Sulfonylurea and glinide reduce insulin content, functional expression of K(ATP) channels, and accelerate apoptotic beta-cell death in the chronic phase.

We previously found that chronic exposure to glibenclamide inhibits acute glibenclamide-induced insulin secretion by reducing the number of functional ATP-sensitive K(+) (K(ATP)) channels on the plasma membrane of pancreatic beta-cells. In the present study, we compared sulfonylurea-induced and glinide-induced insulin secretion in pancreatic beta-cells chronically exposed to these widely used oral hypoglycemic agents. Chronic exposure of pancreatic beta-cells to sulfonylureas (glibenclamide or tolbutamide) and glinide (nateglinide) similarly impaired their acute effectiveness by reducing the insulin content and the number of functional K(ATP) channels on the plasma membrane. Functional expression of the voltage-dependent Ca(2+) channels (VDCCs), ion channels that play a critical role in the K(ATP) channel dependent insulin secretory pathway, was similar to that in drug-untreated cells. Chronic exposure to each of the three agents similarly accelerated apoptotic beta-cell death. Thus, reduction of the insulin content, reduction of the number of functional K(ATP) channels on the plasma membrane, and acceleration of apoptotic beta-cell death all are involved in impaired insulinotropic agent-induced acute insulin secretion in the chronic phase of sulfonylurea and glinide treatment. These findings help to clarify the mechanism of secondary failure after long-term therapy by these hypoglycemic agents, and should have important clinical implications regarding pharmacotherapy for type 2 diabetes.

Roles of 14-3-3 and calmodulin binding in subcellular localization and function of the small G-protein Rem2.

kir/Gem, Rad, Rem and Rem2 comprise the RGK (Rad/Gem/kir) family of Ras-related small G-proteins. Two important functions of RGK proteins are the regulation of the VDCC (voltage-dependent Ca2+ channel) activity and cell-shape remodelling. RGK proteins interact with 14-3-3 and CaM (calmodulin), but their role on RGK protein function is poorly understood. In contrast with the other RGK family members, Rem2 has been reported to bind neither 14-3-3 nor induce membrane extensions. Furthermore, although Rem2 inhibits VDCC activity, it does not prevent cell-surface transport of Ca2+ channels as has been shown for kir/Gem. In the present study, we re-examined the functions of Rem2 and its interaction with 14-3-3 and CaM. We show that Rem2 in fact does interact with 14-3-3 and CaM and induces dendrite-like extensions in COS cells. 14-3-3, together with CaM, regulates the subcellular distribution of Rem2 between the cytoplasm and the nucleus. Rem2 also interacts with the beta-subunits of VDCCs in a GTP-dependent fashion and inhibits Ca2+ channel activity by blocking the alpha-subunit expression at the cell surface. Thus Rem2 shares many previously unrecognized features with the other RGK family members.

Sulfonylurea and non-sulfonylurea hypoglycemic agents: pharmachological properties and tissue selectivity.

ATP-sensitive K+ (K(ATP)) channels play many important roles in cellular functions, including control of membrane excitability of skeletal muscle and neurons, K+ recycling in renal epithelia, cytoprotection in cardiac ischemia, and insulin secretion from pancreatic beta-cells. K(ATP) channels are composed of pore-forming inwardly rectifying potassium channel (Kir6.2 or Kir6.1) subunits and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits. Kir6.2 or Kir6.1 subunits conjoined with a SUR subunit constitute the various tissue-specific K(ATP) channels with distinct pharmacological properties. Both sulfonylureas and non-sulfonylurea hypoglycemic agents are used in treatment of type 2 diabetes mellitus. While the sulfonylurea receptor (SUR) is the target molecule of all of these hypoglycemic agents, the binding sites differ according to the moiety containing in the agent, and alter the pharmachological properties. In addition, chronic exposure of pancreatic beta-cells to the various agents affects the agent-specific sensitivities differently. Here we distinguish differences in pharmacological profile among the various hypoglycemic agents that reflect their chemical composition. We also suggest possible risk in the use of certain hypoglycemic agents in patients with ischemic heart disease.

A case of normoreninemic aldosterone-producing adenoma associated with chronic renal failure: case report and literature review.

The diagnosis of aldosterone-producing adenoma (APA) is challenging for endocrinologists, as APA does not always present with the typical constellation of clinical and laboratory features, such as hypertension, hypokalemia, suppressed plasma renin activity (PRA), and high plasma aldosterone concentration (PAC). Very recently, several studies have indicated that APA can be discovered even in normokalemic subjects with normal PRA more frequently than previously considered. Here we report a case of APA associated with chronic renal failure, which showed normokalemia and normal PRA. The patient was referred to our clinic for evaluation of an incidentally discovered adrenal mass with abnormally high PAC. After 6 yr, it was found that the right adrenal tumor showed a marked increase in size. Endocrinological examinations indicated normal PRA and markedly high PAC. Aldosterone showed a better response to the upright posture test than that to ACTH stimulation test. The diagnosis of APA was made based on the markedly high PAC to PRA ratio and the adrenocortical scintigraphy, which showed unequivocal uptake into the tumor. Right laparoscopic adrenalectomy was performed, revealing a right adrenocortical adenoma with massive hemorrhage. Histopathological examinations revealed the presence of two independent adrenocortical adenomas, one APA with predominant clear tumor cells and few c17 (17alpha-hydroxylase) immunoreactivity and the other, cortisol producing adenoma with compact cytoplasm and abundant C17 immunoreactivity. This case indicates a difficulty of diagnosis of "normoreninemic APA" with renal failure. This case is in line with the recent concept that APA is a continuous condition in which only a minority of patients have the classical clinical picture of primary aldosteronism such as hypokalemia. It is possible that normokalemic APA constitutes the most common presentation of the disease.

High-dose calcium stimulation test in a case of insulinoma masquerading as hysteria.

It is reported that some cases with insulinoma present with neuropsychiatric symptoms and are often misdiagnosed as psychosis. Here we report a case of insulinoma masquerading as hysteria, whose final diagnosis could be made using high-dose calcium stimulation test. A 28-yr-old woman was referred presenting with substupor, mutism, mannerism, restlessness, and incoherence. Laboratory examinations revealed hypoglycemia (33 mg/dL) and detectable insulin levels (9.7 microU/mL), suggesting the diagnosis of insulinoma. However, neither imaging studies nor selective arterial calcium injection (SACI) test with a conventional dose of calcium (0.025 mEq/kg) indicated the tumor. High-dose calcium injection (0.05 mEq/kg) evoked insulin secretion when injected into superior mesenteric artery. A solitary tumor in the head of the pancreas was resected, and her plasma glucose returned to normal. Postoperatively, iv injection of secretin resulted in a normal response of insulin, which was not found preoperatively. This case suggests the usefulness of the SACI test with high-dose of calcium in the case of insulinoma when the standard dose fails to detect such a tumor.