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Morrish F, Gingras H, Noonan J, Huang L, Sweet IR, Kuok IT, Knoblaugh SE, Hockenbery DM. Mitochondrial diabetes in mice expressing a dominant-negative allele of nuclear respiratory factor-1 (Nrf1) in pancreatic β-cells. Biochem Biophys Res Commun 2024; 737:150478. [PMID: 39128225 DOI: 10.1016/j.bbrc.2024.150478] [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: 05/03/2024] [Revised: 07/17/2024] [Accepted: 07/29/2024] [Indexed: 08/13/2024]
Abstract
Genetic polymorphisms in nuclear respiratory factor-1 (Nrf1), a key transcriptional regulator of nuclear-encoded mitochondrial proteins, have been linked to diabetes. Homozygous deletion of Nrf1 is embryonic lethal in mice. Our goal was to generate mice with β-cell-specific reduction in NRF1 function to investigate the relationship between NRF1 and diabetes. We report the generation of mice expressing a dominant-negative allele of Nrf1 (DNNRF1) in pancreatic β-cells. Heterozygous transgenic mice had high fed blood glucose levels detected at 3 wks of age, which persisted through adulthood. Plasma insulin levels in DNNRF1 transgenic mice were reduced, while insulin sensitivity remained intact in young animals. Islet size was reduced with increased numbers of apoptotic cells, and insulin content in islets by immunohistochemistry was low. Glucose-stimulated insulin secretion in isolated islets was reduced in DNNRF1-mice, but partially rescued by KCl, suggesting that decreased mitochondrial function contributed to the insulin secretory defect. Electron micrographs demonstrated abnormal mitochondrial morphology in β-cells. Expression of NRF1 target genes Tfam, Tfb1m and Tfb2m, and islet cytochrome c oxidase and succinate dehydrogenase activities were reduced in DNNRF1-mice. Rescue of mitochondrial function with low level activation of transgenic c-Myc in β-cells was sufficient to restore β-cell mass and prevent diabetes. This study demonstrates that reduced NRF1 function can lead to loss of β-cell function and establishes a model to study the interplay between regulators of bi-genomic gene transcription in diabetes.
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Affiliation(s)
- Fionnuala Morrish
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Helene Gingras
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Joanna Noonan
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Li Huang
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Ian R Sweet
- University of Washington Diabetes Institute, University of Washington, Seattle, WA, USA
| | - Iok Teng Kuok
- University of Washington Diabetes Institute, University of Washington, Seattle, WA, USA
| | - Sue E Knoblaugh
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - David M Hockenbery
- Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA.
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Luo S, Zheng X, Bao W, Nie S, Ding Y, Yue T, Zhou Y, Hu Y, Li H, Yang Q, Wan Q, Liu B, Xu H, Li G, Xu G, Chen C, Liu H, Shi Y, Zha Y, Kong Y, Su G, Tang Y, Gong M, Ji L, Hou FF, Weng J. Real-world effectiveness of early insulin therapy on the incidence of cardiovascular events in newly diagnosed type 2 diabetes. Signal Transduct Target Ther 2024; 9:154. [PMID: 38844816 PMCID: PMC11156919 DOI: 10.1038/s41392-024-01854-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 04/06/2024] [Accepted: 05/04/2024] [Indexed: 06/09/2024] Open
Abstract
Early insulin therapy is capable to achieve glycemic control and restore β-cell function in newly diagnosed type 2 diabetes (T2D), but its effect on cardiovascular outcomes in these patients remains unclear. In this nationwide real-world study, we analyzed electronic health record data from 19 medical centers across China between 1 January 2000, and 26 May 2022. We included 5424 eligible patients (mean age 56 years, 2176 women/3248 men) who were diagnosed T2D within six months and did not have prior cardiovascular disease. Multivariable Cox regression models were used to estimate the associations of early insulin therapy (defined as the first-line therapy for at least two weeks in newly diagnosed T2D patients) with the incidence of major cardiovascular events including coronary heart disease (CHD), stroke, and hospitalization for heart failure (HF). During 17,158 persons years of observation, we documented 834 incident CHD cases, 719 stroke cases, and 230 hospitalized cases for HF. Newly diagnosed T2D patients who received early insulin therapy, compared with those who did not receive such treatment, had 31% lower risk of incident stroke, and 28% lower risk of hospitalization for HF. No significant difference in the risk of CHD was observed. We found similar results when repeating the aforesaid analysis in a propensity-score matched population of 4578 patients and with inverse probability of treatment weighting models. These findings suggest that early insulin therapy in newly diagnosed T2D may have cardiovascular benefits by reducing the risk of incident stroke and hospitalization for HF.
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Affiliation(s)
- Sihui Luo
- Department of Endocrinology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
| | - Xueying Zheng
- Department of Endocrinology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
| | - Wei Bao
- Department of Endocrinology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
- Institute of Public Health Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Sheng Nie
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Ding
- Department of Endocrinology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
| | - Tong Yue
- Department of Endocrinology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China
| | - Yilun Zhou
- Department of Nephrology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Ying Hu
- The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Hua Li
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiongqiong Yang
- Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qijun Wan
- The Second People's Hospital of Shenzhen, Shenzhen University, Shenzhen, China
| | - Bicheng Liu
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, China
| | - Hong Xu
- Children's Hospital of Fudan University, Shanghai, China
| | - Guisen Li
- Renal Department and Institute of Nephrology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Sichuan Clinical Research Center for Kidney Diseases, Chengdu, China
| | - Gang Xu
- Division of Nephrology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunbo Chen
- Department of Critical Care Medicine, Maoming People's Hospital, Maoming, China
| | - Huafeng Liu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yongjun Shi
- Huizhou Central People's Hospital, Sun Yat-Sen University, Huizhou, China
| | - Yan Zha
- Guizhou Provincial People's Hospital, Guizhou University, Guiyang, China
| | - Yaozhong Kong
- Department of Nephrology, the First People's Hospital of Foshan, Foshan, China
| | - Guobin Su
- Department of Nephrology, Guangdong Provincial Hospital of Chinese Medicine, the Second Affiliated Hospital, the Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Tang
- The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Mengchun Gong
- Institute of Health Management, Southern Medical University, Guangzhou, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Fan Fan Hou
- Division of Nephrology, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Jianping Weng
- Department of Endocrinology, First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China.
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Mittal M, Porchezhian P, Kapoor N. Honeymoon phase in type 1 diabetes mellitus: A window of opportunity for diabetes reversal? World J Clin Cases 2024; 12:9-14. [PMID: 38292619 PMCID: PMC10824181 DOI: 10.12998/wjcc.v12.i1.9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 12/08/2023] [Accepted: 12/14/2023] [Indexed: 01/02/2024] Open
Abstract
The knowledge of the pathogenesis of type 1 diabetes mellitus (T1DM) continues to rapidly evolve. The natural course of the disease can be described in four clinical stages based on the autoimmune markers and glycemic status. Not all individuals of T1DM progress in that specific sequence. We hereby present a case of T1DM with a classical third phase (honeymoon phase) and discuss the intricacies of this interesting phase along with a possible future promise of "cure" with the use of immunotherapies. We now know that the course of T1DM may not be in only one direction towards further progression; rather the disease may have a waxing and waning course with even reversal of type 1 diabetes concept being discussed. The third phase popularly called the "honeymoon phase", is of special interest as this phase is complex in its pathogenesis. The honeymoon phase of T1DM seems to provide the best window of opportunity for using targeted therapies using various immunomodulatory agents leading to the possibility of achieving the elusive "diabetes reversal" in T1DM. Identifying this phase is therefore the key, with a lot of varying criteria having been proposed.
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Affiliation(s)
- Madhukar Mittal
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Jodhpur, Jodhpur 342005, India
| | - Pradakshna Porchezhian
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences Jodhpur, Jodhpur 342005, India
| | - Nitin Kapoor
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore 632004, Tamil Nadu, India
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Morrish F, Gingras H, Noonan J, Huang L, Sweet IR, Kuok IT, Knoblaugh SE, Hockenbery DM. Mitochondrial diabetes in mice expressing a dominant-negative allele of nuclear respiratory factor-1 ( Nrf1 ) in pancreatic β-cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.22.524153. [PMID: 38014068 PMCID: PMC10680558 DOI: 10.1101/2023.01.22.524153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Genetic polymorphisms in nuclear respiratory factor-1 ( NRF1 ), a key transcriptional regulator of nuclear-encoded mitochondrial proteins, have been linked to diabetes. Homozygous deletion of Nrf1 is embryonic lethal in mice. Our goal was to generate mice with β-cell-specific reduction in NRF1 function to investigate the relationship between NRF1 and diabetes. We report the generation of mice expressing a dominant-negative allele of Nrf1 (DNNRF1) in pancreatic β-cells. Heterozygous transgenic mice had high fed blood glucose levels detected at 3 wks of age, which persisted through adulthood. Plasma insulin levels in DNNRF1 transgenic mice were reduced, while insulin sensitivity remained intact in young animals. Islet size was reduced with increased numbers of apoptotic cells, and insulin content in islets by immunohistochemistry was low. Glucose-stimulated insulin secretion in isolated islets was reduced in DNNRF1-mice, but partially rescued by KCl, suggesting that decreased mitochondrial function contributed to the insulin secretory defect. Electron micrographs demonstrated abnormal mitochondrial morphology in β- cells. Expression of NRF1 target genes Tfam , T@1m and T@2m , and islet cytochrome c oxidase and succinate dehydrogenase activities were reduced in DNNRF1-mice. Rescue of mitochondrial function with low level activation of transgenic c-Myc in β-cells was sufficient to restore β-cell mass and prevent diabetes. This study demonstrates that reduced NRF1 function can lead to loss of β-cell function and establishes a model to study the interplay between regulators of bi- genomic gene transcription in diabetes.
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Castera L, Cusi K. Diabetes and cirrhosis: Current concepts on diagnosis and management. Hepatology 2023; 77:2128-2146. [PMID: 36631005 DOI: 10.1097/hep.0000000000000263] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/03/2022] [Indexed: 01/13/2023]
Abstract
Type 2 diabetes mellitus is often associated with cirrhosis as comorbidities, acute illness, medications, and other conditions profoundly alter glucose metabolism. Both conditions are closely related in NAFLD, the leading cause of chronic liver disease, and given its rising burden worldwide, management of type 2 diabetes mellitus in cirrhosis will be an increasingly common dilemma. Having diabetes increases cirrhosis-related complications, including HCC as well as overall mortality. In the absence of effective treatments for cirrhosis, patients with type 2 diabetes mellitus should be systematically screened as early as possible for NAFLD-related fibrosis/cirrhosis using noninvasive tools, starting with a FIB-4 index followed by transient elastography, if available. In people with cirrhosis, an early diagnosis of diabetes is critical for an optimal management strategy (ie, nutritional goals, and glycemic targets). Diagnosis of diabetes may be missed if based on A1C in patients with cirrhosis and impaired liver function (Child-Pugh B-C) as anemia may turn the test unreliable. Clinicians must also become aware of their high risk of hypoglycemia, especially in decompensated cirrhosis where insulin is the only therapy. Care should be within multidisciplinary teams (nutritionists, obesity management teams, endocrinologists, hepatologists, and others) and take advantage of novel glucose-monitoring devices. Clinicians should become familiar with the safety and efficacy of diabetes medications for patients with advanced fibrosis and compensated cirrhosis. Management is conditioned by whether the patient has either compensated or decompensated cirrhosis. This review gives an update on the complex relationship between cirrhosis and type 2 diabetes mellitus, with a focus on its diagnosis and treatment, and highlights knowledge gaps and future directions.
