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Bidne KL, Erickson KE, Powell TL, Jansson T. Mechanistic target of rapamycin signaling activity in the human placenta across gestation and in maternal obesity†. Biol Reprod 2025; 112:540-549. [PMID: 39804001 PMCID: PMC11911553 DOI: 10.1093/biolre/ioaf007] [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: 06/13/2024] [Revised: 11/29/2024] [Accepted: 01/09/2025] [Indexed: 03/18/2025] Open
Abstract
The mechanistic target of rapamycin system is vital to placental development, formation, and function. Alterations in this system in the placenta have been associated with altered fetal growth. However, changes in placental mechanistic target of rapamycin signaling across gestation are poorly understood. We collected 81 human placental samples from 4 to 40 weeks gestation to test the hypothesis that placental mechanistic target of rapamycin signaling activity increases over gestation and is activated in maternal obesity in early gestation. Proteins involved in upstream mechanistic target of rapamycin regulation and mTORC1/2 downstream signaling were quantified using immunoblotting in placentas of male or female fetuses. Readouts of mTORC1 activation, phospho-rpS6, and phospho-4EBP1 were highest in first trimester and decreased across gestation. Phosphorylation of AKT (308 and 473) increased over gestation. Interestingly, abundance of cytochrome c oxidase I and mitochondrial ATP synthase, key subunits of mitochondrial complexes III/IV and V, respectively, were elevated in first trimester obese placentas compared to control, but only in placenta from female fetuses. We suggest that the high placental mechanistic target of rapamycin signaling activity in early pregnancy may be related to the high anabolism and active trophoblast proliferation and invasion in the second half of the first trimester. In addition, we conclude that maternal obesity has only limited impact on this key placental signaling pathway across gestation in women.
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Affiliation(s)
- Katie L Bidne
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kathryn E Erickson
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Theresa L Powell
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
- Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Thomas Jansson
- Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
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Wong A, Alejandro EU. Post translational modification regulation of transcription factors governing pancreatic β-cell identity and functional mass. Front Endocrinol (Lausanne) 2025; 16:1562646. [PMID: 40134803 PMCID: PMC11932907 DOI: 10.3389/fendo.2025.1562646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
Dysfunction of the insulin-secreting β-cells is a key hallmark of Type 2 diabetes (T2D). In the natural history of the progression of T2D, factors such as genetics, early life exposures, lifestyle, and obesity dictate an individual's susceptibility risk to disease. Obesity is associated with insulin resistance and increased demand for insulin to maintain glucose homeostasis. Studies in both mouse and human islets have implicated the β-cell's ability to compensate through proliferation and survival (increasing functional β-cell mass) as a tipping point toward the development of disease. A growing body of evidence suggests the reduction of β-cell mass in T2D is driven majorly by loss of β-cell identity, rather than by apoptosis alone. The development and maintenance of pancreatic β-cell identity, function, and adaptation to stress is governed, in part, by the spatiotemporal expression of transcription factors (TFs), whose activity is regulated by signal-dependent post-translational modifications (PTM). In this review, we examine the role of these TFs in the developing pancreas and in the mature β-cell. We discuss functional implications of post-translational modifications on these transcription factors' activities and how an understanding of the pathways they regulate can inform therapies to promoteβ-cell regeneration, proliferation, and survival in diabetes.
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Affiliation(s)
- Alicia Wong
- Department of Genetics, Cell Biology, and Development, University of Minnesota Twin Cities, Minneapolis, MN, United States
| | - Emilyn U. Alejandro
- Department of Integrative Biology and Physiology, University of Minnesota Twin Cities, Minneapolis, MN, United States
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Tűű L, Nas K, Török M, Várbíró S. SHBG Levels Do Not Correlate with Insulin Levels in PCOS with Appropriate Fasting Insulin Sensitivity. J Clin Med 2024; 13:838. [PMID: 38337532 PMCID: PMC10856642 DOI: 10.3390/jcm13030838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 01/25/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Introduction: There are several phenotypes of polycystic ovarian syndrome (PCOS), and the different phenotypes may differ metabolically. Methods: In the present retrospective study, women with PCOS having normal fasting insulin sensitivity (n = 88) were compared with women with PCOS showing impaired insulin sensitivity (n = 46) using the HPCOS (Hungarian Polycystic ovarian syndrome) database. Results: The impaired insulin sensitivity group has significantly higher body mass index (BMI) and HOMA index than the normal fasting insulin sensitivity group (BMI (kg/m2): 22.0 vs. 28.1, p < 0.0001, HOMA index: 0.96 vs. 2.38, p < 0.0001). The sex hormone binding globulin (SHBG) level was significantly lower, and the free androgen index proved itself significantly higher in the impaired insulin sensitivity group (p < 0.05). Linear regression analysis showed a negative association of BMI with SHBG levels in both groups, while BMI had a positive correlation with insulin concentrations in both groups. However, the SHBG levels were negatively associated with insulin concentrations in the impaired insulin sensitivity group, but this inverse association could not be observed in the normal fasting insulin sensitivity group. Conclusions: The inverse linear correlation of SHBG with HOMA index and serum insulin level is not evident in all PCO syndrome phenotypes, thus SHBG has limited applicability for characterizing carbohydrate metabolism and serum insulin sensitivity.
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Affiliation(s)
- László Tűű
- EndoCare Institute, Endocrinology Center, 1095 Budapest, Hungary; (L.T.); (K.N.)
- School of PhD Studies, Semmelweis University, 1085 Budapest, Hungary
| | - Katalin Nas
- EndoCare Institute, Endocrinology Center, 1095 Budapest, Hungary; (L.T.); (K.N.)
- School of PhD Studies, Semmelweis University, 1085 Budapest, Hungary
| | - Marianna Török
- Department of Obstetrics and Gynecology, Semmelweis University, 1082 Budapest, Hungary
- Workgroup of Research Management, Doctoral School, Semmelweis University, 1085 Budapest, Hungary
| | - Szabolcs Várbíró
- Department of Obstetrics and Gynecology, Semmelweis University, 1082 Budapest, Hungary
- Workgroup of Research Management, Doctoral School, Semmelweis University, 1085 Budapest, Hungary
- Department of Obstetrics and Gynecology, University of Szeged, 6725 Szeged, Hungary
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Nomoto H, Takahashi A, Nakamura A, Kurihara H, Takeuchi J, Nagai S, Taneda S, Miya A, Kameda H, Cho KY, Miyoshi H, Atsumi T. Add-on imeglimin versus metformin dose escalation regarding glycemic control in patients with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor plus low-dose metformin: study protocol for a multicenter, prospective, randomized, open-label, parallel-group comparison study (MEGMI study). BMJ Open Diabetes Res Care 2022; 10:10/6/e002988. [PMID: 36379585 PMCID: PMC9667996 DOI: 10.1136/bmjdrc-2022-002988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 11/05/2022] [Indexed: 11/16/2022] Open
Abstract
INTRODUCTION Imeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little is known about its effectiveness in daily clinical practice settings, especially compared with metformin. Therefore, we aim to clarify the efficacy of imeglimin in patients with type 2 diabetes (T2D) being treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor plus low-dose metformin. RESEARCH DESIGN AND METHODS This is a multicenter, randomized, prospective, open-label, parallel-group trial. Seventy participants with T2D treated with a DPP-4 inhibitor plus metformin (500-1000 mg/day) for more than 12 weeks and a glycated hemoglobin (HbA1c) level of 52-85 mmol/mol (7.0%-9.9%) will be randomized to receive add-on imeglimin 1000 mg two times per day or metformin dose escalation for 24 weeks. Biochemical analyses and physical assessments will be performed at baseline and at the end of the study, and adverse events will be recorded. The primary endpoint is the change in HbA1c after 24 weeks. The secondary endpoints comprise the changes in blood pressure, pulse rate, body weight, abdominal circumference, and other laboratory parameters; the relationship between improvements of biological parameters including glycemic control and patient background characteristics; and side effects. RESULTS This study will reveal new insights into the incorporation of imeglimin into the diabetes treatment strategy. CONCLUSIONS This will be the first randomized controlled trial to compare the efficacy of adding imeglimin versus metformin dose escalation on glycemic control in patients with T2D. TRIAL REGISTRATION NUMBER jRCT1011220005.
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Affiliation(s)
- Hiroshi Nomoto
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akihiro Takahashi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Akinobu Nakamura
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | | | - Jun Takeuchi
- Sapporo Diabetes and Thyroid Clinic, Sapporo, Japan
| | - So Nagai
- Division of Diabetes and Endocrinology, Department of Medicine, NTT East Corporation, Sapporo, Japan
| | - Shinji Taneda
- Diabetes Center, Manda Memorial Hospital, Sapporo, Japan
| | - Aika Miya
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiraku Kameda
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kyu Yong Cho
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo, Japan
| | - Hideaki Miyoshi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
- Aoki Clinic, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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Diagnostic and Prognostic Protein Biomarkers of β-Cell Function in Type 2 Diabetes and Their Modulation with Glucose Normalization. Metabolites 2022; 12:metabo12030196. [PMID: 35323639 PMCID: PMC8950787 DOI: 10.3390/metabo12030196] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 01/29/2022] [Accepted: 02/12/2022] [Indexed: 12/04/2022] Open
Abstract
Development of type-2 diabetes(T2D) is preceded by β-cell dysfunction and loss. However, accurate measurement of β-cell function remains elusive. Biomarkers have been reported to predict β-cell functional decline but require validation. Therefore, we determined whether reported protein biomarkers could distinguish patients with T2D (onset < 10-years) from controls. A prospective, parallel study in T2D (n = 23) and controls (n = 23) was undertaken. In T2D subjects, insulin-induced blood glucose normalization from baseline 7.6 ± 0.4 mmol/L (136.8 ± 7.2 mg/dL) to 4.5 ± 0.07 mmol/L (81 ± 1.2 mg/dL) was maintained for 1-h. Controls were maintained at 4.9 ± 0.1 mmol/L (88.2 ± 1.8 mg/dL). Slow Off-rate Modified Aptamer (SOMA) -scan plasma protein measurement determined a 43-protein panel reported as diagnostic and/or prognostic for T2D. At baseline, 9 proteins were altered in T2D. Three of 13 prognostic/diagnostic proteins were lower in T2D: Adiponectin (p < 0.0001), Endocan (p < 0.05) and Mast/stem cell growth factor receptor-Kit (KIT) (p < 0.01). Two of 14 prognostic proteins [Cathepsin-D (p < 0.05) and Cadherin-E (p < 0.005)], and four of 16 diagnostic proteins [Kallikrein-4 (p = 0.001), Aminoacylase-1 (p = 0.001), Insulin-like growth factor-binding protein-4 (IGFBP4) (p < 0.05) and Reticulon-4 receptor (RTN4R) (p < 0.001)] were higher in T2D. Protein levels were unchanged following glucose normalization in T2D. Our results suggest that a focused biomarker panel may be useful for assessing β-cell dysfunction and may complement clinical decision-making on insulin therapy. Unchanged post-glucose normalization levels indicate these are not acute-phase proteins or affected by glucose variability.
