deposition in skeletal muscle. The link between skeletal muscle lipid content and insulin sensitivity, as well as the mechanisms of lipid-induced insulin resistance and potential therapeutic strategies to alleviate lipotoxic lipid pressure in skeletal muscle will be discussed.
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40
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Cardoso L, Vicente N, Rodrigues D, Gomes L, Carrilho F. Controversies in the management of hyperglycaemic emergencies in adults with diabetes. Metabolism 2017; 68:43-54. [PMID: 28183452 DOI: 10.1016/j.metabol.2016.11.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Revised: 11/15/2016] [Accepted: 11/22/2016] [Indexed: 01/22/2023]
Abstract
Hyperglycaemic emergencies are associated with significant morbi-mortality and healthcare costs. Management consists on fluid replacement, insulin therapy, and electrolyte correction. However, some areas of patient management remain debatable. In patients without respiratory failure or haemodynamic instability, arterial and venous pH and bicarbonate measurements are comparable. Fluid choice varies upon replenishment phase and patient's condition. If patient is severely hypovolaemic, normal saline solution should be the first option. However, if patient has mild/moderate dehydration, fluid choice must take in consideration sodium concentration. Insulin therapy should be guided by β-hydroxybutyrate normalization and not by blood glucose. Variations of conventional insulin infusion protocols emerged recently. Priming dose of insulin may not be required, and fixed rate insulin infusion represents the best option to suppress hepatic glucose production, ketogenesis, and lipolysis. Concomitant administration of basal insulin analogues with regular insulin infusion accelerates ketoacidosis resolution and prevents rebound hyperglycaemia. Simpler protocols using subcutaneous rapid-acting insulin analogues for mild/moderate diabetic ketoacidosis treatment have proven to be safe and effective, but further studies are required to confirm these results. Treatment with bicarbonate, phosphate, and low-molecular-weight heparin is still disputable, and randomized controlled trials are urgently needed to optimize patient management and decrease the morbi-mortality of hyperglycaemic emergencies.
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Affiliation(s)
- Luís Cardoso
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
| | - Nuno Vicente
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
| | - Dírcea Rodrigues
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Leonor Gomes
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal
| | - Francisco Carrilho
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
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Jiang L, Yao L, Yang Y, Ke D, Batey R, Wang J, Li Y. Jiangzhi Capsule improves fructose-induced insulin resistance in rats: Association with repair of the impaired sarcolemmal glucose transporter-4 recycling. JOURNAL OF ETHNOPHARMACOLOGY 2016; 194:288-298. [PMID: 27616031 DOI: 10.1016/j.jep.2016.09.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Revised: 09/06/2016] [Accepted: 09/07/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Jiangzhi Capsule, originated from an experienced formula in traditional Chinese Medicine, has been listed and used for the management of metabolic abnormalities in Australia for a long time. To better understand Jiangzhi Capsule, this study investigated its effect on insulin resistance. MATERIALS AND METHODS Male rats were treated with liquid fructose in their drinking water over 14 weeks. Jiangzhi Capsule was co-administered (once daily, by oral gavage) during the last 7 weeks. Indexes of lipid and glucose homeostasis were determined enzymatically, by ELISA and/or histologically. Gene expression was analyzed by real-time PCR, Western blot and/or immunohistochemistry. RESULTS Treatment with Jiangzhi Capsule (100mg/kg) attenuated fructose overconsumption-induced increases in basal plasma insulin concentrations, the homeostasis model assessment of insulin resistance index and the adipose tissue insulin resistance index in rats. The increased plasma glucose concentrations during oral glucose tolerance test were also inhibited. Furthermore, Jiangzhi Capsule had a trend to attenuate the decreased ratios of glucose and non-esterified fatty acids to plasma insulin concentrations. Mechanistically, this insulin-sensitizing action was accompanied by normalization of the downregulated sarcolemmal glucose transporter (GLUT)-4 protein expression and the decreased phosphorylated Akt to total Akt protein ratio in gastrocnemius. CONCLUSIONS These results suggest that Jiangzhi Capsule ameliorates fructose-induced insulin resistance with a link to repair of the impaired sarcolemmal GLUT-4 recycling through modulation of the ratio of phosphorylated Akt to total Akt in gastrocnemius. Our findings provide an evidence-based and mechanistic understanding of Jiangzhi Capsule for the management of insulin resistance-associated disorders.
