Skip to main content
Log in

Vitamin D, sub-inflammation and insulin resistance. A window on a potential role for the interaction between bone and glucose metabolism

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

Vitamin D is a key hormone involved in the regulation of calcium/phosphorous balance and recently it has been implicated in the pathogenesis of sub-inflammation, insulin resistance and obesity. The two main forms of vitamin D are cholecalciferol (Vitamin D3) and ergocalciferol (Vitamin D2): the active form (1,25-dihydroxyvitamin D) is the result of two hydroxylations that take place in liver, kidney, pancreas and immune cells. Vitamin D increases the production of some anti-inflammatory cytokines and reduces the release of some pro-inflammatory cytokines. Low levels of Vitamin D are also associated with an up-regulation of TLRs expression and a pro-inflammatory state. Regardless of the effect on inflammation, Vitamin D seems to directly increase insulin sensitivity and secretion, through different mechanisms. Considering the importance of low grade chronic inflammation in metabolic syndrome, obesity and diabetes, many authors hypothesized the involvement of this nutrient/hormone in the pathogenesis of these diseases. Vitamin D status could alter the balance between pro and anti-inflammatory cytokines and thus affect insulin action, lipid metabolism and adipose tissue function and structure. Numerous studies have shown that Vitamin D concentrations are inversely associated with pro-inflammatory markers, insulin resistance, glucose intolerance and obesity. Interestingly, some longitudinal trials suggested also an inverse association between vitamin D status and incident type 2 diabetes mellitus. However, vitamin D supplementation in humans showed controversial effects: with some studies demonstrating improvements in insulin sensitivity, glucose and lipid metabolism while others showing no beneficial effect on glycemic control and on inflammation. In conclusion, although the evidences of a significant role of Vitamin D on inflammation, insulin resistance and insulin secretion in the pathogenesis of obesity, metabolic syndrome and type 2 diabetes, its potential function in treatment and prevention of type 2 diabetes mellitus is unclear. Encouraging results have emerged from Vitamin D supplementation trials on patients at risk of developing diabetes and further studies are needed to fully explore and understand its clinical applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Muscogiuri G, Altieri B, Annweiler C, Balercia G, Pal HB, Boucher BJ, et al. Vitamin D and chronic diseases: the current state of the art. Arch Toxicol. 2016.

  2. Muscogiuri G, Mitri J. MathieuC, Badenhoop K, tamer G, Orio F et al. mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur J Endocrinol. 2014;171:101–10.

    Article  CAS  Google Scholar 

  3. Barragan M, Good M, Kolls JK. Regulation of dendritic cell function by vitamin D. Nutrients. 2015;7:8127–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McGill A-T, Stewart JM, Lithander FE, Strik CM, Poppitt SD. Relationships of low serum vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. Nutr J. 2008;28:7–4.

    Google Scholar 

  5. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. Dietary reference intakes for calcium and vitamin D. In: Committee to review dietary reference intakes for calcium and vitamin D. Washington (DC): National Academies Press (USA); 2011.

  6. Mitri J, Pittas AG. Vitamin D and diabetes. Endocrinol Metab Clin N Am. 2014;43:205–32.

    Article  Google Scholar 

  7. Schuster I. Cytochromes P450 are essential players in the vitamin D signaling system. Biochim Biophys Acta. 1814;2011:186–99.

    Google Scholar 

  8. Baeke F, Gysemans C, Korf H, Mathieu C. Vitamin D insufficiency: implications for the immune system. Pediatr Nephrol. 2010;25:1597–606.

    Article  PubMed  Google Scholar 

  9. Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE, Hewison M. Expression of 25-hydroxyvitamin D3-1alphahydroxylase in pancreatic islets. J Steroid Biochem Mol Biol. 2004;89-90:121–5.

    Article  CAS  PubMed  Google Scholar 

  10. Dusso AS, Brown AJ, Slatopolsky E. Vitamin D. Am J Physiol Renal Physiol. 2005;289:F8–F28.

    Article  CAS  PubMed  Google Scholar 

  11. Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiol Rev. 1998;78:1193–231.

    CAS  PubMed  Google Scholar 

  12. Wamberg L, Pedersen SB, Rejnmark L, Richelsen B. Causes of vitamin D deficiency and effect of vitamin D supplementation on metabolic complications in obesity: a review. Curr Obes Rep. 2015;4:429–40.

