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

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‐ sulin secretion in a glucose-dependent manner. Due to their dependence on ambient glucose for action, they are emerging as important new therapeutic agents to promote insulin secretion without accompanying hypoglycemia (a common complication of sulfonylurea treatment).

type 1 diabetes requires beta-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. Therefore, beta-cell replacement, regeneration and proliferation emerge as a new research focus on therapy for type 1 diabetes; however, its application is limited by the shortage of pancreas donors. In-vitro expansion of human cadaveric islet beta cells represents an attractive strategy for generation of abundant beta-like cells. Human beta cells patent a very low proliferation capacity in vivo, and intact isolated islets cultured in suspension do not proliferate, although they remain functional for months. When islets are allowed to attach, limited replication of beta cells can be induced by growth factors or ex‐ tracellular matrix components before the beta-cell phenotype is lost. Previous accepting of the determinants of tissue mass during adult life is still rudimentary. Insights into this prob‐ lem may suggest novel approaches for the treatment of neoplastic as well as degenerative diseases. In the case of the pancreas, elucidating the mechanisms that govern β cell mass will be important for the design of regenerative therapy for both type 1 and type 2 diabetes, diseases characterized by an insufficient mass of β cells. It is clear that β cell mass increase during pregnancy and in insulin-resistant states, but evidence on the ability of β cells to re‐ generate from a severe, diabetogenic injury is conflicting. Whereas autoimmune diabetes is normally irreversible, recent evidence from both humans and rodents suggests that β cell function (i.e., insulin production and the maintenance of glucose homeostasis) can partly re‐

Beta-Cell Function and Failure http://dx.doi.org/10.5772/52153 121

Islet beta-cell regeneration and development are controlled by many growth factors, espe‐ cially insulin-like growth factor-1 (IGF-1). Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on β-cells. Igf1 has been shown to influence β-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2. Some study showed that IGF-1 can protect beta-cells from the destruction of apoptosis factors and promoting beta-cell survival and proliferation. Interleukin-1beta (IL-1 beta) is a potent pro-inflammatory cytokine that has been shown to inhibit islet beta cell function as well as to activate Fas-mediated apoptosis in a nitric oxide-dependent manner. Furthermore, this cytokine is effective in recruiting lymphocytes that mediate beta cell de‐ struction in type one diabetes. IGF-I has been shown to block IL-1beta actions in vitro.

Glucagon like peptide 1 (GLP-1) is a potent insulin secretagogue released by L-cells of the distal large intestine in response to meal ingestion and, together with glucose-dependent in‐ sulinotropic polypeptide (GIP), account for 90% of the incretin effect. Type 2 diabetic pa‐ tients are characterized by severely impaired β-cell function, reduced plasma GLP-1 response to meal/glucose ingestion that correlates with reduced insulin secretion, and severe β-cell resistance to the stimulatory effect of GLP-1 on insulin secretion. GLP-1 also inhibits glucagon secretion, delays gastric emptying, and promotes weight loss by its appetite-sup‐ pressant effect. GLP-1 analogs also stimulate islet neogenesis and β-cell replication and in‐ hibit islet apoptosis. The gluco-incretin hormones GLP-1 and GIP can protect beta-cell against apoptosis induced by cytokines or glucose and free fatty acids. Both hormones bind to specific Gs-coupled receptors, which trigger cAMPformation. In beta-cells, basal cAMP levels controls glucose competence, i.e., the magnitude of the insulin secretion response to a given increase in extracellular glucose concentration. Increases in cAMP levels, for instance

cover if autoimmunity is blocked.

Unlike sulfonylureas, incretins act by activating Gs (a G-protein that activates adenylyl cy‐ clase) to increase cAMP in beta cells. cAmp, like ATP, is an important signal that regulates insulin release. Typically, the main mechanism of action of cAMP is by activation of an en‐ zyme called protein kinase A (PKA) that, in turn, phosphorylates other substrates to turn on (or off) vital cell functions. Using a biochemical assay called the yeast hybrid screening method to identify and isolate new proteins, some researchers identified a novel protein, cAMP-GEF II, a cAMP sensor (cAMPS) that forms a complex with other intracellular pro‐ teins (Rim2 and Rab3) to directly regulate insulin exocytosis. Then, using molecular reagents that antagonize the effects of cAMPS, they observed that incretin-potentiated insulin secre‐ tion is attenuated. These results provide a mechanism whereby cAMP can directly promote exocytosis of insulin granules without activation of PKA (ie, a PKA-independent pathway), and thereby provide additional molecular targets for therapeutic intervention.