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Zhu Y, Lin Q, Zhang Y, Deng H, Hu X, Yang X, Yao B. Mid-upper arm circumference as a simple tool for identifying central obesity and insulin resistance in type 2 diabetes. PLoS One 2020; 15:e0231308. [PMID: 32437358 PMCID: PMC7241705 DOI: 10.1371/journal.pone.0231308] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 03/20/2020] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Our research aimed to explore the correlation between mid-upper arm circumference (MUAC) and central obesity and insulin resistance (IR) in Chinese subjects with type 2 diabetes. MATERIALS A total of 103 participants (60 men) were recruited in our study. MUAC was measured around the mid-arm between the shoulder and elbow. Waist circumference (WC) was obtained as central obesity parameter, and the IR parameter of Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) was calculated. The subjects were divided into three groups according to the tertiles cut-points of MUAC level. RESULTS Body mass index (BMI), WC, the percentages of central obesity and HOMA-IR were significantly higher in the groups with higher MUAC than those in the group with lower MUAC (all P < 0.05). Pearson analysis showed that MUAC was correlated with BMI, WC, waist-to-hip ratio (WHR), logHOMA-IR, low density lipoprotein cholesterol (LDL-C), uric acid (UA) and high density lipoprotein cholesterol (HDL-C) in all subjects. Multivariate linear regression analysis revealed that MUAC was independently associated with logHOMA-IR (β = 0.036, P<0.001) after adjusting for age, gender, WHR, UA, TG, LDL-C and HDL-C. Binary logistic regression analysis revealed that MUAC was an independent predictor of central obesity (OR: 2.129, 95%CI: 1.311-3.457, P = 0.002). Furthermore, MUAC≥30.9cm for male and ≥30.0cm for female were the optimal cutoff values for identifying central obesity. CONCLUSIONS Our study indicated that among Chinese subjects with type 2 diabetes, MUAC is a simple and effective tool for the determination of central obesity and IR. Additionally, the larger MUAC is proved to be more associated with metabolic risk factors of higher UA and LDL-C and lowever HDL-C.
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Affiliation(s)
- Yanhua Zhu
- Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiongyan Lin
- Department of Endocrinology, Jieyang People’s Hospital (Jieyang Affiliated Hospital, Sun Yat-sen University), Jieyang, Guangdong, China
| | - Yao Zhang
- Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hongrong Deng
- Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiling Hu
- Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xubin Yang
- Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- * E-mail: (BY); (XY)
| | - Bin Yao
- Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- * E-mail: (BY); (XY)
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Sekijima H, Goto K, Hiramoto K, Komori R, Ooi K. Characterization of dry skin associating with type 2 diabetes mellitus using a KK-Ay/TaJcl mouse model. Cutan Ocul Toxicol 2018; 37:391-395. [DOI: 10.1080/15569527.2018.1490746] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Hidehisa Sekijima
- Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka, Japan
| | - Kenji Goto
- Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka, Japan
| | - Keiichi Hiramoto
- Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka, Japan
| | - Rio Komori
- Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka, Japan
| | - Kazuya Ooi
- Faculty of Pharmaceutical Science, Suzuka University of Medical Science, Suzuka, Japan
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Nakadate Y, Sato H, Sato T, Codere-Maruyama T, Matsukawa T, Schricker T. Body mass index predicts insulin sensitivity during cardiac surgery: a prospective observational study. Can J Anaesth 2018; 65:551-559. [DOI: 10.1007/s12630-018-1081-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/28/2017] [Accepted: 12/30/2017] [Indexed: 01/08/2023] Open
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Bonadonna RC, Blonde L, Antsiferov M, Berria R, Gourdy P, Hatunic M, Mohan V, Horowitz M. Lixisenatide as add-on treatment among patients with different β-cell function levels as assessed by HOMA-β index. Diabetes Metab Res Rev 2017; 33:e2897. [PMID: 28303626 PMCID: PMC5600123 DOI: 10.1002/dmrr.2897] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 02/22/2017] [Accepted: 02/26/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND The effect of lixisenatide-a prandial once-daily glucagon-like peptide-1 receptor agonist-on glycaemic control in patients with inadequately controlled type 2 diabetes mellitus (T2DM), stratified by baseline β-cell function, was assessed. METHODS The 24-week GetGoal-M, -P and -S trials evaluated the efficacy and safety of lixisenatide in combination with oral antidiabetic agents. This post hoc analysis used data from patients receiving lixisenatide in these trials, divided into matched cohorts by propensity scoring, and stratified according to baseline homeostasis model assessment of β-cell function (HOMA-β) index levels, high HOMA-β: > median HOMA-β (28.49%); low HOMA-β: ≤ median. RESULTS The matched "low" and "high" HOMA-β index cohorts (N = 546 patients) had comparable baseline parameters. Mean change from baseline in glycated haemoglobin (HbA1c ) was -0.85% and -0.94% for low and high HOMA-β cohorts, respectively (P = .2607). Reductions from baseline in fasting plasma glucose (FPG; -0.77 vs -1.04 mmol/L; P = .1496) and postprandial plasma glucose (PPG; -5.82 vs -5.61 mmol/L; P = .7511) were similar in the low versus high HOMA-β index cohorts. Reduction in body weight was significantly greater in the low versus high HOMA-β index cohort (-2.06 vs -1.13 kg, respectively; P = .0006). CONCLUSIONS In patients with T2DM, lixisenatide was associated with reduction in HbA1c and improvements in both FPG and PPG, regardless of β-cell function, indicating that lixisenatide is effective in reducing hyperglycaemia, even in patients with more advanced stages of T2DM and poor residual β-cell function.
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Affiliation(s)
| | - Lawrence Blonde
- Frank Riddick Diabetes InstituteDepartment of Endocrinology, Ochsner Medical CenterNew OrleansLAUSA
| | | | | | - Pierre Gourdy
- Diabetology DepartmentToulouse University HospitalToulouseFrance
| | - Mensud Hatunic
- Department of EndocrinologyMater Misericordiae University HospitalDublinIreland
| | - Viswanathan Mohan
- Madras Diabetes Research Foundation & Dr Mohan's Diabetes Specialities CentreChennaiIndia
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Abstract
PURPOSE OF REVIEW This perspective is motivated by the need to question dogma that does not work: that the problem is insulin resistance (IR). We highlight the need to investigate potential environmental obesogens and toxins. RECENT FINDINGS The prequel to severe metabolic disease includes three interacting components that are abnormal: (a) IR, (b) elevated lipids and (c) elevated basal insulin (HI). HI is more common than IR and is a significant independent predictor of diabetes. We hypothesize that (1) the initiating defect is HI that increases nutrient consumption and hyperlipidemia (HL); (2) the cause of HI may include food additives, environmental obesogens or toxins that have entered our food supply since 1980; and (3) HI is sustained by HL derived from increased adipose mass and leads to IR. We suggest that HI and HL are early indicators of metabolic dysfunction and treating and reversing these abnormalities may prevent the development of more serious metabolic disease.
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Affiliation(s)
- Karel A. Erion
- 0000 0004 0367 5222grid.475010.7Obesity Research Center, Department of Medicine, Boston University School of Medicine, 650 Albany St, Boston, MA 02118 USA
- 0000 0000 9632 6718grid.19006.3eDivision of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA USA
| | - Barbara E. Corkey
- 0000 0004 0367 5222grid.475010.7Obesity Research Center, Department of Medicine, Boston University School of Medicine, 650 Albany St, Boston, MA 02118 USA
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In Vivo Interrelationship between Insulin Resistance and Interferon Gamma Production: Protective and Therapeutic Effect of Berberine. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2016; 2016:2039897. [PMID: 27642351 PMCID: PMC5013203 DOI: 10.1155/2016/2039897] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Accepted: 07/31/2016] [Indexed: 12/14/2022]
Abstract
This research was conducted to investigate if there is a relation between insulin resistance incidence and inhibition of interferon gamma production or not. Firstly, insulin resistance was induced by high fat diet (HFD) intake for 6 weeks. Secondly, berberine was used as protective/curative compound for insulin resistance. Results revealed that feeding rats HFD for 6 weeks developed features of insulin resistance (IR) syndrome. These features presented in increased body weight, hyperglycemia, hyperinsulinemia, hypercholesterolemia (with increased LDL-cholesterol and decreased HDL-cholesterol), and hypertriglyceridemia. Level of antioxidant enzymes in HFD group was higher than in normal one. Also there was an increasing in level of proinflammatory cytokines as interleukin- (IL-) 6 and IL-12 in HFD group. Feeding rats HFD for 6 weeks also decreased level of interferon gamma (IFN-γ). The decreased level of IFN-γ has been shown to predict infection with infectious diseases especially viral infection. Treatment and protection with berberine 50 mg/kg/day for 2 weeks were found to be effective against the features of insulin resistance syndrome, improved levels of insulin resistance parameters, lipid profile, antioxidant enzymes, proinflammatory cytokines, and IFN-γ.
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Kirby TJ, Walton RG, Finlin B, Zhu B, Unal R, Rasouli N, Peterson CA, Kern PA. Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue. Physiol Genomics 2016; 48:145-53. [PMID: 26672043 PMCID: PMC4729698 DOI: 10.1152/physiolgenomics.00071.2015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Accepted: 12/11/2015] [Indexed: 01/17/2023] Open
Abstract
Adipose tissue has profound effects on whole-body insulin sensitivity. However, the underlying biological processes are quite complex and likely multifactorial. For instance, the adipose transcriptome is posttranscriptionally modulated by microRNAs, but the relationship between microRNAs and insulin sensitivity in humans remains to be determined. To this end, we utilized an integrative mRNA-microRNA microarray approach to identify putative molecular interactions that regulate the transcriptome in subcutaneous adipose tissue of insulin-sensitive (IS) and insulin-resistant (IR) individuals. Using the NanoString nCounter Human v1 microRNA Expression Assay, we show that 17 microRNAs are differentially expressed in IR vs. IS. Of these, 16 microRNAs (94%) are downregulated in IR vs. IS, including miR-26b, miR-30b, and miR-145. Using Agilent Human Whole Genome arrays, we identified genes that were predicted targets of miR-26b, miR-30b, and miR-145 and were upregulated in IR subjects. This analysis produced ADAM22, MYO5A, LOX, and GM2A as predicted gene targets of these microRNAs. We then validated that miR-145 and miR-30b regulate these mRNAs in differentiated human adipose stem cells. We suggest that use of bioinformatic integration of mRNA and microRNA arrays yields verifiable mRNA-microRNA pairs that are associated with insulin resistance and can be validated in vitro.
