Role of Zinc Homeostasis in the Pathogenesis of Diabetes and Obesity.

Zinc deficiency is a risk factor for obesity and diabetes. However, until recently, the underlying molecular mechanisms remained unclear. The breakthrough discovery that the common polymorphism in zinc transporter SLC30A8/ZnT8 may increase susceptibility to type 2 diabetes provided novel insights into the role of zinc in diabetes. Our group and others showed that altered ZnT8 function may be involved in the pathogenesis of type 2 diabetes, indicating that the precise control of zinc homeostasis is crucial for maintaining health and preventing various diseases, including lifestyle-associated diseases. Recently, the role of the zinc transporter ZIP13 in the regulation of beige adipocyte biogenesis was clarified, which indicated zinc homeostasis regulation as a possible therapeutic target for obesity and metabolic syndrome. Here we review advances in the role of zinc homeostasis in the pathophysiology of diabetes, and propose that inadequate zinc distribution may affect the onset of diabetes and metabolic diseases by regulating various critical biological events.

Beneficial effects of vildagliptin combined with miglitol on glucose tolerance and islet morphology in diet-controlled db/db mice.

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes primarily by increasing plasma active glucagon-like peptide-1 (GLP-1) levels. While various combination therapies based on DPP-4 inhibitors have been proposed for treatment of type 2 diabetes, the effects of combination therapy of DPP-4 inhibitors and alpha-glucosidase inhibitors on ß-cell function are less characterized. We evaluated the effects of long-term treatment with vildagliptin, a DPP-4 inhibitor, on metabolic parameters and ß-cell function, in combination with miglitol, an alpha-glucosidase inhibitor, in diet-controlled db/db mice. In this study, 6-week-old male db/db mice were provided with standard chow twice a day for 6 weeks. Meal tolerance tests and glucose tolerance tests showed that the combination therapy of vildagliptin with miglitol, but not each alone, suppressed postprandial glycemic excursion, enhanced postprandial active GLP-1 levels and prevented deterioration of glucose tolerance in the db/db mice. The combination treatment did not alter ß-cell mass, but resulted in preserved expression of glucose transporter 2, Zinc transporter 8 and MafA and reduced the number of α cells. These results suggest that the combination of vildagliptin and miglitol prevents the development of overt diabetes in diet-controlled pre-diabetic db/db mice by normalizing postprandial glucose and incretin response, and by preserving ß-cell structure and the expression of factors essential for ß-cell function.

Miglitol suppresses the postprandial increase in interleukin 6 and enhances active glucagon-like peptide 1 secretion in viscerally obese subjects.

Visceral obesity and insulin resistance are regarded as risk factors for atherosclerosis. Epidemiologic studies have demonstrated long-term anti-atherosclerotic effects with administration of alpha-glucosidase inhibitors. Alpha-glucosidase inhibitors also have been reported to enhance glucagon-like peptide 1 (GLP-1) secretion. We compared the postprandial effects of a single administration of miglitol and acarbose on glucose and lipid metabolism, on insulin requirement, on GLP-1 secretion, and on inflammatory and endothelial markers in viscerally obese subjects. Twenty-four viscerally obese subjects with relative insulin resistance participated in this study. Subjects were given a single dose of miglitol (50 mg), acarbose (100 mg), or placebo blindly and randomly before a meal in a crossover design. The meal loads after drug administration were tested 3 times within 2 weeks. We measured glucose, insulin, lipids, lipoprotein lipase, interleukin 6, intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and active GLP-1 at before and various minutes after the meal. Single administration of both alpha-glucosidase inhibitors had several beneficial effects in improving postprandial hyperglycemia and reducing postprandial insulin requirement approximately 25% of placebo without adversely affecting lipid profiles. Although lipoprotein lipase levels within 2 hours after the meal did not show differences among miglitol, acarbose, and placebo administrations, miglitol significantly suppressed the increases in triglycerides, remnant-like particle triglycerides, and remnant-like particle cholesterol compared to acarbose and placebo in the early phase. Miglitol also significantly enhanced active GLP-1 secretion to a greater extent than acarbose (P < .01) and placebo (P < .001), and significantly suppressed the postprandial increase in interleukin 6 compared to placebo (P < .01). The results point to the potential suitability of miglitol as an anti-atherosclerotic effect in viscerally obese subjects, in preference to acarbose. Further studies are needed to elucidate the long-term effects on enhanced GLP-1 secretion and anti-atherosclerosis.

Effects of changes in basal/total daily insulin ratio in type 2 diabetes patients on intensive insulin therapy including insulin glargine (JUN-LAN Study 6).

Intensive insulin therapy composed of bolus and basal insulin has been believed as the most powerful recipe for glycemic control of both type 1 and type 2 diabetes. In this study, we investigated the effects of changes in basal/total daily insulin ratio (B/TD ratio) in type 2 diabetes patients on intensive insulin therapy including insulin glargine. The B/TD ratio used in our Japanese patients was about 0.35, and the ratio was increased up to about 0.46+/-0.12 without change of total insulin daily dose. After 24-week-treatment, mean glycated albumin of the patients whose B/TD ratio was increased was significantly lower than those of the patients whose B/TD ratio was not changed. Our results suggest that adequate supplementation of basal insulin may be important for maximum effect of bolus insulin even in Japanese who have serious defect in postprandial rapid insulin secretion.