Diabetes and Insulin Secretion

Abstract

The ATP-sensitive K ؉ channel (K ATP channel) senses metabolic changes in the pancreatic ␤-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. When K ATP channels open, ␤-cells hyperpolarize and insulin secretion is suppressed. The prediction that K ATP channel "overactivity" should cause a diabetic state due to undersecretion of insulin has been dramatically borne out by recent genetic studies implicating "activating" mutations in the Kir6.2 subunit of K ATP channel as causal in human diabetes. This article summarizes the emerging picture of K ATP channel as a major cause of neonatal diabetes and of a polymorphism in K ATP channel (E23K) as a type 2 diabetes risk factor. The degree of K ATP channel "overactivity" correlates with the severity of the diabetic phenotype. At one end of the spectrum, polymorphisms that result in a modest increase in K ATP channel activity represent a risk factor for development of lateonset diabetes. At the other end, severe "activating" mutations underlie syndromic neonatal diabetes, with multiple organ involvement and complete failure of glucose-dependent insulin secretion, reflecting K ATP channel "overactivity" in both pancreatic and extrapancreatic tissues. Diabetes 54:3065-3072, 2005

β‐cell hyperexcitability: from hyperinsulinism to diabetes

“…Conversely, gain-of-function mutations of Kir6.2 or SUR1 are expected to cause an undersecreting phenotype and hypoinsulinaemia. Consistent with this expectation, activating mutations cause both permanent and transient neonatal diabetes in mice and humans [13,14].…”

New ABCC8 Mutations in Relapsing Neonatal Diabetes and Clinical Features

“…Therefore, penetrance of dominant mutations and variability in their clinical expressivity may also be explained by the influence of other genetic determinants and epistasis effects, by behavioral factors such as physical activity, body composition, and age on the clinical phenotype, as seen in other monogenic subtypes of diabetes (23). The functional properties of the new SUR1 mutations on electrophysiological parameters of the K ATP channel may give a valuable estimate on their pathological impact, although it may be difficult to demonstrate an effect such as in the case of the E23K polymorphism of the Kir6.2 subunit of the K ATP channel (24).…”

Expression of ATP-Insensitive KATP Channels in Pancreatic β-Cells Underlies a Spectrum of Diabetic Phenotypes

“…A persistent hyperexcitabilty of the ␤-cell results in unregulated insulin release and underlies hyperinsulinism with hypoglycemia in humans (1). Conversely, it is now clear that hypoexcitability can suppress insulin release and contribute to the converse disorder of diabetes (2).…”

“…A clear picture is now emerging from both animal and human studies that such K ATP mutations can cause hyposecretion and underlie diabetes (2). Genetic studies have now identified mutations in the pore-forming Kir6.2 subunit of K ATP (KCNJ11) as a common cause of neonatal diabetes mellitus (NDM) in humans (3)(4)(5)(6)(7)(8)(9).…”

“…All transgenic offspring of four founder lines (A-C and E) expressing the Kir6. 2[⌬N30] transgene exhibited hypoinsulinemia with ketoacidosis and usually died within the 1st week of life. Islet morphology and insulin localization was normal at the earliest stages of the disease, implicating reduced insulin secretion as causal.…”