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Affiliation(s)
- Tyler J Kirby
- College of Health Sciences, University of Kentucky, Lexington, Kentucky
| | - R Grace Walton
- College of Health Sciences, University of Kentucky, Lexington, Kentucky
| | - Brian Finlin
- Department of Medicine, Division of Endocrinology, and Barnstable Brown Diabetes and Obesity Center; University of Kentucky, Lexington, Kentucky; and
| | - Beibei Zhu
- Department of Medicine, Division of Endocrinology, and Barnstable Brown Diabetes and Obesity Center; University of Kentucky, Lexington, Kentucky; and
| | - Resat Unal
- Department of Medicine, Division of Endocrinology, and Barnstable Brown Diabetes and Obesity Center; University of Kentucky, Lexington, Kentucky; and
| | - Neda Rasouli
- Department of Internal Medicine, Division of Endocrinology, University of Colorado, Aurora, Colorado
| | | | - Philip A Kern
- Department of Medicine, Division of Endocrinology, and Barnstable Brown Diabetes and Obesity Center; University of Kentucky, Lexington, Kentucky; and
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Behboudi-Gandevani S, Ramezani Tehrani F, Rostami Dovom M, Farahmand M, Bahri Khomami M, Noroozzadeh M, Kabir A, Azizi F. Insulin resistance in obesity and polycystic ovary syndrome: systematic review and meta-analysis of observational studies. Gynecol Endocrinol 2016; 32:343-353. [PMID: 27052492 DOI: 10.3109/09513590.2015.1117069] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 10/16/2015] [Accepted: 11/03/2015] [Indexed: 11/13/2022] Open
Abstract
We aimed at investigating whether insulin resistance (IR)/sensitivity are impaired in obese/non-obese polycystic ovary syndrome (PCOS) and obese/non-obese healthy controls. A comprehensive literature search was performed for observational, English language studies. Meta-analysis was performed with the random effects model according to the heterogeneity. Eligible studies, involving 3037 women in four groups of: 1-obese, PCOS; 2-non-obese, PCOS, 3-obese, non-PCOS and 4-Non-obese, non-PCOS were included. Based on the insulin resistance index (HOMA-IR) analysis, the pooled mean (95% Conf. Interval) of HOMA IR in groups 1-4 were 4.38 (3.84, 4.92), 2.68 (2.16, 3.20), 2.44 (2.06, 2.82) and 1.34 (1.06, 1.63), respectively. Meta-analysis showed that group 1 (obese, PCOS patients) statistically have the highest IR and group 4 (non-obese, non-PCOS women) have the highest insulin sensitivity. Group 2 (non-obese, PCOS patients) and group 3 (obese, non-PCOS women) were between this range and they had lower IR than group 1 (obese, PCOS) and lower insulin sensitivity than group 4 (non-obese, non-PCOS). So, there were statistical differences between all groups except between groups 2 and 3. Insulin sensitivity indexes (quickie and ISI), also confirm the IR index (HOMA-IR) results. Based on different IR/sensitivity indexes, we found no evidence of any different effects of BMI ≥ 30 kg/m(2) on IR/sensitivity. In conclusion, PCOS status intensifies the adverse effects of obesity on IR, it has to be appropriately addressed in primary and secondary preventive cares and treatments provided for these women.
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Affiliation(s)
- Samira Behboudi-Gandevani
- a Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Fahimeh Ramezani Tehrani
- a Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Marzieh Rostami Dovom
- a Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Maryam Farahmand
- a Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Mahnaz Bahri Khomami
- a Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Mahsa Noroozzadeh
- a Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran
| | - Ali Kabir
- c Minimally Invasive Surgery Research Center, Department of Community Medicine, School of Medicine, Iran University of Medical Sciences , Tehran , Iran
| | - Fereidoun Azizi
- b Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences , Tehran , Iran , and
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Lim JS, Choi YJ, Kim SK, Huh BW, Lee EJ, Huh KB. Optimal Waist Circumference Cutoff Value Based on Insulin Resistance and Visceral Obesity in Koreans with Type 2 Diabetes. Diabetes Metab J 2015; 39:253-63. [PMID: 26124996 PMCID: PMC4483611 DOI: 10.4093/dmj.2015.39.3.253] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 09/15/2014] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Visceral obesity is the most powerful contributor to the development of metabolic syndrome (MetS) and cardiovascular diseases. In light of visceral obesity, however, there is a paucity of data on the appropriate cutoff point of waist circumference (WC) in subjects with type 2 diabetes. The aim of this study was to investigate the optimal cutoff value for WC that signals insulin resistance (IR) and visceral obesity in Koreans with type 2 diabetes. METHODS We evaluated 4,252 patients with type 2 diabetes (male 2,220, female 2,032, mean age 57.24 years) who visited our clinic between January 2003 and June 2009. WC was measured at the midpoint between the lower rib and the iliac crest, and insulin sensitivity was assessed by the rate constant of plasma glucose disappearance (Kitt %/min) using an insulin tolerance test. Visceral fat thickness was measured using ultrasonography. Statistical analysis was performed using receiver operating characteristic curve. RESULTS The optimal cutoff points for WC for identifying the presence of IR and visceral obesity, as well as two or more metabolic components, were 87 cm for men and 81 cm for women. Moreover, these cutoff points had the highest predictive powers for the presence of visceral obesity. The MetS defined by new criteria correlated with the increased carotid intima-media thickness in female subjects. CONCLUSION Our results suggest that the optimal cutoff values for WC in Koreans with type 2 diabetes should be reestablished based on IR and visceral obesity.
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Affiliation(s)
- Jung Soo Lim
- Division of Endocrinology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Young Ju Choi
- Huh's Diabetes Center and the 21C Diabetes and Vascular Research Institute, Seoul, Korea
| | - Soo-Kyung Kim
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Byoung Wook Huh
- Huh's Diabetes Center and the 21C Diabetes and Vascular Research Institute, Seoul, Korea
| | - Eun Jig Lee
- Division of Endocrinology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Kap Bum Huh
- Huh's Diabetes Center and the 21C Diabetes and Vascular Research Institute, Seoul, Korea
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15
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Tucker LA, Erickson A, LeCheminant JD, Bailey BW. Dairy consumption and insulin resistance: the role of body fat, physical activity, and energy intake. J Diabetes Res 2015; 2015:206959. [PMID: 25710041 PMCID: PMC4325471 DOI: 10.1155/2015/206959] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 12/26/2014] [Accepted: 01/09/2015] [Indexed: 11/19/2022] Open
Abstract
The relationship between dairy consumption and insulin resistance was ascertained in 272 middle-aged, nondiabetic women using a cross-sectional design. Participants kept 7-day, weighed food records to report their diets, including dairy intake. Insulin resistance was assessed using the homeostatic model assessment (HOMA). The Bod Pod was used to measure body fat percentage, and accelerometry for 7 days was used to objectively index physical activity. Regression analysis was used to determine the extent to which mean HOMA levels differed across low, moderate, and high dairy intake categories. Results showed that women in the highest quartile of dairy consumption had significantly greater log-transformed HOMA values (0.41 ± 0.53) than those in the middle-two quartiles (0.22 ± 0.55) or the lowest quartile (0.19 ± 0.58) (F = 6.90, P = 0.0091). The association remained significant after controlling for each potential confounder individually and all covariates simultaneously. Adjusting for differences in energy intake weakened the relationship most, but the association remained significant. Of the 11 potential confounders, only protein intake differed significantly across the dairy categories, with those consuming high dairy also consuming more total protein than their counterparts. Apparently, high dairy intake is a significant predictor of insulin resistance in middle-aged, nondiabetic women.
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Affiliation(s)
- Larry A. Tucker
- College of Life Sciences, Brigham Young University, Provo, UT 84602, USA
- *Larry A. Tucker:
| | - Andrea Erickson
- College of Life Sciences, Brigham Young University, Provo, UT 84602, USA
| | | | - Bruce W. Bailey
- College of Life Sciences, Brigham Young University, Provo, UT 84602, USA
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Abstract
In recent years, obesity and related medical conditions have become leading public health concerns worldwide. Policy measures to combat or prevent obesity have been instated in a number of countries, with varying degrees of success. To stress the importance of obesity as a health issue, many professional health organizations, including the American Medical Association, have defined obesity itself as a disease. While this may be somewhat controversial, the high risk of comorbid conditions in obese individuals, the significant changes from healthy physiology that are present in the obese state, and the need for further public policies to address the public health threat and economic impact of obesity in the population are strong supporting arguments to label obesity as a disease.
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Affiliation(s)
- Michael A Via
- Division of Endocrinology and Metabolism, Beth Israel Medical Center, Icahn School of Medicine at Mount Sinai, 55 East 34th St., New York, NY, 10016, USA.
| | - Jeffrey I Mechanick
- Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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17
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Shikha D, Singla M, Walia R, Potter N, Mercado A, Winer N. Vascular compliance in lean, obese, and diabetic children and adolescents: a cross-sectional study in a minority population. Cardiorenal Med 2014; 4:161-7. [PMID: 25737680 DOI: 10.1159/000365937] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 07/09/2014] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND In adults, both obesity and type 2 diabetes mellitus (T2DM) are positively correlated with cardiovascular disease mortality and arterial stiffness. Several studies of adults have shown that both obesity and T2DM are independently associated with increased arterial stiffness. However, little is known about the relationship between arterial compliance and cardiovascular disease risk in children. We assessed whether large and small arterial compliance is impaired in obese and diabetic pubertal children. METHODS One hundred children of African-Caribbean ethnicity, aged 14-16 years, including 21 lean children (between the 25th and 75th percentile), 40 obese children (>95th percentile), and 39 children with T2DM diagnosed by American Diabetes Association criteria were studied. Arterial compliance of the large (C1) and small (C2) vessels was measured using radial arterial diastolic pulse wave contour analysis. RESULTS C1 did not differ significantly between lean, obese, and T2DM subjects. C2 was significantly greater in obese and T2DM subjects (10.9 ± 1 and 10.4 ± 0.7 ml/mm Hg × 100 ml, respectively) compared to lean subjects (7.8 ± 0.8 ml/mm Hg × 100 ml; p < 0.05). C2 was also significantly greater in T2DM subjects receiving antihypertensive drug therapy than in diabetic subjects not on antihypertensive treatment. CONCLUSION Increased compliance in diabetic and obese children compared to lean subjects could be secondary to premature maturation of the vascular system; whether this early maturation can translate into a subsequent rise in the incidence of cardiovascular events related to diabetes and obesity can only be determined by long-term follow-up of these patients.