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Affiliation(s)
- Lirong Jiang
- Faculty of Basic Medical Sciences, Chongqing Medical University, China.
| | - Ling Yao
- Laboratory of Traditional Chinese Medicine, Chongqing Medical University, China.
| | - Yifan Yang
- Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Australia.
| | - Dazhi Ke
- The Second Affiliated Hospital, Chongqing Medical University, China.
| | - Robert Batey
- Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Australia.
| | - Jianwei Wang
- Laboratory of Traditional Chinese Medicine, Chongqing Medical University, China.
| | - Yuhao Li
- Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, Australia.
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Bacha F, Klinepeter Bartz S. Insulin resistance, role of metformin and other non-insulin therapies in pediatric type 1 diabetes. Pediatr Diabetes 2016; 17:545-558. [PMID: 26592507 DOI: 10.1111/pedi.12337] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 09/17/2015] [Accepted: 10/12/2015] [Indexed: 12/28/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) in youth is a challenging chronic medical condition. Its management should address not only the glycemic control but also insulin resistance and cardiovascular disease risk factors which are increasingly recognized to be present in youth with TID. Current knowledge on the mechanisms of insulin resistance in T1DM is reviewed. The use of adjunctive therapies that are beneficial to achieve adequate glycemic control while mitigating the effects of insulin resistance are discussed with a focus on metformin therapy and an overview of other new pharmacologic agents.
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Affiliation(s)
- Fida Bacha
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA. .,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
| | - Sara Klinepeter Bartz
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA.,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
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43
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Abstract
Insulin resistance is a component of several health disorders, most notably impaired glucose tolerance and type 2 diabetes mellitus. Insulin-resistant individuals have an impaired biological response to the usual action of insulin; that is, they have reduced insulin sensitivity. Various methods are used to assess insulin sensitivity both in individuals and in study populations. Validity, reproducibility, cost, and degree of subject burden are important factors for both clinicians and researchers to consider when weighing the merits of a particular method. This article describes several in vivo methods used to assess insulin sensitivity and presents the advantages and disadvantages of each.
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Affiliation(s)
- Kimberly K Trout
- Villanova University College of Nursing, Villanova, Pennsylvania 19085, USA.
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Gancheva S, Bierwagen A, Kaul K, Herder C, Nowotny P, Kahl S, Giani G, Klueppelholz B, Knebel B, Begovatz P, Strassburger K, Al-Hasani H, Lundbom J, Szendroedi J, Roden M. Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes. Diabetes 2016; 65:1849-57. [PMID: 27207512 DOI: 10.2337/db16-0162] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 04/12/2016] [Indexed: 01/21/2023]
Abstract
Type 1 diabetes has been recently linked to nonalcoholic fatty liver disease (NAFLD), which is known to associate with insulin resistance, obesity, and type 2 diabetes. However, the role of insulin resistance and hyperglycemia for hepatic energy metabolism is yet unclear. To analyze early abnormalities in hepatic energy metabolism, we examined 55 patients with recently diagnosed type 1 diabetes. They underwent hyperinsulinemic-normoglycemic clamps with [6,6-(2)H2]glucose to assess whole-body and hepatic insulin sensitivity. Hepatic γATP, inorganic phosphate (Pi), and triglyceride concentrations (hepatocellular lipid content [HCL]) were measured with multinuclei magnetic resonance spectroscopy ((31)P/(1)H-MRS). Glucose-tolerant humans served as control (CON) (n = 57). Whole-body insulin sensitivity was 44% lower in patients than in age- and BMI-matched CON. Hepatic γATP was 15% reduced (2.3 ± 0.6 vs. 2.7 ± 0.6 mmol/L, P < 0.001), whereas hepatic Pi and HCL were similar in patients when compared with CON. Across all participants, hepatic γATP correlated negatively with glycemia and oxidized LDL. Carriers of the PPARG G allele (rs1801282) and noncarriers of PPARGC1A A allele (rs8192678) had 21 and 13% lower hepatic ATP concentrations. Variations in genes controlling oxidative metabolism contribute to a reduction in hepatic ATP in the absence of NAFLD, suggesting that alterations in hepatic mitochondrial function may precede diabetes-related liver diseases.
