Involvement of cAMP/EPAC/TRPM2 Activation in Glucose- and Incretin-Induced Insulin Secretion

Abstract

In pancreatic b-cells, closure of the ATP-sensitive K + (K ATP ) channel is an initial process triggering glucosestimulated insulin secretion. In addition, constitutive opening of background nonselective cation channels (NSCCs) is essentially required to effectively evoke depolarization as a consequence of K ATP channel closure. Thus, it is hypothesized that further opening of NSCC facilitates membrane excitability. We identified a class of NSCC that was activated by exendin (ex)-4, GLP-1, and its analog liraglutide at picomolar levels. This NSCC was also activated by increasing the glucose concentration. NSCC activation by glucose and GLP-1 was a consequence of the activated cAMP/EPAC-mediated pathway and was attenuated in TRPM2-deficient mice. The NSCC was not activated by protein kinase A (PKA) activators and was activated by ex-4 in the presence of PKA inhibitors. These results suggest that glucose-and incretinactivated NSCC (TRPM2) works in concert with closure of the K ATP channel to effectively induce membrane depolarization to initiate insulin secretion. The current study reveals a new mechanism for regulating electrical excitability in b-cells and for mediating the action of glucose and incretin to evoke insulin secretion, thereby providing an innovative target for the treatment of type 2 diabetes.It has been long proposed that glucose-stimulated insulin secretion in pancreatic b-cells is initiated by closure of the ATP-sensitive K + (K ATP ) channel, followed by membrane depolarization (1). In theory, closure of the K ATP channel is an important process but is not sufficient to induce the shift of the membrane potential toward a threshold level, as membrane potential is determined by the overall balance of outward and inward currents. Modest constitutive opening of background inward current through nonselective cation channels (NSCCs) is crucial to facilitate depolarization after K ATP channel closure (2). This idea suggests that further regulated opening of a class of NSCCs may bring about greater depolarization. However, whether glucose metabolism regulates NSCC activity remains unclear.The incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), potentiate insulin secretion in association with increased intracellular Ca 2+ concentrations at insulin-secreting glucose concentrations (3-5). GLP-1 fails to increase insulin secretion from the islets of mice deficient in transmembrane receptor potential (TRP) melastatin 2 (TRPM2) (6,7), a type of NSCC, suggesting that the TRPM2 channel is essential for GLP-1-induced potentiation of glucose-stimulated insulin secretion (8). GLP-1 depolarizes the plasma membrane by the opening of NSCC in b-cells (2). Several types of NSCC (TRPs) are expressed in insulin-secreting cells (9). The aims of the current study were to determine 1) the type of NSCC activation (through TRPM2 or other TRPs) that is crucial for signaling after stimulation of the incretin receptor, 2) whether the NSCC is modulated by glucose

Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus

“…The pancreas plays a central role in modulating blood glucose levels [6–9]. Pancreatic β cells produce insulin, which decreases blood glucose levels, and pancreatic α cells produce glucagon, which increases blood glucose levels [6–9].…”

“…Pancreatic β cells produce insulin, which decreases blood glucose levels, and pancreatic α cells produce glucagon, which increases blood glucose levels [6–9]. Many gene therapies with delivery systems using nano-sized carriers have targeted the pancreas in attempts to modulate blood glucose levels for the treatment of diabetes mellitus.…”

“…Intestinal L cells secrete glucagon-like peptide-1 (GLP-1), which enhances insulin secretion from β cells and decreases glucagon secretion from α cells in the pancreas [6–9]. …”

“…GLP-1 is an incretin hormone that contributes to insulin secretion from β cells and decreases glucagon secretion from α cells of the pancreas [6–9]. GLP-1 is secreted from intestinal L cells in response to glucose and fatty acids [6–9].…”

“…GLP-1 is secreted from intestinal L cells in response to glucose and fatty acids [6–9]. Numerous studies have reported on the efficacy of GLP-1 transgene delivery to the intestines with viral vectors in animal models of diabetes mellitus in vivo .…”