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Affiliation(s)
- Deep Shikha
- Division of Endocrinology, Department of Internal Medicine, Downstate Medical Center, Brooklyn, N.Y., USA
| | - Montish Singla
- Division of Nephrology, Department of Internal Medicine, Metropolitan Hospital Center, New York, N.Y., USA
| | - Rachna Walia
- Division of Endocrinology, Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, N.Y., USA
| | - Natia Potter
- Division of Endocrinology, Department of Internal Medicine, Downstate Medical Center, Brooklyn, N.Y., USA
| | - Arlene Mercado
- Division of Endocrinology, Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, N.Y., USA
| | - Nathaniel Winer
- Division of Endocrinology, Department of Internal Medicine, Downstate Medical Center, Brooklyn, N.Y., USA
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Nakamura K. Impact of cardiovascular risk factors on medical expenditure: evidence from epidemiological studies analysing data on health checkups and medical insurance. J Epidemiol 2014; 24:437-43. [PMID: 25070209 PMCID: PMC4213217 DOI: 10.2188/jea.je20140096] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Concerns have increasingly been raised about the medical economic burden in Japan, of which approximately 20% is attributable to cardiovascular disease, including coronary heart disease and stroke. Because the management of risk factors is essential for the prevention of cardiovascular disease, it is important to understand the relationship between cardiovascular risk factors and medical expenditure in the Japanese population. However, only a few Japanese epidemiological studies analysing data on health checkups and medical insurance have provided evidence on this topic. Patients with cardiovascular risk factors, including obesity, hypertension, and diabetes, may incur medical expenditures through treatment of the risk factors themselves and through procedures for associated diseases that usually require hospitalization and sometimes result in death. Untreated risk factors may cause medical expenditure surges, mainly due to long-term hospitalization, more often than risk factors preventively treated by medication. On an individual patient level, medical expenditures increase with the number of concomitant cardiovascular risk factors. For single risk factors, personal medical expenditure may increase with the severity of that factor. However, on a population level, the medical economic burden attributable to cardiovascular risk factors results largely from a single, particularly prevalent risk factor, especially from mildly-to-moderately abnormal levels of the factor. Therefore, cardiovascular risk factors require management on the basis of both a cost-effective strategy of treating high-risk patients and a population strategy for reducing both the ill health and medical economic burdens that result from cardiovascular disease.
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Affiliation(s)
- Koshi Nakamura
- Department of Epidemiology and Public Health, Kanazawa Medical University
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Nakamura K, Okamura T, Miura K, Okayama A. Hypertension and medical expenditure in the Japanese population: Review of prospective studies. World J Cardiol 2014; 6:531-538. [PMID: 25068014 PMCID: PMC4110602 DOI: 10.4330/wjc.v6.i7.531] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 02/11/2014] [Accepted: 05/16/2014] [Indexed: 02/06/2023] Open
Abstract
Hypertension is a major determinant of health and is likely to have an effect on medical economics. The economic burden due to hypertension may be attributable not only to antihypertensive medication but also to the very expensive procedures required for cases of cardiovascular disease that occur more frequently in hypertensive compared with normotensive individuals. The objective of this article was to review articles published on prospective cohort studies that measured medical expenditure attributable to hypertension in community-dwelling populations in Japan. Many medical services in these populations are provided under the medical insurance system that requires the enrolment of all Japanese residents. Personal medical expenditure attributable to hypertension increases with worsening severity of the condition. Medical expenditure was increased further in cases of hypertensive patients who have another concomitant cardiovascular risk factor. In particular, hypertension, especially moderate-to-severe untreated hypertension, increases the risk of long-term hospitalization resulting in considerably higher medical expenditure, compared with non-hospitalized cases. Therefore, assuming that the use of antihypertensive medication is essential for hypertensive patients to prevent serious vascular diseases, a cost-effective high-risk strategy needs to be considered to reduce both ill-health and the economic burden due to hypertension. However, from a population perspective, medical expenditure attributable to hypertension comes mainly from pre-to-mild hypertension. Therefore, there is also a need to consider a population strategy that aims to shift the entire population to lower levels of blood pressure.
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Nishiyama Y, Otsuka T, Ueda M, Inagaki H, Muraga K, Abe A, Kawada T, Katayama Y. Asymmetric dimethylarginine is related to the predicted stroke risk in middle-aged Japanese men. J Neurol Sci 2014; 338:87-91. [DOI: 10.1016/j.jns.2013.12.021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2013] [Revised: 12/11/2013] [Accepted: 12/11/2013] [Indexed: 09/30/2022]
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Mor A, Tabone L, Omotosho P, Torquati A. Improved insulin sensitivity after gastric bypass correlates with decreased total body fat, but not with changes in free fatty acids. Surg Endosc 2013; 28:1489-1493. [PMID: 24317547 DOI: 10.1007/s00464-013-3338-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 11/12/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND Increased plasma free fatty acids (FFAs) are considered one of the key elements in the pathogenesis of insulin resistance (IR) and type 2 diabetes (T2DM). We hypothesize that, in diabetic patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGB), a postoperative decrease in FFA will correlate with improved insulin sensitivity (Si). METHODS A total of 30 obese [body mass index ((BMI) >35 kg/m(2)] patients with a diagnosis of T2DM were studied preoperatively and 12 months after LRYGB in a prospective cohort study. Collected data included intravenous glucose tolerance test (IVGTT), total body composition by dual-energy X-ray absorptiometry and plasma levels of FFA. Si analysis from the IVGTT was estimated from minimal model analysis. Pre- and postoperative variables were compared using a paired sample t test. Relationships between changes in variables were determined with Pearson's correlation test. RESULTS Twelve months after LRYGB the study population showed a significant decrease in BMI (p = 0.001), FFA (p = 0.03), and total body fat (p = 0.03), with an increase in Si (p = 0.001). Postoperative changes in Si significantly correlated (Pearson's r = -0.53, p = 0.01) with change in total body fat, but not with changes in plasma FFA (Pearson's r = -0.22, p = 0.31). CONCLUSIONS Our study challenges the notion that IR is mediated to a significant degree by changes in plasma FFA concentration. Instead, changes in adiposity and consequently changes in adipokine release can be the key players in determining remission of T2DM after LRYGB.
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Abstract
Aims/hypothesis The actions of peripherally administered nesfatin-1 on glucose homeostasis remain controversial. The aim of this study was to characterize the mechanisms by which peripheral nesfatin-1 regulates glucose metabolism. Methods The effects of nesfatin-1 on glucose metabolism were examined in mice by continuous infusion of the peptide via osmotic pumps. Changes in AKT phosphorylation and Glut4 were investigated by Western blotting and immnuofluorescent staining. Primary myocytes, adipocytes and hepatocytes were isolated from male mice. Results Continuous peripheral infusion of nesfatin-1 altered glucose tolerance and insulin sensitivity in mice fed either normal or high fat diet, while central administration of nesfatin-1 demonstrated no effect. Nesfatin-1 increases insulin secretion in vivo, and in vitro in cultured min6 cells. In addition, nesfatin-1 up-regulates the phosphorylation of AKT in pancreas and min6 islet cells. In mice fed normal diet, peripheral nesfatin-1 significantly increased insulin-stimulated phosphorylation of AKT in skeletal muscle, adipose tissue and liver; similar effects were observed in skeletal muscle and adipose tissue in mice fed high fat diet. At basal conditions and after insulin stimulation, peripheral nesfatin-1 markedly increased GLUT4 membrane translocation in skeletal muscle and adipose tissue in mice fed either diet. In vitro studies showed that nesfatin-1 increased both basal and insulin-stimulated levels of AKT phosphorylation in cells derived from skeletal muscle, adipose tissue and liver. Conclusions Our studies demonstrate that nesfatin-1 alters glucose metabolism by mechanisms which increase insulin secretion and insulin sensitivity via altering AKT phosphorylation and GLUT 4 membrane translocation in the skeletal muscle, adipose tissue and liver.
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Matsumoto K, Kanazawa A, Ikeda F, Ohmura C, Shimizu T, Tamura Y, Fujitani Y, Kawamori R, Watada H. The area of abdominal subcutaneous adipose tissue is independently correlated with C-peptide increment during glucagon load in Japanese patients with type 2 diabetes. Diabetol Int 2013. [DOI: 10.1007/s13340-013-0123-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Nollevaux MC, Rahier J, Marchandise J, Thurion P, Godecharles S, Van den Steen G, Jamart J, Sempoux C, Jacquemin P, Guiot Y. Characterization of β-cell plasticity mechanisms induced in mice by a transient source of exogenous insulin. Am J Physiol Endocrinol Metab 2013; 304:E711-23. [PMID: 23403947 PMCID: PMC3625751 DOI: 10.1152/ajpendo.00304.2012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
β-Cell plasticity governs the adjustment of β-cell mass and function to ensure normoglycemia. The study of how β-cell mass is controlled and the identification of alternative sources of β-cells are active fields of research. β-Cell plasticity has been implicated in numerous physiological and pathological conditions. We developed a mice model in which we induced major β-cell mass atrophy by implanting insulin pellets (IPI) for 7 or 10 days. The implants were then removed (IPR) to observe the timing and characteristics of β-cell regeneration in parallel to changes in glycemia. Following IPR, the endocrine mass was reduced by 60% at day 7 and by 75% at day 10, and transient hyperglycemia was observed, which resolved within 1 wk. Five days after IPR, enhanced β-cell proliferation and an increased frequency of small islets were observed in 7-day IPI mice. β-Cell mass was fully restored after an additional 2 days. For the 10-day IPI group, β-cell and endocrine mass were no longer significantly different from those of the control group at 2 wk post-IPR. Furthermore, real-time quantitative PCR analysis of endocrine structures isolated by laser capture microdissection indicated sequentially enhanced expression of the pancreatic transcription factors β(2)/NeuroD and Pdx-1 post-IPR. Thus, our data suggest this mouse model of β-cell plasticity not only relies on replication but also involves enhanced cell differentiation plasticity.
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Affiliation(s)
- M-C Nollevaux
- Service d’Anatomie Pathologique, CHU Mont-Godinne, Institut de recherche expérimentale et clinique, Université catholique de Louvain, Yvoir, Brussels, Belgium.