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Affiliation(s)
- Laurent Castera
- Departement of Hepatology, Hospital Beaujon, Assistance Publique-Hôpitaux de Paris, INSERM UMR 1149, Université Paris Cité, Clichy, France
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, The University of Florida, Gainesville, Florida, USA
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Basavarajappa HD, Irimia JM, Bauer BM, Fueger PT. The Adaptor Protein NumbL Is Involved in the Control of Glucolipotoxicity-Induced Pancreatic Beta Cell Apoptosis. Int J Mol Sci 2023; 24:ijms24043308. [PMID: 36834720 PMCID: PMC9959170 DOI: 10.3390/ijms24043308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/30/2023] [Accepted: 02/01/2023] [Indexed: 02/10/2023] Open
Abstract
Avoiding the loss of functional beta cell mass is critical for preventing or treating diabetes. Currently, the molecular mechanisms underlying beta cell death are partially understood, and there is a need to identify new targets for developing novel therapeutics to treat diabetes. Previously, our group established that Mig6, an inhibitor of EGF signaling, mediates beta cell death under diabetogenic conditions. The objective here was to clarify the mechanisms linking diabetogenic stimuli to beta cell death by investigating Mig6-interacting proteins. Using co-immunoprecipitation and mass spectrometry, we evaluated the binding partners of Mig6 under both normal glucose (NG) and glucolipotoxic (GLT) conditions in beta cells. We identified that Mig6 interacted dynamically with NumbL, whereas Mig6 associated with NumbL under NG, and this interaction was disrupted under GLT conditions. Further, we demonstrated that the siRNA-mediated suppression of NumbL expression in beta cells prevented apoptosis under GLT conditions by blocking the activation of NF-κB signaling. Using co-immunoprecipitation experiments, we observed that NumbL's interactions with TRAF6, a key component of NFκB signaling, were increased under GLT conditions. The interactions among Mig6, NumbL, and TRAF6 were dynamic and context-dependent. We proposed a model wherein these interactions activated pro-apoptotic NF-κB signaling while blocking pro-survival EGF signaling under diabetogenic conditions, leading to beta cell apoptosis. These findings indicated that NumbL should be further investigated as a candidate anti-diabetic therapeutic target.
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Affiliation(s)
- Halesha D. Basavarajappa
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Jose M. Irimia
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
- Comprehensive Metabolic Phenotyping Core, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
| | - Brandon M. Bauer
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
| | - Patrick T. Fueger
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA 91010, USA
- Comprehensive Metabolic Phenotyping Core, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA
- Correspondence: ; Tel.: +1-626-218-0620
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Boutsen L, Costenoble E, Pollé O, Erdem K, Bugli C, Lysy PA. Influence of the occurrence and duration of partial remission on short-term metabolic control in type 1 diabetes: the DIABHONEY pediatric study. Ther Adv Endocrinol Metab 2023; 14:20420188221145550. [PMID: 36699944 PMCID: PMC9869204 DOI: 10.1177/20420188221145550] [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: 04/29/2022] [Accepted: 11/26/2022] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE To evaluate the residual effect of partial remission (PR) on immediate post-PR glycemic control according to its occurrence and duration in a cohort of children with type 1 diabetes mellitus (T1DM). PATIENTS AND METHODS Values of glycemic control parameters [i.e. HbA1C, insulin dose-adjusted hemoglobin A1C (IDAA1C), glycemic target-adjusted HbA1C (GTAA1C)] and data from glucose monitoring devices from 189 pediatric patients with new-onset type 1 diabetes were collected retrospectively from 24 months. Patients were characterized according to their remission status (PR+ and PR-). PR+ patients were subdivided into three subgroups regarding PR duration [i.e. short (⩾3-⩽6 months), intermediate (>6-⩽12 months), and long PR (>12-⩽14 months)]. We compared glycemic control data from each PR+ subgroup at +6 and +12 months post-PR with PR- patients at the same postdiagnosis time. Second, PR+ subgroups were compared with each other. RESULTS PR+ patients showed improved glycemic control (i.e. HbA1C, IDAA1C, and GTAA1C) at + 6 months post-PR when compared with nonremitters (PR-), independently of the PR duration subgroups (p < 0.05). Interestingly, patients in long PR+ subgroup exhibited higher positive residual effect than short PR+ subgroup with lower GTAA1C scores (p = 0.02), better time in range (TIR) (p = 0.003), less time in hypoglycemia (10.45 versus 16.13%, p = 0.03) and less glycemic variability (83.1 mg/dl versus 98.84 mg/dl, p = 0.03). No significant differences were found for glucose control between PR+ and PR- patients at +12 months post-PR. CONCLUSION This study supports the positive impact of PR occurrence and duration on short-term metabolic control (better HbA1C levels, IDAA1C and GTAA1C scores, TIR, and less glycemic variability) with the residual effect increasing according to PR duration.
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Affiliation(s)
| | | | | | - Kezban Erdem
- Pediatric Endocrinology Unit, Cliniques universitaires Saint Luc, Bruxelles, Belgium
| | - Céline Bugli
- Pôle Epidémiologie et Biostatistique, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
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Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions. Biomolecules 2021; 11:biom11121892. [PMID: 34944536 PMCID: PMC8699500 DOI: 10.3390/biom11121892] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 12/14/2022] Open
Abstract
Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.
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Kant R, Yadav P, Garg M, Bahurupi Y, Kumar B. Safety and Efficacy of Long-Acting Insulins Degludec and Glargine Among Asian Patients With Type 2 Diabetes Mellitus: A Meta-Analysis. Cureus 2021; 13:e16046. [PMID: 34345540 PMCID: PMC8322718 DOI: 10.7759/cureus.16046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2021] [Indexed: 12/31/2022] Open
Abstract
Background Global variation in susceptibility to diabetes, insulin sensitivity, and regimen intensity poses a challenge for clinicians regarding the optimal choice of insulin therapy. The current study was carried out to see the relative safety and efficacy of currently available long-acting insulins among the type 2 diabetic Asian population. Methods A systematic literature search was done using various search engines (PubMed, Cochrane, Google Scholar, Scopus, and Embase) and included published randomized controlled trials (RCTs) in English before December 2019. Further, a manual search was performed by screening the reference list of the identified articles. Results We included four RCTs with 534 participants (349 in the insulin degludec group and 185 in the insulin glargine group) with type 2 diabetes mellitus (T2DM). Results show that both insulin glargine and degludec are equally efficacious in reducing fasting blood glucose (mean difference is -4.45, confidence interval -13.32- 4.43, I2=67%) and HbA1c (glycosylated hemoglobin) (mean difference is 0.12, confidence interval -0.12-0.35, I2=0%). However, insulin glargine was associated with lower risks of hypoglycemia (risk ratio = 0.9684, confidence interval- 0.8003- 1.1717, I2=30%). Conclusion Insulin glargine and degludec are comparable in achieving glycemic control with fewer hypoglycemic episodes in the insulin glargine-treated group.
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Affiliation(s)
- Ravi Kant
- General Medicine, All India Institute of Medical Sciences, Rishikesh, IND
| | - Poonam Yadav
- College of Nursing, All India Institute of Medical Sciences, Rishikesh, IND
| | - Mohit Garg
- General Medicine, Government Medical College, Khandawa, IND
| | - Yogesh Bahurupi
- Community and Family Medicine, All India Institute of Medical Sciences, Rishikesh, IND
| | - Barun Kumar
- Cardiology, All India Institute of Medical Sciences, Rishikesh, IND
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Abstract
An excessive and prolonged increase in glucose levels causes β-cell dysregulation, which is accompanied by impaired insulin synthesis and secretion, a condition known as glucotoxicity. Although it is known that both Lin28a and Lin28b regulate glucose metabolism, other molecular mechanisms that may protect against glucotoxicity are poorly understood. We investigated whether Lin28a overexpression can improve glucotoxicity-induced β-cell dysregulation in INS-1 and primary rat islet cells. INS-1, a rat insulinoma cell line was cultured and primary rat islet cells were isolated from SD-rats. To define the effect of Lin28a in chronic high glucose-induced β-cell dysregulation, we performed several in vitro and ex-vivo experiments. Chronic exposure to high glucose led to a downregulation of Lin28a mRNA and protein expression, followed by a decrease in insulin mRNA expression and secretion in β-cells. The mRNA and protein expression levels of PDX-1 and BETA2, were reduced; The levels of apoptotic factors, including c-caspase3 and the Bax/Bcl-2 ratio, were increased due to glucotoxicity. Adenovirus-mediated Lin28a overexpression in β-cells reversed the glucotoxicity-induced reduction of insulin secretion and insulin mRNA expression via regulation of β-cell-enriched transcription factors such as PDX-1 and BETA2. Adenovirus-mediated overexpression of Lin28a downregulated the glucotoxicity-induced upregulation of c-caspase3 levels and the Bax/Bcl-2 ratio, while inhibition of endogenous Lin28a by small interfering RNA resulted in their up-regulation. Lin28a counteracted glucotoxicity-induced downregulation of p-Akt and p-mTOR. Our results suggest that Lin28a protects pancreatic β-cells from glucotoxicity through inhibition of apoptotic factors via the PI3 kinase/Akt/mTOR pathway.
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Affiliation(s)
- Yeo Jin Hwang
- Division of Electronics & Information System, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea
| | - Gwon-Soo Jung
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea
| | - WonBae Jeon
- Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea
| | - Kyeong-Min Lee
- Division of Biotechnology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea
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11
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Yang G, Li L, Liu Y, Liang K, Wei L, Chen L. Hyperglycemia-Induced Dysregulated Fusion Intermediates in Insulin-Secreting Cells Visualized by Super-Resolution Microscopy. Front Cell Dev Biol 2021; 9:650167. [PMID: 33937248 PMCID: PMC8083903 DOI: 10.3389/fcell.2021.650167] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 03/15/2021] [Indexed: 11/23/2022] Open
Abstract
Impaired insulin release is a hallmark of type 2 diabetes and is closely related to chronically elevated glucose concentrations, known as “glucotoxicity.” However, the molecular mechanisms by which glucotoxicity impairs insulin secretion remain poorly understood. In addition to known kiss-and-run and kiss-and-stay fusion events in INS-1 cells, ultrafast Hessian structured illumination microscopy (Hessian SIM) enables full fusion to be categorized according to the newly identified structures, such as ring fusion (those with enlarged pores) or dot fusion (those without apparent pores). In addition, we identified four fusion intermediates during insulin exocytosis: initial pore opening, vesicle collapse, enlarged pore formation, and final pore dilation. Long-term incubation in supraphysiological doses of glucose reduced exocytosis in general and increased the occurrence of kiss-and-run events at the expense of reduced full fusion. In addition, hyperglycemia delayed pore opening, vesicle collapse, and enlarged pore formation in full fusion events. It also reduced the size of apparently enlarged pores, all of which contributed to the compromised insulin secretion. These phenotypes were mostly due to the hyperglycemia-induced reduction in syntaxin-1A (Stx-1A) and SNAP-25 protein, since they could be recapitulated by the knockdown of endogenous Stx-1A and SNAP-25. These findings suggest essential roles for the vesicle fusion type and intermediates in regulating insulin secretion from pancreatic beta cells in normal and disease conditions.