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Affiliation(s)
- Sofiya Gancheva
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Alessandra Bierwagen
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Kirti Kaul
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Peter Nowotny
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Sabine Kahl
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Guido Giani
- German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Birgit Klueppelholz
- German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Birgit Knebel
- German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Paul Begovatz
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Klaus Strassburger
- German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Hadi Al-Hasani
- German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany
| | - Jesper Lundbom
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Julia Szendroedi
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany German Center of Diabetes Research (DZD e.V.), München-Neuherberg, Germany Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
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Duvnjak L, Blaslov K. Statin treatment is associated with insulin sensitivity decrease in type 1 diabetes mellitus: A prospective, observational 56-month follow-up study. J Clin Lipidol 2016; 10:1004-1010. [PMID: 27578133 DOI: 10.1016/j.jacl.2016.04.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 04/20/2016] [Accepted: 04/29/2016] [Indexed: 11/18/2022]
Abstract
BACKGROUND Statins are effective in the primary and secondary prevention of cardiovascular events in individuals with and without diabetes. Emerging evidence, however, suggests that statins might reduce insulin sensitivity and secretion in healthy population and in type 2 diabetes. OBJECTIVE We aimed to investigate the effect of statin therapy introduction on insulin sensitivity in patients with type 1 diabetes mellitus (T1DM). METHODS This prospective observational 56-month long study included 832 randomly selected T1DM patients aged 25 to 61 years. Uncontrolled dyslipidemia and clinician-perceived need for treatment, rather than randomization, were basis for individuals being started on either atorvastatin or simvastatin (10-40 mg); N = 345, 41.47%. Patients on statin treatment were compared with those unexposed to statin. Insulin sensitivity was assessed using equation derived from euglycemic-hyperinsulinemic clamp studies-estimated glucose disposal rate. RESULTS Patients who started statin therapy (N = 345, 59.42% atorvastatin and 40.58% simvastatin) experienced a greater decrease in insulin sensitivity (19.27% vs 12.82% P < .001) and metabolic control deterioration compared with statin-free group. The risk of decrease in insulin sensitivity attributable to statin use was 36.7% (hazard ratio 1.36; 95% confidence interval 1.31-1.43) after adjustment for age, gender, disease duration, smoking status, and the concomitant antihypertensive therapy. CONCLUSION Although there is still a lack of a clear molecular explanation on the adverse effects of statin therapy on insulin sensitivity, we showed that it deteriorates insulin sensitivity in T1DM. The cardiovascular benefits of statin treatment might outweigh the risk of developing insulin resistance, but, the possible metabolic control worsening merits to be considered.
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Affiliation(s)
- Lea Duvnjak
- Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia; School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Kristina Blaslov
- Vuk Vrhovac Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia.
