Glucose regulation of insulin secretion in health and diabetes

The anabolic hormone insulin is secreted by the pancreatic �-cell of the islet of Langerhans. A human adult pancreas contains approximately 1 million islets which form about 1% of the total tissue mass and each islet contains about 3000 �-cells. The activity of the �-cell is modulated by a variety of agonists including calorigenic nutrients and neuromodulators. Insulin secretion plays a central role in glucose homeostasis and alterations of pancreatic �-cell function result in metabolic disorders such as diabetes mellitus and obesity. Glucose is the pre-eminent regulator of insulin release but several additional nutrients including some amino acids and fatty acids induce secretion as well. Thus the islet of Langerhans is a fuel responsive micro-organ which constantly " senses " all circulating nutrients and integrates these signals to secrete insulin according to the needs of an organism. The �-cell possesses a unique signal transduction system which requires metabolism of the fuel stimulus to initiate secretion. This is markedly different feature from that of neurotransmitters and various hormonal factors which modulate secretion through binding to plasma membrane receptors.

The exact biochemical nature of the signals that couple nutrient metabolism to insulin release are not well defined. Why, despite such considerable effort, does the fuel sensing process of the �-cell remains largely a mystery? It is perhaps precisely due to this unique feature that activation of intermediary metabolism which is so complex, is instrumental in the process. It is generally believed that glycolytic and oxydative events leading to accelerated ATP generation are the key transduction phenomenon in �-cell signaling (see Figure X). A rise in the cytosolic ATP/ADP ratio and in particular a fall in MgATP is thought to close metabolically sensitive KATP channels resulting in depolarization of the �-cell, activation of voltage-gated Ca2+ channels and a rise in cytoplasmic Ca2+ which promotes secretion. This picture is nonetheless incomplete and in recent years it has become apparent that second messengers and factors other than adenine nucleotides, KATP channels and Ca2+ play essential role in nutrient induced insulin secretion.

An important area of research of our laboratory concerns the identification of the coupling factors which mediate the link between glucose metabolism in the �-cell and insulin secretion. The most likely candidates are high energy currency molecules which are common to all metabolic pathways. These may include adenine nucleotides, acyl-CoA compounds and pyrydine nucleotides. Our work has increased our understanding of the �-cell fuel sensing process by providing support for several new concepts and hypotheses. These include in particular that: 1) A rise in cytosolic Ca2+ is not sufficient to explain the kinetics and extent of secretion induced by glucose; 2) Variations in ADP, rather than ATP, regulate �-cell metabolism and the KATP channel; 3) Anaplerosis ( the replenishment of the citric acid cycle with intermediates) is essential for �-cell activation; 4) A shift from fatty acid oxidation to esterification is an important event in �-cell signaling; 5) Malonyl-CoA and long chain acyl-CoA esters may act as metabolic coupling factors; 6) Glycolytic oscillations underlie, in part, oscillations in electrical activity, cytosolic Ca2+ and insulin release. In addition we have proposed a metabolic model of fuel sensing which integrates the mode of action of all classes of nutrient secretagogues (Figure Y). Finally we have cloned �-cell malonyl-CoA decarboxylase, the enzymes which degrades malonyl-CoA, a metabolite which can be considered as an intracellular signal of fuel abundance. We are currently studying the role of this enzyme in health and diabetes and determining whether malonyl-CoA is implicated in the short and/or long term control of insulin secretion. The identification of the precise mechanism by which glucose promotes insulin secretion and the key metabolic enzyme implicated should prove relevant to the development of drugs and therapeutic strategies for the treatment of both type 1 and type 2 diabetes.

Type 2 diabetes is a heterogeneous disease characterized by strong genetic background which frequently implicates environmental factors for its expression. Most type 2 diabetics are obese, insulin resistant and display abnormal islet function. It is generally believed that pre-diabetic obese subjects which are insulin resistant have a hyperinsulinemia that compensates for the insulin resistance with a resulting near-normal glucose tolerance. When the endocrine pancreas becomes progressively defective and can no longer produce