Sitagliptin lowers glucagon and improves glucose tolerance in prediabetic obese SHROB rats

The SHROB (spontaneously hypertensive rat - obese strain) is a model of prediabetes and metabolic syndrome with insulin resistance, glucose intolerance and hypertension. Inhibitors of dipeptidyl dipeptidase IV (DPP-IV) are effective hypoglycemic agents in type 2 diabetes through potentiation of incr...

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Bibliographic Details
Published in:	Experimental biology and medicine (Maywood, N.J.) Vol. 236; no. 3; p. 309
Main Authors:	Chen, Brian, Moore, Alex, Escobedo, Liza V S, Koletsky, Matthew S, Hou, Diana, Koletsky, Richard J, Ernsberger, Paul
Format:	Journal Article
Language:	English
Published:	England 01-03-2011
Subjects:	Animals Blood Glucose - analysis Body Weight Diabetes Mellitus, Type 2 - prevention & control Disease Models, Animal Feeding Behavior Glucagon - antagonists & inhibitors Glucagon - metabolism Glucagon-Like Peptide 1 - metabolism Glyburide - administration & dosage Hypoglycemic Agents - administration & dosage Insulin - metabolism Insulin Secretion Pyrazines - administration & dosage Rats Sitagliptin Phosphate Triazoles - administration & dosage
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Summary:	The SHROB (spontaneously hypertensive rat - obese strain) is a model of prediabetes and metabolic syndrome with insulin resistance, glucose intolerance and hypertension. Inhibitors of dipeptidyl dipeptidase IV (DPP-IV) are effective hypoglycemic agents in type 2 diabetes through potentiation of incretin hormones that act in the pancreas to increase insulin and decrease glucagon release. We sought to determine whether the DPP-IV inhibitor sitagliptin might be effective in prediabetes relative to standard therapy with the sulfonylurea glyburide, by using the SHROB model. SHROB show normal fasting glucose but are insulin resistant and hyperglucagonemic. SHROB were treated for six weeks with vehicle, sitagliptin (30 mg/kg/d) or glyburide (1 mg/kg/d) and compared with untreated lean spontaneously hypertensive rats. Body weight, food intake and fasting glucose were all unchanged in all three SHROB groups, but glucagon was reduced by 33% by sitagliptin while remaining unchanged following glyburide or vehicle. In oral glucose (6 g/kg) tolerance testing, both sitagliptin and glyburide lowered plasma glucose. Both sitagliptin and glyburide shifted peak insulin secretion earlier (30 min for glyburide and 60 min for sitagliptin but 240 min for vehicle). Only sitagliptin significantly enhanced insulin secretion. Sitagliptin is effective in normalizing excess glucagon levels and delaying exaggerated insulin secretion in response to a glucose challenge in a prediabetic model.
ISSN:	1535-3699
DOI:	10.1258/ebm.2010.010161