Vitamin D and diabetes

Abstract

There has been increasing evidence that vitamin D may have a role in modifying risk of diabetes. Vitamin D has both direct and indirect effects on various mechanisms related to the pathophysiology of type 2 diabetes, including pancreatic beta cell dysfunction, impaired insulin action and systemic inflammation. This article describes the biologic plausibility behind the potential association between vitamin D and type 2 diabetes and summarizes the current evidence from human studies that suggests but does not prove a relation between vitamin D and type 2 diabetes, and briefly reports on the potential association between vitamin D and type 1 diabetes.

Keywords: 25-hydroxyvitamin D; Insulin resistance; Insulin sensitivity; Type 2 diabetes; Vitamin D.

Figure 1

Vitamin D and insulin secretion. Vitamin D can promote pancreatic beta cell function in several ways. The active form of vitamin D, (1,25OH2D), enters the beta cell from the circulation and interacts with the vitamin D receptor-retinoic acid x-receptor complex (VDR-RXR), which binds to the vitamin D response element (VDRE) found in the human insulin gene promoter, to enhance the transcriptional activation of the insulin gene and increase the synthesis of insulin. Vitamin D may promote beta-cell survival by modulating the generation (through inactivation of nuclear factor-kB [NF-kb]) and effects of cytokines. The anti-apoptotic effect of vitamin D may also be mediated by downregulating the Fas-related pathways (Fas/Fas-L). Activation of vitamin D also occurs intracellularly by 1-alpha hydroxylase, which is expressed in pancreatic beta cells. Vitamin D also regulates calbindin, a cytosolic calcium-binding protein found in beta cells, which acts as a modulator of depolarization-stimulated insulin release via regulatation of intracellular calcium. Calbindin may also protect against apoptotic cell death via its ability to buffer intracellular calcium. The effects of vitamin D may be mediated indirectly via its important and well-recognized role in regulating extracellular calcium (Ca2+), calcium flux through the beta cell and intracellular calcium (Ca2+)i. Alterations in calcium flux can directly influence insulin secretion, which is a calcium-dependent process.

Figure 2

Vitamin D and insulin action. In peripheral insulin-target cells, vitamin D may directly enhance insulin sensitivity by stimulating the expression of insulin receptors (INS-R) and/or by activating peroxisome proliferator-activated receptor (PPAR-δ), a transcription factor implicated in the regulation of fatty acid metabolism in skeletal muscle and adipose tissue. The effects of vitamin D may be mediated indirectly via its important and well-recognized role in regulating extracellular calcium (Ca2+), calcium flux through the cell and intracellular calcium (Ca2+)i. Vitamin D may promote beta-cell survival by modulating the generation (through inactivation of nuclear factor-kB [NF-kb]) and effects of cytokines. Vitamin D may also affect insulin resistance indirectly through the renin-angiotensin (AII)-aldosterone system.

Figure 3

A random-effects meta-analysis of 21 independent prospective studies with adjusted RR and 95% CI of type 2 diabetes in relation to serum 25(OH)D levels (the highest category versus the lowest category).