Thus the evidence favors the idea that T2DM is a disease of impaired β-cell function, resulting from a reduction in insulin content, and a failure of the β-cell to respond to glucose stimulation with insulin secretion. Furthermore, there is evidence that β-cell mass in T2DM may have been underestimated due to equating a reduction in insulin staining/content with a reduction in β-cell number ( 97, 429, 667). Although T2DM is associated with a reduction in β-cell mass, this is too small to account for the reduced insulin secretion. It is now clear that although both defective insulin secretion and impaired insulin action in peripheral tissues contribute to T2DM, the principal defect lies in the pancreatic β-cell (reviewed in Refs. This requires a better understanding of the disease etiology.Īll forms of diabetes are characterized by elevated blood glucose due to an insufficiency (absolute or relative) of the hormone insulin, which is secreted by the β-cells of the pancreatic islets. Thus it is important to identify the cause of diabetes and ways in which it may be ameliorated. Costs associated with diabetes consume (at least) $322 billion per year, and one in five healthcare dollars is spent caring for people with diabetes (see This burden is rapidly becoming unaffordable. As a result, it causes a marked increase in both morbidity and mortality. Impaired microvascular function combined with peripheral neuropathy make diabetes the most common cause of nontraumatic amputation. Diabetes increases the risk of secondary complications such as cardiac disease, renal failure, and retinopathy. Currently, it is conservatively estimated that more than 400 million people are affected worldwide, and it is predicted that cases will exceed 500 million by 2030. 2 Arguably, the adult human β-cell and its physiological regulation represent the ‟gold standardˮ for new therapies based on surrogate β-cells ( 546).Īn updated review of the physiology of insulin secretion is particularly timely, given the current pandemic of T2DM, which shows no sign of abating. Thus the aim of this review is to summarize these findings and attempt to synthesize them into a coherent picture of insulin secretion. We also have a better understanding of how insulin secretion is regulated in health and disease. 1 Genetic studies have identified the genes responsible for the most common forms of monogenic diabetes and numerous single nucleotide polymorphisms (SNPs) associated with an increased risk of type 2 diabetes (T2DM) ( 79, 519). Transcriptome analysis of purified human ( 68, 475) and mouse ( 3, 56) β-cells is finally available. We now know substantially more about the electrical activity of the β-cell and about the mechanisms of exocytosis. Eliot once bemoaned, ‟twenty years largely wasted.ˮ Although our writing style may not have improved, the field has made enormous progress. It is now almost 30 yr since we wrote our first review on the electrophysiology of the pancreatic β-cell ( 31). Since then, we have engaged in a scientific dance, collaborating at times, competing (in a friendly fashion) at others. We first met in a swimming pool, on a hot sunny day in Alicante in 1985, at the inaugural meeting of what was to become the Islet Study Group of the European Association for the Study of Diabetes.

We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity, and insulin exocytosis. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca 2+ concentration and initiation of Ca 2+-dependent exocytosis of insulin-containing secretory granules.

The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. Impaired insulin secretion results in the chronic hyperglycemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration.

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