calcitriol and Insulin-Resistance

Type 1 (T1D) and type 2 (T2D) diabetes are considered multifactorial diseases in which both genetic predisposition and environmental factors participate in their development. Many cellular, preclinical, and observational studies support a role for vitamin D in the pathogenesis of both types of diabetes including: (1) T1D and T2D patients have a higher incidence of hypovitaminosis D; (2) pancreatic tissue (more specifically the insulin-producing beta-cells) as well as numerous cell types of the immune system express the vitamin D receptor (VDR) and vitamin D-binding protein (DBP); and (3) some allelic variations in genes involved in vitamin D metabolism and VDR are associated with glucose (in)tolerance, insulin secretion, and sensitivity, as well as inflammation. Moreover, pharmacologic doses of 1,25-dihydroxyvitamin D (1,25(OH)(2)D), the active form of vitamin D, prevent insulitis and T1D in nonobese diabetic (NOD) mice and other models of T1D, possibly by immune modulation as well as by direct effects on beta-cell function. In T2D, vitamin D supplementation can increase insulin sensitivity and decrease inflammation. This article reviews the role of vitamin D in the pathogenesis of T1D and T2D, focusing on the therapeutic potential for vitamin D in the prevention/intervention of T1D and T2D as well as its complications.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Supplements; Female; Genetic Predisposition to Disease; Glucose Intolerance; Humans; Immune System; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Mice; Pancreatitis; Rats; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency; Vitamin D-Binding Protein

Topics: Adult; Blood Glucose; Cholecalciferol; Dietary Supplements; Double-Blind Method; Fasting; Female; Humans; Insulin; Insulin Resistance; Japan; Male; Middle Aged; Reference Values; Vitamin D

The association between low vitamin D status and the development of type 2 diabetes mellitus is well established; however, intervention trials that increased serum vitamin D (through ultraviolet B exposure or dietary supplementation) provide mixed outcomes. Recent evidence suggests that metabolites directly related to vitamin D receptor activation-1α,25-dihydroxyvitamin D

Topics: Adult; Aged; Asian People; Calcifediol; Diabetes Mellitus, Type 2; Female; Glucose; Homeostasis; Humans; Insulin Resistance; Insulin Secretion; Intra-Abdominal Fat; Male; Middle Aged; Oxygen; Oxygen Consumption; Triglycerides; Vitamin D; Vitamin D Deficiency

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic macrophage inflammation, steatosis and fibrosis. Liposomes injected intravenously passively target hepatic myeloid cells and have potential to deliver immunomodulatory compounds and treat disease. We investigated targeting, delivery, immunomodulation and efficacy of liposomes in mice with diet-induced NASH.. Liposome-encapsulated lipophilic curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol) were injected intravenously into mice with diet-induced NASH. Liver and cell liposome uptake was assessed by in vivo imaging and flow cytometry. Immunomodulation of targeted cells were assessed by RNA transcriptome sequencing. NASH was assessed by histological scoring, serum liver enzymes and fasting glucose/insulin and liver RNA transcriptome sequencing.. Liposomes targeted lipid containing MHC class-II. Liposomes are a new strategy to target lipid rich inflammatory dendritic cells and have potential to deliver immunomodulatory compounds to treat NASH.

Topics: Animals; Curcumin; Diet, High-Fat; Disease Progression; Female; Fibrosis; Hepatocytes; Immunologic Factors; Inflammation; Insulin Resistance; Liposomes; Liver; Liver Cirrhosis; Macrophages; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Transcriptome; Vitamin D

Advancing age is accompanied by changes in metabolic characteristics, such as reduced insulin sensitivity and low levels of vitamin D, which may exacerbate age-related declines in physical function.. The aim of the present study was to determine the associations between insulin-glucose dynamics, vitamin D metabolites, and performance on a battery of motor tasks in healthy, non-diabetic older adults.. Sixty-nine community-dwelling men and women (65-90 years) were recruited. Insulin-glucose dynamics were determined by an intravenous glucose tolerance test, and vitamin D metabolites were measured. Motor function was characterized by the time to walk 500 m, chair-rise time, lower body strength, dorsiflexor steadiness and endurance time, and muscle coactivation.. Significant unadjusted correlations were found between insulin-glucose dynamics and 1,25-dihydroxyvitamin D [1,25(OH)2D] with walk time, strength, steadiness, endurance time, and muscle activation (p < 0.05). A significant amount of the variance in walking endurance was explained by the sex of the individual, 1,25(OH)2D, and fasting blood insulin (R (2) = 0.36, p < 0.001). Strength could be partially explained by age, body fatness, and fasting glucose (R (2) = 0.55, p < 0.001).. Poor motor function in non-diabetic older men and women was associated with indices of insulin-glucose dynamics and the bio-active vitamin D metabolite 1,25(OH)2D. Walking endurance and strength were explained by 1,25(OH)2D and fasting blood glucose and insulin, even after adjusting for age, sex, and body fat.. Motor function in a relatively small sample of non-diabetic older men and women was associated with metabolic factors that increase in prevalence with aging.

