Combination treatment with alogliptin and voglibose increases active GLP-1 circulation, prevents the development of diabetes and preserves pancreatic beta-cells in prediabetic db/db mice.

AIM: 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. METHODS: Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice. RESULTS: 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. CONCLUSIONS: 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.

Somatostatin release, electrical activity, membrane currents and exocytosis in human pancreatic delta cells.

AIMS/HYPOTHESIS: The aim of this study was to characterise electrical activity, ion channels, exocytosis and somatostatin release in human delta cells/pancreatic islets. METHODS: Glucose-stimulated somatostatin release was measured from intact human islets. Membrane potential, currents and changes in membrane capacitance (reflecting exocytosis) were recorded from individual human delta cells identified by immunocytochemistry. RESULTS: Somatostatin secretion from human islets was stimulated by glucose and tolbutamide and inhibited by diazoxide. Human delta cells generated bursting or sporadic electrical activity, which was enhanced by tolbutamide but unaffected by glucose. Delta cells contained a tolbutamide-insensitive, Ba(2+)-sensitive inwardly rectifying K(+) current and two types of voltage-gated K(+) currents, sensitive to tetraethylammonium/stromatoxin (delayed rectifying, Kv2.1/2.2) and 4-aminopyridine (A current). Voltage-gated tetrodotoxin (TTX)-sensitive Na(+) currents contributed to the action potential upstroke but TTX had no effect on somatostatin release. Delta cells are equipped with Ca(2+) channels blocked by isradipine (L), omega-agatoxin (P/Q) and NNC 55-0396 (T). Blockade of any of these channels interferes with delta cell electrical activity and abolishes glucose-stimulated somatostatin release. Capacitance measurements revealed a slow component of depolarisation-evoked exocytosis sensitive to omega-agatoxin. CONCLUSIONS/INTERPRETATION: Action potential firing in delta cells is modulated by ATP-sensitive K(+)-channel activity. The membrane potential is stabilised by Ba(2+)-sensitive inwardly rectifying K(+) channels. Voltage-gated L- and T-type Ca(2+) channels are required for electrical activity, whereas Na(+) currents and P/Q-type Ca(2+) channels contribute to (but are not necessary for) the upstroke of the action potential. Action potential repolarisation is mediated by A-type and Kv2.1/2.2 K(+) channels. Exocytosis is tightly linked to Ca(2+)-influx via P/Q-type Ca(2+) channels. Glucose stimulation of somatostatin secretion involves both K(ATP) channel-dependent and -independent processes.

Combining a dipeptidyl peptidase-4 inhibitor, alogliptin, with pioglitazone improves glycaemic control, lipid profiles and beta-cell function in db/db mice.

BACKGROUND AND PURPOSE: Alogliptin, a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, enhances incretin action and pioglitazone enhances hepatic and peripheral insulin actions. Here, we have evaluated the effects of combining these agents in diabetic mice. EXPERIMENTAL APPROACH: Effects of short-term treatment with alogliptin alone (0.01%-0.1% in diet), and chronic combination treatment with alogliptin (0.03% in diet) and pioglitazone (0.0075% in diet) were evaluated in db/db mice exhibiting early stages of diabetes. KEY RESULTS: Alogliptin inhibited plasma DPP-4 activity up to 84% and increased plasma active glucagon-like peptide-1 by 4.4- to 4.9-fold. Unexpectedly, alogliptin alone lacked clear efficacy for improving glucose levels. However, alogliptin in combination with pioglitazone clearly enhanced the effects of pioglitazone alone. After 3-4 weeks of treatment, combination treatment increased plasma insulin by 3.8-fold, decreased plasma glucagon by 41%, both of which were greater than each drug alone, and increased plasma adiponectin by 2.4-fold. In addition, combination treatment decreased glycosylated haemoglobin by 2.2%, plasma glucose by 52%, plasma triglycerides by 77% and non-esterified fatty acids by 48%, all of which were greater than each drug alone. Combination treatment also increased expression of insulin and pancreatic and duodenal homeobox 1 (PDX1), maintained normal beta-cell/alpha-cell distribution in islets and restored pancreatic insulin content to levels comparable to non-diabetic mice. CONCLUSIONS AND IMPLICATIONS: These results indicate that combination treatment with alogliptin and pioglitazone at an early stage of diabetes improved metabolic profiles and indices that measure beta-cell function, and maintained islet structure in db/db mice, compared with either alogliptin or pioglitazone monotherapy.