Reduced cell proliferation and neuroblast differentiation in the dentate gyrus of high fat diet-fed mice are ameliorated by metformin and glimepiride treatment.
ABSTRACT We investigated the effects of a high-fat diet (HFD) and the subsequent treatment of metformin (met) and glimepiride (glim), which are widely prescribed for type 2 diabetes, on cell proliferation and neuroblast differentiation using Ki67 and doublecortin (DCX) immunohistochemistry, respectively. Animals were fed low-fat diet (LFD) or HFD for 8 weeks. After 5 weeks of the HFD treatment, met alone or met + glim was administered orally once a day for 3 weeks. Body weight and food intake were much higher in the HFD + vehicle-treated group than the LFD-treated group. The administration of met or met + glim to the HFD-treated group resulted in a decrease in weight gain and food intake. Ki67-immunoreactive ((+)) nuclei, DCX(+) neuroblasts and brain-derived neurotrophic factor (BDNF) protein levels were markedly decreased in the dentate gyrus (DG) of the HFD + vehicle-treated group compared to the LFD-treated group. The administration of met or met + glim to the HFD-treated group prevented the reduction of Ki67(+) nuclei, DCX(+) neuroblasts, BDNF levels in the DG. The intraventricular injection of K252a (a BDNF receptor blocker) to the HFD-treated group treated met or met + glim distinctively lowered the reduction of cell proliferation and neuroblast differentiation induced by HFD. These results suggest that a HFD significantly reduces cell proliferation and neuroblast differentiation by reducing BDNF levels and these effects are ameliorated by treatment with met or met + glim.
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ABSTRACT: Plasma adiponectin levels increase after the administration of glimepiride. This unique effects would also be expected to improve other adipocytokines and have anti-atherosclerotic action in patients with metabolic syndrome. Thirty-four patients with type 2 diabetes mellitus who were administrated glibenclamide were randomly divided into two groups. In 20 patients glibenclamide was changed to glimepiride (GP group), and the administration of glibenclamide (GB group) was continued in 14 patients. Twelve patients receiving insulin therapy (INS group) were enrolled for comparison. The levels of plasma adiponectin, high sensitive-CRP, TNF-alpha, interleukin-6, homeostasis model assessment-insulin resistance (HOMA-IR), brachial-ankle pulse wave velocity (baPWV) and augmentation index (AI) were measured before and 28 weeks after the therapy. HOMA-IR in the GP group was significantly decreased compared to the GB group. Plasma adiponectin levels were significantly increased in the GP group but not in the other groups. TNF-alpha, interleukin-6 and high sensitive-CRP levels were significantly decreased in the GP group, but not in the other groups. The baPWV and AI levels did not change in either the GB or the INS group, but were significantly decreased in the GP group. Glimepiride appears to improve insulin resistance and atherosclerotic disorders.The Journal of Medical Investigation 03/2006; 53(1-2):87-94.
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ABSTRACT: Here we summarize recent progress in the biology of leptin, concentrating on its central nervous system (CNS) actions. The product of the ob gene, leptin is a circulating hormone produced by white adipose tissue that has potent effects on feeding behavior, thermogenesis and neuroendocrine responses. Leptin regulates energy homeostasis, as its absence in rodents and humans causes severe obesity. We consider the physiological mechanisms underlying leptin action, along with several novel hypothalamic neuropeptides that affect food intake and body weight. The molecular causes of several other obesity syndromes are discussed to illuminate how the CNS regulates body weight. We describe neural circuits that are downstream of leptin receptors and propose a model linking populations of leptin-responsive neurons with effector neurons underlying leptin's endocrine, autonomic and behavioral effects.Nature Neuroscience 11/1998; 1(6):445-50. · 15.25 Impact Factor
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ABSTRACT: Sulphonylureas are effective and well tolerated in patients with Type 2 diabetes, but may be associated with weight gain, and lack of compliance due to multiple daily dosing. This open, uncontrolled surveillance study examined the efficacy and safety of glimepiride, a new sulphonylurea, administered once daily in patients with Type 2 diabetes. A total of 1,770 patients were enrolled in the study, and 284 patients were selected for follow-up. Patients received 0.5 to >4 mg glimepiride once daily for 1.5 years. HbA(1c) was reduced from 8.4% at baseline to 7.1% after 4 months and 6.9% after 1 and 1.5 years (median intra-individual change from baseline: -1.4, -1.5, and -1.7%, respectively; P<0.0001). Treatment with glimepiride also resulted in significant and stable weight loss relative to baseline, with the exception of patients with a body mass index of <25 kg/m(2). Mean body weight was reduced from 79.8 kg at baseline to 77.9 kg after 4 months, 77.2 kg after 1 year, and 76.9 kg after 1.5 years (mean intra-individual change from baseline: -1.9 kg, P<0.0001; -2.9 kg, P<0.05; -3.0 kg, P<0.005, respectively). Therefore, once daily glimepiride provides effective glycaemic control, and may have advantages over other sulphonylureas, because it exhibits weight neutralizing/reducing effects in patients with Type 2 diabetes.Diabetes Research and Clinical Practice 08/2003; 61(1):13-9. · 2.74 Impact Factor