β Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice

• Published in: Cardiovascular diabetology Vol. 17; no. 1; p. 103
• Main Authors: Tauscher, Sabine, Nakagawa, Hitoshi, Völker, Katharina, Werner, Franziska, Krebes, Lisa, Potapenko, Tamara, Doose, Sören, Birkenfeld, Andreas L, Baba, Hideo A, Kuhn, Michaela
• Format: Journal Article
• Language: English
• Published: England BioMed Central 17-07-2018; BMC
• Subjects: Animals; Atrial Natriuretic Factor - metabolism; Atrial natriuretic peptide; Blood Glucose - metabolism; Blood pressure; Cell morphology; Cell Proliferation; Cell size; Clonal deletion; Complications; Cyclic GMP; Cytology; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Disease Models, Animal; Disease Progression; Energy metabolism; Gene Deletion; Genetic Predisposition to Disease; Glucose; Glucose Intolerance - enzymology; Glucose Intolerance - etiology; Glucose Intolerance - genetics; Glucose Intolerance - pathology; Glucose tolerance; Guanylate cyclase; Guanylyl cyclase-A; Heart; High fat diet; Homeostasis; Immunofluorescence; Inactivation; Insulin; Insulin - blood; Insulin resistance; Insulin secretion; Insulin-Secreting Cells - enzymology; Insulin-Secreting Cells - pathology; Intolerance; Islets of Langerhans; Kinases; Mice; Mice, Knockout; Morphometry; Natriuretic Peptide, Brain - metabolism; Natriuretic peptides; Obesity; Obesity - complications; Obesity - enzymology; Obesity - genetics; Original Investigation; Pancreas; Peptides; Phenotype; Physiology; Receptors, Atrial Natriuretic Factor - deficiency; Receptors, Atrial Natriuretic Factor - genetics; Rodents; Secretion; Sensitivity; Signal Transduction; Tissue Culture Techniques; β-Cells; Obesity; Insulin; Cyclic GMP; β-Cells; Guanylyl cyclase-A; Natriuretic peptides
• DOI: 10.1186/s12933-018-0747-3
• EISSN: 1475-2840

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 β-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 β-cells under (patho)physiological conditions in vivo, here we generated a novel genetic mouse model with selective disruption of the GC-A receptor in β-cells.
Mice with a floxed GC-A gene were bred to Rip-Cre
mice, thereby deleting GC-A selectively in β-cells (β 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. β-cell size and number were measured by immunofluorescence-based islet morphometry.
In vitro, the insulinotropic and proliferative actions of ANP were abolished in islets isolated from β 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 β GC-A KO mice, corroborating the efficient inactivation of the GC-A receptor in β-cells. Despite this under physiological, ND conditions, fasted and fed insulin levels, glucose-induced insulin secretion, glucose tolerance and β-cell morphology were similar in β GC-A KO mice and control littermates. However, HFD-fed β GC-A KO animals had accelerated glucose intolerance and diminished adaptative β-cell proliferation.
Our studies of β GC-A KO mice demonstrate that the cardiac hormones ANP and BNP do not modulate β-cell's growth and secretory functions under physiological, normal dietary conditions. However, endogenous NP/GC-A signaling improves the initial adaptative response of β-cells to HFD-induced obesity. Impaired β-cell NP/GC-A signaling in obese individuals might contribute to the development of type 2 diabetes.