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Pop A, Clenciu D, Anghel M, Radu S, Socea B, Mota E, Mota M, Panduru NM. Insulin resistance is associated with all chronic complications in type 1 diabetes. J Diabetes 2016; 8:220-228. [PMID: 25753338 DOI: 10.1111/1753-0407.12283] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Revised: 02/08/2015] [Accepted: 02/20/2015] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Insulin resistance (IR) is present in type 1 diabetes mellitus (T1DM) and is suggested to be related to chronic diabetic complications. The primary aim of our study was to assess IR in T1DM patients with and without chronic complications. A secondary aim was to evaluate the possible association between IR and chronic diabetic complications. METHODS This cross-sectional study enrolled 272 patients with T1DM. Insulin resistance was quantified using the estimated glucose disposal rate (eGDR). Associations between eGDR and each diabetes complication were first evaluated using binary logistic regression, then multiparametric logistic regression with stepwise selection of covariates. The discriminative value of eGDR was assessed by receiver operating characteristic (ROC) curve analysis. RESULTS Estimated GDR was lower in patients with chronic diabetic complications (6.1 vs. 6.9 mg/kg per min [P = 0.02] for retinopathy; 6.3 vs. 7.3 mg/kg per min [P < 0.01] for nephropathy; 6.5 vs. 7.6 mg/kg per min [P < 0.01] for neuropathy; and 5.2 vs. 7.5 mg/kg per min [P < 0.01] for cardiovascular complications). In univariate analysis eGDR was associated all diabetic complications. These associations remained significant after adjustment for different variables in the final regression models. In addition, eGDR was a good discriminator for each diabetic complication, with an area under the curve between 0.609 and 0.759. CONCLUSIONS Patients with chronic diabetic complications are more insulin resistant than those without complications. Moreover, IR was independently associated with the presence of each chronic diabetic complication, and seems to be a good discriminator for them all.
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Affiliation(s)
- Andrei Pop
- Department of Cardiology, Professor Dr C. C. Iliescu Institute of Cardiovascular Diseases, Bucharest, Romania
| | - Diana Clenciu
- Filantropia City Hospital, Diabetes Nutrition and Metabolic Diseases Department, Craiova, Romania
| | - Monica Anghel
- 1st Diabetes Clinic, N. C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
| | - Stefania Radu
- 1st Diabetes Clinic, N. C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
| | - Bogdan Socea
- 3rd Clinical Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Eugen Mota
- 3rd Department-Medical Specialties I, University of Medicine and Pharmacy, Craiova, Romania
| | - Maria Mota
- 3rd Department-Medical Specialties I, University of Medicine and Pharmacy, Craiova, Romania
| | - Nicolae M Panduru
- 2nd Clinical Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Afrin R, Arumugam S, Wahed MII, Pitchaimani V, Karuppagounder V, Sreedhar R, Harima M, Suzuki H, Miyashita S, Nakamura T, Suzuki K, Nakamura M, Ueno K, Watanabe K. Attenuation of Endoplasmic Reticulum Stress-Mediated Liver Damage by Mulberry Leaf Diet in Streptozotocin-Induced Diabetic Rats. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2016; 44:87-101. [DOI: 10.1142/s0192415x16500063] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Endoplasmic reticulum stress (ERS) plays a crucial role in the development of insulin resistance and diabetes mellitus. Although antidiabetic use of mulberry leaves (MLs) has been popular due to their many anti-oxidative flavonoid compounds and free radical scavenging effects, ML’s effects on ERS in experimental diabetic hepatocyte injury remain unknown. To investigate how ML affect ERS in diabetic liver, Sprague–Dawley (SD) rats were assigned to induce diabetes by a single intraperitoneal injection of streptozocin (STZ; 55 mg/kg) and fed with either normal chow or a diet containing 25% mulberry leaf powder diet (MLD) and examined for 56 days. We observed that MLD improved the rats’ morphological and histopathological changes. Levels of ERS markers such as phosphorylated double-stranded RNA-dependent protein kinase-like endoplasmic reticulum kinase (PERK) and X-box binding protein 1 (XBP1) and the protein expression of glucose regulated protein 78 (GRP78) were significantly higher in the diabetic liver compared to normal liver. MLD for 8 weeks significantly reduced all of these markers. MLD also significantly decreased hepatocyte apoptosis, hepatic macrophage recruitment, cellular infiltration, and CCAAT/enhancer–binding protein homologous protein (CHOP), tumor necrosis factor receptor associated factor 2 (TRAF2), interleukin 1[Formula: see text] (IL-1[Formula: see text]) and sterol regulatory element binding protein isoform 1c (SREBP 1c) levels in diabetic liver. These results may suggest that MLs can preserve hepatic function in experimental diabetes by modulating ERS mediated apoptosis and liver damage.