    Article  PubMed  Google Scholar 

  13. Mawer EB, Backhouse J, Holman CA, et al. The distribution and storage of vitamin D and its metabolites in human tissues. Clin Sci. 1972;43:413–31.

    Article  CAS  PubMed  Google Scholar 

  14. Blum M, Dolnikowski G, Seyoum E, et al. Vitamin D (3) in fat tissue. Endocrine. 2008;33:90–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Pramyothin P, Biancuzzo RM, Lu Z, et al. Vitamin D in adipose tissue and serum 25-hydroxyvitamin D after roux-en-Y gastric bypass. Obesity (Silver Spring). 2011;19:2228–34.

    Article  CAS  Google Scholar 

  16. Landrier JF, Marcotorchino J, Tourniaire F. Lipophilic micronutrients and adipose tissue biology. Nutrients. 2012;4:1622–49.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Marcotorchino J, Tourniaire F, Landrier JF. Vitamin D, adipose tissue, and obesity. Horm Mol Biol Clin Investig. 2013;15:123–8.

    CAS  PubMed  Google Scholar 

  18. Beckman LM, Earthman CP, Thomas W, et al. Serum 25(OH) vitamin D concentration changes after roux-en-Y gastric bypass surgery. Obesity (Silver Spring). 2013;21:E599–606.

    Article  CAS  PubMed Central  Google Scholar 

  19. Hollick MF, Vitamin D. Deficiency. N Engl J Med. 2007;357:266–81.

    Article  Google Scholar 

  20. Holick MF. The vitamin D deficiency pandemic and consequences for nonskeletal health: mechanisms of action. Mol Asp Med. 2008;29:361–8.

    Article  CAS  Google Scholar 

  21. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6

  22. Kahn CR, White MF, Shoelson SE, Backer JM, Araki E, Cheatham B, Csermely P, Folli F, Goldstein BJ, Huertas P, et al. The insulin receptor and its substrate: molecular determinants of early events in insulin action. Recent Prog Horm Res. 1993;48:291–339.

    Article  CAS  PubMed  Google Scholar 

  23. Kahn CR, Folli F. Molecular determinants of insulin action. Horm Res. 1993;39:93–101.

    Article  CAS  PubMed  Google Scholar 

  24. DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care. 1992;15:318–68.

    Article  CAS  PubMed  Google Scholar 

  25. Martin BC, Warram JH, Krolewski AS, Bergman RN, Soeldner JS, Kahn CR. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992;340:925–9.

    Article  CAS  PubMed  Google Scholar 

  26. Chavez AO, Lopez-Alvarenga JC, Tejero ME, Triplitt C, Bastarrachea RA, Sriwijitkamol A, Tantiwong P, Voruganti VS, Musi N, Comuzzie AG, DeFronzo RA, Folli F. Physiological and molecular determinants of insulin action in the baboon. Diabetes. 2008;57:899–908.

    Article  CAS  PubMed  Google Scholar 

  27. Chavez AO, Gastaldelli A, Guardado-Mendoza R, Lopez-Alvarenga JC, Leland MM, Tejero ME, Sorice G, Casiraghi F, Davalli A, Bastarrachea RA, Comuzzie AG, DeFronzo RA, Folli F. Predictive models of insulin resistance derived from simple morphometric and biochemical indices related to obesity and the metabolic syndrome in baboons. Cardiovasc Diabetol. 2009;8:22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Guardado-Mendoza R, Davalli AM, Chavez AO, Hubbard GB, Dick EJ, Majluf-Cruz A, Tene-Perez CE, Goldschmidt L, Hart J, Perego C, Comuzzie AG, Tejero ME, Finzi G, Placidi C, La Rosa S, Capella C, Halff G, Gastaldelli A, DeFronzo RA, Folli F. Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons. Proc Natl Acad Sci U S A. 2009;106:13992–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Guardado-Mendoza R, Jimenez-Ceja L, Majluf-Cruz A, Kamath S, Fiorentino TV, Casiraghi F, Velazquez AO, DeFronzo RA, Dick E, Davalli A, Folli F. Impact of obesity severity and duration on pancreatic β- and α-cell dynamics in normoglycemic non-human primates. Int J Obes. 2013;37:1071–8.