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Affiliation(s)
- Guoyi Yang
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Peking University, Beijing, China
| | - Liuju Li
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Peking University, Beijing, China
| | - Yanmei Liu
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Peking University, Beijing, China.,Institute for Brain Research and Rehabilitation, Key Laboratory of Brain, Cognition and Education Science, South China Normal University, Guangzhou, China
| | - Kuo Liang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Lisi Wei
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Peking University, Beijing, China
| | - Liangyi Chen
- State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Peking University, Beijing, China.,PKU-IDG/McGovern Institute for Brain Research, Beijing, China.,Beijing Academy of Artificial Intelligence, Beijing, China.,Shenzhen Bay Laboratory, Shenzhen, China
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12
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Liu Z, Zhu H, He C, He T, Pan S, Zhao N, Zhu L, Guan G, Liu P, Zhang Y, Wang J. Nicorandil attenuates high glucose-induced insulin resistance by suppressing oxidative stress-mediated ER stress PERK signaling pathway. BMJ Open Diabetes Res Care 2021; 9:9/1/e001884. [PMID: 33888540 PMCID: PMC8070885 DOI: 10.1136/bmjdrc-2020-001884] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 03/03/2021] [Accepted: 03/28/2021] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Glucose-induced insulin resistance is a typical character of diabetes. Nicorandil is now widely used in ischemic heart disease. Nicorandil shows protective effects against oxidative and endoplasmic reticulum (ER) stress, which are involved in insulin resistance. Here, we investigated mechanisms of nicorandil's novel pharmacological activity on insulin resistance in diabetes. RESEARCH DESIGN AND METHODS Nicorandil was administrated to streptozotocin-induced animals with diabetes and high glucose exposed skeletal muscle cells. Insulin resistance and glucose tolerance were evaluated. Molecular mechanisms concerning oxidative stress, ER stress signaling activation and glucose uptake were assessed. RESULTS Nicorandil attenuated high glucose-induced insulin resistance without affecting fasting blood glucose and glucose tolerance in whole body and skeletal muscle in rats with diabetes. Nicorandil treatment suppressed protein kinase C/nicotinamide adenine dinucleotide phosphate oxidases system activities by reducing cytoplasmic free calcium level in skeletal muscle cells exposed to high glucose. As a result, the oxidative stress-mediated ER stress protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α/activating transcription factor 4/CEBP homologous protein/tribbles homolog (TRB)3 signaling pathway activation was inhibited. Nicorandil downregulated expression of TRB3 and thus facilitated Akt phosphorylation in response to insulin stimulation, leading to glucose transporter4 plasma membrane translocation which promoted glucose uptake capability of skeletal muscle cells. CONCLUSIONS By reducing cytoplasmic calcium, nicorandil alleviated high glucose-induced insulin resistance by inhibiting oxidative stress-mediated ER stress PERK pathway.
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Affiliation(s)
- Zhongwei Liu
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
| | - Haitao Zhu
- Department of Pediatrics, Northwest Women's and Children's Hospital, Xi'an, China
| | - Chunhui He
- Department of Cardiology, Fuwai Hospital State Key Laboratory of Cardiovascular Disease, Beijing, China
| | - Ting He
- Department of Cardiology, Fuwai Hospital State Key Laboratory of Cardiovascular Disease, Beijing, China
| | - Shuo Pan
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
| | - Na Zhao
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
| | - Ling Zhu
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
| | - Gongchang Guan
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
| | - Peng Liu
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
| | - Yong Zhang
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
| | - Junkui Wang
- Department of Cardiology, Affiliated Shaanxi Provincial People's Hospital, Northwestern Polytechnical University, Xi'an, China
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Possik E, Al-Mass A, Peyot ML, Ahmad R, Al-Mulla F, Madiraju SRM, Prentki M. New Mammalian Glycerol-3-Phosphate Phosphatase: Role in β-Cell, Liver and Adipocyte Metabolism. Front Endocrinol (Lausanne) 2021; 12:706607. [PMID: 34326816 PMCID: PMC8313997 DOI: 10.3389/fendo.2021.706607] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 06/25/2021] [Indexed: 11/25/2022] Open
Abstract
Cardiometabolic diseases, including type 2 diabetes, obesity and non-alcoholic fatty liver disease, have enormous impact on modern societies worldwide. Excess nutritional burden and nutri-stress together with sedentary lifestyles lead to these diseases. Deranged glucose, fat, and energy metabolism is at the center of nutri-stress, and glycolysis-derived glycerol-3-phosphate (Gro3P) is at the crossroads of these metabolic pathways. Cellular levels of Gro3P can be controlled by its synthesis, utilization or hydrolysis. The belief that mammalian cells do not possess an enzyme that hydrolyzes Gro3P, as in lower organisms and plants, is challenged by our recent work showing the presence of a Gro3P phosphatase (G3PP) in mammalian cells. A previously described phosphoglycolate phosphatase (PGP) in mammalian cells, with no established physiological function, has been shown to actually function as G3PP, under physiological conditions, particularly at elevated glucose levels. In the present review, we summarize evidence that supports the view that G3PP plays an important role in the regulation of gluconeogenesis and fat storage in hepatocytes, glucose stimulated insulin secretion and nutri-stress in β-cells, and lipogenesis in adipocytes. We provide a balanced perspective on the pathophysiological significance of G3PP in mammals with specific reference to cardiometabolic diseases.
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Affiliation(s)
- Elite Possik
- Departments of Nutrition, Biochemistry and Molecular Medicine, and Montreal Diabetes Research Center, CRCHUM, Montréal, QC, Canada
| | - Anfal Al-Mass
- Departments of Nutrition, Biochemistry and Molecular Medicine, and Montreal Diabetes Research Center, CRCHUM, Montréal, QC, Canada
- Department of Medicine, McGill University, Montréal, QC, Canada
| | - Marie-Line Peyot
- Departments of Nutrition, Biochemistry and Molecular Medicine, and Montreal Diabetes Research Center, CRCHUM, Montréal, QC, Canada
| | - Rasheed Ahmad
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fahd Al-Mulla
- Immunology & Microbiology Department, Dasman Diabetes Institute, Dasman, Kuwait
| | - S. R. Murthy Madiraju
- Departments of Nutrition, Biochemistry and Molecular Medicine, and Montreal Diabetes Research Center, CRCHUM, Montréal, QC, Canada
- *Correspondence: Marc Prentki, ; S. R. Murthy Madiraju,
| | - Marc Prentki
- Departments of Nutrition, Biochemistry and Molecular Medicine, and Montreal Diabetes Research Center, CRCHUM, Montréal, QC, Canada
- *Correspondence: Marc Prentki, ; S. R. Murthy Madiraju,
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Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 75:525-538. [PMID: 32029136 DOI: 10.1016/j.jacc.2019.11.044] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/06/2019] [Accepted: 11/17/2019] [Indexed: 02/07/2023]
Abstract
A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.
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15
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Abstract
A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.
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Alnahdi A, John A, Raza H. Mitigation of Glucolipotoxicity-Induced Apoptosis, Mitochondrial Dysfunction, and Metabolic Stress by N-Acetyl Cysteine in Pancreatic β-Cells. Biomolecules 2020; 10:biom10020239. [PMID: 32033264 PMCID: PMC7072690 DOI: 10.3390/biom10020239] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/19/2020] [Accepted: 01/24/2020] [Indexed: 12/18/2022] Open
Abstract
Glucolipotoxicity caused by hyperglycemia and hyperlipidemia are the common features of diabetes-induced complications. Metabolic adaptation, particularly in energy metabolism; mitochondrial dysfunction; and increased inflammatory and oxidative stress responses are considered to be the main characteristics of diabetes and metabolic syndrome. However, due to various fluctuating endogenous and exogenous stimuli, the precise role of these factors under in vivo conditions is not clearly understood. In the present study, we used pancreatic β-cells, Rin-5F, to elucidate the molecular and metabolic changes in glucolipotoxicity. Cells treated with high glucose (25 mM) and high palmitic acid (up to 0.3 mM) for 24 h exhibited increased caspase/poly-ADP ribose polymerase (PARP)-dependent apoptosis followed by DNA fragmentation, alterations in mitochondrial membrane permeability, and bioenergetics, accompanied by alterations in glycolytic and mitochondrial energy metabolism. Our results also demonstrated alterations in the expression of mammalian target of rapamycin (mTOR)/5′ adenosine monophosphate-activated protein kinase (AMPK)-dependent apoptotic and autophagy markers. Furthermore, pre-treatment of cells with 10 mM N-acetyl cysteine attenuated the deleterious effects of high glucose and high palmitic acid with improved cellular functions and survival. These results suggest that the presence of high energy metabolites enhance mitochondrial dysfunction and apoptosis by suppressing autophagy and adapting energy metabolism, mediated, at least in part, via enhanced oxidative DNA damage and mTOR/AMPK-dependent cell signaling.
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Human Physiology of Genetic Defects Causing Beta-cell Dysfunction. J Mol Biol 2020; 432:1579-1598. [PMID: 31953147 DOI: 10.1016/j.jmb.2019.12.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/17/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
The last decade has revealed hundreds of genetic variants associated with type 2 diabetes, many especially with insulin secretion. However, the evidence for their single or combined effect on beta-cell function relies mostly on genetic association of the variants or genetic risk scores with simple traits, and few have been functionally fully characterized even in cell or animal models. Translating the measured traits into human physiology is not straightforward: none of the various indices for beta-cell function or insulin sensitivity recapitulates the dynamic interplay between glucose sensing, endogenous glucose production, insulin production and secretion, insulin clearance, insulin resistance-to name just a few factors. Because insulin sensitivity is a major determinant of physiological need of insulin, insulin secretion should be evaluated in parallel with insulin sensitivity. On the other hand, multiple physiological or pathogenic processes can either mask or unmask subtle defects in beta-cell function. Even in monogenic diabetes, a clearly pathogenic genetic variant can result in different phenotypic characteristics-or no phenotype at all. In this review, we evaluate the methods available for studying beta-cell function in humans, critically examine the evidence linking some identified variants to a specific beta-cell phenotype, and highlight areas requiring further study.
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18
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Zaccarelli-Marino MA, Fonseca FLA, Gascón TM, Filipini R. Profile of Overweight and Obesity in Children and Adolescents and Frequency of Type 2 Diabetes Mellitus and Glucose Intolerance: A Study in Public School in Brazil. Diabetes Metab Syndr Obes 2020; 13:1733-1741. [PMID: 32547135 PMCID: PMC7247719 DOI: 10.2147/dmso.s246061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/29/2020] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVE To verify if there is an increase in frequency of type 2 diabetes mellitus (DM2) and glucose intolerance in children and adolescents who are overweight and obese. METHODS This was a cross-sectional survey. The study population consisted of 2757 students of both sexes (1415 girls and 1342 boys) attending public schools in São Paulo state, Brazil,aged 10-19 years, from 2011 to 2012. Students not within this age range and those with type 1 diabetes mellitus were excluded. Upon interview, anthropometry, capillary blood glucose testing, fasting glucosemia (FG) and glucosemia 2 hours after 75 g of dextrose (AD) variables were obtained. We emphasize that, inspite of the 2757 students included in the next stage, only 88 students agreed to participate, and low compliance of those participants is due to the fact that they were children and adolescents who depend on the authorization of their parents or tutors, who have demonstrated deficient knowledge of familial chronic diseases such as obesity and its consequences, and the risk of DM2. RESULTS More often girls, 1415 (51.3%). A total of 27.3% was overweight/obese/severely obese. Capillary blood glucose testing was performed in 88 (3.2%) children and adolescents with low values of glycemic results after the glucose load. There was no statistical significance between sex and glucosemia, with an average FG and AD of 92.8 mg/dL (male), 91.8 mg/dL (female) and 89.1 mg/dL (male) and 88.9 mg/dL (female), respectively. CONCLUSION This survey emphasizes that more attention should be paid to diet interventions and practicing of physical activities demanding habit changes and acquisition of special behaviour for self-care, and provision of a better educational health program, suggesting the effective participation of the family.
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Affiliation(s)
| | - Fernando Luiz Affonso Fonseca
- Clinical Laboratory Analysis of ABC Medical School Foundation, Santo André, SP, Brazil
- Federal University of São Paulo, Diadema, SP, Brazil
| | - Thaís Moura Gascón
- Clinical Laboratory Analysis of ABC Medical School Foundation, Santo André, SP, Brazil
- Correspondence: Thaís Moura Gascón Clinical Analysis Laboratory of Faculdade de Medicina ABC, 2000, Lauro Gomes Avenue, Santo AndréCEP 09060-650, SP, BrazilTel +55 11 972280763 Email
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Alnahdi A, John A, Raza H. N-acetyl cysteine attenuates oxidative stress and glutathione-dependent redox imbalance caused by high glucose/high palmitic acid treatment in pancreatic Rin-5F cells. PLoS One 2019; 14:e0226696. [PMID: 31860682 PMCID: PMC6924679 DOI: 10.1371/journal.pone.0226696] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 12/02/2019] [Indexed: 02/07/2023] Open
Abstract
Elevated levels of glucose and fatty acids are the main characteristics of diabetes, obesity and other metabolic disorders, associated with increased oxidative stress, mitochondrial dysfunction and inflammation. Once the primary pathogenesis of diabetes is established, which is potentially linked to both genetic and environmental factors, hyperglycemia and hyperlipidemia exert further destructive and/or toxic effects on β-cells. The concept of glucolipotoxicity has arisen from the combination of deleterious effects of chronic elevation of glucose and fatty acid levels on pancreatic β- cell function and/or survival. Though numerous studies have been conducted in this field, the exact molecular mechanisms and causative factors still need to be established. The aim of the present work was to elucidate the molecular mechanisms of oxidative stress, and inflammatory/antioxidant responses in the presence of high concentrations of glucose/fatty acids in a cell-culture system using an insulin-secreting pancreatic β-cell line (Rin-5F) and to study the effects of the antioxidant, N-acetyl cysteine (NAC) on β-cell toxicity. In our study, we investigated the molecular mechanism of cytotoxicity in the presence of high glucose (up to 25 mM) and high palmitic acid (up to 0.3 mM) on Rin-5F cells. Our results suggest that the cellular and molecular mechanisms underlying β-cell toxicity are mediated by increased oxidative stress, imbalance of redox homeostasis, glutathione (GSH) metabolism and alterations in inflammatory responses. Pre-treatment with NAC attenuated oxidative stress and alterations in GSH metabolism associated with β-cells cytotoxicity.
