Peter Proks

Abstract:

The patient was a 69-year-old woman with a family history of type 2 diabetes. Her body mass index was 31.5. She was diagnosed as type 2 diabetes 32 years previously, and treated with insulin for 8 years. She had no episode of weight loss. She was hospitalized with diabetic ketoacidosis for the first time. Her GAD antibodies were not detected. However, ICA antibodies and insulin antibodies were positively detected. She was diagnosed with type 1 diabetes. Interestingly, her diabetes state was controlled to the same level after recovery from ketoacidosis.

Abstract:

Clostridium infections are rare but frequently associated with malignancy, and mortality approaches 100% if care is not rendered within 12 to 24 h. These infections are associated with various medical problems including diabetes mellitus. In this report, we describe a unique case of sepsis and a gas-forming splenic abscess caused by Clostridium septicum in a type 2 diabetes patient which was treatable solely with antibiotics.

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.