Topics: Aged; Aged, 80 and over; Aging; Blood Glucose; Cross-Sectional Studies; Female; Humans; Insulin; Insulin Resistance; Male; Motor Skills; Muscle Strength; Physical Endurance; Vitamin D

The vitamin D receptor (VDR) is expressed in human adipocytes and is transiently induced during early adipogenesis in mesenchymal progenitor cell models. VDR null mice exhibit enhanced energy expenditure and reduced adiposity even when fed high fat diets. Adipocyte-specific transgenic-expression of human VDR in mice enhances adipose tissue mass, indicating that VDR activation in adipocytes enhances lipid storage in vivo. In these studies, we conducted genomic profiling and differentiation assays in primary cultures of human adipose-derived mesenchymal progenitor cells to define the role of the VDR and its ligand 1,25-dihydroxyvitamin D3 (1,25D) in adipogenesis. In the presence of adipogenic media, 1,25D promoted lipid accumulation and enhanced the expression of FABP4, FASN, and PPARγ. Mesenchymal cells derived from 6-month old VDR null mice exhibited impaired adipogenesis ex vivo but differentiation was restored by stable expression of human VDR. STEAP4, a gene that encodes a metalloreductase linked to obesity, insulin sensitivity, metabolic homeostasis and inflammation, was highly induced in human adipose cells differentiated in the presence of 1,25D but was minimally affected by 1,25D in undifferentiated precursors. These studies provide a molecular basis for recent epidemiological associations between vitamin D status, body weight and insulin resistance which may have relevance for prevention or treatment of metabolic syndrome and obesity.

Topics: Adipogenesis; Adipose Tissue; Adult; Animals; Body Weight; Cell Differentiation; Cells, Cultured; Fatty Acid Synthase, Type I; Fatty Acid-Binding Proteins; Female; Humans; Insulin Resistance; Lipid Metabolism; Membrane Proteins; Mesenchymal Stem Cells; Mice; Mice, Knockout; Middle Aged; Oxidoreductases; PPAR gamma; Stem Cells; Vitamin D

Adipose tissue expansion during obesity is associated with a state of low-grade inflammation and an increase in macrophage infiltration, which predisposes to insulin resistance and vascular malfunction. Growing evidence suggests that vitamin D3 has immunoregulatory effects and adipose tissue could be a target for vitamin D3 action. Preadipocytes, one of the major cell types in adipose tissue, are actively involved in inflammatory processes.. This study investigated whether the active form of vitamin D3 (1,25(OH)2D3) affects the production of proinflammatory chemokines/cytokines and the monocyte recruitment by human preadipocytes.. The secretion levels of monocyte chemoattractant proteint-1 (MCP-1), IL-8 and IL-6 were significantly higher in preadipocytes than in differentiated adipocytes, suggesting that preadipocytes could be a major source of proinflammatory mediators. Cytokine profile analysis revealed that 1,25(OH)2D3 (10 nM) markedly reduced the release of MCP-1, IL-6 and IL-8 by preadipocytes. The involvement of NFκB signalling was shown by the upregulation of IκBα protein abundance by 1,25(OH)2D3 in preadipocytes. In addition, 1,25(OH)2D3 was able to decrease the migration of THP-1 monocytes. Treatment with proinflammatory stimuli, including macrophage-conditioned (MC) medium, TNFα and IL-1β, led to a marked increase in protein release of MCP-1 and IL-6 by preadipocytes. Pretreatment with 1,25(OH)2D3 (10 nM and 100 nM) significantly decreased the stimulatory effects of MC medium, TNFα and IL-1β on MCP-1 expression and protein release, although the effect on stimulated release of IL-6 was less potent.. These results demonstrate that 1,25(OH)2D3 decreases the production of MCP-1 and other proinflammatory mediators by preadipocytes and reduces monocyte migration. Thus, vitamin D3 may protect against adipose tissue inflammation by disrupting the deleterious cycle of macrophage recruitment.

