Leucine metabolism in regulation of insulin secretion from pancreatic beta cells

Abstract

Leucine, a branched-chain amino acid that must be supplied in the daily diet, plays an important role in controlling protein synthesis and regulating cell metabolism in various cell types. In pancreatic beta cells, leucine acutely stimulates insulin secretion by serving as both metabolic fuel and allosteric activator of glutamate dehydrogenase to enhance glutaminolysis. Leucine has also been shown to regulate gene transcription and protein synthesis in pancreatic islet beta cells via both mTOR-dependent and -independent pathways at physiological concentrations. Long-term treatment with leucine has been shown to improve insulin secretory dysfunction of human diabetic islets via upregulation of certain key metabolic genes. In vivo, leucine administration improves glycemic control in humans and rodents with type 2 diabetes. This review summarizes and discusses the recent findings regarding the effects of leucine metabolism on pancreatic beta-cell function.

Figures

Figure 1. Association of reduced ATP synthesis in mitochondria with obesity-induced pancreatic β cell dysfunction

Decrease in ATP synthesis is the central event in the progression of islet dysfunction under insulin-resistant conditions. UCP2: uncoupling protein 2; iNOS: inducible nitrogen synthase; ATPβ: ATP synthase β subunit; ATPs: ATP synthase complex; ROS: reactive oxygen species; ETC: electron transport chain.

Figure 2. Leucine plays diverse roles in regulation of insulin secretion in pancreatic β cell via acute and chronic effects

Further demonstration of the mechanisms by which leucine regulates GDH activity and upregulates other key metabolic genes will shed new light on prevention and treatment of type 2 diabetes. GDH: glutamate dehydrogenase; mTOR: mammalian target of rapamycin.