Peter Proks

Abstract:

SUR1 is an ATP-binding cassette (ABC) transporter with a novel function. In contrast to other ABC proteins, it serves as the regulatory subunit of an ion channel. The ATP-sensitive (KATP) channel is an octameric complex of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits, and it links cell metabolism to electrical activity in many cell types. ATPase activity at the nucleotide-binding domains of SUR results in an increase in KATP channel open probability. Conversely, ATP binding to Kir6.2 closes the channel. Metabolic regulation is achieved by the balance between these two opposing effects. Precisely how SUR1 talks to Kir6.2 remains unclear, but recent studies have identified some residues and domains that are involved in both physical and functional interactions between the two proteins. The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes. This paper reviews recent data on the regulation of Kir6.2 by SUR1 and considers the molecular mechanisms by which SUR1 mutations produce disease.

Abstract:

Neonatal diabetes is a rare monogenic form of diabetes that usually presents within the first six months of life. It is commonly caused by gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of the plasmalemmal ATP-sensitive K+ (KATP) channel. To better understand this disease, we generated a mouse expressing a Kir6.2 mutation (V59M) that causes neonatal diabetes in humans and we used Cre-lox technology to express the mutation specifically in pancreatic beta cells. These beta-V59M mice developed severe diabetes soon after birth, and by 5 weeks of age, blood glucose levels were markedly increased and insulin was undetectable. Islets isolated from beta-V59M mice secreted substantially less insulin and showed a smaller increase in intracellular calcium in response to glucose. This was due to a reduced sensitivity of KATP channels in pancreatic beta cells to inhibition by ATP or glucose. In contrast, the sulfonylurea tolbutamide, a specific blocker of KATP channels, closed KATP channels, elevated intracellular calcium levels, and stimulated insulin release in beta-V59M beta cells, indicating that events downstream of KATP channel closure remained intact. Expression of the V59M Kir6.2 mutation in pancreatic beta cells alone is thus sufficient to recapitulate the neonatal diabetes observed in humans. beta-V59M islets also displayed a reduced percentage of beta cells, abnormal morphology, lower insulin content, and decreased expression of Kir6.2, SUR1, and insulin mRNA. All these changes are expected to contribute to the diabetes of beta-V59M mice. Their cause requires further investigation.

Abstract:

BACKGROUND: Disopyramide, an antiarrhythmia drug, has been reported to cause hypoglycaemia. Pre-existing factors that increase the concentration of the drug in the blood increase the risk of hypoglycaemia. Furthermore, other factors can also increase the risk of hypoglycaemia even when disopyramide levels are in the therapeutic range. It has been proposed that disopyramide-induced hypoglycaemia is caused by inhibition of the pancreatic B-cell K(ATP) channels. CASE REPORT: We report a case of severe disopyramide-induced hypoglycaemia in a 62-year-old woman with Type 2 diabetes taking low-dose glimepiride treatment. She had not experienced hypoglycaemia prior to the start of disopyramide therapy. No further hypoglycaemic episodes occurred following withdrawal of disopyramide therapy. FUNCTIONAL STUDY: Current recordings of K(ATP) channels expressed in Xenopus oocytes showed that at their estimated therapeutic concentrations, disopyramide and glimepiride inhibited K(ATP) channels by about 50-60%. However, when both drugs were applied together, K(ATP) channels were almost completely closed (approximately 95%). Such dramatic inhibition of K(ATP) channels is sufficient to cause B-cell membrane depolarization and stimulate insulin secretion. CONCLUSIONS: Disopyramide therapy is not recommended for patients treated with K(ATP) channel inhibitors.

Abstract:

ATP-sensitive potassium (K(ATP)) channels couple cell metabolism to plasmalemmal potassium fluxes in a variety of cell types. The activity of these channels is primarily determined by intracellular adenosine nucleotides, which have both inhibitory and stimulatory effects. The role of K(ATP) channels has been studied most extensively in pancreatic beta-cells, where they link glucose metabolism to insulin secretion. Many mutations in K(ATP) channel subunits (Kir6.2, SUR1) have been identified that cause either neonatal diabetes or congenital hyperinsulinism. Thus, a mechanistic understanding of K(ATP) channel behavior is necessary for modeling beta-cell electrical activity and insulin release in both health and disease. Here, we review recent advances in the K(ATP) channel structure and function. We focus on the molecular mechanisms of K(ATP) channel gating by adenosine nucleotides, phospholipids and sulphonylureas and consider the advantages and limitations of various mathematical models of macroscopic and single-channel K(ATP) currents. Finally, we outline future directions for the development of more realistic models of K(ATP) channel gating.

Abstract:

We performed a receiver operator characteristic (ROC) curve analysis of 3915 men and 2032 women. Subjects who were diagnosed with two or more factors among high blood pressure, hyperglycaemia or high triglyceride and/or low HDL were classified as the metabolic syndrome group. By performing a ROC curve analysis, we have determined the cut-off point of waist circumference (WC) and BMI to define metabolic syndrome and further calculated the sensitivity and specificity of these two factors for the diagnosis. Cut-off point for the diagnosis of metabolic syndrome was 85 cm (men) and 80 cm (women) in WC and 24 (men) and 23 (women) in BMI. By combining these two factors, the sensitivity for the diagnosis increased to more than 80%. We conclude that it is beneficial to combine both WC and BMI for diagnosis of metabolic syndrome.