The Atrial Natriuretic Peptide and Guanylyl Cyclase-A System Modulates Pancreatic β-Cell Function

Abstract

Atrial natriuretic peptide (ANP) and its guanylyl cyclase-A (GC-A) receptor are being involved in metabolism, although their role in the endocrine pancreas is still greatly unknown. The aim of this work is to study a possible role for the ANP/GC-A system in modulating pancreatic beta-cell function. The results presented here show a direct effect of the GC-A receptor in regulating glucose-stimulated insulin secretion (GSIS) and beta-cell mass. GC-A activation by its natural ligand, ANP, rapidly blocked ATP-dependent potassium (K(ATP)) channel activity, increased glucose-elicited Ca(2+) signals, and enhanced GSIS in islets of Langerhans. The effect in GSIS was inhibited in islets from GC-A knockout (KO) mice. Pancreatic islets from GC-A KO mice responded to increasing glucose concentrations with enhanced insulin secretion compared with wild type (WT). Remarkably, islets from GC-A KO mice were smaller, presented lower beta-cell mass and decreased insulin content. However, glucose-induced Ca(2+) response was more vigorous in GC-A KO islets, and basal K(ATP) channel activity in GC-A KO beta-cells was greatly diminished compared with WT. When protein levels of the two K(ATP) channel constitutive subunits sulfonylurea receptor 1 and Inward rectifier potassium channel 6.2 were measured, both were diminished in GC-A KO islets. These alterations on beta-cell function were not associated with disruption of glucose tolerance or insulin sensitivity in vivo. Glucose and insulin tolerance tests were similar in WT and GC-A KO mice. Our data suggest that the ANP/GC-A system may have a modulating effect on beta-cell function.

Long-term treatment with atrial natriuretic peptide inhibits ATP production and insulin secretion in rat pancreatic islets

“…In NPR-A knockout mice, there was increased glucosestimulated islet insulin secretion (39), supporting the conclusion that ANP receptors exert an inhibitory effect on insulin secretion. Since islet total insulin storage levels after 7-day ANP treatment were normal, insulin storage does not account for reduced secretion.…”

“…ANP was reported to inhibit glucose-stimulated intracellular phase 0 [Ca 2ϩ ] changes that regulate insulin secretion in rat islet ␤-cells (25) and to inhibit insulin secretion in rats and mice (1) and glucagon secretion in isolated rat pancreatic islets (52). There are also reports of a lack of effect of ANP on insulin secretion (51) or of a stimulatory effect (39,50). The aforementioned in vitro studies were short term (hours) and did not fully elucidate the cellular mechanisms of ANP action on insulin secretion.…”

“…The aforementioned in vitro studies were short term (hours) and did not fully elucidate the cellular mechanisms of ANP action on insulin secretion. In guanylyl cyclase A receptor knockout mice, insulin secretion in response to glucose stimulation was enhanced (39). In long-term in vitro studies (up to 7 days) ANP has been reported to promote rat islet ␤-cell Ser-Thr kinase Akt/PKB, FoxO1a and cyclin D2 signaling, and cell growth by a process mediated by phosphatidylinositol 3=-kinase (PI3K) activation (59).…”

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…When studied in a mouse model, ANP was found to block ATP‐dependent potassium channel activity in pancreatic β‐cells, to increase glucose‐elicited calcium signaling and enhance glucose‐stimulated insulin secretion in islets of Langerhans 97. It should be noted, however, that long‐term exposure to ANP may inhibit glucose‐stimulated insulin secretion from isolated islets, which is accompanied with reduced ATP generation in β‐cells in response to glucose 98…”

Involvement of guanylin and GC-C in rat mesenteric macrophages in resistance to a high-fat diet

“…Guanylin and uroguanylin were identifi ed in the gastrointestinal tract as endogenous ligands for GC-C ( 11-16 ) and have since been thought to help maintain fl uid and salt homeostasis in a paracrine manner. GCs or their ligands, or both cascades, have recently been shown to contribute to energy metabolism ( 20,(35)(36)(37)(38). When fed an HFD, rats transgenic for BNP are protected from obesity and insulin resistance, and GC-A knockout mice have diet-induced obesity and glucose intolerance ( 20 ).…”