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Exendin-4 ameliorates diabetic symptoms through activation of glucokinase.

Abstract：

BACKGROUND:Glucagon-like peptide-1 (GLP-1) and its stable analogue exendin-4 maintain glucose homeostasis by modulating insulin secretion from pancreatic β-cells and controlling hepatic glucose output. Glucokinase (GK), by catalysing the first step in glycolysis, plays an important role in glucose-stimulated insulin secretion and hepatic glucose metabolism. In the present study, we investigated the effects of exendin-4 on GK in high fat-fed and alloxan-treated diabetic mice. METHODS:The effects of alloxan (5, 10 and 20 μmol/L) on insulin release from isolated murine islets, as well as glycogen synthesis by isolated murine hepatocytes, were assessed. The effects of exendin-4 (10 nmol/kg, twice daily for 4 weeks) were assessed in high fat-fed, alloxan (50 mg/kg, i.v.)-treated C57 mice. Glucokinase activity was assessed in the same model. RESULTS:Pretreatment with exendin-4 attenuated alloxan-induced decreases in insulin release and glycogen synthesis in islets and hepatocytes. The alloxan-induced decrease in the GK activity in islets and hepatocytes was also ameliorated by exendin-4 treatment. Pretreatment with the GLP-1 receptor antagonist exendin-9 (100 nmol/L) blocked the effects of exendin-4 on the liver and pancreas. Treatment of high-fat fed, alloxan-treated diabetic mice with exendin-4 (10 nmol/L, i.p.) reduced the severity of diabetic symptoms. Specifically, exendin-4 treatment reduced serum glucose by 50% and %HbA1c by 24% compared with control and significantly decreased HOMA-IR by 39% and increased HOMA-β by 150%. In addition, exendin-4 treatment significantly reduced body weight by 6.8% and serum triglycerides by 35%. CONCLUSIONS:The results indicate that glucose-stimulated insulin release and glycogen synthesis are decreased by alloxan due to reduced GK activity. These findings provide further insight into the mechanism by which exendin-4 regulates glucose homeostasis.

journal_name

J Diabetes

journal_title

Journal of diabetes

authors

Dhanesha N,Joharapurkar A,Shah G,Dhote V,Kshirsagar S,Bahekar R,Jain M

doi

10.1111/j.1753-0407.2012.00193.x

subject

Has Abstract

pub_date

2012-12-01 00:00:00

pages

369-77

issue

eissn

1753-0393

issn

1753-0407

journal_volume

pub_type

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Exendin-4 ameliorates diabetic symptoms through activation of glucokinase.