Original Data

Expression Analysis of cPLA2 Alpha Interacting TIP60 in Diabetic KKAy and Non-Diabetic C57BL Wild-Type Mice: No Impact of Transient and Stable TIP60 Overexpression on Glucose-Stimulated Insulin Secretion in Pancreatic Beta-Cells

Iver Nordentoft¹, Per B. Jeppesen¹, Anders L. Nielsen², Poul Jorgensen³, Kjeld Hermansen¹

Abstract

In the present study we investigate the expression levels of cytosolic phospholipase A₂ α (cPLA2α) interacting histone acetyl transferase proteins TIP60α and TIP60β in non-diabetic C57BL wild-type mice and obese type 2 diabetic KKAy model mice. The aim was to test our hypothesis that TIP60 plays a regulatory role in glucose-stimulated insulin secretion from pancreatic β-cells. MATERIAL AND METHODS: Ten obese diabetic KKAy mice and ten non-diabetic C57BL mice were fed a standard chow diet. After nine weeks, islet RNA was purified and used to measure TIP60 expression. We investigated the effect of TIP60α and TIP60β on glucose-stimulated insulin secretion by transient and stable overexpression in the pancreatic mouse β-cell line MIN6 and the rat β-cell line INS-1E. RESULTS: We found that non-diabetic C57BL mice and diabetic KKAy mice have the same level of both the α and β splice forms of TIP60. Furthermore, we demonstrated that transient and stable expression of TIP60 in INS-1E cells affects neither glucose-stimulated insulin secretion, insulin output nor cell insulin content. Also susceptibility to developing gluco-toxicity was unaffected. CONCLUSION: TIP60 over-expression does not affect glucose stimulated insulin secretion, insulin content or abnormal β-cell function during glucotoxicity.

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Diabetic Cardiomyopathy in OVE26 Mice Shows Mitochondrial ROS Production and Divergence Between In Vivo and In Vitro Contractility

Ye Song¹, Yibo Du¹, Sumanth D. Prabhu², Paul N. Epstein¹

Abstract

Many diabetic patients suffer from a cardiomyopathy that cannot be explained solely by poor coronary perfusion. This cardiomyopathy may be due to either organ-based damage like fibrosis, or to direct damage to cardiomyocytes. Mitochondrial-derived reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. To address these questions, we used the OVE26 mouse model of severe type 1 diabetes to measure contractility in isolated cardiomyocytes by edge detection and in vivo with echocardiography. We also assessed the source of ROS generation using both a general and a mitochondrial specific indicator. When contractility was assayed in freshly isolated myocytes, contraction was much stronger in control myocytes. However, contractility of normal myocytes became weaker during 24 hours of in vitro culture. In contrast, contractility of diabetic OVE26 myocytes remains stable during culture. Echocardiography revealed normal or hyperdynamic function in OVE26 hearts under basal conditions but with a sharply reduced response to isoproterenol, a β-adrenergic agonist. For ROS generation, we found that ROS production in diabetic myocytes was elevated after exposure to either high glucose or angiotensin II (AngII). Superoxide detection with the mitochondrial sensor MitoSOX Red confirmed that mitochondria are a major source of ROS generation in diabetic myocytes. These results show that contractile deficits in OVE26 diabetic hearts are due primarily to cardiomyocyte impairment and that ROS from mitochondria are a cause of that impairment.

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Diabetes and Impaired Glucose Regulation in First-Degree Relatives of Patients with Type 2 Diabetes in Isfahan, Iran: Prevalence and Risk Factors