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Affiliation(s)
- Arwa Alnahdi
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Annie John
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Haider Raza
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- * E-mail:
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20
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Kang YM, Jung CH, Lee SH, Kim SW, Song KH, Kim SG, Kim JH, Cho YM, Park TS, Ku BJ, Koh G, Kim DM, Lee BW, Park JY. Effectiveness and Safety of Adding Basal Insulin Glargine in Patients with Type 2 Diabetes Mellitus Exhibiting Inadequate Response to Metformin and DPP-4 Inhibitors with or without Sulfonylurea. Diabetes Metab J 2019; 43:432-446. [PMID: 31237133 PMCID: PMC6712234 DOI: 10.4093/dmj.2018.0092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 12/08/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND We aimed to investigate the effectiveness and safety of adding basal insulin to initiating dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin and/or sulfonylurea (SU) in achieving the target glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM). METHODS This was a single-arm, multicenter, 24-week, open-label, phase 4 study in patients with inadequately controlled (HbA1c ≥7.5%) T2DM despite the use of DPP-4 inhibitor and metformin. A total of 108 patients received insulin glargine while continuing oral antidiabetic drugs (OADs). The primary efficacy endpoint was the percentage of subjects achieving HbA1c ≤7.0%. Other glycemic profiles were also evaluated, and the safety endpoints were adverse events (AEs) and hypoglycemia. RESULTS The median HbA1c at baseline (8.9%; range, 7.5% to 11.1%) decreased to 7.6% (5.5% to 11.7%) at 24 weeks. Overall, 31.7% subjects (n=33) achieved the target HbA1c level of ≤7.0%. The mean differences in body weight and fasting plasma glucose were 1.2±3.4 kg and 56.0±49.8 mg/dL, respectively. Hypoglycemia was reported in 36 subjects (33.3%, 112 episodes), all of which were fully recovered. There was no serious AE attributed to insulin glargine. Body weight change was significantly different between SU users and nonusers (1.5±2.5 kg vs. -0.9±6.0 kg, P=0.011). CONCLUSION The combination add-on therapy of insulin glargine, on metformin and DPP-4 inhibitors with or without SU was safe and efficient in reducing HbA1c levels and thus, is a preferable option in managing T2DM patients exhibiting dysglycemia despite the use of OADs.
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Affiliation(s)
- Yu Mi Kang
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chang Hee Jung
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung Hwan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sang Wook Kim
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Kee Ho Song
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Sin Gon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Tae Sun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonbuk National University Hospital, Chonbuk National University Medical School, Jeonju, Korea
| | - Bon Jeong Ku
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon, Korea
| | - Gwanpyo Koh
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
| | - Dol Mi Kim
- Medical Department of Diabetes and Cardiovascular, Sanofi-Korea, Seoul, Korea
| | - Byung Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea.
| | - Joong Yeol Park
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Wang X, Gao YT, Jiang D, Wang Y, Du H, Lv J, Li SJ. Hv1-deficiency protects β cells from glucotoxicity through regulation of NOX4 level. Biochem Biophys Res Commun 2019; 513:434-438. [PMID: 30967259 DOI: 10.1016/j.bbrc.2019.03.195] [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: 03/24/2019] [Accepted: 03/29/2019] [Indexed: 11/27/2022]
Abstract
High glucose (HG)-induced oxidative stress contributes to the dysfunction of pancreatic β cells in diabetes. The voltage-gated proton channel Hv1 has been proposed to support reactive oxygen species (ROS) production during respiratory bursts. However, the effect of Hv1 on glucotoxicity in pancreatic β cells is not clear yet. In this study, we examined the protective effects of Hv1-deficiency in HG cultured β cells. Following 48 h of treatment with 30 mM high glucose, Hv1 KO β cells showed higher cell viability, lower cell apoptosis and a more stable insulin gene expression level compared to WT β cells. In both control and HG cultured β cells, deficiency of Hv1 decreased the glucose- and PMA-induced ROS production. Finally, HG incubation led to NOX4 upregulation in WT β cells, which could be inhibited by HV1 deficiency. In conclusion, Hv1-deficiency prevents the HG treatment-induced NOX4 upregulation and protects β cells from glucotoxicity.
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Affiliation(s)
- Xudong Wang
- Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, 300071, PR China
| | - Ying-Tang Gao
- Key Laboratory of Artificial Cell, Third Central Clinical College of Tianjin Medical University, Tianjin, 300170, PR China
| | - Dan Jiang
- Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, 300071, PR China
| | - Yuzhou Wang
- Laboratory Animal Center, College of Life Sciences, Nankai University, Tianjin, 300071, PR China
| | - Hongyan Du
- Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, 300071, PR China
| | - Jili Lv
- Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, 300071, PR China
| | - Shu Jie Li
- Department of Biophysics, School of Physics Science, The Key Laboratory of Bioactive Materials, Ministry of Education, Nankai University, Tianjin, 300071, PR China.
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Vijayakumar V, Samal SK, Mohanty S, Nayak SK. Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management. Int J Biol Macromol 2018; 122:137-148. [PMID: 30342131 DOI: 10.1016/j.ijbiomac.2018.10.120] [Citation(s) in RCA: 211] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 09/26/2018] [Accepted: 10/14/2018] [Indexed: 01/13/2023]
Abstract
Currently, diabetes mellitus (DM) accelerated diabetic foot ulcer (DFU) remains vivacious health problem related with delayed healing and high amputation rates which leads to enormous clinical obligation. Keeping in view of the foregoing, researchers have been made in their efforts to develop novel materials which accelerate delayed wound healing in the diabetic patient and reduce the adversative influences of DFUs. The most prominent materials used for the wound healing application have biocompatibility, low cytotoxicity, excellent biodegradable properties, and antimicrobial activity properties. Utilization of nanoparticles has emerged as a protruding scientific and technological revolution in controlling DFUs. Biopolymers in combination with bioactive nanoparticles having antimicrobial, antibacterial, and anti-inflammatory properties have great potential in wound care to enhance the healing process of diabetic wound infectious. Combination of antibacterial nanoparticles like silver nanoparticles (AgNPs), gold nanoparticles (AuNPs), copper nanoparticles (CuNPs) etc. with polymeric matrix could efficiently inhibit bacterial growth and at the same time fastens the healing process of a wound. This review briefed the recent development of different natural polymers and antibacterial nanoparticles to mitigate the diabetes mellitus based DFU.
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Affiliation(s)
- Veena Vijayakumar
- School for Advanced Research in Polymers (SARP)-Laboratory for Advanced Research in Polymeric Materials (LARPM), Central Institute of Plastics Engineering and Technology (CIPET), B-25, CNI Complex, Patia, Bhubaneswar, Odisha 751024, India
| | - Sushanta K Samal
- School for Advanced Research in Polymers (SARP)-Laboratory for Advanced Research in Polymeric Materials (LARPM), Central Institute of Plastics Engineering and Technology (CIPET), B-25, CNI Complex, Patia, Bhubaneswar, Odisha 751024, India.
| | - Smita Mohanty
- School for Advanced Research in Polymers (SARP)-Laboratory for Advanced Research in Polymeric Materials (LARPM), Central Institute of Plastics Engineering and Technology (CIPET), B-25, CNI Complex, Patia, Bhubaneswar, Odisha 751024, India
| | - Sanjay K Nayak
- School for Advanced Research in Polymers (SARP)-Laboratory for Advanced Research in Polymeric Materials (LARPM), Central Institute of Plastics Engineering and Technology (CIPET), B-25, CNI Complex, Patia, Bhubaneswar, Odisha 751024, India
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Park CH, Park KH, Hong SG, Lee JS, Baek JH, Lee GI, Heo JW, Yokozawa T. Oligonol, a low-molecular-weight polyphenol derived from lychee peel, attenuates diabetes-induced pancreatic damage by inhibiting inflammatory responses via oxidative stress-dependent mitogen-activated protein kinase/nuclear factor-kappa B signaling. Phytother Res 2018; 32:2541-2550. [DOI: 10.1002/ptr.6194] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 08/23/2018] [Accepted: 08/24/2018] [Indexed: 11/11/2022]
Affiliation(s)
- Chan Hum Park
- Department of Medicinal Crop Research; National Institute of Horticultural and Herbal Science, Rural Development Administration; Eumseong Republic of Korea
| | - Kyeong Hun Park
- Department of Medicinal Crop Research; National Institute of Horticultural and Herbal Science, Rural Development Administration; Eumseong Republic of Korea
| | - Seung Gil Hong
- Department of Agricultural Engineering; National Institute of Agricultural Sciences, Rural Development Administration; Jeonju Republic of Korea
| | - Jae Su Lee
- Department of Agricultural Engineering; National Institute of Agricultural Sciences, Rural Development Administration; Jeonju Republic of Korea
| | - Jeong Hyun Baek
- Department of Agricultural Engineering; National Institute of Agricultural Sciences, Rural Development Administration; Jeonju Republic of Korea
| | - Gong In Lee
- Department of Agricultural Engineering; National Institute of Agricultural Sciences, Rural Development Administration; Jeonju Republic of Korea
| | - Jeong Wook Heo
- Department of Agricultural Engineering; National Institute of Agricultural Sciences, Rural Development Administration; Jeonju Republic of Korea
| | - Takako Yokozawa
- Graduate School of Science and Engineering for Research; University of Toyama; Toyama Japan
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24
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Han KT, Kim SJ, Kim DJ, Kim SJ. Does the active use of nutrition labeling reduce the risk of diabetes mellitus? Results of insulin resistance using Korean National Health and Nutrition Examination Survey. Prim Care Diabetes 2018; 12:445-452. [PMID: 29858117 DOI: 10.1016/j.pcd.2018.05.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Revised: 04/09/2018] [Accepted: 05/10/2018] [Indexed: 01/22/2023]
Abstract
AIMS In 1995, nutrition labeling became mandatory in South Korea. These regulations help consumers make reasonable choices when purchasing food based on nutritional value by providing the nutritional properties of processed foods. We investigated the association between perceptions about nutrition labeling and insulin resistance (IR) in people with no diagnosis of diabetes mellitus (DM). METHODS This study used data from the sixth Korea National Health and Nutrition Examination Survey (KNHANES VI-3 in 2015, n=2931). We used multiple regression analysis to investigate the relationship between perceptions about nutrition labeling and the homeostatic model assessment for insulin resistance (HOMA-IR). RESULTS 75.2% of participants were aware of nutrition labeling and 24.8% of participants checked nutrition labeling and actively used the information. "Actively checked and used the nutrition labeling" was inversely associated with HOMA-IR scores (check nutrition facts and make labeling-dependent purchase decisions: β=-0.108, p=0.0164). These associations were more significant in people who were obese or paid more attention to their health. CONCLUSION High levels of perceptions about nutrition labeling and active use of such information could have positive effects on reducing IR and preventing DM. Therefore, it is necessary to improve public perception for effective implementation of healthcare programs.