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Svingos RS, Fernandez EM, Reeder DN, Parker JJ. Life-Threatening Hypoglycemia Associated with Intentional Insulin Ingestion. Pharmacotherapy 2013; 33:e28-33. [DOI: 10.1002/phar.1207] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Affiliation(s)
- Robert S. Svingos
- Pharmacy/Emergency Department; Department of Veterans Affairs Medical Center; North Florida/South Georgia Veterans Health System; Gainesville Florida
| | - Erica M. Fernandez
- Pharmacy Department; Department of Veterans Affairs Medical Center; North Florida/South Georgia Veterans Health System; Gainesville Florida
| | - Don N. Reeder
- Pharmacy/Emergency Department; Department of Veterans Affairs Medical Center; North Florida/South Georgia Veterans Health System; Gainesville Florida
| | - John J. Parker
- Medicine/Emergency Department; Department of Veterans Affairs Medical Center; North Florida/South Georgia Veterans Health System; Gainesville Florida
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Dietary fibre consumption and insulin resistance - the role of body fat and physical activity. Br J Nutr 2012; 110:375-83. [PMID: 23218116 DOI: 10.1017/s0007114512004953] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The present study was conducted to determine the association between fibre intake and insulin resistance in 264 women using a cross-sectional design. Insulin resistance was indexed using homeostasis model assessment of insulin resistance (HOMA-IR) (US formula: fasting insulin (μU/ml) × fasting glucose (mg/dl)/405 international formula: fasting glucose (mmol/l) × fasting insulin (μU/l)/22.5). Fibre and energy consumption were assessed using 7 d weighed food records. Fibre was expressed as g/4184 kJ (1000 kcal). Body fat percentage (BF%) was measured using the BOD POD, and physical activity (PA) was ascertained using Actigraph accelerometers (Health One Technology) worn for seven consecutive days. Women with high total fibre intakes (F= 4·58, P= 0·0332) or high soluble fibre intakes (F= 7·97, P= 0·0051) had significantly less insulin resistance than their counterparts. Participants with high insoluble fibre intakes did not differ from their counterparts (F= 0·7, P= 0·6875). Adjusting for either PA or BF% weakened the relationships significantly. Controlling for BF% nullified the total fibre–HOMA-IR link (F= 1·96, P= 0·1631) and attenuated the association between soluble fibre and HOMA-IR by 32 % (F= 6·86, P= 0·0094). To create dichotomous variables, fibre intake and HOMA-IR were each divided into two categories using the median (low and high). In women who had high soluble fibre intake (upper 50 %), the OR of having an elevated HOMA-IR level was 0·58 (95 % CI 0·36, 0·94) times that of women with low soluble fibre intake (lower 50 %). After controlling for all of the potential confounding factors simultaneously, the OR was 0·52 (95 % CI 0·29, 0·93). High fibre intake, particularly soluble fibre, is significantly related to lower levels of insulin resistance in women. Part of this association is a function of differences in PA and BF%.
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Genetic dissection of complex genetic factor involved in NIDDM of OLETF rat. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:582546. [PMID: 23118743 PMCID: PMC3478749 DOI: 10.1155/2012/582546] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Accepted: 09/20/2012] [Indexed: 11/17/2022]
Abstract
The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, noninsulin-dependent diabetes mellitus (NIDDM) in humans. NIDDM in this rat model was shown to be regulated by multiple genes. We have identified 14 quantitative trait loci (QTLs) responsible for NIDDM (Nidd1-14/of) on chromosomes 1, 5, 7, 8, 9, 11, 12, 14, 16, and 17 by a whole genome search in 160 F2 progenies obtained by mating the OLETF and the F344 rats. Among these loci, two QTLs, Nidd1 and 2/of, were declared significant loci at a genome-wide level. Nidd3, 8, 9, and 13/of exhibited heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. We also found evidence for interaction (epistasis) between Nidd1/of and Nidd2/of, between Nidd1/of and Nidd10/of, between Nidd2/of and Nidd8/of, and between Nidd2/of and Nidd14/of. Furthermore, Nidd6 and 11/of showed linkage with body weight, and Nidd1, 2, 8, 9, 10, and 12/of had an interaction with body weight. These indicated that NIDDM in the OLETF would have a higher degree of genetic complexity. We suggest several interesting candidate genes located in rat genomic regions for Nidd1-14/of or the syntenic regions in human genome.
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Takai T, Sakura H, Uchigata Y, Iwamoto Y. Insulin sensitivity and secretion indices in Japanese subjects with normal and impaired glucose tolerance. Diabetol Int 2012. [DOI: 10.1007/s13340-011-0064-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Chalmers LJ, Copeland KC, Hester CN, Fields DA, Gardner AW. Paradoxical Increase in Arterial Compliance in Obese Pubertal Children. Angiology 2011; 62:565-70. [DOI: 10.1177/0003319711399117] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We determined whether arterial compliance measured by pulse wave analysis is impaired in obese pubertal children compared to normal weight controls, and assessed whether arterial compliance is associated with ambulatory activity. Body fat percentage was significantly different between the normal (n = 33) and obese (n = 34) participants ( P < .001). Large ( P = .012) and small ( P < .001) arterial compliance were lower in the normal-weight group. After adjusting for height, systolic and diastolic blood pressure, race, sex, and Tanner stage, large arterial compliance was no longer different between groups ( P = .066), whereas small arterial compliance remained higher in the obese group ( P < .001). Obese pubertal children have paradoxically increased small arterial compliance compared to that of normal weight children, even after adjusting for height, blood pressure, race, sex, and Tanner stage. Thus, obesity in adolescence is not associated with impairments in small arterial compliance.
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Affiliation(s)
- Laura J. Chalmers
- CMRI Diabetes and Metabolic Research Program, Section of Diabetes/Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Oklahoma Diabetes Center, Department of Pediatrics, University of Oklahoma College of Medicine-Tulsa, Tulsa, OK, USA
| | - Kenneth C. Copeland
- CMRI Diabetes and Metabolic Research Program, Section of Diabetes/Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Oklahoma Diabetes Center, Department of Pediatrics, University of Oklahoma College of Medicine-Tulsa, Tulsa, OK, USA
| | - Casey N. Hester
- CMRI Diabetes and Metabolic Research Program, Section of Diabetes/Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - David A. Fields
- CMRI Diabetes and Metabolic Research Program, Section of Diabetes/Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Oklahoma Diabetes Center, Department of Pediatrics, University of Oklahoma College of Medicine-Tulsa, Tulsa, OK, USA
| | - Andrew W. Gardner
- CMRI Diabetes and Metabolic Research Program, Section of Diabetes/Endocrinology, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
- Harold Hamm Oklahoma Diabetes Center, Department of Pediatrics, University of Oklahoma College of Medicine-Tulsa, Tulsa, OK, USA
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Utzschneider KM, Van de Lagemaat A, Faulenbach MV, Goedecke JH, Carr DB, Boyko EJ, Fujimoto WY, Kahn SE. Insulin resistance is the best predictor of the metabolic syndrome in subjects with a first-degree relative with type 2 diabetes. Obesity (Silver Spring) 2010; 18:1781-7. [PMID: 20379148 DOI: 10.1038/oby.2010.77] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Although obesity is associated with insulin resistance and the metabolic syndrome (MetS), some obese individuals are metabolically healthy. Conversely, some lean individuals are insulin resistant (IR) and at increased cardiometabolic risk. To determine the relative importance of insulin sensitivity, BMI and waist circumference (WC) in predicting MetS, we studied these two extreme groups in a high-risk population. One thousand seven hundred and sixty six subjects with a first-degree relative with type 2 diabetes were stratified by BMI and homeostasis model assessment of insulin resistance (HOMA(IR)) into groups. IR groups had higher triglycerides, fasting glucose, and more diabetes than their BMI-group insulin sensitive (IS) counterparts. Within both IS and IR groups, obesity was associated with higher HOMA(IR) and diastolic blood pressure (BP), but no difference in other metabolic variables. MetS (Adult Treatment Panel III (ATPIII)) prevalence was higher in IR groups (P < 0.001) and more subjects met each MetS criterion (P < 0.001). Within each BMI category, HOMA(IR) independently predicted MetS (P < 0.001) whereas WC did not. Within IS and IR groups, age and WC, but not BMI, were independent determinants of MetS (P < 0.001). WC was a less meaningful predictor of MetS at higher values of HOMA(IR). HOMA(IR) was a better predictor of MetS than WC or BMI (receiver operating characteristic (ROC) area under the curve 0.76 vs. 0.65 vs. 0.59, P < 0.001). In conclusion, insulin sensitivity rather than obesity is the major predictor of MetS and is better than WC at identifying obese individuals with a healthier metabolic profile. Further, as many lean individuals with a first-degree relative with type 2 diabetes are IR and metabolically unhealthy, they may all benefit from metabolic testing.
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Nakamura K, Sakurai M, Miura K, Morikawa Y, Ishizaki M, Yoshita K, Kido T, Naruse Y, Nakagawa H. Homeostasis model assessment of insulin resistance and the risk of cardiovascular events in middle-aged non-diabetic Japanese men. Diabetologia 2010; 53:1894-902. [PMID: 20502862 DOI: 10.1007/s00125-010-1803-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2010] [Accepted: 04/27/2010] [Indexed: 10/19/2022]
Abstract
AIMS/HYPOTHESIS Little is known about the relationship between the HOMA of insulin resistance (HOMA-IR) and the risk of cardiovascular events in Asian populations, which have lower levels of HOMA-IR than Western populations. Accordingly, we determined the predictive value of HOMA-IR for cardiovascular risk in a Japanese population that was apparently free of diabetes, addressing whether insulin resistance itself increases cardiovascular risk independently of other relevant metabolic disorders. METHODS We followed 2,548 non-diabetic men aged 35 to 59 years for 11 years. The hazard ratios for the incidence of cardiovascular events due to increased HOMA-IR were estimated using a Cox proportional hazards model that was adjusted for potential confounding factors. RESULTS The multivariate-adjusted hazard ratio for cardiovascular events compared with the first quartile of HOMA-IR (<or=0.66) was 1.07 (95% CI 0.44-2.64) for the second (HOMA-IR 0.67-1.01), 1.36 (0.56-3.28) for the third (HOMA-IR 1.02-1.51) and 2.50 (1.02-6.10) for the fourth quartile (HOMA-IR >or=1.52). The hazard ratio associated with a one SD (0.61) increment in log-transformed HOMA-IR was 1.51 (1.13-2.02). A similar positive relationship was observed for coronary events and stroke. In addition, the relationship between HOMA-IR and cardiovascular risk was broadly similar in participants with and without hypertension, dyslipidaemia (elevated triacylglycerol and/or reduced HDL-cholesterol), abdominal obesity and current smoking. CONCLUSIONS/INTERPRETATION Increased HOMA-IR predicted subsequent cardiovascular events in non-diabetic Japanese men. The association was independent of traditional cardiovascular risk factors and other relevant metabolic disorders.
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Affiliation(s)
- K Nakamura
- Department of Epidemiology and Public Health, Kanazawa Medical University, Uchinada, Ishikawa, Japan.
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Cerf ME. High fat programming of beta-cell failure. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 654:77-89. [PMID: 20217495 DOI: 10.1007/978-90-481-3271-3_5] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
High saturated fat intake contributes to insulin resistance, beta-cell failure, and type 2 diabetes. Developmental programming refers to a stimulus or insult during critical periods of life which includes fetal and subsequent early neonatal life. Programming alters offspring physiology and metabolism with both immediate and lasting consequences. Maternal nutrition in gestation and lactation shapes offspring development and health. A high saturated fat diet ingested by mothers during gestation and/or lactation is a form of nutritional insult that induces diabetogenic changes in offspring physiology and metabolism. High fat programming is induced by maternal high saturated fat intake during defined periods of gestation and/or lactation and programs the physiology and metabolism of the offspring in early life. This more recently adopted form of developmental programming reflects society in both affluent and developing countries. High fat programming induces adverse changes in beta-cell development and function in neonatal and weanling offspring. These changes are characterized by compromised beta-cell development and function, evident by altered expression of key factors that maintain the beta-cell phenotype. High fat programming is likely to result in beta-cell failure and eventual type 2 diabetes.