Masoud Amini¹, Mohsen Janghorbani^1,2

Abstract

OBJECTIVES: The aim of this study was to estimate the prevalence of diabetes, impaired glucose tolerance (IGT), and impaired fasting glucose (IFG) in first-degree relatives (FDR) of people with type 2 diabetes mellitus. METHODS: A cross-sectional study of FDR of type 2 diabetes patients was conducted between 2003 and 2005. A total of 2,368 FDR of type 2 diabetes outpatients aged 30-60 years (614 men and 1754 women) from Isfahan Endocrine and Metabolism Research Center (Iran) were examined. All subjects underwent a standard 75 g 2-h oral glucose tolerance test (OGTT). IGT, IFG and type 2 diabetes were diagnosed according to the criteria of the American Diabetes Association (ADA). The mean (SD) age of participants was 43.1 (6.9) years. RESULTS: The prevalence of type 2 diabetes, IGT and IFG were 10.3% (95% CI: 9.1-11.5), 19.5% (17.9-21.1) and 17.3% (15.8-18.8) respectively. The prevalence rates were significantly higher than those reported for a control population of the same age (type 2 diabetes, 6.0% (95% CI: 5.7-6.2) and IGT 9.6 (95% CI: 9.3-9.9)). IGT was more frequent among women (OR: 0.66; 95% CI: 0.51-0.87), whereas diabetes (OR: 1.31; 95% CI: 0.96-1.78) and IFG (OR: 1.41; 95% CI: 1.10-1.80) were higher in men. Multivariate analysis revealed that age and obesity or abdominal obesity were significantly associated with diabetes, IGT and IFG. CONCLUSIONS: FDR of people with type 2 diabetes in Iran are at higher risk of IGT and type 2 diabetes than the population at large. Risk increases with age and obesity. These findings may be useful for the identification of persons at risk of developing type 2 diabetes and strongly support the regular screening of FDR of type 2 diabetes patients.

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Impact of Metabolic Syndrome Risk Factors in First-Degree Relatives of Type 2 Diabetic Patients

Susana Siewert¹, Sergio Filipuzzi², Leticia Codazzi², Irma Gonzalez¹, Marta S. Ojeda¹

Abstract

OBJECTIVE: Family members of patients with an established diagnosis of type 2 diabetes mellitus (T2DM) are theoretically at risk of having the metabolic syndrome (MetS). A sample of these family members was studied from a population in a small township in Argentina, which has a high prevalence of T2DM. METHODS: We examined the clinical and metabolic characteristics of 132 first-degree relatives of T2DM patients (FDR) and 112 age-matched controls. The subjects were categorized according to the International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) criteria for MetS. RESULTS: The prevalence of MetS in the FDR group was 34.8 (IDF) and 26.5% (NCEP-ATPIII) respectively, which was significantly different to the prevalence in controls (p < 0.025). According to IDF criteria, the most prevalent factors among FDR subjects with MetS were low HDL-cholesterol (87%) followed by hypertriglyceridemia (69.5%). In the MetS group, which ranged between 20-29 years old (36%), the major risk factor in women was a low HDL-cholesterol serum level. In the MetS group, which ranged between 30-39 years old (44.4%), the most important risk factor in men was hypertriglyceridemia. CONCLUSION: This study revealed that the prevalence of MetS is high in young FDR adults, who need urgent preventive treatment, including lifestyle changes. The risk of developing T2DM is five times higher in non-diabetic people with MetS than in those without the syndrome.

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Bromocriptine-Induced Hyperglycemia in Nonobese Diabetic Mice: Kinetics and Mechanisms of Action

Sylvie Durant¹, Josiane Coulaud², Francoise Homo-Delarche²

Abstract

The effects of bromocriptine (10 mg/kg), known to inhibit prolactin secretion and lower autoimmune processes, were studied on glucose homeostasis in non-fasted non-obese diabetic mice, a spontaneous model of type 1 diabetes. Hyperglycemia was observed 120 and 240 min after i.p. but not s.c. injection. Bromocriptine administration i.p. led to rapid and marked hyperglycemia characterized by sexual dimorphism with males having higher glycemia than females. Bromocriptine induced a rapid but transient decrease in insulinemia in males only and biphasic increases in glucagon levels and a sustained stimulatory effect on circulating corticosterone in both sexes. Bromocriptine-induced hyperglycemia involved D2-dopaminergic receptors, as demonstrated by the inhibitory effect of the D2-dopamine antagonist, metoclopramide (10 mg/kg). Simultaneous injection of bromocriptine and metoclopramide also blocked the rise in blood corticosterone. In conclusion, by inducing hyperglycemia, i.p. bromocriptine administration to prediabetic autoimmune mice may counteract its beneficial anti-immunostimulatory effects.

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