    Article  CAS  Google Scholar 

  30. Guardado Mendoza R, Perego C, Finzi G, La Rosa S, Capella C, Jimenez-Ceja LM, Velloso LA, Saad MJ, Sessa F, Bertuzzi F, Moretti S, Dick Jr EJ, Davalli AM, Folli F. Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas). Diabetologia. 2015;58:1814–26.

    Article  CAS  PubMed  Google Scholar 

  31. Folli F, Saad MJ, Backer JM, Kahn CR. Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. J Clin Invest. 1993;92:1787–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Saad MJ, Folli F, Kahn JA, Kahn CR. Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats. J Clin Invest. 1993;92:2065–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Saad MJ, Folli F, Araki E, Hashimoto N, Csermely P, Kahn CR. Regulation of insulin receptor, insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-F442A adipocytes. Effects of differentiation, insulin, and dexamethasone. Mol Endocrinol. 1994;8:545–57.

    CAS  PubMed  Google Scholar 

  34. Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams Jr HP, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, JR O’L, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, winder TR for the IRIS trial investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374:1321–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Reaven G. Insulin resistance and coronary heart disease in nondiabetic individuals. Arterioscler Thromb Vasc Biol. 2012;32:1754–9.

    Article  CAS  PubMed  Google Scholar 

  36. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M, Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance in essential hypertension. N Engl J Med. 1987;317:350–7.

    Article  CAS  PubMed  Google Scholar 

  37. Velloso LA, Folli F, Sun XJ, White MF, Saad MJ, Kahn CR. Cross-talk between the insulin and angiotensin signaling systems. Proc Natl Acad Sci U S A. 1996;93:12490–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vicari AM, Monzani ML, Pellegatta F, Ronchi P, Galli L, Folli F. Platelet calcium homeostasis is abnormal in patients with severe arteriosclerosis. Arterioscler Thromb. 1994;14:1420–4.

    Article  CAS  PubMed  Google Scholar 

  39. Tripathy D, Daniele G, Fiorentino TV, Perez-Cadena Z, Chavez-Velasquez A, Kamath S, Fanti P, Jenkinson C, Andreozzi F, Federici M, Gastaldelli A, Defronzo RA, Folli F. Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3-TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study. Diabetologia. 2013;56:2153–63.

    Article  CAS  PubMed  Google Scholar 

  40. Crook M. Type 2 diabetes mellitus: a disease of the innate immune system? An update Diabetic Medicine. 2004;21:203–7.

    Article  CAS  PubMed  Google Scholar 

  41. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280:E745–51.

    CAS  PubMed  Google Scholar 

  42. Velloso LA, Folli F, Saad MJ. TLR4 at the crossroads of Nutrients, gut Microbiota, and metabolic inflammation. Endocr Rev. 2015;36:245–27.

    Article  CAS  PubMed  Google Scholar 

  43. Scherer PE. The multifaceted roles of adipose tissue- therapeutic targets for diabetes and beyond. Diabetes. 2016;65:1452–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Daniele G, Guardado Mendoza R, Winnier D, Fiorentino TV, Pengou Z, Cornell J, Andreozzi F, Jenkinson C, Cersosimo E, Federici M, Tripathy D, Folli F. The inflammatory status score including IL-6, TNF-a, osteopontin, fractalkine, MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus. Acta Diabetol. 2014;51:123–31.

    Article  CAS  PubMed  Google Scholar 

  45. Federici M, Hribal ML, Menghini R, Kanno H, Marchetti V, Porzio O, Sunnarborg SW, Rizza S, Serino M, Cunsolo V, Lauro D, Mauriello A, Smookler DS, Sbraccia P, Sesti G, Lee DC, Khokha R, Accili D, Lauro R. Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. J Clin Invest. 2005;115:3494–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Monroy A, Kamath S, Chavez AO, Centonze VE, Veerasamy M, Barrentine A, Wewer JJ, Coletta DK, Jenkinson C, Jhingan RM, Smokler D, Reyna S, Musi N, Khokka R, Federici M, Tripathy D, DeFronzo RA, Folli F. Impaired regulation of the TNF-α converting enzyme/tissue inhibitor of metalloproteinase 3 proteolytic system in skeletal muscle of obese type 2 diabetic patients: a new mechanism of insulin resistance in human. Diabetologia. 2009;52:2169–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pontiroli AE, Pizzocri P, Paroni R, Folli F. Sympathetic Overactivity, endothelial dysfunction, inflammation, and metabolic abnormalities cluster in grade III (World Health Organization) obesity. Diabetes Care. 2006;29:12.

