**3. Mechanisms of insulin secretion from beta cells**

The secretion of insulin from pancreatic beta cells is a complex process involving the inte‐ gration and interaction of multiple external and internal stimuli. Thus, nutrients, hormones, neurotransmitters, and drugs all activate or inhibit insulin secretion. The primary stimulus for insulin release is the beta-cell response to changes in glucose concentration. Normally, glucose induces a biphasic pattern of insulin release. First-phase insulin release occurs with‐ in the first few minutes after exposure to an elevated glucose level; this is followed by a more permanent second phase of insulin release. Of particular importance is the observation that first-phase insulin secretion is lost in patients with type 2 diabetes. Thus, molecular mechanisms involved in phasic insulin secretion are important. This processes discussed as follow (fig 2).

**Figure 2.** The beta cell structure

Insulin is a hormone that controls the blood glucose concentration. The liver maintains the base-line glucose level, but the beta cells can respond quickly to spikes in blood glucose by releasing some of its stored insulin while simultaneously producing more. The response

**Figure 1** Mouse pancreatic islet as seen by light microscopy. Beta cells can be recognized by the green insulin staining.

Apart from insulin, beta cells release C-peptide, a consequence of insulin production, into the bloodstream in equimolar amounts. C-peptide helps to prevent neuropathy and other symptoms of diabetes related to vascular deterioration.Measuring the levels of C-peptide

Beta-cells also produce amylin, also known as IAPP, islet amyloid polypeptide. Amylin functions as part of the endocrine pancreas and contributes to glycemic control. Amylin's metabolic function is now somewhat well characterized as an inhibitor of the appearance of nutrient [especially glucose] in the plasma. Thus, it functions as a synergistic partner to in‐ sulin. Whereas insulin regulates long-term food intake, increased amylin decreases food in‐

GABA (γ amino butyric acid) is produced by pancreatic beta cell. GABA released from beta cells can act on GABA Areceptor in the α cells, causing membrane hyperpolarization and hence suppressing glucagon secretion. An impaired insulin-Akt-GABAA receptors glucagon secretory pathway in the islet may be an underlying mechanism for unsuppressed glucagon secretion, despite hyperglycemia, in diabetic subjects. Some studies demonstrated that beta cells also express GABA A receptors, forming an autocrine GABA signaling system. Howev‐ er, the role of this autocrine GABA signaling in the regulation of beta cell functions remains

Zinc is needed by over 300 enzyme systems.Some of those are involved with the metabolism of blood sugar and are so important that a lack of zinc, in and of itself, can cause type I or

Zinc is highly concentrated in the insulin-secreting beta cells of our pancreas. Zinc can keep in‐ sulin molecules together in the beta cells.Beta cells must have zinc to function. In fact, beta cells

time is very quick.

116 Type 1 Diabetes

Glucagon is labeled in red and the nuclei in blue

take in the short term.

largely unknown.

type II diabetes.

can give a practitioner an idea of the viable beta cell mass.

A widely accepted sequence of events involved in glucose-induced insulin secretion is as follows:

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

(membrane depolarization). Thus, like neurons, beta cells are electrically excitable and capa‐ ble of generating Ca2+ action potentials that are important in synchronizing islet cell activity and insulin release. In addition to being signal targets for glucose, KATP channels are the targets for sulfonylureas, which are commonly prescribed oral agents in the treatment of type 2 diabetes. The sulfonylureas, like glucose, induce closure of KATP channels and stim‐

Beta-Cell Function and Failure http://dx.doi.org/10.5772/52153 119

The beta-cell KATP channel is a complex octameric unit of 2 different proteins: the sulfony‐ lurea receptor (SUR-1) and an inward rectifier (Kir6.2). The sulfonylurea receptor belongs to a superfamily of ATP-binding cassette proteins and contains the binding site for sulfonylur‐ ea drugs and nucleotides. The inward rectifier represents the K+ conducting pore and is also regulated by ATP. It is interesting that KATP channels are present in other tissues of the body, including heart (SUR-2A/Kir 6.2), smooth muscle (SUR-2B/Kir 6.2), and brain (SUR-1/Kir 6.2). Recently, Mark L. Evans, MD, Yale University Medical School, New Haven, Connecticut, and colleagues have suggested that glucose sensing in the brain during hypo‐ glycemia may be mediated by KATP channels located in brain hypothalamic neurons. Thus, these molecules may also serve as new therapeutic targets for the restoration of impaired

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+

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 incretins are another set of factors that are important hormonal regulators of insulin secre‐ tion. The incretins are polypeptide hormones released in the gut after a meal that potentiate in‐

hypoglycemia awareness and glucose counterregulation in type 1 diabetes.

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

increases and C-peptide secretion in an insulin-secreting cell line.

**6. Novel cAMP signaling pathways of insulin release**

the disease etiology of type 2 diabetes.

ulate insulin secretion.


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 evoking PKA-mediated Ca2+ influx.