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Affiliation(s)
- Rejina Afrin
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Somasundaram Arumugam
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Mir Imam Ibne Wahed
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
- Department of Pharmacy, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Vigneshwaran Pitchaimani
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Vengadeshprabhu Karuppagounder
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Remya Sreedhar
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Meilei Harima
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Hiroshi Suzuki
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
- Department of Hematology, Endocrinology and Metabolism, Niigata University of Graduate School of Medicine and Dental Sciences, Niigata City 951-8510, Japan
| | - Shizuka Miyashita
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Takashi Nakamura
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Kenji Suzuki
- Department of Gastroenterology, Niigata University of Graduate School of Medicine and Dental Sciences, Niigata City 951-8510, Japan
| | - Masahiko Nakamura
- Department of Cardiology, Yamanashi Prefectural Central Hospital, Kofu Yamanashi 400-8506, Japan
| | - Kazuyuki Ueno
- Department of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
| | - Kenichi Watanabe
- Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 956-8603, Japan
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da Silva E, Natali AJ, da Silva MF, Gomes GDJ, da Cunha DNQ, Toledo MM, Drummond FR, Ramos RMS, Dos Santos EC, Novaes RD, de Oliveira LL, Maldonado IRDSC. Swimming training attenuates the morphological reorganization of the myocardium and local inflammation in the left ventricle of growing rats with untreated experimental diabetes. Pathol Res Pract 2016; 212:325-34. [PMID: 26896925 DOI: 10.1016/j.prp.2016.02.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 12/19/2015] [Accepted: 02/01/2016] [Indexed: 01/27/2023]
Abstract
Diabetic cardiomyopathy is associated with cardiac remodeling, myocardial dysfunction, low-grade inflammation, and reduced cardiac adiponectin in patients with type 1 diabetes mellitus (T1DM). Alternatively, physical exercise is an important strategy for the management of diabetes. This study aimed to investigate the influence of low-intensity swimming training in cardiac cytokines, structural remodeling, and cardiomyocyte contractile dysfunction in growing rats with untreated experimental DM. Thirty-day-old male Wistar rats were divided into four groups (n=14, per group): sedentary control (SC), exercised control (EC), sedentary diabetic (SD), and exercised diabetic (ED). Diabetes was induced by streptozotocin (60 mg kg(-1), i.p.). Animals from exercised groups swam (5 days/week, 90 min/day, loading up to 5% body weight around the animal's chest) for 8 weeks. The left ventricle (LV) was removed for molecular, morphological, and cardiomyocyte mechanical analysis. Diabetic animals presented cardiac remodeling with myocardial histoarchitectural disorganization, fibrosis, and necrosis. The capillary density was lower in diabetic animals. LV cardiomyocytes from diabetic animals exhibited more prolonged time to the peak of contraction and time to half relaxation than those from control animals. The cardiac levels of interleukin 10, nitric oxide, and total and high molecular weight (HMW) adiponectin were significantly decreased in diabetic animals. Exercise training reduced the level of TNF-α, increased capillary density, and attenuated the histopathological parameters assessed in diabetic rats. In conclusion, the cardiac structural remodeling coexists with reduced levels of total and HMW adiponectin, inflammation, and cardiomyocyte contractility dysfunction in experimental DM. More important, low-intensity swimming training attenuates part of these pathological changes, indicating the beneficial role for exercise in untreated T1DM.