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Affiliation(s)
- Kyu-Tae Han
- Research and Analysis Team, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea; Institute of Health Services Research, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Ju Kim
- Department of Nursing, College of Nursing, Eulji University, Seongnam, Republic of Korea
| | - Dong Jun Kim
- Department of Health Administration and Management, Soonchunhyang University, Asan, Republic of Korea
| | - Sun Jung Kim
- Department of Health Administration and Management, Soonchunhyang University, Asan, Republic of Korea.
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25
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Punthakee Z, Goldenberg R, Katz P. Definition, Classification and Diagnosis of Diabetes, Prediabetes and Metabolic Syndrome. Can J Diabetes 2018; 42 Suppl 1:S10-S15. [PMID: 29650080 DOI: 10.1016/j.jcjd.2017.10.003] [Citation(s) in RCA: 417] [Impact Index Per Article: 59.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Indexed: 12/16/2022]
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26
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Pyo SE, Choi JS, Kim MR. Anti-diabetic mechanism of melania snail (Semisulcospira libertina) protamex hydrolysates. KOREAN JOURNAL OF FOOD PRESERVATION 2017; 24:1007-1016. [DOI: 10.11002/kjfp.2017.24.7.1007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Melania snail (Semisulcospira libertina) was traditionally used as the healthy food in Korea. It was generally known to improve liver function and heal a diabetes. The aim of this study was to elucidate the anti-diabetic mechanism of melanian snail hydrolysates treated with protamex (MPH) by investigating the inhibitory action on protein tyrosine phosphatase 1B (PTP1B), the improving effect on the insulin resistance in C2C12 myoblast and the protective effect for pancreatic beta-cell (INS-1) under the glucose toxicity. The melania snail hydrolysates treated with protamex (MPH), which showed the highest degree of hydrolysis (43%), and inhibited effectively PTP1B activity (IC50=15.42±1.1 μg/mL), of which inhibitory effect was higher than usolic acid, positive control (IC50=16.65 μg/mL). MPH increased the glucose uptake in C2C12 myoblast treated with palmitic acid. In addition, MPH increased insulin mRNA expression level by over 160% with enhanced cell viability in INS-1 cell under the high glucose concentration (30 mM). These results suggest that MHP may improve the diabetic symptom by the inhibiting the PTP1B activity, increasing the glucose uptake in muscle cell and protecting the pancreatic beta-cell from glucose toxicity.
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27
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Ray S, Mukherjee JJ. Combination therapy with multiple oral hypoglycaemic agents together with short-term basal insulin in new-onset Type 2 diabetes mellitus with marked hyperglycaemia. Diabet Med 2017; 34:1322-1323. [PMID: 28586518 DOI: 10.1111/dme.13393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- S Ray
- Division of Diabetes & Endocrinology, Department of Medicine, Apollo Gleneagles Hospitals, Kolkata, India
| | - J J Mukherjee
- Division of Diabetes & Endocrinology, Department of Medicine, Apollo Gleneagles Hospitals, Kolkata, India
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28
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Nagl K, Hermann JM, Plamper M, Schröder C, Dost A, Kordonouri O, Rami-Merhar B, Holl RW. Factors contributing to partial remission in type 1 diabetes: analysis based on the insulin dose-adjusted HbA1c in 3657 children and adolescents from Germany and Austria. Pediatr Diabetes 2017; 18:428-434. [PMID: 27416952 DOI: 10.1111/pedi.12413] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 05/24/2016] [Accepted: 06/07/2016] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE Insulin dose-adjusted hemoglobin A1c (HbA1C, IDAA1c) correlates well with stimulated C-peptide levels, but has not yet been evaluated in a large cohort of patients with Type 1 diabetes (T1D). METHODS We investigated prevalence of partial remission (PREM) defined by IDAA1c ≤9 in 3657 in children with new-onset T1D who were continuously followed over 6 years. We evaluated the predictors of PREM using the multicenter database from the DPV (Diabetes Patienten Verlaufsdokumentation) registry. RESULTS PREM occurred in 71% of patients. Median duration was 9 (0-21) months. Compared to children <5 years at T1D onset, those aged 5-10 and ≥10 years had twice the chance of developing PREM (OR: 2.08, CI: 1.67-2.60; P < .001 and OR: 2.16, CI: 1.70-2.75; P < .001). Boys were more likely to develop PREM than girls (OR 1.41, CI: 1.18-1.69; P = .0002). Further predictors for PREM were: ketoacidosis, autoantibodies, and HbA1c at T1D onset. These results were confirmed by quantile regression analysis with duration of PREM as dependent variable. CONCLUSION This research on a large cohort provides insight into epidemiologic characteristics of PREM in T1D defined by IDAA1c. As IDAA1c does not discriminate between insulin sensitivity and secretion, available data cannot resolve whether the sex-difference in PREM reflects innate higher insulin resistance in girls, or better beta-cell recovery in boys. Further research is needed to clarify the usefulness and performance of IDAA1c in clinical practice.
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Affiliation(s)
- Katrin Nagl
- Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Austria
| | - Julia M Hermann
- Epidemiology and Medical Biometry, University of Ulm, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | | | | | - Axel Dost
- Department of Pediatrics, University Hospital Jena, Germany
| | | | - Birgit Rami-Merhar
- Department of Pediatrics and Adolescent Medicine, Medical University Vienna, Austria
| | - Reinhard W Holl
- Epidemiology and Medical Biometry, University of Ulm, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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29
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Gupta A, Delhiwala KS, Raman RPG, Sharma T, Srinivasan S, Kulothungan V. Failure to initiate early insulin therapy - A risk factor for diabetic retinopathy in insulin users with Type 2 diabetes mellitus: Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN-DREAMS, Report number 35). Indian J Ophthalmol 2017; 64:440-5. [PMID: 27488152 PMCID: PMC4991171 DOI: 10.4103/0301-4738.187668] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Context: Insulin users have been reported to have a higher incidence of diabetic retinopathy (DR). Aim: The aim was to elucidate the factors associated with DR among insulin users, especially association between duration, prior to initiating insulin for Type 2 diabetes mellitus (DM) and developing DR. Materials and Methods: Retrospective cross-sectional observational study included 1414 subjects having Type 2 DM. Insulin users were defined as subjects using insulin for glycemic control, and insulin nonusers as those either not using any antidiabetic treatment or using diet control or oral medications. The duration before initiating insulin after diagnosis was calculated by subtracting the duration of insulin usage from the duration of DM. DR was clinically graded using Klein's classification. SPSS (version 9.0) was used for statistical analysis. Results: Insulin users had more incidence of DR (52.9% vs. 16.3%, P < 0.0001) and sight threatening DR (19.1% vs. 2.4%, P < 0.0001) in comparison to insulin nonusers. Among insulin users, longer duration of DM (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.00–1.25, P = 0.044) and abdominal obesity (OR 1.15, 95% CI 1.02–1.29, P = 0.021) was associated with DR. The presence of DR was significantly associated with longer duration (≥5 years) prior to initiating insulin therapy, overall (38.0% vs. 62.0%, P = 0.013), and in subjects with suboptimal glycemic control (32.5% vs. 67.5%, P = 0.022). Conclusions: The presence of DR is significantly associated with longer duration of diabetes (>5 years) and sub-optimal glycemic control (glycosylated hemoglobin <7.0%). Among insulin users, abdominal obesity was found to be a significant predictor of DR; DR is associated with longer duration prior to initiating insulin therapy in Type 2 DM subjects with suboptimal glycemic control.
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Affiliation(s)
- Aditi Gupta
- Shri Bhagwan Mahavir Vitreoretinal Services, Chennai, Tamil Nadu, India
| | | | - Rajiv P G Raman
- Shri Bhagwan Mahavir Vitreoretinal Services, Chennai, Tamil Nadu, India
| | - Tarun Sharma
- Shri Bhagwan Mahavir Vitreoretinal Services, Chennai, Tamil Nadu, India
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O'Brien TP, Jenkins EC, Estes SK, Castaneda AV, Ueta K, Farmer TD, Puglisi AE, Swift LL, Printz RL, Shiota M. Correcting Postprandial Hyperglycemia in Zucker Diabetic Fatty Rats With an SGLT2 Inhibitor Restores Glucose Effectiveness in the Liver and Reduces Insulin Resistance in Skeletal Muscle. Diabetes 2017; 66:1172-1184. [PMID: 28246292 PMCID: PMC5399614 DOI: 10.2337/db16-1410] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 02/17/2017] [Indexed: 12/11/2022]
Abstract
Ten-week-old Zucker diabetic fatty (ZDF) rats at an early stage of diabetes embody metabolic characteristics of obese human patients with type 2 diabetes, such as severe insulin and glucose intolerance in muscle and the liver, excessive postprandial excursion of plasma glucose and insulin, and a loss of metabolic flexibility with decreased lipid oxidation. Metabolic flexibility and glucose flux were examined in ZDF rats during fasting and near-normal postprandial insulinemia and glycemia after correcting excessive postprandial hyperglycemia using treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2-I) for 7 days. Preprandial lipid oxidation was normalized, and with fasting, endogenous glucose production (EGP) increased by 30% and endogenous glucose disposal (E-Rd) decreased by 40%. During a postprandial hyperglycemic-hyperinsulinemic clamp after SGLT2-I treatment, E-Rd increased by normalizing glucose effectiveness to suppress EGP and stimulate hepatic glucose uptake; activation of glucokinase was restored and insulin action was improved, stimulating muscle glucose uptake in association with decreased intracellular triglyceride content. In conclusion, SGLT2-I treatment improves impaired glucose effectiveness in the liver and insulin sensitivity in muscle by eliminating glucotoxicity, which reinstates metabolic flexibility with restored preprandial lipid oxidation and postprandial glucose flux in ZDF rats.
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Affiliation(s)
- Tracy P O'Brien
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Erin C Jenkins
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Shanea K Estes
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Antonio V Castaneda
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Kiichiro Ueta
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Tiffany D Farmer
- Diabetes Research Training Center, Vanderbilt University School of Medicine, Nashville, TN
| | - Allison E Puglisi
- Diabetes Research Training Center, Vanderbilt University School of Medicine, Nashville, TN
| | - Larry L Swift
- Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN
| | - Richard L Printz
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
| | - Masakazu Shiota
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN
- Diabetes Research Training Center, Vanderbilt University School of Medicine, Nashville, TN
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31
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Yang Y, Shin JA, Yang HK, Lee SH, Ko SH, Ahn YB, Yoon KH, Cho JH. Reduction of Sulfonylurea with the Initiation of Basal Insulin in Patients with Inadequately Controlled Type 2 Diabetes Mellitus Undergoing Long-Term Sulfonylurea-Based Treatment. Diabetes Metab J 2016; 40:454-462. [PMID: 27766795 PMCID: PMC5167710 DOI: 10.4093/dmj.2016.40.6.454] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 08/08/2016] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND There were a limited number of studies about β-cell function after insulin initiation in patients exposed to long durations of sulfonylurea treatment. In this study, we aimed to evaluate the recovery of β-cell function and the efficacy of concurrent sulfonylurea use after the start of long-acting insulin. METHODS In this randomized controlled study, patients with type 2 diabetes mellitus (T2DM), receiving sulfonylurea for at least 2 years with glycosylated hemoglobin (HbA1c) >7%, were randomly assigned to two groups: sulfonylurea maintenance (SM) and sulfonylurea reduction (SR). Following a 75-g oral glucose tolerance test (OGTT), we administered long-acting basal insulin to the two groups. After a 6-month follow-up, we repeated the OGTT. RESULTS Among 69 enrolled patients, 57 completed the study and were analyzed: 31 in the SM and 26 in the SR group. At baseline, there was no significant difference except for the longer duration of diabetes and lower triglycerides in the SR group. After 6 months, the HbA1c was similarly reduced in both groups, but there was little difference in the insulin dose. In addition, insulin secretion during OGTT was significantly increased by 20% to 30% in both groups. A significant weight gain was observed in the SM group only. The insulinogenic index was more significantly improved in the SR group. CONCLUSION Long-acting basal insulin replacement could improve the glycemic status and restore β-cell function in the T2DM patients undergoing sulfonylurea-based treatment, irrespective of the sulfonylurea dose reduction. The dose reduction of the concurrent sulfonylurea might be beneficial with regard to weight grain.
