Targeting β-cell cyclic 3′5′adenosine monophosphate for the development of novel drugs for treating type 2 diabetes mellitus. A review

Abstract

Cyclic 3'5'AMP is an important physiological amplifier of glucose-induced insulin secretion by the pancreatic islet -cell, where it is formed by the activity of adenylyl cyclase, especially in response to the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). These hormones are secreted from the small intestine during and following a meal, and are important in producing a full insulin secretory response to nutrient stimuli. Cyclic AMP influences many steps involved in glucose-induced insulin secretion and may be important in regulating pancreatic islet -cell differentiation, growth and survival. Cyclic AMP (cAMP) itself is rapidly degraded in the pancreatic islet -cell by cyclic nucleotide phosphodiesterase (PDE) enzymes. This review discusses the possibility of targeting cAMP mechanisms in the treatment of type 2 diabetes mellitus, in which insulin release in response to glucose is impaired. This could be achieved by the use of GLP-1 or GIP to elevate cAMP in the pancreatic islet -cell. However, these peptides are normally rapidly degraded by dipeptidyl peptidase IV (DPP IV). Thus longer-acting analogues of GLP-1 and GIP, resistant to enzymic degradation, and orally active inhibitors of DPP IV have also been developed, and these agents were found to improve metabolic control in experimentally diabetic animals and in patients with type 2 diabetes. The use of selective inhibitors of type 3 phosphodiesterase (PDE3B), which is probably the important pancreatic islet -cell PDE isoform, would require their targeting to the islet -cell, because inhibition of PDE3B in adipocytes and hepatocytes would induce insulin resistance.

cAMP-mediated signaling normalizes glucose-stimulated insulin secretion in uncoupling protein-2 overexpressing β-cells

“…In neonatal streptozotocin diabetic rats, agents that induce b-cell cAMP also enhance GSIS, although not to control levels (Dachicourt et al 1996). Our data, together with other published reports, support the development of new treatment modalities for type-2 diabetes mellitus that target cAMP, such as long-acting stimulants of cAMP production or phosphodiesterase inhibitors (Furman et al 2004). However, caution against chronic amplification of cAMP-mediated effects is warranted in light of the upregulation of ucp2 mRNA observed in this study and the accompanying exaggerated basal insulin secretion.…”

A-kinase anchoring proteins take shape

“…Several of these processes contribute to various disease states. PKA is implicated in pancreatic β-cell function and may provide a novel means for combating diabetes [49]. PKA is also important in the molecular mechanisms of learning and memory, making it an attractive target for therapies seeking to inhibit cognitive decline resulting from neurodegenerative diseases [50,51].…”

cAMP Mediators of Pulsatile Insulin Secretion from Glucose-stimulated Single β-Cells

“…Glucose induces oscillations of [Ca 2ϩ ] i in ␤-cells (7), and these oscillations seem to underlie pulsatile release of insulin from isolated islets (8,9) and individual ␤-cells (10 -12). Ca 2ϩ -triggered exocytosis is potently amplified by cAMP (13), and this messenger has long been known to mediate the insulinotropic action of glucagon and the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (13)(14)(15). In contrast, the role of cAMP in glucoseinduced insulin secretion has been uncertain.…”