Retinoic acid receptor signaling is required to maintain glucose‐stimulated insulin secretion and β‐cell mass

Abstract

Retinoic acid signaling is required for maintaining a range of cellular processes, including cell differentiation, proliferation, and apoptosis. We investigated the actions of all-trans-retinoic acid (atRA) signaling in pancreatic b-cells of adult mice. atRA signaling was ablated in b-cells by overexpressing a dominant-negative retinoic acid receptor (RAR)-a mutant (RARdn) using an inducible Cre-Lox system under the control of the pancreas duodenal homeobox gene promoter. Our studies establish that hypomorphism for RAR in b-cells leads to an age-dependent decrease in plasma insulin in the fed state and in response to a glucose challenge. Glucose-stimulated insulin secretion was also impaired in islets isolated from mice expressing RARdn. Among genes that are atRA responsive, Glut2 and Gck mRNA levels were decreased in isolated islets from RARdn-expressing mice. Histologic analyses of RARdn-expressing pancreata revealed a decrease in b-cell mass and insulin per b-cell 1 mo after induction of the RARdn. Our results indicate that atRA signaling mediated by RARs is required in the adult pancreas for maintaining both b-cell function and mass, and provide insights into molecular mechanisms underlying these actions.-Brun, P.-J., Grijalva, A., Rausch, R., Watson, E., Yuen, J. J., Das, B. C., Shudo, K., Kagechika, H., Leibel, R. L., Blaner, W. S. Retinoic acid receptor signaling is required to maintain glucose-stimulated insulin secretion and b-cell mass. FASEB J. 29, 671-683 (2015). www.fasebj.orgHUMANS AND OTHER VERTEBRATES must acquire retinoids (vitamin A and its metabolites) from the diet in order to maintain normal health (1). Retinoids regulate many cellular processes including cellular proliferation, differentiation, and apoptosis, and hence, they have roles in many essential physiologic processes including the maintenance of immunity, reproduction, and embryonic development (2, 3). These essential actions are thought to be mediated primarily by the all-trans-retinoic acid (atRA) and 9-cis-retinoic acid (9cRA), which regulate transcription by serving as ligands for nuclear hormone receptors (4, 5). atRA serves as the natural ligand for the 3 retinoic acid receptors (RARs; a, b, and g); whereas 9cRA is proposed to be a natural ligand for the 3 retinoid X receptors (RXRs; a, b, and g) (6). Over 500 genes are reported to be responsive to either atRA or 9cRA (7).An extensive literature supports a role for retinoids in the maintenance of pancreatic endocrine functions (8-18). Pancreatic islets express genes encoding retinoland retinoic acid-binding proteins, as well as RARs and RXRs (14,19,20). Isolated pancreatic islets from rats fed a vitamin A-deficient diet display a markedly diminished capacity to secrete insulin in response to a glucose challenge (10). This phenotype was reversed by administering either retinyl ester or atRA to the rats prior to islet isolation. Two recent reports have identified a function for 9cRA and RXR signaling in the regulation of insulin secretion. Using an inducible dominant-ne...

Vitamin A: a missing link in diabetes?

“…Studies from our laboratory are in agreement with others that vitamin A can favorably regulate metabolic pathways central to the pathogenesis of T2D, such as pancreatic β-cell mass and function[36,37], obesity[38] and lipid metabolism[39]. Therefore it is our opinion that further research is warranted to determine if compromised vitamin A status may negatively affect these pathways and increase risk for the development of T2D.…”

“…Taken together, data from Trasino et al [36], point to a major role of vitamin A in maintaining β-cell numbers and β-cell functions in the adult pancreas. Consistent with this, Brun et al [37], demonstrated that pancreatic vitamin A signaling through RA receptors is essential for maintaining normoglycemia, β-cell mass and insulin secretion in mice[37]. Interestingly, VAD had no effect on peripheral insulin sensitivity[36], a critical pathological feature of early T2D, but instead VAD recapitulated some of the pancreatic endocrine profiles of individuals with advanced T2D and some features of T1D (e.g., marked β-cell apoptosis and increased presence of glucagon producing α cells)[64,65].…”

“…However, there is increasing consensus that diabetes compromises immune responses and increases risk for TB[73,75]. If the latter is true, there still remains a rationale to determine the vitamin A status and the effects of oral vitamin A therapy in populations with diabetes-associated TB, given the compelling evidence of a role of vitamin A in glycemic control and diabetes[36–37,44]. …”

Actions of β-apo-carotenoids in differentiating cells: Differential effects in P19 cells and 3T3-L1 adipocytes

“…P19 cells failed to respond to treatment with either β-apo-13-carotenone or β-apo-14′-carotenal. It should be noted that LE 540, which is reported in the literature to be a very potent RAR antagonist (34), including in cultured cells (43), also did not have a large effect on all- trans -retinoic acid-induced P19 cell differentiation either. We take our data collectively to indicate that the P19 cell model is not amenable for investigating β-apo-carotenoid antagonism of RAR signaling.…”

Molecular and genetic regulation of pig pancreatic islet cell development

“…Additionally, we found significant enrichment of band a-cell gene sets involved in specific developmental signaling pathways. However only a subset of these pathways, like mTOR, retinoic acid receptor, glutamate receptor and TGF-b signaling, have been previously linked to b-and a-cell biology [72][73][74][75] The cost basis of pancreas procurement and islet isolation from pigs is currently lower than for humans. In 2019, reimbursement for a single human cadaveric donor pancreas is between $4,500 and $7,000 (US dollars).…”