**5. Voltage-dependent Ca2+ channels: Novel regulators**

**1.** Glucose is transported into beta cells through facilitated diffusion of GLUT2 glucose

**3.** Elevation in the ATP/ADP ratio induces closure of cell-surface ATP-sensitive K+

**4.** Cell-surface voltage-dependent Ca2+ channels (VDCC) are opened, facilitating extracel‐

It is understood that glucose stimulates insulin secretion in the pancreatic beta cell by means of a synergistic interaction between at least two signaling pathways. In the K (ATP) channel-de‐ pendent pathway, glucose stimulation increases the entry of extrinsic Ca2+ through voltagegated channels by closure of the K (ATP) channels and depolarization of the beta cell membrane. The resulting increase in intracellular Ca2+ stimulates insulin exocytosis. While in the GTP-dependent pathway, intracellular Ca2+ is elevated by GTP-dependent proteins and augments the Ca2+-stimulated release. Secretagogues and insulin secretion inhibitors act at in‐ termediate steps of these signaling pathways and influence the process of insulin exocytosis. Several researchers have investigated this intricate mode of known secretagogue action using isolated islets as an *in vitro* model. To quote a few; imidazoline antagonists of alpha 2-adrenore‐ ceptors increase insulin release *in vitro* by inhibiting ATP-sensitive K+ channels in pancreatic beta cells. Some researchers have evaluated the properties of sulphonylurea receptors (SUR) of human islets of Langerhans. They studied the binding affinity of various oral hypoglycaemic agents to the receptor and also tested insulinotropic action of the drugs on intact human islets. This binding potency order was parallel with the insulinotropic potency of the evaluated com‐ pounds. Some investigators have shown an insulinotropic effect of Triglitazone (CS-045) and have shown its mode of action to be distinct from glibenclamide (a sulphonylurea drug). A-4166, a derivative of D-phenylalanine, evokes a rapid and short-lived hypoglycaemic action *in vivo*. It has been shown to act via the tolbutamide binding sites14. Some studies showed S21403, a meglitinide analogue to be a novel insulinotropic tool in the treatment of type 2 diabe‐ tes, as it affected cationic fluxes and the drugs secretary responses displayed favourable time course of prompt, and not unduly prolonged, activation of beta cells. Some studies demon‐ strated that tetracaine (an anaesthetic) stimulates insulin secretion by release of intracellular calcium and for the first time elucidated the role of intracellular calcium stores in stimulus-se‐ cretion coupling in the pancreatic beta cells. JTT-608, is a nonsulphonylurea oral hypoglycae‐ mic agent which stimulates insulin release at elevated but not low glucose concentrations by

The KATP channels play an integral role in glucose-stimulated insulin secretion by serving as the transducer of a glucose-generated metabolic signal (ie, ATP) to cell electrical activity

transporters.

118 Type 1 Diabetes

**2.** Intracellular glucose is metabolized to ATP.

lular Ca2+ influx into the beta cell.

evoking PKA-mediated Ca2+ influx.

**4. The importance of KATP channels**

(KATP) channels, leading to cell membrane depolarization.

**5.** A rise in free cytosolic Ca2+ triggers the exocytosis of insulin.

Extracellular Ca2+ influx through L-type voltage-dependent Ca2+ channels (VDCC) raises free cytoplasmic Ca2+ levels and triggers insulin secretion. The structure of the VDCC is complex and consists of 5 subunits: alpha1, alpha2, beta, gamma, and delta units. The alpha subunit constitutes the ion-conducting pore, whereas the other units serve a regulatory role. Previous work has identified that isoforms of alpha1 subunits interact with exocytotic pro‐ teins. More recently, using the yeast hybrid screening method, a novel protein, Kir-GEM, in‐ teracting with the beta3 isoform of the VDCC, has been identified by Seino and colleagues. Furthermore, it has been determined that Kir-GEM inhibits alpha ionic activity and prevents cell-surface expression of alpha subunits. The investigators have proposed that in the pres‐ ence of Ca2+, Kir-GEM binds to the beta isoform, and this interaction interferes in the traf‐ ficking or translocation of alpha subunits to the plasma membrane. The relevance of Kir-GEM in insulin secretion was made evident by its attenuation of glucose-stimulated Ca2+ increases and C-peptide secretion in an insulin-secreting cell line.

The potential therapeutic role of Kir-GEM lies in the inhibitory effects on VDCC activity that may serve to protect beta cells from overstimulation and subsequent failure, which is part of the disease etiology of type 2 diabetes.