    Article  Google Scholar 

  48. Vicari AM, Taglietti MV, Pellegatta F, Spotti D, Melandri M, Galli L, Ronchi P, Folli F. Deranged platelet calcium homeostasis in diabetic patients with end-stage renal failure. A possible link to increased cardiovascular mortality? Diabetes Care. 1996;19:1062–6.

    Article  CAS  PubMed  Google Scholar 

  49. Pellegatta F, Folli F, Ronchi P, Caspani L, Galli L, Vicari AM. Deranged platelet calcium homeostasis in poorly controlled IDDM patients. Diabetes Care. 1993;16:178–83.

    Article  CAS  PubMed  Google Scholar 

  50. Fiorentino TV, Prioletta A, Zuo P, Folli F. Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases. Curr Pharm Des. 2013;19:5695–703.

    Article  CAS  PubMed  Google Scholar 

  51. Hotamisligil GS, Shargill NS. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance., Spiegelman BM. Science. 1993;259:87–91.

    Article  CAS  PubMed  Google Scholar 

  52. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science. 1996;271:665–8.

    Article  CAS  PubMed  Google Scholar 

  53. Arruda AP, Hotamisligil GS. Calcium homeostasis and organelle function in the pathogenesis of obesity and diabetes. Cell Metab. 2015;22:381–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li B, Baylink DJ, Deb C, Zannetti C, Rajaallah F, Xing W, Walter MH, Lau K-HW, Qin X. 1, 25-Dihydroxyvitamin D3 suppresses TLR8 expression and TLR8-mediated inflammatory responses in monocytes in vitro and experimental autoimmune encephalomyelitis in vivo. PLoS One. 2013;8:e58808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Gao D, Trayhurn P, Bing C. 1, 25-Dihydroxyvitamin D3 inhibits the cytokine-induced secretion of MCP-1 and reduces monocyte recruitment by human preadipocytes. Int J Obes. 2013;37:357–65.

    Article  CAS  Google Scholar 

  56. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.

    Article  CAS  PubMed  Google Scholar 

  57. Vlasova M, Purhonen A, Jarvelin M, Rodilla E, Pascual J, Herzig K. Role of adipokines in obesity-associated hypertension. Acta Physiol. 2010;200:107–27.

    Article  CAS  Google Scholar 

  58. Calton EK, Keane KN, Newsholme P, Soares MJ. Impact of vitamin D levels on inflammatory status: a systematic review of immune cell studies. PLoS One. 2015;10:e0141770.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Gonzalez-Molero I, Rojo-Martinez G, Morcillo S, Gutierrez C, Rubio E, Perez-Valero V, et al. Hypovitaminosis D and incidence of obesity: a prospective study. Eur J Clin Nutr. 2013;

  60. Landrier JF, Karkeni E, Marcotorchino J, Bonnet L, Tourniaire F. Vitamin D modulates adipose tissue biology: possible consequences for obesity? Proc Nutr Soc. 2016;75:38–46.

    Article  CAS  PubMed  Google Scholar 

  61. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermato-Endocrinology. 2014;6:1.

    Article  Google Scholar 

  62. Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins a and D take centre stage. Nat Rev Immunol. 2008;8:685–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C. Monocytes from type 2 diabetic patients have a pro-inflammatory profile.1,25-DihydroxyvitaminD (3) works as anti-inflammatory. Diabetes Res Clin Pract. 2007;77:47–57.

    Article  CAS  PubMed  Google Scholar 

  64. Neve A, Corrado A. CantatoreF. Immunomodulatory effects of vitamin D in peripheral blood monocyte derived macrophages from patients with rheumatoid arthritis. Clin Exp Med. 2013:1–9.

  65. Sloka S, Silva C, Wang J, Yong VW. Predominance of Th2 polarization by VitaminD through a STAT6 dependent mechanism. J Neuroinflammation. 2011;8

  66. Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L. Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol. 2001;167:1945–53.

    Article  CAS  PubMed  Google Scholar 

  67. Tezza S, Nasr MB, Vergani A, Valderrama Vasquez A, Maestroni A, Abdi R, Secchi A, Fiorina P. Novel immunological strategies for islet transplantation. Pharmacol Res. 2015;98:69–75.