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Affiliation(s)
- Edson da Silva
- Department of General Biology, Federal University of Viçosa, Viçosa, MG, Brazil; Department of Basic Sciences, Federal University of Jequitinhonha and Mucuri Valleys, Diamantina, MG, Brazil.
| | - Antônio José Natali
- Department of Physical Education, Federal University of Viçosa, Viçosa, MG, Brazil
| | | | - Gilton de Jesus Gomes
- Department of Physical Education, Federal University of Viçosa, Viçosa, MG, Brazil; Department of Physical Education, Federal University of Jequitinhonha and Mucuri Valleys, Diamantina, MG, Brazil
| | | | | | - Filipe Rios Drummond
- Department of Physical Education, Federal University of Viçosa, Viçosa, MG, Brazil
| | | | - Eliziária Cardoso Dos Santos
- Department of General Biology, Federal University of Viçosa, Viçosa, MG, Brazil; Faculty of Medicine, Federal University of Jequitinhonha and Mucuri Valleys, Diamantina, MG, Brazil
| | - Rômulo Dias Novaes
- Department of General Biology, Federal University of Viçosa, Viçosa, MG, Brazil; Biomedical Sciences Institute, Federal University of Alfenas, MG, Brazil
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Duca LM, Maahs DM, Schauer IE, Bergman BC, Nadeau KJ, Bjornstad P, Rewers M, Snell-Bergeon JK. Development and Validation of a Method to Estimate Insulin Sensitivity in Patients With and Without Type 1 Diabetes. J Clin Endocrinol Metab 2016; 101:686-95. [PMID: 26672636 PMCID: PMC4880115 DOI: 10.1210/jc.2015-3272] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
CONTEXT People with type 1 diabetes (T1D) have markedly reduced insulin sensitivity (IS) compared to their nondiabetic counterparts, and reduced IS is linked to higher cardiovascular risk. OBJECTIVE This study aimed to develop and validate an improved method for estimating IS in people with T1D. DESIGN Prospective cohort. SETTING Adults (36 with T1D, 41 nondiabetic) were recruited from the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study for measurement of IS by hyperinsulinemic-euglycemic clamp to develop a clinically useful IS prediction equation (eIS) for T1D and nondiabetic individuals. These equations were then compared with previously published equations from the SEARCH and Pittsburgh Epidemiology of Diabetes Complications studies for the ability to predict measured IS in test sets of adults and adolescents from independent clamp studies. INTERVENTION None. MAIN OUTCOME MEASURE Comparison of clamp-measured IS to estimated IS. RESULTS The best-fit prediction model (eIS) differed by diabetes status and included waist circumference, triglycerides, adiponectin, and diastolic blood pressure in all CACTI adults and insulin dose in adults with T1D (adjusted R(2) = 0.64) or fasting glucose and hemoglobin A1c (HbA1c) in nondiabetic adults (adjusted R(2) = 0.63). The eIS highly correlated with clamp-measured IS in all of the non-CACTI comparison populations (r = 0.83, P = .0002 in T1D adults; r = 0.71, P = .01 in nondiabetic adults; r = 0.44, P = .008 in T1D adolescents; r = 0.44, P = .006 in nondiabetic adolescents). CONCLUSIONS eIS performed better than previous equations for estimating IS in individuals with and without T1D. These equations could simplify point-of-care assessment of IS to identify patients who could benefit from targeted intervention.
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Affiliation(s)
- Lindsey M Duca
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - David M Maahs
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Irene E Schauer
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Bryan C Bergman
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Kristen J Nadeau
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Petter Bjornstad
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Marian Rewers
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
| | - Janet K Snell-Bergeon
- Barbara Davis Center for Diabetes (L.M.D., D.M.M., P.B., M.R., J.K.S.-B.), School of Medicine, University of Colorado, Aurora, Colorado 80045; Colorado School of Public Health (L.M.D., D.M.M., J.K.S.-B.), University of Colorado, Aurora, Colorado 80045; Division of Endocrinology, Metabolism, and Diabetes (I.E.S., B.C.B.), Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado 80045; Division of Pediatric Endocrinology (K.J.N.), Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045; and Denver VA Medical Center (I.E.S.), Denver, Colorado 80220
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