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Affiliation(s)
- Marlon E Cerf
- Diabetes Discovery Platform, Medical Research Council, Tygerberg, 7505, Cape Town, South Africa.
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Chen PH, Chen JD, Lin YC. A better parameter in predicting insulin resistance: Obesity plus elevated alanine aminotransferase. World J Gastroenterol 2009; 15:5598-603. [PMID: 19938201 PMCID: PMC2785065 DOI: 10.3748/wjg.15.5598] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association of obesity and elevated alanine aminotransferase with insulin resistance and compare these factors with metabolic syndrome.
METHODS: We enrolled a total of 1308 male workers aged from 22 to 63 years. Data was extracted from the workers’ periodic health check-ups in hospitals. All cases were from the community of northern Taiwan. This was a cross-sectional observational study from July to September in 2004. We grouped all cases into four groups, based on the quartile of homeostasis model assessment. The top fourth quartile group was defined as the group with insulin resistance. We performed multivariate logistic regression analysis for the odds ratio of the risk factors for insulin resistance.
RESULTS: Compared with metabolic syndrome, the coexistence of both factors had a 4.3-fold (95% CI: 2.7-6.8) increased risk, which was more than metabolic syndrome with a 3.6-fold (95% CI: 2.6-5.0) increased risk. The two factors had a synergistic effect. The synergistic index of obesity and elevated alanine aminotransferase (ALT) was 2.1 (95% CI: 1.01-4.3).
CONCLUSION: Obesity and elevated ALT are associated with insulin resistance. The effects are synergistic. Coexistence of them is better than metabolic syndrome in predicting insulin resistance.
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Mortensen B, Poulsen P, Wegner L, Stender-Petersen KL, Ribel-Madsen R, Friedrichsen M, Birk JB, Vaag A, Wojtaszewski JFP. Genetic and metabolic effects on skeletal muscle AMPK in young and older twins. Am J Physiol Endocrinol Metab 2009; 297:E956-64. [PMID: 19671840 DOI: 10.1152/ajpendo.00058.2009] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The protein complex AMP-activated protein kinase (AMPK) is believed to play an important role in the regulation of skeletal muscle glucose and lipid metabolism. Defects in the AMPK system might therefore be an important factor in the pathogenesis of type 2 diabetes. We aimed to identify genetic and environmental mechanisms involved in the regulation of AMPK expression and activity and to examine the association between AMPK protein levels and activity on the one hand, and glucose and fat metabolism on the other. We investigated skeletal muscle biopsies from 100 young and 82 older mono- and dizygotic nondiabetic twins excised during the basal and insulin-stimulated states of a physiological hyperinsulinemic-euglycemic clamp. AMPKalpha1, -alpha2, and -gamma3 mRNA expression was investigated using real-time PCR, and Western blotting was employed to measure protein levels. Multiple regression analyses indicated that skeletal muscle AMPK mRNA and protein expression as well as activity were regulated by sex, age, obesity, and aerobic capacity. Comparison of intraclass correlations on AMPK measurements from mono- and dizygotic twins suggested that skeletal muscle AMPK expression was under minor genetic influence. AMPKgamma3 protein expression and activity were negatively related to whole body glucose uptake through the nonoxidative metabolic pathway and positively related to phosphorylation of glycogen synthase. Our results suggest that skeletal muscle AMPK expression is under minor genetic control but regulated by age and sex and associated with obesity and aerobic capacity. Furthermore, our results indicate a role for gamma3-containing AMPK complexes in downregulation of insulin-stimulated nonoxidative glucose metabolism possibly through inhibition of glycogen synthase activity.
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Affiliation(s)
- Brynjulf Mortensen
- Department of Exercise and Sport Sciences, University of Copenhagen, Denmark.
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Chamson-Reig A, Thyssen SM, Hill DJ, Arany E. Exposure of the pregnant rat to low protein diet causes impaired glucose homeostasis in the young adult offspring by different mechanisms in males and females. Exp Biol Med (Maywood) 2009; 234:1425-36. [PMID: 19657071 DOI: 10.3181/0902-rm-69] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
The understanding of the mechanisms by which gender dimorphisms are involved in the modulation of insulin sensitivity and glucose tolerance can be crucial to unravel the development of type 2 diabetes. Rats treated with a low protein diet (LP, 8% protein content) during pregnancy and lactation have a reduced beta-cell mass at birth and a reduced insulin secretion at weaning. In this study we examined the effect of LP diet on glucose homeostasis from birth to adulthood when offspring previously exposed to LP were subsequently switched to control diet (C, 20% protein content) at weaning. The LP group had a reduced body weight after weaning compared to the C-fed rats, although their food intake was not significantly different. Furthermore, LP males had a significant increase in visceral adiposity relative to their body weight (P < 0.05). Intraperitoneal glucose tolerance test (IGTT) showed that glucose clearance was unchanged until 130 days of age when LP-fed females showed elevated blood glucose compared to C, despite similar plasma insulin levels. Females also demonstrated a significant reduction in mean pancreatic islet number, individual islet size and beta cell mass. However, no differences in IGTT or islet morphometry were observed in LP males, although basal insulin levels were twofold higher. Akt phosphorylation in response to insulin was reduced in adipose and skeletal muscle of adult rats following exposure to LP diet in early life when compared to control-fed animals, but this was only apparent in males. Plasma testosterone levels were also reduced in males at 130 days age. These data suggest that the development of impaired glucose homeostasis in offspring of LP-fed rats is likely to occur by different mechanisms in males and females.
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Affiliation(s)
- Astrid Chamson-Reig
- Lawson Health Research Institute, St. Joseph's Health Care, 268 Grosvenor Street, London, Ontario, N6A 4V2, Canada.
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Nunemaker CS, Chen M, Pei H, Kimble SD, Keller SR, Carter JD, Yang Z, Smith KM, Wu R, Bevard MH, Garmey JC, Nadler JL. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. Am J Physiol Endocrinol Metab 2008; 295:E1065-75. [PMID: 18780776 PMCID: PMC2584815 DOI: 10.1152/ajpendo.90371.2008] [Citation(s) in RCA: 113] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory damage triggered by stressors such as obesity and insulin resistance. We hypothesized that mice lacking 12-LO are protected against inflammatory-mediated damage associated with a "western" diet. To test this hypothesis, age-matched male 12-LO knockout (12-LOKO) and wild-type C57BL/6 (B6) mice were fed either a standard chow or western diet and assessed for several inflammatory markers. Western-fed B6 mice showed expected reductions in glucose and insulin tolerance compared with chow-fed mice. In contrast, western-fed 12-LOKO mice maintained glucose and insulin tolerance similar to chow-fed mice. Circulating proinflammatory cytokines, tumor necrosis factor-alpha and interleukin-6, were increased in western B6 mice but not 12-LOKO mice, whereas the reported protective adipokine, adiponectin, was decreased only in western B6 mice. 12-LO activity was significantly elevated by western diet in islets from B6 mice. Islets from 12-LOKO mice did not show western-diet-induced islet hyperplasia or increases in caspase-3 apoptotic staining observed in western-fed B6 mice. Islets from 12-LOKO mice were also protected from reduced glucose-stimulated insulin secretion observed in islets from western-fed B6 mice. In visceral fat, macrophage numbers and monocyte chemoattractant protein-1 expression were elevated in western B6 mice but not 12-LOKO mice. These data suggest that 12-LO activation plays a role in western-diet-induced damage in visceral fat and islets. Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammation-mediated metabolic consequences of excess fat intake.
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Affiliation(s)
- Craig S Nunemaker
- Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, Virginia, USA
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Chailurkit LO, Chanprasertyothin S, Jongjaroenprasert W, Ongphiphadhanakul B. Differences in insulin sensitivity, pancreatic beta cell function and circulating adiponectin across glucose tolerance status in Thai obese and non-obese women. Endocrine 2008; 33:84-9. [PMID: 18389389 DOI: 10.1007/s12020-008-9057-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2008] [Revised: 03/12/2008] [Accepted: 03/19/2008] [Indexed: 10/22/2022]
Abstract
Although adiponectin levels are associated with obesity and insulin insensitivity, the role of adiponectin in the progression to diabetes in non-obese subjects is unclear. Therefore, 289 women aged 50-80 years without previous history of diabetes or impaired glucose tolerance (IGT) were studied. They were classified as normal glucose tolerance (NGT), IGT or diabetes based on WHO criteria. Insulin sensitivity (S) and beta cell function (B) indices were calculated using homeostasis model assessment (HOMA). In obese women with BMI > or = 25 kg/m(2) (n = 161), there were declines in HOMA-%S (P < 0.001), HOMA-%B (P < 0.05) and circulating adiponectin (P < 0.001) across glucose tolerance status. In non-obese women with BMI < 25 kg/m(2) (n = 128), there was no significant change in HOMA-%S in women with IGT and diabetes as compared to women with NGT. However, HOMA-%B (P < 0.05) and serum adiponectin levels (P < 0.001) were significantly decreased across glucose tolerance. Serum adiponectin levels were correlated to HOMA-%S in both obese and non-obese women while negative correlations between circulating adiponectin and HOMA-%B were demonstrated only in obese women. We have demonstrated in the present study the predominant role of beta cell dysfunction as compared to that of insulin resistance in the deterioration of glucose tolerance in non-obese women. Circulating adiponectin appears to be inversely related to beta cell dysfunction in addition to insulin resistance only in obese women.
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Affiliation(s)
- La-Or Chailurkit
- Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama 6 Rd, Rajthevi, Bangkok, 10400, Thailand.
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Burns N, Finucane FM, Hatunic M, Gilman M, Murphy M, Gasparro D, Mari A, Gastaldelli A, Nolan JJ. Early-onset type 2 diabetes in obese white subjects is characterised by a marked defect in beta cell insulin secretion, severe insulin resistance and a lack of response to aerobic exercise training. Diabetologia 2007; 50:1500-8. [PMID: 17393133 DOI: 10.1007/s00125-007-0655-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2007] [Accepted: 02/23/2007] [Indexed: 12/16/2022]
Abstract
AIMS/HYPOTHESIS Early-onset type 2 diabetes is associated with marked visceral obesity and extreme insulin resistance, but its pathogenesis and response to treatment are not completely understood. We studied physical fitness, whole-body and hepatic glucose turnover, and insulin secretion in young obese Irish subjects before and after 3 months of aerobic exercise training. We hypothesised that exercise alone, with stable diet, should improve insulin sensitivity. MATERIALS AND METHODS Anthropometric parameters and maximum volume of oxygen utilisation (VO(2max)) were measured in 13 subjects with type 2 diabetes and 18 non-diabetic control subjects, matched for age and BMI. Insulin sensitivity and hepatic glucose turnover were measured using the hyperinsulinaemic-euglycaemic clamp. Insulin secretion was assessed from an OGTT and a modified intravenous glucose tolerance test. Some subjects (seven type 2 diabetic, 14 non-diabetic control subjects) then completed a 12-week supervised aerobic exercise programme. All measurements were repeated on completion of the exercise programme. RESULTS Type 2 diabetic subjects had higher WHR, systolic blood pressure and triacylglycerols than non-diabetic control subjects. They were significantly more insulin-resistant as measured both by the clamp and oral glucose insulin sensitivity. They also displayed marked defects in insulin secretion in response to oral and intravenous glucose challenges. Exercise intervention had no significant effect on whole-body or hepatic insulin sensitivity or insulin secretion. VO(2max) increased significantly in the non-diabetic control subjects, but not in the type 2 diabetic subjects after exercise training. CONCLUSIONS/INTERPRETATION Young obese subjects with type 2 diabetes are severely insulin-resistant with marked loss of beta cell function compared with control subjects matched for age and obesity. Neither group responded metabolically to aerobic exercise intervention.