    Article  CAS  PubMed  Google Scholar 

  68. Nasr MB, D'Addio F, Usuelli V, Tezza S, Abdi R, Fiorina P. The rise, fall, and resurgence of immunotherapy in type 1 diabetes. Pharmacol Res. 2015;98:31–8.

    Article  PubMed  CAS  Google Scholar 

  69. Bassi R, Fiorina P. Impact of islet transplantation on diabetes complications and quality of life. Current diabetes reports. 2011;11:355.

    Article  PubMed  Google Scholar 

  70. Calton EK, Keane KN, Newsholme P, Soares MJ. The impact of vitamin D levels on inflammatory status: a systematic review of immune cell studies. PLoS One. 2015; doi:10.1371/journal.pone.0141770.

    PubMed  PubMed Central  Google Scholar 

  71. Plum LA, DeLuca HF. Vitamin D, disease and therapeutic opportunities. Nat Rev Drug Discov. 2010:941–55.

  72. Harinarayan CV, Arvind S, Joshi S, Thennarasu K, Vedavyas V, Baindur A. Improvement in pancreatic β cell function with vitamin D and calcium supplementation in vitamin D deficient non-diabetic subjects. Endocr Pract. 2013;6:1–33.

    Google Scholar 

  73. Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007;92:2017–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Clemente-Postigo M, Muñoz-Garach A, Serrano M, Garrido-Sánchez L, Bernal-López MR, Fernández-García D, Moreno-Santos I, Garriga N, Castellano-Castillo D, Camargo A, Fernández-Real JM, Cardona F, Tinahones FJ, Macías-González M. Serum 25-hydroxyvitamin D and adipose tissue vitamin D receptor gene expression: relationship with obesity and type 2 diabetes. J Clin Endocrinol Metab. 2015;100:591–5.

    Article  CAS  Google Scholar 

  75. Vin hquốcLu'o'ng K, Nguyễn LT. The beneficial role of vitamin D in obesity: possible genetic and cell signaling mechanisms. Nutr J. 2013:12–89.

  76. Vitseva OI, Tanriverdi K, Tchkonia TT, Kirkland JL, McDonnell ME, Apovian CM, Freedman J, Gokce N. Inducible toll-like receptor and NF-jB regulatory pathway expression in human adipose tissue. Obesity (Silver Spring). 2008;16:932–7.

    Article  CAS  Google Scholar 

  77. Khoo AL, Chai L, Koenen H, Sweep F, Joosten I, Netea M, van der Ven A. Regulation of cytokine responses by seasonality of vitamin D status in healthy individuals. Clin Exp Immunol. 2011;164:72–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Bolland MJ, Grey AB, Ames RW, Mason BH, Horne AM, Gamble GD, Reid IR. The effects of seasonal variation of 25-hydroxyvitamin D and fat mass on a diagnosis of vitamin D sufficiency. Am J Clin Nutr. 2007;86:959–64.

    CAS  PubMed  Google Scholar 

  79. Simpson RU, Thomas GA, Arnold AJ. Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle. J Biol Chem. 1985;260:8882–91.

    CAS  PubMed  Google Scholar 

  80. Maestro B, Campión J, Dávila N, Calle C. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J. 2000;47:383–39.

    Article  CAS  PubMed  Google Scholar 

  81. Dunlop TW, Väisänen S, Frank C, Molnár F, Sinkkonen L, Carlberg C. The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol. 2005;349:248–60.

    Article  CAS  PubMed  Google Scholar 

  82. Luquet S, Gaudel C, Holst D, Lopez-Soriano J, Jehl-Pietri C, Fredenrich A, Grimaldi PA. Roles of PPAR delta in lipid absorption and metabolism: a new target for the treatment of type 2 diabetes. Biochim Biophys Acta. 1740;2005:313–7.

    Google Scholar 

  83. Wei Y, Sowers JR, Clark SE, Li W, Ferrario CM, Stump CS. Angiotensin IIinduced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. Am J Physiol Endocrinol Metab. 2008;294:E345–51.

    Article  CAS  PubMed  Google Scholar 

  84. Wright DC, Hucker KA, Holloszy JO, Han DH. Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions. Diabetes. 2004;53:330–5.