Topics: Adipocytes; Adipose Tissue, White; Adult; Blotting, Western; Cell Differentiation; Chemokine CCL2; Cytokines; Female; Humans; Inflammation; Inflammation Mediators; Insulin Resistance; Interleukin-6; Interleukin-8; Monocytes; NF-kappa B; Obesity; Signal Transduction; Tumor Necrosis Factor-alpha; Vitamin D

To investigate whether abnormalities in serum concentrations of 1,25-dihydroxyvitamin D [1,25(OH)(2)D], 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), calcium, and phosphorus were associated with risk of polycystic ovary syndrome (PCOS) and obesity. The possible correlations of the calciotropic hormones with insulin resistance were also examined.. Case-control study.. Department of Genetics, Royan Institute.. Eighty-five women with PCOS and 115 control women were recruited.. None.. Serum levels of glucose, insulin, total calcium, phosphorus, PTH, 25(OH)D, and 1,25(OH)(2)D were measured in all 200 subjects.. The presence of PCOS had age- and body mass index (BMI)-independent positive effects on serum phosphorus, PTH, 25(OH)D, and insulin concentrations as well as on insulin resistance. Furthermore, overweight/obese (BMI > or =25 kg/m(2)) women with PCOS had significantly decreased levels of 1,25(OH)(2)D and glucose compared with normal-weight (BMI <25 kg/m(2)) women with PCOS. In women with PCOS, phosphorus was correlated negatively with insulin and insulin resistance and positively with 1,25(OH)(2) D. In addition, in normal-weight patients, PTH correlated positively with insulin and insulin resistance.. It is possible that elevated levels of phosphorus and PTH in women with PCOS, at least in part, through their effects on insulin levels and insulin resistance, are involved in pathogenesis of the syndrome.

Topics: Adolescent; Adult; Calcium; Case-Control Studies; Female; Homeostasis; Humans; Insulin; Insulin Resistance; Middle Aged; Parathyroid Hormone; Phosphorus; Polycystic Ovary Syndrome; Vitamin D; Young Adult

Previous studies have suggested a link between circulating levels of 25-hydroxyvitamin D (25-D) and dyslipidaemias. However, it is not known whether 25-D and the active hormone 1,25-dihydroxyvitamin D (1,25-D) have similar associations with dyslipidaemias. Therefore, we studied the associations between both 25-D and 1,25-D and total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides in a population-based study.. Cross-sectional population-based study.. Kuopio, Eastern Finland.. A total of 909 men, aged from 45 to 70 years, who were not receiving antidiabetic medication were enrolled.. Fasting serum samples were obtained for measurement of 25-D, 1,25-D and lipid levels. An oral glucose tolerance test was performed, and insulin sensitivity was evaluated using the Matsuda insulin sensitivity index (Matsuda ISI).. We found a significant inverse association between 25-D and total-C, LDL-C and triglycerides (β = -0.15, -0.13 and -0.17, respectively, P < 0.001), but no association between 25-D and HDL-C was observed. By contrast, 1,25-D was associated with HDL-C (β = 0.18, P < 0.001), whereas no relationship was found between 1,25-D and LDL-C or triglycerides. The associations remained significant after the exclusion of subjects receiving statin treatment and after adjustment for age, waist circumference, body mass index, alcohol consumption, smoking, renal function, glucose tolerance and Matsuda ISI.. Low levels of active vitamin D (1,25-D) are associated with low HDL-C levels, whereas low levels of the storage form 25-D are associated with high levels of total-C, LDL-C and triglycerides. Our findings may provide new insights into the understanding of the link between vitamin D deficiency and cardiovascular disease.

Topics: Aged; Blood Glucose; Cholesterol; Cross-Sectional Studies; Dyslipidemias; Glucose Tolerance Test; Humans; Insulin Resistance; Lipids; Male; Middle Aged; Vitamin D

1alpha,25-Dihydroxy vitamin D3 (1,25D3) activates conventional PKC and may subsequently lead to insulin resistance. Previous studies from our laboratory have shown that pretreatment with 10 nM-10 microM 1,25D3 dose-responsively suppressed insulin-induced glucose. To assess PKC(beta)-mediated inhibition of insulin-induced glucose uptake in rat adipocytes, we preincubated with Go6976 and LY379196, conventional PKC inhibitors, and found they abolished the 1,25D3-mediated inhibitory effect on insulin-induced 2-deoxyglucose (DOG) uptake. Moreover, the inhibitory effect of 1,25D3 on insulin-induced DOG uptake was abrogated in adipocytes overexpressed with dominant negative PKC(beta), but not in those overexpressed with wild type PKC(beta). These results suggest that 1,25D3 reduces insulin-induced glucose uptake via activation of PKC(beta) in rat adipocytes.

Topics: Adipocytes; Animals; Biological Transport; Deoxyglucose; Enzyme Inhibitors; Gene Expression; Genes, Dominant; Insulin; Insulin Resistance; Mutation; Protein Kinase C; Protein Kinase C beta; Rats; Swine; Vitamin D