Modulation of hypovitaminosis D-induced islet dysfunction and insulin resistance through direct suppression of the pancreatic islet renin–angiotensin system in mice

Abstract

Aims/hypothesis Vitamin D is necessary for normal insulin action and suppresses renin production. Increased renin-angiotensin system (RAS) activity causes islet damage, including reduced insulin secretion. We therefore sought to determine whether hypovitaminosis D-induced upregulation of islet RAS in vivo impairs islet cell function and increases insulin resistance, and whether pharmacological suppression of the RAS during continuing vitamin D deficiency might correct this. Methods C57BL/6 mice were rendered vitamin D-deficient by diet, and glucose and insulin tolerance was assessed. The expression and translation of islet functional, and islet RAS, genes were measured and the effects of pharmacological renin suppression examined. Results Mice with diet-induced hypovitaminosis D developed impaired glucose tolerance, increased RAS component expression and impaired islet function gene transcription. Treatment with pharmacological renin inhibition (aliskiren), without vitamin D status correction, reduced islet RAS overreactivity, islet dysfunction and insulin resistance, and improved glucose tolerance. Conclusions/interpretation Upregulation of islet RAS genes can contribute to hypovitaminosis D-induced impairment of islet function and increase insulin resistance independently of vitamin D status. Thus, our findings support the use of RAS inhibitors in impaired glucose homeostasis or early diabetes. They also suggest that combining RAS inhibition with correction of hypovitaminosis D might be useful in treating impaired glycaemic control and also in type 2 diabetes prevention. However, the use of aliskiren in established diabetes is contraindicated due to the increased risk of side effects such as hyperkalaemia, so other more suitable RAS blockers need to be identified.

Ultraviolet radiation, vitamin D and the development of obesity, metabolic syndrome and type-2 diabetes

“…IU/kg). 13 This contrary result could be explained by a differing capacity of female mice 13 to respond to dietary vitamin D (as compared to the results obtained using male mice described above 11,12 In other studies, we observed no significant effect of lower doses of dietary vitamin [33][34][35] with the VDR -/-mice also exhibiting reduced fasting glucose and insulin levels. 33 The VDR may also be important for mediating the progression of non-alcoholic fatty liver disease (NAFLD) and insulin resistance as reduced hepatic steatosis and triglyceride levels were observed in apoE -/-VDR -/-mice fed a high fat diet.…”

A prospective randomized controlled trial of the effects of vitamin D supplementation on long-term glycemic control in type 2 diabetes mellitus of Korea

“…[12] and insulin action [13,14], as well as components of inflammation [34,35] and all of these may have an influence on insulin resistance (IR) and development of T2DM. Vitamin D may modulate the local pancreatic islet renin-angiotensin system (RAS) whilst improving islet beta cell secretory function and prevents or can correct induction of RAS component production under conditions of metabolic stress in vitro studies [36,37].…”

No Effect of High-Dose Vitamin D Supplementation on Glycemic Status or Cardiovascular Risk Factors in Subjects With Prediabetes

“…§ §Data missing for 10 subjects. (32). Upon renin-angiotensin system inhibition, the islets' function improved in mice with diabetes, thus leading to a hypothesis that vitamin D supplementation might improve islet cell function before too much damage occurs in the islet cells (32).…”