    Article  CAS  PubMed  Google Scholar 

  85. Muscogiuri G, Chavez AO, Gastaldelli A, Perego L, Tripathy D, Saad MJ, Velloso L, Folli F. The crosstalk between insulin and renin-angiotensin-aldosterone signaling systems and its effect on glucose metabolism and diabetes prevention. Curr Vasc Pharmacol. 2008;6:301–12.

    Article  CAS  PubMed  Google Scholar 

  86. Altieri B, Grant WB, Casa SD, Orio F, Pontecorvi A, Colao A, Sarno G, Muscogiuri G. Vitamin D and pancreas: the role of sunshine vitamin in the pathogenesis of diabetes mellitus and pancreatic cancer. Crit Rev Food Sci Nutr. 2016; doi:10.1080/10408398.2015.1136922.

    Google Scholar 

  87. Galbiati F, Polastri L, Thorens B, Dupraz P, Fiorina P, Cavallaro U, Christofori G, Davalli AM. Molecular pathways involved in the antineoplastic effects of calcitriol on insulinoma cells. Endocrinology. 2003;144:1832–41.

    Article  CAS  PubMed  Google Scholar 

  88. Galbiati F, Polastri L, Gregori S, Freschi M, Casorati M, Cavallaro U, Fiorina P, Bertuzzi F, Zerbi A, Pozza G, Adorini L, Folli F, Christofori G, Davalli AM. Antitumorigenic and antiinsulinogenic effects of calcitriol on insulinoma cells and solid beta-cell tumors. Endocrinology. 2002;143:4018–30.

    Article  CAS  PubMed  Google Scholar 

  89. Khoo A-L, Chai LY, Koenen HJ, Kullberg B-J, Joosten I, van der Ven AJ, Netea MG. 1, 25-Dihydroxyvitamin D3 modulates cytokine production induced by Candida albicans: impact of seasonal variation of immune responses. J Infect Dis. 2011;203:122–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006;83:754–9.

    CAS  PubMed  Google Scholar 

  91. Petchey WG, Johnson DW, Isbel NM. Shining D’light on chronic kidney disease: mechanisms that may underpin the cardiovascular benefit of vitamin D. Nephrology (Carlton). 2011;16:351–67.

    Article  CAS  Google Scholar 

  92. Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79:820–5.

    CAS  PubMed  Google Scholar 

  93. Dutta D, Maisnam I, Shrivastava A, Sinha A, Ghosh S, Mukhopadhyay P, et al. Serum vitamin-D predicts insulin resistance in individuals with prediabetes. Indian J Med Res. 2013;138:853–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Manickam B, Neagu V, Kukreja SC, Barengolts E. Relationship between glycated hemoglobin and circulating 25-hydroxyvitamin D concentration in African American and Caucasian American men. Endocr Pract. 2013;19:73–80.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the third National Health and Nutrition examination survey. Diabetes Care. 2004;27:2813–8.

    Article  CAS  PubMed  Google Scholar 

  96. Chandler PD, Scott JB, Drake BF, Ng K, Manson JE, Rifai N, et al. Impact of vitamin D supplementation of inflammatory markers in African Americans: results of a four-arm, randomized, placebo-controlled trial. Cancer Prev Res. 2014;7:218–25.

    Article  CAS  Google Scholar 

  97. Laird E, McNulty H, Ward M, Hoey L, McSorley E, Wallace JM, et al. Vitamin D deficiency is associated with inflammation in older Irish adults. J Clin Endocrinol Metab. 2014;99:1807–15.

    Article  CAS  PubMed  Google Scholar 

  98. Ganji V, Zhang X, Shaikh N, Tangpricha V. Serum 25-hydroxyvitamin D concentrations are associated with prevalence of metabolic syndrome and various cardiometabolic risk factors in US children and adolescents based on assay-adjustedserum25-hydroxyvitaminD. Am J Clin Nutr. 2011;94:225–33.

    Article  CAS  PubMed  Google Scholar 

  99. Tepper S, Shahar D, Geva D etal. Identifying the threshold for vitamin D insufficiency in relation to cardio-metabolic markers. Nutr Metab Cardiovasc Dis 2014; 24: 489–494.

  100. Knekt P, Laaksonen M, Mattila C, et al. Serum vitaminD and subsequent occurrence of type 2 diabetes. Epidemiology. 2008;19:666–71.

    Article  PubMed  Google Scholar 

  101. Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care. 2006;29:650–6.

