| First Author | Tauscher S | Year | 2018 |
| Journal | Cardiovasc Diabetol | Volume | 17 |
| Issue | 1 | Pages | 103 |
| PubMed ID | 30016962 | Mgi Jnum | J:289235 |
| Mgi Id | MGI:6434701 | Doi | 10.1186/s12933-018-0747-3 |
| Citation | Tauscher S, et al. (2018) beta Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice. Cardiovasc Diabetol 17(1):103 |
| abstractText | BACKGROUND: The cardiac hormones atrial (ANP) and B-type natriuretic peptides (BNP) moderate arterial blood pressure and improve energy metabolism as well as insulin sensitivity via their shared cGMP-producing guanylyl cyclase-A (GC-A) receptor. Obesity is associated with impaired NP/GC-A/cGMP signaling, which possibly contributes to the development of type 2 diabetes and its cardiometabolic complications. In vitro, synthetic ANP, via GC-A, stimulates glucose-dependent insulin release from cultured pancreatic islets and beta-cell proliferation. However, the relevance for systemic glucose homeostasis in vivo is not known. To dissect whether the endogenous cardiac hormones modulate the secretory function and/or proliferation of beta-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in beta-cells. METHODS: Mice with a floxed GC-A gene were bred to Rip-Cre(TG) mice, thereby deleting GC-A selectively in beta-cells (beta GC-A KO). Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion were monitored in normal diet (ND)- and high-fat diet (HFD)-fed mice. beta-cell size and number were measured by immunofluorescence-based islet morphometry. RESULTS: In vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from beta GC-A KO mice. Concordantly, in vivo, infusion of BNP mildly enhanced baseline plasma insulin levels and glucose-induced insulin secretion in control mice. This effect of exogenous BNP was abolished in beta GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in beta-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and beta-cell morphology were similar in beta GC-A KO mice and control littermates. However, HFD-fed beta GC-A KO animals had accelerated glucose intolerance and diminished adaptative beta-cell proliferation. CONCLUSIONS: Our studies of beta GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate beta-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of beta-cells to HFD-induced obesity. Impaired beta-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes. |