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Affiliation(s)
- Yeoree Yang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jeong Ah Shin
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Serim Hospital, Incheon, Korea
| | - Hae Kyung Yang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Hwan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Hyun Ko
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Yu Bae Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Kun Ho Yoon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Hyoung Cho
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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32
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Zhang W, Wu M, Kim T, Jariwala RH, Garvey WJ, Luo N, Kang M, Ma E, Tian L, Steverson D, Yang Q, Fu Y, Garvey WT. Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High- Fat Diet-Induced Insulin Resistance. Diabetes 2016; 65:2380-91. [PMID: 27207527 PMCID: PMC4955990 DOI: 10.2337/db16-0154] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 04/26/2016] [Indexed: 01/05/2023]
Abstract
In the current study, we used muscle-specific TRIB3 overexpressing (MOE) and knockout (MKO) mice to determine whether TRIB3 mediates glucose-induced insulin resistance in diabetes and whether alterations in TRIB3 expression as a function of nutrient availability have a regulatory role in metabolism. In streptozotocin diabetic mice, TRIB3 MOE exacerbated, whereas MKO prevented, glucose-induced insulin resistance and impaired glucose oxidation and defects in insulin signal transduction compared with wild-type (WT) mice, indicating that glucose-induced insulin resistance was dependent on TRIB3. In response to a high-fat diet, TRIB3 MOE mice exhibited greater weight gain and worse insulin resistance in vivo compared with WT mice, coupled with decreased AKT phosphorylation, increased inflammation and oxidative stress, and upregulation of lipid metabolic genes coupled with downregulation of glucose metabolic genes in skeletal muscle. These effects were prevented in the TRIB3 MKO mice relative to WT mice. In conclusion, TRIB3 has a pathophysiological role in diabetes and a physiological role in metabolism. Glucose-induced insulin resistance and insulin resistance due to diet-induced obesity both depend on muscle TRIB3. Under physiological conditions, muscle TRIB3 also influences energy expenditure and substrate metabolism, indicating that the decrease and increase in muscle TRIB3 under fasting and nutrient excess, respectively, are critical for metabolic homeostasis.
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Affiliation(s)
- Wei Zhang
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Mengrui Wu
- Department of Molecular & Cellular Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Teayoun Kim
- Department of Medicine-Endocrinology, Diabetes & Metabolism, University of Alabama at Birmingham, Birmingham, AL
| | - Ravi H Jariwala
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - W John Garvey
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Nanlan Luo
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Minsung Kang
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Elizabeth Ma
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Ling Tian
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Dennis Steverson
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Qinglin Yang
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - Yuchang Fu
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL
| | - W Timothy Garvey
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL Birmingham Veterans Affairs Medical Center, Birmingham, AL
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Abstract
The recent recognition of the clinical association between type 2 diabetes (T2D) and several types of human cancer has been further highlighted by reports of antidiabetic drugs treating or promoting cancer. At the cellular level, a plethora of molecules operating within distinct signaling pathways suggests cross-talk between the multiple pathways at the interface of the diabetes–cancer link. Additionally, a growing body of emerging evidence implicates homeostatic pathways that may become imbalanced during the pathogenesis of T2D or cancer or that become chronically deregulated by prolonged drug administration, leading to the development of cancer in diabetes and vice versa. This notion underscores the importance of combining clinical and basic mechanistic studies not only to unravel mechanisms of disease development but also to understand mechanisms of drug action. In turn, this may help the development of personalized strategies in which drug doses and administration durations are tailored to individual cases at different stages of the disease progression to achieve more efficacious treatments that undermine the diabetes–cancer association.
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Affiliation(s)
- Slavica Tudzarova
- Wolfson Institute for Biomedical Research, University College London, London WC1E6BT, UK
| | - Mahasin A Osman
- Department of Molecular Physiology, Pharmacology and Biotechnology, Division of Biology and Medicine, Warren Alpert Medical School, Brown University, Providence, RI 02912 Department of Chemistry and Forensic Sciences, College of Sciences and Technology, Savannah State University, Savannah, GA 41404
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34
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Grundy SM. Overnutrition, ectopic lipid and the metabolic syndrome. J Investig Med 2016; 64:1082-6. [DOI: 10.1136/jim-2016-000155] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2016] [Indexed: 12/20/2022]
Abstract
The metabolic syndrome is a constellation of metabolic risk factors including atherogenic dyslipidemia (elevated serum triglycerides, reduced high-density lipoprotein (HDL) cholesterol), elevated blood pressure, dysglycemia (insulin resistance and elevated serum glucose), a pro-inflammatory state, and a prothrombotic state. Most persons with metabolic syndrome are obese, and usually have abdominal obesity. Generally, obesity is a reflection of overnutrition. A current view is that when adipose tissue fails to store all excess nutrients as triglyceride, lipid begins to accumulate in various tissues (eg, muscle, liver, pancreas, and heart). This accumulation is called ectopic lipid. Various mechanisms have been proposed whereby ectopic lipid is detrimental in different tissues; these derangements induce metabolic risk factors. The foundation of the metabolic syndrome thus appears to be overnutrition, that is, more nutrient intake than can be safely disposed by lipid oxidation. Excess dietary carbohydrate also induces ectopic lipid. Of interest, less than half of obese individuals develop metabolic syndrome. Through various mechanisms they adapt to overnutrition so as to minimize lipid overload in tissues, and consequently, prevent the syndrome.
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35
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Singh SP, Misra B, Kar SK, Panigrahi MK, Misra D, Bhuyan P, Pattnaik K, Meher C, Agrawal O, Rout N, Swain M. Nonalcoholic fatty liver disease (NAFLD) without insulin resistance: Is it different? Clin Res Hepatol Gastroenterol 2015; 39:482-8. [PMID: 25543522 DOI: 10.1016/j.clinre.2014.08.014] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2013] [Revised: 07/04/2014] [Accepted: 08/12/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of insulin resistance [IR]. However, a significant proportion of NAFLD patients are devoid of IR. Is NAFLD sans IR a different entity? The aim of the study was to compare the anthropometric, metabolic, biochemical, ultrasonography, and histological profile of NAFLD patients with and without IR. METHODS Retrospective analyses of 336 NAFLD patients diagnosed during the last two years was done. Patients without IR were compared with those with IR. RESULTS Out of 336 patients, 153 [45.53%] were without IR. Although age, gender, BMI and transaminase levels were comparable, significantly higher proportion of patients in non-IR group were non-obese [43.14% vs. 25/14%; P=0.0005], and had mild fatty change on ultrasonography; [78.43% vs. 67.21%; P=0.022]. Higher proportion of them had elevated transaminases; [67.97% vs. 56.83%; P=0.036]. Serum triglyceride [178.52±78.78 vs. 204.86±94.72 mg/dl; P=0.02], FBG [85.39±13.80 vs. 98.93±31.56 mg/dl; P=0.00], PGBG [123.76±36.77 vs. 148.07±64.67m g/dl; P=0.00], and serum insulin [6.33±2.18 vs. 15.39±12.56 μIU/ml; P=0.00] were significantly lower in patients without IR. Although there was no difference in histology, interestingly fibrosis was seen in one third of patients despite absence of IR. CONCLUSION Nearly half of our NAFLD population was without IR; one third of them had significant fibrosis. NAFLD is probably a heterogeneous disease and IR is not the sole factor responsible for NAFLD; further studies are needed to find out other possible etiological factors.
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Affiliation(s)
| | - Bijay Misra
- Department of Gastroenterology, S.C.B. Medical College, 753007 Cuttack, India
| | - Sanjib Kumar Kar
- Department of Gastroenterology, S.C.B. Medical College, 753007 Cuttack, India
| | | | - Debasis Misra
- Department of Gastroenterology, S.C.B. Medical College, 753007 Cuttack, India
| | - Pallavi Bhuyan
- Department of Pathology, S.C.B. Medical College, 753007 Cuttack, India
| | - Kaumudee Pattnaik
- Department of Pathology, S.C.B. Medical College, 753007 Cuttack, India
| | - Chudamani Meher
- Department of Radiology, Beam Diagnostics Centre, Bajrakabati Road, 753001 Cuttack, India
| | - Omprakash Agrawal
- Department of Radiology, Beam Diagnostics Centre, Bajrakabati Road, 753001 Cuttack, India
| | - Niranjan Rout
- Department of Oncopathology, A.H. Regional Cancer Center, 753001 Cuttack, India
| | - Manorama Swain
- Department of Biochemistry, S.C.B. Medical College, 753007 Cuttack, India
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Lv L, Chen H, Sun J, Lu D, Chen C, Liu D. PRMT1 promotes glucose toxicity-induced β cell dysfunction by regulating the nucleo-cytoplasmic trafficking of PDX-1 in a FOXO1-dependent manner in INS-1 cells. Endocrine 2015; 49:669-82. [PMID: 25874535 DOI: 10.1007/s12020-015-0543-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 01/27/2015] [Indexed: 11/26/2022]
Abstract
Protein N-arginine methyltransferase-1 (PRMT1), the major asymmetric arginine methyltransferase, plays important roles in various cellular processes. Previous reports have demonstrated that levels and activities of PRMT1 can vary in animals with type 2 diabetes mellitus. The aim of this study was to assess the expression and mechanism of action of PRMT1 during glucose toxicity-induced β cell dysfunction. Liposome-mediated gene transfection was used to transfect INS-1 cells with siPRMT1, which inhibits PRMT1 expression, and pALTER-FOXO1, which overexpresses forkhead box protein O1 (FOXO1). The cells were then cultured in media containing 5.6 or 25 mmol/L glucose with or without the small molecule PRMT1 inhibitor AMI-1 for 48 h. The protein levels of PRMT1, the arginine methylated protein α-metR, FOXO1, Phospho-FOXO1, pancreas duodenum homeobox-1 (PDX-1), and the intracellular localization of PDX-1 and FOXO1 were then measured by western blotting. FOXO1 methylation was detected by immunoprecipitated with anti-PRMT1 antibody and were immunoblotted with α-metR. The levels of insulin mRNA were measured by real-time fluorescence quantitative PCR. Glucose-stimulated insulin secretion (GSIS) and intracellular insulin content were measured using radioimmunoassays. Intracellular Ca(2+) ([Ca(2+)]i) was detected using Fura-2 AM. Intracellular cAMP levels were measured using ELISA. Chronic exposure to high glucose impaired insulin secretion, decreased insulin mRNA levels and insulin content, increased intracellular [Ca(2+)]i and cAMP levels, and abolishes their responses to glucose. Inhibiting PRMT1 expression improved insulin secretion, increased mRNA levels and insulin content by regulating the intracellular translocation of PDX-1 and FOXO1, decreasing the methylation of FOXO1, and reducing intracellular [Ca(2+)]i and cAMP concentrations. Transient overexpression of constitutively active FOXO1 in nuclear reversed the AMI-1-induced improvement of β cell function without changing arginine methylation. It is concluded therefore that PRMT1 regulates GSIS in INS-1 cells, through enhanced methylation-induced nuclear localization of FOXO1, which subsequently suppresses the nuclear localization of PDX-1. Our results suggest a novel mechanism that might contribute to the deficient insulin secretion observed under conditions of chronically hyperglycemia.