    Article  CAS  PubMed  Google Scholar 

  102. Liu S, Song Y, Ford ES, Manson JE, Buring JE, Ridker PM. Dietary calcium, vitaminD, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005;28:2926–32.

    Article  CAS  PubMed  Google Scholar 

  103. Kayaniyil S, Vieth R, Retnakaran R, et al. Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes. DiabetesCare. 2010;33:1379–81.

    Google Scholar 

  104. Broder AR, Tobin JN, Putterman C. Disease-specific definitions of vitamin D deficiency need to be established in autoimmune and non-autoimmune chronic diseases: a retrospective comparison of three chronic diseases. Arthritis Res Ther. 2010;12:R191.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Hypponen E, Boucher BJ, Berry DJ, et al. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British birth cohort. Diabetes. 2008;57:298–305.

    Article  CAS  PubMed  Google Scholar 

  106. Lu L, Yu Z, Pan A, et al. Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals. Diabetes Care. 2009;32:1278–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Heaney RP, French CB, Nguyen S, Ferreira M, Baggerly LL, Brunel L, Veugelers PA. Novel Approach Localizes the Association of Vitamin D Status With Insulin Resistance to One Region of the 25-Hydroxyvitamin D Continuum. Adv Nutr. 2013;4:303–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Garcia OP, Long KZ, Rosado JL. Impact of micronutrient deficiencies on obesity. Nutr Rev. 2009;67:559–72.

    Article  PubMed  Google Scholar 

  109. Cheng S, Massaro JM, Fox CS, et al. Adiposity, cardiometabolic risk, and vitamin D status: the Framingham heart study. Diabetes. 2010;59:242–8.

    Article  CAS  PubMed  Google Scholar 

  110. Gallagher JC, Yalamanchili V, Smith LM. The effect of vitamin D supplementation on serum 25OHD in thin and obese women. J Steroid Biochem Mol Biol. 2013;136:195–200.

    Article  CAS  PubMed  Google Scholar 

  111. Pereira-Santos M, Costa PR, Assis AM, et al. Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes Rev. 2015;16:341–9.

    Article  CAS  PubMed  Google Scholar 

  112. Dhaliwal R, Mikhail M, Feuerman M, Aloia JF. The vitamin D dose response in obesity. Endocr Pract. 2014;20:1258–64.

    PubMed  Google Scholar 

  113. Wright CS, Weinheimer-Haus EM, Fleet JC, Peacock M, Campbell WW. The apparent relation between plasma25-hydroxyvitaminD and insulin resistance is largely attributable to central adiposity in overweight and obese adults. JNutr. 2015;145:2683–9.

    CAS  Google Scholar 

  114. Wortsman J, Matsuoka LY, Chen TC, et al. Decreased bioavailability of vitamin D in obesity. Am J Clin Nutr. 2000;72:690–3.

    CAS  PubMed  Google Scholar 

  115. Drincic AT, Armas LA, Van Diest EE, et al. Volumetric dilution, rather than sequestration best explains the low vitamin d status of obesity. Obesity (Silver Spring). 2012;20:1444–8.

    Article  CAS  Google Scholar 

  116. Oh J, Weng S, Feltonetal SK. 1,25(OH) 2 vitamin D inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation. 2009;120:687–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Joergensen C, Gall MA, Schmedes A, Tarnow L, Parving HH, Rossing P. Vitamin D levels and mortality in type 2 diabetes. Diabetes Care. 2010;33:2238–43.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Astorri E, Fiorina P, Gavaruzzi G, Astorri A, Magnati G. Left ventricular function in insulin-dependent and in non-insulin-dependent diabetic patients: radionuclide assessment. Cardiology. 1997;88:152–5.

    Article  CAS  PubMed  Google Scholar 

  119. Perseghin G, Fiorina P, De Cobelli F, Scifo P, Esposito A, Canu T, Danna M, Gremizzi C. Cross-sectional assessment of the effect of kidney and kidney-pancreas transplantation on resting left ventricular energy metabolism in type 1 diabetic-uremic patients: a phosphorous-31 magnetic resonance spectroscopy study. Journal of the American College of Cardiology. 2005;46:1085–92.

    Article  PubMed  Google Scholar 

  120. Lee TI, Kao YH, Chen YC, Tsai WC, Chung CC, Chen YJ. Cardiac metabolism, inflammation, and peroxisome proliferator-activated receptors modulated by 1,25-dihydroxyvitamin D3 in diabetic rats. Int J Cardiol. 2014;176:151–7.

