Table 1.

Potential mechanisms and evidence to support a benefit for vitamin D and calcium in type 2 diabetes

Mechanisms	Evidence
Improvement in Pancreatic Beta Cell Function
Direct effect of Vitamin D on insulin secretion	Presence of specific vitamin D receptors in pancreatic beta cells (94)
	Expression of 1-alpha-hydroxylase enzyme in pancreatic beta cells (15)
	Impaired insulin secretory response in mice lacking functional vitamin D receptors (14)
	Presence of the vitamin D response element in the human insulin gene promoter (95)
	Transcriptional activation of the human insulin gene by 1,25-OHD (96)
	Vitamin D deficiency impairs glucose-mediated insulin secretion from rat pancreatic beta cells in vitro (13, 97-99) and in vivo (100, 101)
	Supplementation with vitamin D restores insulin secretion in animals (13, 97, 99, 100, 102)
Indirect Effect of vitamin D on insulin secretion	Vitamin D contributes to normalization of extracellular calcium ensuring normal calcium flux through cell membranes and adequate intracellular cytosolic calcium [Ca2+]i pool
	Regulation of calcium flux and [Ca2+]i in the pancreatic beta cell via regulation of calbindin, a cytosolic calcium-binding protein (103)
Calcium effect on insulin secretion	Alterations in calcium flux can have adverse effects on insulin secretion, a calcium-dependent process (16)
	Calcium repletion alone normalized glucose tolerance and insulin secretion in vitamin D-depleted rats (104)
	In people without diabetes, hypocalcemia is associated with impairment of insulin release (105, 106)
	In diabetes patients, an oral calcium load augments glucose-induced insulin secretion (107)
	Patients with resistance to 1,25-OHD were found to have abnormal insulin secretion only if they were hypocalcemic (108)
Improvement in Insulin Action
Direct effect of Vitamin D on insulin action	Inverse association between 25-OHD levels and sarcopenia (109)
	Presence of vitamin D receptor in skeletal muscle (110)
	Vitamin D stimulates the expression of insulin receptor and enhances insulin responsiveness for glucose transport in vitro (26)
	Vitamin D directly activates peroxisome proliferator activator receptor-delta (111), a transcription factor implicated in the regulation of fatty acid metabolism in skeletal muscle and adipose tissue (112)
Indirect effect of Vitamin D on insulin action	Vitamin D contributes to normalization of extracellular calcium ensuring normal calcium influx through cell membranes and adequate intracellular cytosolic calcium [Ca2+]i pool
Calcium effect on insulin action	Calcium is essential for insulin-mediated intracellular processes in insulin-responsive tissues such as skeletal muscle and adipose tissue (27-29) with a very narrow range of [Ca2+]i needed for optimal insulin-mediated functions (30)
	Changes in [Ca2+]i in primary insulin target tissues contributes to alterations in insulin action (30-37)
	Impairment of insulin receptor phosphorylation, a calcium-dependent process (113) leading to impaired insulin signal transduction (29, 34) and decreased GLUT-4 activity (34, 38)
	Changes in [Ca2+]i modulate adipocyte metabolism which may promotes triglyceride accumulation via increased de novo lipogenesis and inability to suppress insulin-mediated lipolysis leading to fat ccumulation (114, 115)
	Patients with type 2 diabetes exhibit impaired cellular calcium homeostasis including defects in skeletal muscle, adipocytes, and liver (116)
Improvement in Systemic Inflammation
Effects of vitamin D on cytokines	Vitamin D interacts with vitamin D response elements in the promoter region of cytokine genes tointerfere with nuclear transcription factors implicated in cytokine generation and action (117-119)
	Vitamin D can down regulate activation of NF-kB (117, 119, 120), which is an important regulatorof genes encoding pro-inflammatory cytokines implicated in insulin resistance (121)
	Vitamin D interferes with cytokine generation by upregulating expression of calbindin (94, 122, 123), a cytosolic calcium-binding protein found in many tissues including pancreatic beta cells (94, 123) Calbindin has been shown to protect against cytokine-induced apoptosis that may occur after a rise in cytosolic free calcium [Ca2+]I (124)
Effects of calcium on cytokines	Changes in [Ca2+]I may lead to cytokine-induced apoptosis (85)