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Affiliation(s)
- Lixia Lv
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, 76 Linjiang Road, Yuzhong District, Chongqing, 400010, China
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Begovatz P, Koliaki C, Weber K, Strassburger K, Nowotny B, Nowotny P, Müssig K, Bunke J, Pacini G, Szendrödi J, Roden M. Pancreatic adipose tissue infiltration, parenchymal steatosis and beta cell function in humans. Diabetologia 2015; 58:1646-55. [PMID: 25740696 DOI: 10.1007/s00125-015-3544-5] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 02/04/2015] [Indexed: 12/12/2022]
Abstract
AIMS/HYPOTHESIS This study aimed to perform a comprehensive analysis of interlobular, intralobular and parenchymal pancreatic fat in order to assess their respective effects on beta cell function. METHODS Fifty-six participants (normal glucose tolerance [NGT] (n = 28), impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) (n = 14) and patients with type 2 diabetes (n = 14)) underwent a frequent-sampling OGTT and non-invasive magnetic resonance imaging (MRI; whole-body and pancreatic) and proton magnetic resonance spectroscopy ((1)H-MRS; liver and pancreatic fat). Total pancreatic fat was assessed by a standard 2 cm(3) (1)H-MRS method, intralobular fat by 1 cm(3) (1)H-MRS that avoided interlobular fat within modified DIXON (mDIXON) water images, and parenchymal fat by a validated mDIXON-MRI fat-fraction method. RESULTS Comparison of (1)H-MRS techniques revealed an inhomogeneous distribution of interlobular and intralobular adipose tissue, which increased with decreasing glucose tolerance. mDIXON-MRI measurements provided evidence against uniform steatosis, revealing regions of parenchymal tissue void of lipid accumulation in all participants. Total (r = 0.385, p < 0.01) and intralobular pancreas adipose tissue infiltration (r = 0.310, p < 0.05) positively associated with age, but not with fasting or 2 h glucose levels, BMI or visceral fat content (all p > 0.5). Furthermore, no associations were found between total and intralobular pancreatic adipose tissue infiltration and insulin secretion or beta cell function within NGT, IFG/IGT or patients with type 2 diabetes (all p > 0.2). CONCLUSIONS/INTERPRETATION The pancreas does not appear to be another target organ for abnormal endocrine function because of ectopic parenchymal fat storage. No relationship was found between pancreatic adipose tissue infiltration and beta cell function, regardless of glucose tolerance status.
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Affiliation(s)
- Paul Begovatz
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Auf`m Hennekamp 65, 40225, Düsseldorf, Germany
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Tamura K, Minami K, Kudo M, Iemoto K, Takahashi H, Seino S. Liraglutide improves pancreatic Beta cell mass and function in alloxan-induced diabetic mice. PLoS One 2015; 10:e0126003. [PMID: 25938469 PMCID: PMC4418765 DOI: 10.1371/journal.pone.0126003] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 03/27/2015] [Indexed: 11/30/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists potentiate glucose-induced insulin secretion. In addition, they have been reported to increase pancreatic beta cell mass in diabetic rodents. However, the precise mode of action of GLP-1 receptor agonists still needs to be elucidated. Here we clarify the effects of the human GLP-1 analog liraglutide on beta cell fate and function by using an inducible Cre/loxP-based pancreatic beta cell tracing system and alloxan-induced diabetic mice. Liraglutide was subcutaneously administered once daily for 30 days. The changes in beta cell mass were examined as well as glucose tolerance and insulin secretion. We found that chronic liraglutide treatment improved glucose tolerance and insulin response to oral glucose load. Thirty-day treatment with liraglutide resulted in a 2-fold higher mass of pancreatic beta cells than that in vehicle group. Liraglutide increased proliferation rate of pancreatic beta cells and prevented beta cells from apoptotic cells death. However, the relative abundance of YFP-labeled beta cells to total beta cells was no different before and after liraglutide treatment, suggesting no or little contribution of neogenesis to the increase in beta cell mass. Liraglutide reduced oxidative stress in pancreatic islet cells of alloxan-induced diabetic mice. Furthermore, the beneficial effects of liraglutide in these mice were maintained two weeks after drug withdrawal. In conclusion, chronic liraglutide treatment improves hyperglycemia by ameliorating beta cell mass and function in alloxan-induced diabetic mice.
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Affiliation(s)
- Kanako Tamura
- Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kohtaro Minami
- Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- * E-mail: (KM); (SS)
| | - Maya Kudo
- Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Keisuke Iemoto
- Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Harumi Takahashi
- Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Susumu Seino
- Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- * E-mail: (KM); (SS)
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Bock A, François G, Gillet D. A therapy parameter-based model for predicting blood glucose concentrations in patients with type 1 diabetes. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2015; 118:107-123. [PMID: 25577673 DOI: 10.1016/j.cmpb.2014.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 12/02/2014] [Accepted: 12/04/2014] [Indexed: 06/04/2023]
Abstract
In this paper, the problem of predicting blood glucose concentrations (BG) for the treatment of patients with type 1 diabetes, is addressed. Predicting BG is of very high importance as most treatments, which consist in exogenous insulin injections, rely on the availability of BG predictions. Many models that can be used for predicting BG are available in the literature. However, it is widely admitted that it is almost impossible to perfectly model blood glucose dynamics while still being able to identify model parameters using only blood glucose measurements. The main contribution of this work is to propose a simple and identifiable linear dynamical model, which is based on the static prediction model of standard therapy. It is shown that the model parameters are intrinsically correlated with physician-set therapy parameters and that the reduction of the number of model parameters to identify leads to inferior data fits but to equivalent or slightly improved prediction capabilities compared to state-of-the-art models: a sign of an appropriate model structure and superior reliability. The validation of the proposed dynamic model is performed using data from the UVa simulator and real clinical data, and potential uses of the proposed model for state estimation and BG control are discussed.
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Affiliation(s)
- Alain Bock
- React Group, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland.
| | - Grégory François
- Laboratoire d'Automatique, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland.
| | - Denis Gillet
- React Group, École Polytechnique Fédérale de Lausanne (EPFL), Switzerland.
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Gottlieb S, Rand JS, Marshall R, Morton J. Glycemic status and predictors of relapse for diabetic cats in remission. J Vet Intern Med 2014; 29:184-92. [PMID: 25418027 PMCID: PMC4858081 DOI: 10.1111/jvim.12509] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 08/23/2014] [Accepted: 10/23/2014] [Indexed: 11/30/2022] Open
Abstract
Background It is unknown if diabetic cats in remission have persistent abnormalities of glucose metabolism and should be considered prediabetic, or have normal glucose tolerance. Objective To characterize glycemic status of diabetic cats in remission and to determine predictors of relapse. Animals A total of 21 cats in diabetic remission and 28 healthy control cats. Methods At a median of 107 days after remission, screening blood glucose concentration was measured on entry to the clinic. After a 24‐hour fast in hospital, fasting blood glucose, fructosamine and feline pancreatic lipase concentrations were measured, and 3 hours later, a simplified IV glucose tolerance test (1 g glucose/kg) performed. Twenty cats were monitored for relapse for at least 9 months. Results Of the 21 cats in remission, 19% (4/21) had impaired fasting glucose concentration and 76% (16/21) had impaired glucose tolerance. Of cats followed up for 9 months after testing, 30% (6/20) had relapsed and required insulin treatment. Fasting blood glucose concentration ≥7.5 mmol/L (≥135 mg/dL) (odds ratio [OR] = 12.8) and severely impaired glucose tolerance (≥5 hours to return to <6.5 mmol/L or <117 mg/dL; OR = 15.2) were significantly associated with relapse. Blood glucose concentration >14 mmol/L; 252 mg/dL at 3 hours was significantly associated with relapse (OR = 10.1). Conclusion and Clinical Importance Most cats in diabetic remission have impaired glucose tolerance and a minority have impaired fasting glucose concentration and should be considered prediabetic. More severe glucose intolerance and impaired fasting glucose concentration are predictors of relapse. Ongoing glucose monitoring of diabetic cats in remission is recommended.
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Affiliation(s)
- S Gottlieb
- The Cat Clinic, Brisbane, Qld, Australia
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Tros F, Meirhaeghe A, Hadjadj S, Amouyel P, Bougnères P, Fradin D. Hypomethylation of the promoter of the catalytic subunit of protein phosphatase 2A in response to hyperglycemia. Physiol Rep 2014; 2:2/7/e12076. [PMID: 25347859 PMCID: PMC4187575 DOI: 10.14814/phy2.12076] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
In order to identify epigenetic mechanisms through which hyperglycemia can affect gene expression durably in β cells, we screened DNA methylation changes induced by high glucose concentrations (25 mmol/L) in the BTC3 murine cell line, using an epigenome‐wide approach. Exposure of BTC3 cells to high glucose modified the expression of 1612 transcripts while inducing significant methylation changes in 173 regions. Among these 173 glucose‐sensitive differentially methylated regions (DMRs), 14 were associated with changes in gene expression, suggesting an epigenetic effect of high glucose on gene transcription at these loci. Among these 14 DMRs, we selected for further study Pp2ac, a gene previously suspected to play a role in β‐cell physiology and type 2 diabetes. Using RT‐qPCR and bisulfite pyrosequencing, we confirmed our previous observations in BTC3 cells and found that this gene was significantly demethylated in the whole blood cells (WBCs) of type 2 diabetic patients compared to controls. In order to identify epigenetic mechanisms through which hyperglycemia can affect gene expression durably in β cells, we screened DNA methylation changes induced by high glucose concentration in the BTC3 murine cell line. We identified one interesting gene, PP2AC, and confirmed it in type 2 diabetic patients.
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Affiliation(s)
- Fabiola Tros
- INSERM U986, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France UMR1002, Paris, France
| | - Aline Meirhaeghe
- INSERM, U744, Lille, France Institut Pasteur de Lille, Université Lille Nord de France, Lille, France UDSL, Lille, France
| | - Samy Hadjadj
- Department of Diabetology, Poitiers Hospital, INSERM U927, INSERM CIC 802, Université de Poitiers, UFR Médecine Pharmacie, Poitiers, France
| | - Philippe Amouyel
- INSERM, U744, Lille, France Institut Pasteur de Lille, Université Lille Nord de France, Lille, France UDSL, Lille, France
| | - Pierre Bougnères
- INSERM U986, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France Department of Pediatric Endocrinology, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France
| | - Delphine Fradin
- INSERM U986, Bicêtre Hospital, Paris Sud University, Le Kremlin-Bicêtre, France
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Fonseca VA, Haggar MA. Achieving glycaemic targets with basal insulin in T2DM by individualizing treatment. Nat Rev Endocrinol 2014; 10:276-81. [PMID: 24535209 DOI: 10.1038/nrendo.2014.17] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Insulin therapy is an effective method for reducing blood glucose levels in patients with type 2 diabetes mellitus (T2DM), and most patients with T2DM eventually require insulin replacement to attain and preserve satisfactory glycaemic control. All patients with T2DM should be considered as potential candidates for intensive insulin treatment; however, there are certain considerations regarding replacement therapy for different types of people and special populations, such as patients with multiple comorbidities, adolescents, pregnant women and the elderly. Lowering HbA1c levels in isolation without assessing the patient as a whole is becoming redundant. HbA1c targets should be individualized to the specific patient, and insulin treatment ought to be customized accordingly. There are several questions that need to be taken into account when considering adding insulin therapy to other oral antidiabetic agents, for example, for whom and when insulin therapy is indicated and which basal insulin should be utilized. Potential barriers exist related to patients, providers and health-care systems that can delay the start of insulin therapy, and every effort should be made to identify and address these obstacles.
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Affiliation(s)
- Vivian A Fonseca
- Section of Endocrinology, Tulane University Health Sciences Center, Tulane University School of Medicine, 1430 Tulane Avenue, SL 53, New Orleans, LA 70112, USA
| | - Michelle A Haggar
- Section of Endocrinology, Tulane University Health Sciences Center, Tulane University School of Medicine, 1430 Tulane Avenue, SL 53, New Orleans, LA 70112, USA
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Masini M, Anello M, Bugliani M, Marselli L, Filipponi F, Boggi U, Purrello F, Occhipinti M, Martino L, Marchetti P, De Tata V. Prevention by metformin of alterations induced by chronic exposure to high glucose in human islet beta cells is associated with preserved ATP/ADP ratio. Diabetes Res Clin Pract 2014; 104:163-70. [PMID: 24462282 DOI: 10.1016/j.diabres.2013.12.031] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Revised: 12/13/2013] [Accepted: 12/21/2013] [Indexed: 11/25/2022]
Abstract
AIM We have explored whether the insulin secretory defects induced by glucotoxicity in human pancreatic islets could be prevented by metformin and investigated some of the possible mechanisms involved. METHODS Human pancreatic islets and INS-1E cells were cultured for 24h with or without high glucose (16.7mM) concentration in the presence or absence of therapeutical concentration of metformin and then glucose-stimulated insulin release, adenine nucleotide levels and mitochondrial complex I and II activities were measured. Islet ultrastructure was analyzed by electron microscopy. RESULTS Compared to control islets, human islets cultured with high glucose showed a reduced glucose-stimulated insulin secretion that was associated with lower ATP levels and a lower ATP/ADP ratio. These functional and biochemical defects were significantly prevented by the presence of metformin in the culture medium, that was also able to significantly inhibit the activity of mitochondrial complex I especially in beta cells exposed to high glucose. Ultrastructural observations showed that mitochondrial volume density was significantly increased in high glucose cultured islets. The critical involvement of mitochondria was further supported by the observation of remarkably swollen organelles with dispersed matrix and fragmented cristae. Metformin was able to efficiently prevent the appearance of all these ultrastructural alterations in human islets exposed to high glucose. CONCLUSIONS Our results show that the functional, biochemical and ultrastructural abnormalities observed in human islet cells exposed to glucotoxic condition can be significantly prevented by metformin, further highlighting a direct beneficial effect of this drug on the insulin secreting human pancreatic beta cells.