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Affiliation(s)
- N Burns
- Metabolic Research Unit, Department of Endocrinology, Hospital 5, St James' Hospital, Trinity College Dublin, Dublin 8, Ireland
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Hung CJ, Huang PC, Li YH, Lu SC, Ho LT, Chou HF. Taiwanese vegetarians have higher insulin sensitivity than omnivores. Br J Nutr 2007; 95:129-35. [PMID: 16441925 DOI: 10.1079/bjn20051588] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The present study was designed to examine the effects of habitual consumption of Taiwanese vegetarian diets on hormonal secretion, and on lipid and glycaemic control. Of the ninety-eight healthy female adults recruited from Hualien, Taiwan (aged 31–45 years), forty-nine were Buddhist lactovegetarians and forty-nine were omnivores. Dietary intakes were measured, and blood levels of nutrients and hormones were analysed. Vegetarians consumed less energy, fat and protein, but more fibre than the omnivores. Compared with the omnivores, the vegetarians had, on average, lower BMI and smaller waist circumference. Except for slightly lower levels of thyroxine (T4) in vegetarians, vegetarians and omnivores both showed similar levels of triiodothyronine (T3), free T4, thyroid-stimulating hormone, T3:T4 ratio and cortisol. Compared with the omnivores, the vegetarians had significantly lower levels of fasting insulin (median: 35·3 v. 50·6pmol/l) and plasma glucose (mean: 4·7 (se 0·05) v. 4·9 (se 0·05) mmol/l). Insulin resistance, as calculated by the homeostasis model assessment method, was significantly lower in the vegetarians than in the omnivores (median: 1·10 v. 1·56), while β-cell function was not different between the two groups. BMI and diet were both independent predictors for insulin resistance, and contributed 18 and 15% of the variation in insulin resistance, respectively. In conclusion, Taiwanese vegetarians had lower glucose and insulin levels and higher insulin sensitivity than did the omnivores. Diet and lower BMI were partially responsible for the high insulin sensitivity observed in young Taiwanese vegetarians.
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Affiliation(s)
- Chien-Jung Hung
- Department of Biochemistry, College of Medicine, Tzu-Chi University, Taiwan
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Möhlig M, Flöter A, Spranger J, Weickert MO, Schill T, Schlösser HW, Brabant G, Pfeiffer AFH, Selbig J, Schöfl C. Predicting impaired glucose metabolism in women with polycystic ovary syndrome by decision tree modelling. Diabetologia 2006; 49:2572-9. [PMID: 16972044 DOI: 10.1007/s00125-006-0395-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2006] [Accepted: 07/06/2006] [Indexed: 12/15/2022]
Abstract
AIMS/HYPOTHESIS Polycystic ovary syndrome (PCOS) is a risk factor of type 2 diabetes. Screening for impaired glucose metabolism (IGM) with an OGTT has been recommended, but this is relatively time-consuming and inconvenient. Thus, a strategy that could minimise the need for an OGTT would be beneficial. MATERIALS AND METHODS Consecutive PCOS patients (n=118) with fasting glucose <6.1 mmol/l were included in the study. Parameters derived from medical history, clinical examination and fasting blood samples were assessed by decision tree modelling for their ability to discriminate women with IGM (2-h OGTT value >/=7.8 mmol/l) from those with NGT. RESULTS According to the OGTT results, 93 PCOS women had NGT and 25 had IGM. The best decision tree consisted of HOMA-IR, the proinsulin:insulin ratio, proinsulin, 17-OH progesterone and the ratio of luteinising hormone:follicle-stimulating hormone. This tree identified 69 women with NGT. The remaining 49 women included all women with IGM (100% sensitivity, 74% specificity to detect IGM). Pruning this tree to three levels still identified 53 women with NGT (100% sensitivity, 57% specificity to detect IGM). Restricting the data matrix used for tree modelling to medical history and clinical parameters produced a tree using BMI, waist circumference and WHR. Pruning this tree to two levels separated 27 women with NGT (100% sensitivity, 29% specificity to detect IGM). The validity of both trees was tested by a leave-10%-out cross-validation. CONCLUSIONS/INTERPRETATION Decision trees are useful tools for separating PCOS women with NGT from those with IGM. They can be used for stratifying the metabolic screening of PCOS women, whereby the number of OGTTs can be markedly reduced.
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Affiliation(s)
- M Möhlig
- Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, 14558 Nuthetal, Germany.
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Ucak S, Ekmekci TR, Basat O, Koslu A, Altuntas Y. Comparison of various insulin sensitivity indices in psoriatic patients and their relationship with type of psoriasis. J Eur Acad Dermatol Venereol 2006; 20:517-22. [PMID: 16684277 DOI: 10.1111/j.1468-3083.2006.01499.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
AIM We aimed to identify insulin resistance and its possible association with types, duration and severity of psoriasis, and to evaluate various simple insulin-sensitivity indices and beta-cell function in psoriasis. METHODS A cross-sectional study was performed in 110 non-obese adults (18-50 years old): 70 with psoriasis (53 type I, 17 type II psoriasis) and 40 healthy individuals. Blood glucose, insulin and C-peptide levels were measured. Oral glucose tolerance test (OGTT); insulin sensitivity and beta-cell function indices derived from a single sample and OGTT were determined and compared in three groups. RESULTS Total, type I and type II psoriatics had IGT rates of 18.6%, 13.2% and 40%, respectively. In the control group IGT was only 2.5%. Homeostasis Model Assessment (HOMA) beta cell index, fasting insulin, Raynaud index, HOMA-IR and FIRI results were higher in total, type I and type II psoriatics than in controls (P < 0.05, for all). Fasting Belfiore index, QUICKY index, ISI HOMA and FIRI(-1) results were lower in total, type I and type II psoriatics than in controls (P < 0.05, for all), and type I psoriatics had higher levels of these indices than type II psoriatics (P < 0.05, for all). CONCLUSION Our study showed that psoriatic patients were more insulin resistant than healthy subjects and type II psoriatics were more susceptible than type I psoriatics to develop IGT. We suggest that beta-cell function and insulin sensitivity indices are useful methods for measuring insulin resistance in psoriatics. We propose that OGTT should be applied especially in type II psoriatics because of increased rate of IGT in this group.
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Affiliation(s)
- S Ucak
- Department of Diabetes Endocrinology Metabolism, Sisli Etfal Research and Training Hospital, Istanbul, Turkey
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de Fine Olivarius N, Andreasen AH, Siersma V, Richelsen B, Beck-Nielsen H. Changes in patient weight and the impact of antidiabetic therapy during the first 5 years after diagnosis of diabetes mellitus. Diabetologia 2006; 49:2058-67. [PMID: 16841232 DOI: 10.1007/s00125-006-0328-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2005] [Accepted: 05/02/2006] [Indexed: 11/27/2022]
Abstract
AIMS/HYPOTHESIS It is generally thought difficult for type 2 diabetic patients to lose weight. We monitored changes in patients' weight during the first 5 years after diabetes diagnosis in relation to initiation of antidiabetic treatment. SUBJECTS AND METHODS Data from 711 newly diagnosed diabetic patients aged 40 or over were analysed with a random-effect linear-regression model. Patients were included consecutively from a well-defined patient list in general practice. RESULTS In 245 patients whose only treatment was advice on diet, an initial weight loss of 6 to 7 kg was largely maintained over 5 years. Patients receiving metformin (n=86) or sulfonylureas (n=330) maintained an average weight loss of 2 to 4 kg that was dependent on age and sex. Patients' weight did not change on initiation of treatment with sulfonylureas or metformin. Over 5 years, median HbA(1c) increased from 7.0 to 7.8% (reference range 5.4-7.4%) in the diet-alone group. HbA(1c) was approximately 1 percentage point higher for most of the other treatment groups. CONCLUSIONS/INTERPRETATION In newly diagnosed type 2 diabetic patients, long-term weight loss was common and weight loss was not affected by sulfonylurea treatment. The measurements in the study are taken from treatment results achieved in the general population of diabetic patients, who are rarely treated in secondary care and seldom the subject of research; the results thus indicate that weight reduction is a practicable treatment in diabetic patients.
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Affiliation(s)
- N de Fine Olivarius
- The Research Unit for General Practice, University of Copenhagen, Øster Farimagsgade 5, P.O. Box 2099, DK-1014, Copenhagen K, Denmark.
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Slimani L, Oikonen V, Hällsten K, Savisto N, Knuuti J, Nuutila P, Iozzo P. Exercise restores skeletal muscle glucose delivery but not insulin-mediated glucose transport and phosphorylation in obese subjects. J Clin Endocrinol Metab 2006; 91:3394-403. [PMID: 16772346 PMCID: PMC2743828 DOI: 10.1210/jc.2006-0269] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
CONTEXT/OBJECTIVE Insulin resistance in obese subjects results in the impaired disposal of glucose by skeletal muscle. The current study examined the effects of insulin and/or exercise on glucose transport and phosphorylation in skeletal muscle and the influence of obesity on these processes. SUBJECTS/METHODS Seven obese and 12 lean men underwent positron emission tomography with 2-deoxy-2-[(18)F]fluoro-d-glucose in resting and isometrically exercising skeletal muscle during normoglycemic hyperinsulinemia. Data were analyzed by two-tissue compartmental modeling. Perfusion and oxidative capacity were measured during insulin stimulation by [15O]H2O and [15O]O2. RESULTS Exercise increased glucose fractional uptake (K), inward transport rate (K(1)), and the k(3) parameter, combining transport and intracellular phosphorylation, in lean and obese subjects. In each group, there was no statistically significant difference between plasma flow and K(1). At rest, a significant defect in K(1) (P = 0.0016), k(3) (P = 0.016), and K (P = 0.022) was found in obese subjects. Exercise restored K(1), improved but did not normalize K (P = 0.03 vs. lean), and did not ameliorate the more than 60% relative impairment in k(3) in obese individuals (P = 0.002 vs. lean). The glucose oxidative potential tended to be reduced by obesity. CONCLUSIONS/INTERPRETATION The study indicates that exercise restores the impairment in insulin-mediated skeletal muscle perfusion and glucose delivery associated with obesity but does not normalize the defect involving the proximal steps regulating glucose disposal in obese individuals. Our data support the use of 2-deoxy-2-[18F]fluoro-d-glucose-positron emission tomography in the dissection between substrate supply and intrinsic tissue metabolism.
