alogliptin and Prediabetic-State

Impaired β-cell function remains unaddressed in PCOS. The aim of the study was to evaluate whether dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin (ALO) alone or in combination with pioglitazone (PIO) improves β-cell function along with insulin resistance (IR) in metformin (MET) treated obese women with PCOS with persistent IR.. In 12-week randomized study, ALO 25 mg QD (n=15) or ALO 25 mg QD and PIO 30 mg QD (n=15) was added to MET 1000 mg BID in PCOS women (aged 34.4 ± 6.5 years, BMI 39.0 ± 4.9 kg/m. ALO alone and in combination with PIO improved IR along with dynamic IS and meal related β-cell function when added to MET treated PCOS.

Topics: Adult; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Resistance; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Meals; Metformin; Obesity; Pioglitazone; Piperidines; Polycystic Ovary Syndrome; Prediabetic State; Prevalence; Slovenia; Thiazolidinediones; Uracil

Prolonged exposure of pancreatic beta (β) cells to elevated glucose and free fatty acids (FFA) as occurs in type 2 diabetes results in loss of β cell function and survival. In Zucker Diabetic Fatty (ZDF) rats, β cell failure is associated with increased triacylglyceride (TAG) synthesis and disruption of the glycerolipid/FFA (GL/FFA) cycle, a critical arm of glucose-stimulated insulin secretion (GSIS). The aim of this study was to determine the impact of activation of PPARγ and increased incretin action via dipeptidyl-peptidase inhibition using pioglitazone and/or alogliptin, respectively, on islet lipid metabolism in prediabetic and diabetic ZDF rats. Transition of control prediabetic ZDF rats to diabetes was associated with reduced plasma insulin levels, reduced islet insulin content and GSIS, reduced stearoyl-CoA desaturase 2 (SCD 2) expression, and increased islet TAG, diacylglyceride (DAG) and ceramides species containing saturated FA. Treatment of prediabetic ZDF rats with a combination of pioglitazone and alogliptin, but not individually, prevented the transition to diabetes and was associated with marked lowering of islet TAG and DAG levels. Pioglitazone and alogliptin, however, did not restore SCD2 expression, the degree of FA saturation in TAG, DAG or ceramides, islet insulin content, or lower ceramide levels. These findings are consistent with activation of PPARγ and increased incretin action working in concert to restore GL/FFA cycle in β cells of ZDF rats. Restoration of the GL/FFA cycle without correcting islet FA desaturation, production of islet ceramides, and/or insulin sensitivity, however, may place these islets at risk for β cell failure.

Topics: Animals; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Islets of Langerhans; Lipid Metabolism; Male; Pioglitazone; Piperidines; Prediabetic State; Rats; Rats, Zucker; Thiazolidinediones; Uracil

Alogliptin is a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor. The aim of this study was to determine its effects on glucose control and pancreas islet function and to identify the underlying molecular mechanisms after chronic administration, in a non-genetic mouse model of type 2 diabetes.. Alogliptin (5, 15 and 45 mg/kg) was orally administered to high fat diet/streptozotocin (HFD/STZ) diabetic mice daily for 10 weeks. Postprandial and 6-h fasting blood glucose levels, blood A1C level, oral glucose tolerance and pancreas insulin content were measured during or after the treatment period. Alogliptin plasma concentration was determined by an LC/MS/MS method. Islet morphology and architectural changes were evaluated with immunohistochemical analysis. Islet endocrine secretion ability was assessed by measuring insulin release from isolated islets which were challenged with 16 mM glucose and 30 mM potassium chloride, respectively. Gene expression profiles of the pancreas were analysed using the mouse diabetes RT(2) Profiler PCR array which contains 84 genes related to the onset, development and progression of diabetes.. Alogliptin showed dose-dependent reduction of postprandial and fasting blood glucose levels and blood A1C levels. Glucose clearance ability and pancreas insulin content were both increased. Alogliptin significantly restored the β-cell mass and islet morphology, thus preserving islet function of insulin secretion. Expression of 10 genes including Ins1 was significantly changed in the pancreas of diabetic mice. Chronic alogliptin treatment completely or partially reversed the abnormalities in gene expression.. Chronic treatment of alogliptin improved glucose control and facilitated restoration of islet architecture and function in HFD/STZ diabetic mice. The gene expression profiles suggest that the underlying molecular mechanisms of β-cell protection by alogliptin may involve alleviating endoplasmic reticulum burden and mitochondria oxidative stress, increasing β-cell differentiation and proliferation, enhancing islet architecture remodelling and preserving islet function.

Topics: Animals; Diabetes Mellitus, Experimental; Dietary Fats; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Insulin-Secreting Cells; Male; Mice; Mice, Obese; Piperidines; Prediabetic State; Streptozocin; Uracil

Alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and voglibose, an alpha-glucosidase inhibitor, have different but complementary mechanisms of action on glucagon-like peptide-1 (GLP-1) regulation and glucose-lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice.. Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice.. After 3 weeks, voglibose treatment increased GLP-1 secretion (voglibose alone, 1.6-fold; alogliptin plus voglibose, 1.5-fold), while it decreased plasma glucose-dependent insulinotropic polypeptide (GIP) (voglibose alone, -30%; alogliptin plus voglibose, -29%). Alogliptin, voglibose and combination treatment decreased plasma DPP-4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP-1 levels by 4.5-, 1.8- and synergistically by 9.1-fold respectively. Combination treatment increased plasma insulin by 3.6-fold (alogliptin alone, 1.3-fold; voglibose alone, 1.8-fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6-, 3.4- and synergistically by 8.5-fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha-cell distribution in the pancreatic islet.. Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP-1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta-cells and islet structure in prediabetic db/db mice.

Topics: Animals; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Hypoglycemic Agents; Inositol; Insulin-Secreting Cells; Male; Mice; Mice, Inbred C57BL; Piperidines; Prediabetic State; RNA-Binding Proteins; Transcription Factors; Uracil