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Increasing Triglyceride Synthesis Inhibits Glucose-Induced Insulin Secretion in Isolated Rat Islets of Langerhans: A Study Using Adenoviral Expression of Diacylglycerol Acyltransferase

Pacific Northwest Research Institute (C.L.K., L.M.J., V.P.) and Department of Medicine, University of Washington (V.P.), Seattle, Washington 98122

Address all correspondence and requests for reprints to: Vincent Poitout, D.V.M., Ph.D., Pacific Northwest Research Institute, 720 Broadway, Seattle, Washington 98122. E-mail: vpoitout{at}pnri.org.

The mechanisms by which prolonged exposure to elevated levels of fatty acids (FA) adversely affects pancreatic ß-cell function remain unclear. Studies in the Zucker diabetic fatty rat have suggested that excessive accumulation of triglycerides (TG) in islets plays a key role in the deleterious effects of FA. However, a direct relationship between TG accumulation and defective ß-cell function has not been established. The aim of the present study was therefore to determine whether increasing TG synthesis in isolated rat islets of Langerhans impairs insulin secretion. To this end, we infected isolated rat islets with an adenovirus encoding for the enzyme catalyzing the last step of triglyceride synthesis, acyl-coenzyme A:diacylglycerol acyltransferase 1 (DGAT). DGAT overexpression did not modify glucose oxidation nor palmitate oxidation, but increased palmitate incorporation into triglycerides by approximately 2-fold. Islets overexpressing DGAT and cultured in elevated glucose levels for 72 h had markedly impaired insulin secretion in response to glucose, but responded normally to the nonglucose secretagogues glyburide and potassium chloride. The deleterious effects of DGAT overexpression were not additive to those of prolonged exposure to palmitate. We conclude that a selective increase in TG content impairs glucose-induced insulin secretion, a mechanism likely to mediate, at least in part, the deleterious effects of FA on pancreatic ß-cell function.

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