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Affiliation(s)
- Lotfi Slimani
- Turku PET Centre
University of TurkuP.O. Box 52 20521 Turku,FI
- * Correspondence should be adressed to: Lotfi Slimani
| | - Vesa Oikonen
- Turku PET Centre
University of TurkuP.O. Box 52 20521 Turku,FI
| | - Kirsti Hällsten
- Turku PET Centre
University of TurkuP.O. Box 52 20521 Turku,FI
| | - Nina Savisto
- Turku PET Centre
University of TurkuP.O. Box 52 20521 Turku,FI
| | - Juhani Knuuti
- Turku PET Centre
University of TurkuP.O. Box 52 20521 Turku,FI
| | - Pirjo Nuutila
- Turku PET Centre
University of TurkuP.O. Box 52 20521 Turku,FI
- Department of Medicine
University of TurkuTurku,FI
| | - Patricia Iozzo
- Turku PET Centre
University of TurkuP.O. Box 52 20521 Turku,FI
- Institute of Clinical Physiology
National Research Council56100 Pisa,IT
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Abstract
Overweight and obesity are common findings in women of reproductive age in the UK; as 32% of 35- to 64-year-old women are overweight and 21% obese. Obesity causes major changes in many features of maternal intermediary metabolism. Insulin resistance appears to be central to these changes and may also be involved in increased energy accumulation by the fetus. Maternal obesity is associated with many risks to the pregnancy, with increased risk of miscarriage (three-fold) and operative delivery (20.7 versus 33.8% in the obese and 47.4% in the morbidly obese group). Other risks to the mother include an increased risk of pre-eclampsia (3.9 versus 13.5% in the obese group) and thromboembolism (0.05 versus 0.12% in the obese group). There are risks to the fetus with increased perinatal mortality (1.4 per 1000 versus 5.7 per 1000 in the obese group) and macrosomia (>90th centile; 9 versus 17.5% in the obese group). Maternal obesity is associated with an increased risk of obesity in the long term. Obese woman should try to lose weight before pregnancy but probably not during pregnancy. There is no real evidence base for the management of maternal obesity but some practical suggestions are made.
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Affiliation(s)
- C K H Yu
- Department of Obstetrics and Gynaecology, Imperial College School of Medicine at St Mary's Hospital, London, UK
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Petruzzo P, Badet L, Lefrançois N, Berthillot C, Dorel SB, Martin X, Laville M. Metabolic consequences of pancreatic systemic or portal venous drainage in simultaneous pancreas-kidney transplant recipients. Diabet Med 2006; 23:654-9. [PMID: 16759308 DOI: 10.1111/j.1464-5491.2006.01891.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
AIMS The aim was to investigate pancreatic B-cell function and insulin sensitivity in simultaneous pancreas-kidney (SPK) recipients with systemic or portal venous drained pancreas allograft using simple and easy tests. METHODS The study included 44 patients with Type 1 diabetes and end-stage renal disease who had undergone SPK transplantation: 20 recipients received a pancreas allograft with systemic venous drainage (S-SPK) and 24 with portal venous drainage (P-SPK). We studied only recipients with functioning grafts, with normal serum glucose, HbA(1c) and serum creatinine values, on a stable drug regimen. The subjects were studied at 6, 12, 24, 36, 48 and 60 months after transplantation. Insulin sensitivity and B-cell function indices were derived from blood samples and oral glucose tolerance tests. RESULTS All patients from both groups had normal fasting glucose, body mass index and HbA(1c) values by selection. The homeostatic model (HOMA) beta-cell index was significantly lower in P-SPK recipients at several points of the follow-up. HOMA-IR was significantly higher in S-SPK recipients at 6 and 24 months after transplantation and was positively correlated with fasting insulin values, but never exceeded 3.2. There was no significant difference in QUICKI index values between the two groups. Although all patients from both groups always had normal glucose tolerance, the area under the insulin curve was higher in the S-SPK group. Cholesterol, low-density lipoprotein-cholesterol and triglycerides were higher in the P-SPK group. CONCLUSIONS The results suggest sustained long-term endocrine function in both groups and show that portal venous drainage does not offer major metabolic advantages.
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Affiliation(s)
- P Petruzzo
- Department of Surgery, University of Cagliari, Cagliari, Italy.
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47
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Abstract
Insulin lispro has a more rapid onset and a shorter duration of hypoglycaemic action than regular insulin. We report a 39-year-old woman, with no previous medical history, who injected 300 U of the insulin lispro (Humalog) in an attempted suicide. Half an hour later, she was found comatose and brought to our emergency department. On arrival, she was comatose, with capillary glucose of 0.4 mmol/L. She awoke after a 50 ml intravenous bolus of 50% glucose. A continuous infusion of 10% glucose was started. Intermittent hypoglycaemia with neurological signs requiring treatment with 50% glucose was recorded three times during subsequent hospitalization, the last episode being 11 h after insulin injection. The plasma insulin level 4 h after injection was 1465 mU/L, and 18 h after injection was 11 mU/L. Hypoglycaemia after an insulin lispro overdose may last for more than 11 h. Repeated hypoglycaemia after an insulin overdose could be avoided with a glucose infusion rate equivalent to the maximal glucose disposal rate.
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Affiliation(s)
- Miran Brvar
- Poison Control Center, University Medical Center Ljubljana, Zaloska cesta 7, 1000 Ljubljana, Slovenia
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48
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Fatehi-Hassanabad Z, Chan CB. Transcriptional regulation of lipid metabolism by fatty acids: a key determinant of pancreatic beta-cell function. Nutr Metab (Lond) 2005; 2:1. [PMID: 15634355 PMCID: PMC544854 DOI: 10.1186/1743-7075-2-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2004] [Accepted: 01/05/2005] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND: Optimal pancreatic beta-cell function is essential for the regulation of glucose homeostasis in both humans and animals and its impairment leads to the development of diabetes. Type 2 diabetes is a polygenic disease aggravated by environmental factors such as low physical activity or a hypercaloric high-fat diet. RESULTS: Free fatty acids represent an important factor linking excess fat mass to type 2 diabetes. Several studies have shown that chronically elevated free fatty acids have a negative effect on beta-cell function leading to elevated insulin secretion basally but with an impaired response to glucose. The transcription factors PPARalpha, PPARgamma and SREBP-1c respond to changing fat concentrations in tissues, thereby coordinating the genomic response to altered metabolic conditions to promote either fat storage or catabolism. These transcription factors have been identified in beta-cells and it appears that each may exert influence on beta-cell function in health and disease. CONCLUSION: The role of the PPARs and SREBP-1c as potential mediators of lipotoxicity is an emerging area of interest.
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Affiliation(s)
- Zahra Fatehi-Hassanabad
- Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE C1A 4P3 Canada
| | - Catherine B Chan
- Department of Biomedical Sciences, University of Prince Edward Island, 550 University Avenue, Charlottetown, PE C1A 4P3 Canada
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Garca-Estévez DA, Araújo-Vilar D, Saavedra-González A, Fiestras-Janeiro G, Cabezas-Cerrato J. Analysis of the relationship between body mass index, insulin resistance, and beta-cell function: a cross-sectional study using the minimal model. Metabolism 2004; 53:1462-6. [PMID: 15536602 DOI: 10.1016/j.metabol.2004.06.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The objective of our research was to identify the mathematical model that would best define the relationship between obesity, insulin resistance (IR), and beta-cell function. Eighty-seven healthy subjects with a wide range of body mass index (BMI) were studied. Insulin sensitivity (IS) was calculated using Bergman's minimal model. Acute insulin response (AIRg) was calculated as the secretion of insulin during the first 10 minutes following a glucose bolus. IS x AIRg was used as an index of insulin-mediated glucose uptake (IMGU). The relationships among BMI, IS, fasting plasma insulin (FPI), and AIRg were studied in linear relationship terms and in terms of the hyperbolic function. Where the best fit was linear, the Jones and Molitoris method was used to investigate whether the 2-line fit was significantly better. The division of the population into BMI quartiles shows that from the third quartile, IS (12.4 +/- 6.0 v 11.0 +/- 6.4 v 4.8 +/- 1.8 v 3.2 +/- 2.0 E-5 min(-1)[pmol/L](-1), P < .01) diminishes. Nevertheless, a plateau was established between the last 3 quartiles for IS x AIRg. AIRg related to BMI via a breakpoint of 29.3 kg . m(-2). The best fits for both the BMI/IS and BMI/FPI relationships were hyperbolic. Our data indicate that obesity represents a continuum of IR, with severity increasing as BMI increases. Nevertheless, above a value of 29 kg . m(-2) and despite great increases in adiposity, IS tends to descend slowly. Moreover, there seems to be an IMGU threshold at a BMI value of approximately 27 kg . m(-2), above which an increase in adiposity leads to a greater fall in IS x AIRg. Furthermore, this threshold also appears to affect pancreatic response to a glucose stimulus.
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Affiliation(s)
- Daniel A Garca-Estévez
- Division of Endocrinology, Hospital Clínico Universitario de Santiago, 15706 Santiago de Compostela, Spain
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50
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Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004; 59:141-54. [PMID: 14752302 DOI: 10.1097/01.ogx.0000109523.25076.e2] [Citation(s) in RCA: 274] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Approximately 50% to 70% of all women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and this hormone insensitivity probably contributes to the hyperandrogenism that is responsible for the signs and symptoms of PCOS. Although uncertainty exists, early detection and treatment of insulin resistance in this population could ultimately reduce the incidence or severity of diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. Even if that proves to be the case, there are still several problems with our current approach to insulin sensitivity assessment in PCOS, including the apparent lack of consensus on what defines PCOS and "normal" insulin sensitivity, ethnic and genetic variability, the presence of other factors contributing to insulin resistance such as obesity, stress, and aging, and concern about whether simplified models of insulin sensitivity have the precision to predict treatment needs, responses, and future morbidity. Although the hyperinsulinemic-euglycemic clamp technique is the gold standard for measuring insulin sensitivity, it is too expensive, time-consuming, and labor-intensive to be of practical use in an office setting. Homeostatic measurements (fasting glucose/insulin ratio or homeostatic model assessment [HOMA] value) and minimal model tests (particularly the oral glucose tolerance test [OGTT]) represent the easiest office-based assessments of insulin resistance in the PCOS patient. The OGTT is probably the best simple, office-based method to assess women with PCOS because it provides information about both insulin resistance and glucose intolerance. The diagnosis of glucose intolerance holds greater prognostic and treatment implications. All obese women with PCOS should be screened for the presence of insulin resistance by looking for other stigmata of the insulin resistance syndrome such as hypertension, dyslipidemia, central obesity, and glucose intolerance.
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Affiliation(s)
- Richard S Legro
- Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
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