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Affiliation(s)
- M Masini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - M Anello
- Department of Clinical and Molecular Biomedicine, University of Catania, Italy
| | - M Bugliani
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - L Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - F Filipponi
- Department of Surgical Pathology, Medicine, Molecular and Critical Area, University of Pisa, Italy
| | - U Boggi
- Department of Surgical Pathology, Medicine, Molecular and Critical Area, University of Pisa, Italy
| | - F Purrello
- Department of Clinical and Molecular Biomedicine, University of Catania, Italy
| | - M Occhipinti
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - L Martino
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy
| | - P Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Italy
| | - V De Tata
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy.
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Zabielski P, Blachnio-Zabielska A, Lanza IR, Gopala S, Manjunatha S, Jakaitis DR, Persson XM, Gransee J, Klaus KA, Schimke JM, Jensen MD, Nair KS. Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice. Am J Physiol Endocrinol Metab 2014; 306:E529-42. [PMID: 24368672 PMCID: PMC3948970 DOI: 10.1152/ajpendo.00610.2012] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Accepted: 12/18/2013] [Indexed: 12/14/2022]
Abstract
Insulin deprivation in type 1 diabetes (T1D) individuals increases lipolysis and plasma free fatty acids (FFA) concentration, which can stimulate synthesis of intramyocellular bioactive lipids such as ceramides (Cer) and long-chain fatty acid-CoAs (LCFa-CoAs). Ceramide was shown to decrease muscle insulin sensitivity, and at mitochondrial levels it stimulates reactive oxygen species production. Here, we show that insulin deprivation in streptozotocin diabetic C57BL/6 mice increases quadriceps muscle Cer content, which was correlated with a concomitant decrease in the body fat and increased plasma FFA, glycosylated hemoglobin level (%Hb A1c), and muscular LCFa-CoA content. The alternations were accompanied by an increase in protein expression in LCFa-CoA and Cer synthesis (FATP1/ACSVL5, CerS1, CerS5), a decrease in the expression of genes implicated in muscle insulin sensitivity (GLUT4, GYS1), and inhibition of insulin signaling cascade by Aktα and GYS3β phosphorylation under acute insulin stimulation. Both the content and composition of sarcoplasmic fraction sphingolipids were most affected by insulin deprivation, whereas mitochondrial fraction sphingolipids remained stable. The observed effects of insulin deprivation were reversed, except for content and composition of LCFa-CoA, CerS protein expression, GYS1 gene expression, and phosphorylation status of Akt and GYS3β when exogenous insulin was provided by subcutaneous insulin implants. Principal component analysis and Pearson's correlation analysis revealed close relationships between the features of the diabetic phenotype, the content of LCFa-CoAs and Cers containing C18-fatty acids in sarcoplasm, but not in mitochondria. Insulin replacement did not completely rescue the phenotype, especially regarding the content of LCFa-CoA, or proteins implicated in Cer synthesis and muscle insulin sensitivity. These persistent changes might contribute to muscle insulin resistance observed in T1D individuals.
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Affiliation(s)
- Piotr Zabielski
- Division of Endocrinology and Metabolism, Mayo Clinic College of Medicine, Rochester, Minnesota
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TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists. Cell Death Dis 2013; 4:e964. [PMID: 24336084 PMCID: PMC3877573 DOI: 10.1038/cddis.2013.506] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 11/11/2013] [Accepted: 11/13/2013] [Indexed: 01/06/2023]
Abstract
This article is addressed to endocrinologists treating patients with diabetic complications as well as to basic scientists studying an elusive link between diseases and aging. It answers some challenging questions. What is the link between insulin resistance (IR), cellular aging and diseases? Why complications such as retinopathy may paradoxically precede the onset of type II diabetes. Why intensive insulin therapy may initially worsen retinopathy. How nutrient- and insulin-sensing mammalian target of rapamycin (mTOR) pathway can drive insulin resistance and diabetic complications. And how rapamycin, at rational doses and schedules, may prevent IR, retinopathy, nephropathy and beta-cell failure, without causing side effects.
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Zhang W, Liu J, Tian L, Liu Q, Fu Y, Garvey WT. TRIB3 mediates glucose-induced insulin resistance via a mechanism that requires the hexosamine biosynthetic pathway. Diabetes 2013; 62:4192-200. [PMID: 23990361 PMCID: PMC3837074 DOI: 10.2337/db13-0312] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
In the current study, we investigated the role of tribbles homolog 3 (TRIB3) in glucose-induced insulin resistance and whether the induction of TRIB3 by glucose is dependent on the nutrient-sensing hexosamine biosynthetic pathway (HBP) known to mediate glucose toxicity in diabetes. In diabetic rats, TRIB3 expression in skeletal muscle was increased after 10 days of hyperglycemia, and glycemia and muscle TRIB3 were both restored toward normal by insulin therapy. In L6 myocytes, the induction of TRIB3 by high glucose or glucosamine was reversible upon removal of these substrates. To assess the role of HBP in the induction of TRIB3, we demonstrated that the ability of high glucose to augment TRIB3 expression was prevented by azaserine, an inhibitor of glutamine: fructose-6-phosphate amidotransferase (GFAT), which is the rate-limiting enzyme in the HBP pathway. TRIB3 expression was also substantially stimulated by glucosamine, which bypasses GFAT, accompanied by a decrease in the insulin-stimulated glucose transport rate, and neither response was affected by azaserine. Further, knockdown of TRIB3 inhibited, and TRIB3 overexpression enhanced, the ability of both high glucose and glucosamine to induce insulin resistance. These data provide the mechanistic link between the HBP flux and insulin resistance and point to TRIB3 as a novel target for treatment of glucose-induced insulin resistance.
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Affiliation(s)
- Wei Zhang
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama
- Corresponding author: Wei Zhang,
| | - Jiarong Liu
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ling Tian
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama
| | - Qinglan Liu
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Yuchang Fu
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama
| | - W. Timothy Garvey
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama
- Birmingham Veterans Affairs Medical Center, Birmingham, Alabama
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Marciniak A, Selck C, Friedrich B, Speier S. Mouse pancreas tissue slice culture facilitates long-term studies of exocrine and endocrine cell physiology in situ. PLoS One 2013; 8:e78706. [PMID: 24223842 PMCID: PMC3817072 DOI: 10.1371/journal.pone.0078706] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 09/15/2013] [Indexed: 12/24/2022] Open
Abstract
Studies on pancreatic cell physiology rely on the investigation of exocrine and endocrine cells in vitro. Particularly, in the case of the exocrine tissue these studies have suffered from a reduced functional viability of acinar cells in culture. As a result not only investigations on dispersed acinar cells and isolated acini were limited in their potential, but also prolonged studies on pancreatic exocrine and endocrine cells in an intact pancreatic tissue environment were unfeasible. To overcome these limitations, we aimed to establish a pancreas tissue slice culture platform to allow long-term studies on exocrine and endocrine cells in the intact pancreatic environment. Mouse pancreas tissue slice morphology was assessed to determine optimal long-term culture settings for intact pancreatic tissue. Utilizing optimized culture conditions, cell specificity and function of exocrine acinar cells and endocrine beta cells were characterized over a culture period of 7 days. We found pancreas tissue slices cultured under optimized conditions to have intact tissue specific morphology for the entire culture period. Amylase positive intact acini were present at all time points of culture and acinar cells displayed a typical strong cell polarity. Amylase release from pancreas tissue slices decreased during culture, but maintained the characteristic bell-shaped dose-response curve to increasing caerulein concentrations and a ca. 4-fold maximal over basal release. Additionally, endocrine beta cell viability and function was well preserved until the end of the observation period. Our results show that the tissue slice culture platform provides unprecedented maintenance of pancreatic tissue specific morphology and function over a culture period for at least 4 days and in part even up to 1 week. This analytical advancement now allows mid -to long-term studies on the cell biology of pancreatic disorder pathogenesis and therapy in an intact surrounding in situ.
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Affiliation(s)
- Anja Marciniak
- CRTD - DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany
| | - Claudia Selck
- CRTD - DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany
| | - Betty Friedrich
- CRTD - DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany
| | - Stephan Speier
- CRTD - DFG Research Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany
- * E-mail:
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Goldenberg R, Punthakee Z. Définition, classification et diagnostic du diabète, du prédiabète et du syndrome métabolique. Can J Diabetes 2013. [DOI: 10.1016/j.jcjd.2013.07.031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Kim MK, Cho JH, Lee JJ, Cheong YH, Son MH, Lee KJ. Differential protective effects of exenatide, an agonist of GLP-1 receptor and Piragliatin, a glucokinase activator in beta cell response to streptozotocin-induced and endoplasmic reticulum stresses. PLoS One 2013; 8:e73340. [PMID: 24069189 PMCID: PMC3777936 DOI: 10.1371/journal.pone.0073340] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 07/29/2013] [Indexed: 12/27/2022] Open
Abstract
Background Agonists of glucagon-like peptide-1 receptor (GLP-1R) and glucokinase activators (GKA) act as antidiabetic agents by their ability protect beta cells, and stimulate insulin secretion. Oxidative and endoplasmic reticulum (ER) stresses aggravate type 2 diabetes by causing beta cell loss. It was shown that GLP-1R agonists protect beta cells from oxidative and ER stresses. On the other hand, little is known regarding how GKAs protect beta cells. We hypothesized that GKAs protect beta cells by mechanisms distinct from those underlying GLP-1R agonist and tested our hypothesis by comparing the molecular effects of exenatide, a GLP-1R agonist, and piragliatin, a GKA, on INS-1 cells under oxidative and ER-induced stresses. Methods Beta cells were treated with streptozotocin (STZ) to induce oxidative stress and with palmitate or thapsigargin (Tg) to induce ER stress respectively, and the effects of exenatide and piragliatin on these cells were investigated by: a) characterizing the kinases involved employing specific kinase inhibitors, and b) by identifying the differentially regulated proteins in response to stresses with proteomic analysis. Results Exenatide protected INS-1 cells from both ER and STZ-induced death. In contrast, piragliatin rescued the cells only from STZ-induced stress. Akt activation by exenatide appeared to contribute to its protective effects of beta cells while enhanced glucose utilization was the contributing factor in the case of piragliatin. Also, exenatide, not piragliatin, blocked changes in proteins 14-3-3β, ε and θ, and preserved the 14-3-3θ levels under the ER stress. Isoform-specific modifications of 14-3-3, and the reduction of 14-3-3θ, commonly associated with beta cell death were assessed. Conclusions Exenatide and piragliatin exert distinct effects on beta cell survival and thus on type 2 diabetes. This study which confirmed our hypothesis is also the first to observe specific modulation of 14-3-3 isoform in stress-induced beta cell death associated with progressive deterioration of type 2 diabetes.
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Affiliation(s)
- Mi-Kyung Kim
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
- Dong-A ST Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Jin-Hwan Cho
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Jae-Jin Lee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
| | - Ye-Hwang Cheong
- Dong-A ST Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Moon-Ho Son
- Dong-A ST Research Institute, Yongin-si, Gyeonggi-do, Republic of Korea
| | - Kong-Joo Lee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
- * E-mail:
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