    Article  PubMed  Google Scholar 

  121. Sugden JA, Davies JI, Witham MD, Morris AD, Struthers AD. Vitamin D improves endothelial function in patients withType2diabetes mellitus and low vitamin D levels. Diabet Med. 2008;25:20–325.

    Article  CAS  Google Scholar 

  122. Forouhi N, Menon R, Sharp S, et al. Effects of vitamin D2 or D3 supplementation on glycaemic control and cardiometabolic risk among people at risk of type 2 diabetes: results of a randomized double-blind placebo-controlled trial. Diabetes Obes Metab. 2015;18:392–400.

    Article  CAS  Google Scholar 

  123. Witham MD, Dove FJ, Dryburgh M, et al. The effect of different doses of vitamin D (3) on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial. Diabetologia. 2010;53:2112–9.

    Article  CAS  PubMed  Google Scholar 

  124. Asemi Z, Samimi M, Tabassi Z, Shakeri H, Esmaillzadeh A. Vitamin D supplementation affects serum high-sensitivity C-reactive protein, insulin resistance, and biomarkers of oxidative stress in pregnant women. J Nutr. 2013;143:1432–8.

    Article  CAS  PubMed  Google Scholar 

  125. Lind L, Pollare T, Hvarfner A, Lithell H, Sorensen OH, Ljunghall S. Long-term treatment with active vitamin D (alphacalcidol) in middle-age men with impaired glucose tolerance; effects on insulin secretion and sensitivity, glucose tolerance and blood pressure. Diabetes Res. 1989;11:141–7.

    CAS  PubMed  Google Scholar 

  126. Afzal S, Bojesen SE, Nordestgaard BG. Low 25-hydroxyvitamin D and risk of type 2 diabetes: a prospective cohort study and metaanalysis. Clin Chem. 2013;59:381–91.

    Article  CAS  PubMed  Google Scholar 

  127. Song Y, Wang L, Pittas AG, et al. Blood 25-Hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care. 2013;36:1422–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Pittas AG, Harris SS, Stark PC, et al. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care. 2007;30:980–6.

    Article  CAS  PubMed  Google Scholar 

  129. Mitri J, Dawson-Hughes B, Hu FB, et al. Effects of vitamin D and calcium supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the calcium and vitamin D for diabetes mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011;94:486–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Zanetti M, Harris SS, Dawson-Hughes B. Ability of vitamin D to reduce inflammation in adults without acute illness. Nutr Rev. 2014;72:95–8.

    Article  PubMed  Google Scholar 

  131. Tzotzas T, Papadopoulou FG. Tziomalos K etal. Rising serum 25-hydroxy-vitamin D levels after weight loss in obese women correlate with improvement in insulin resistance. J Clin Endocrinol Metab. 2010;95:4251–7.

    Article  CAS  PubMed  Google Scholar 

  132. Shab-Bidar S, Neyestani TR, Djazayery A, et al. Regular consumption of vitamin D-fortified yogurt drink (Doogh) improved endothelial biomarkers in subjects with type 2 diabetes: a randomized double-blind clinical trial. BMC Med. 2011;9:125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jorde R, Figenschau Y. Supplementation with cholecalciferol does not improve glycaemic control in diabetic subjects with normal serum 25-hydroxyvitamin D levels. Eur J Nutr. 2009;48:349–54.

    Article  CAS  PubMed  Google Scholar 

  134. Avenell A, Cook JA, Mac Lennan GS, Mc Pherson GC. Vitamin D supplementation and type 2 diabetes: a substudy of a randomised placebo-controlled trial in older people. Age Ageing. 2009;38:606–9.

    Article  PubMed  Google Scholar 

  135. de Boer IH, Tinker LF, Connelly S, Curb JD, Howard BV, Kestenbaum B, Larson JC, Manson JE, Margolis KL, Siscovick DS. Weiss NS; Women's Health Initiative investigators. Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women's Health Initiative. Diabetes Care. 2008;31:701–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Parekh D, Sarathi V, Shivane VK, Bandgar TR, Menon PS, Shah NS. Pilot study to evaluate the effect of short-term improvement in vitamin D status on glucose tolerance in patients with type 2 diabetes mellitus. Endocr Pract. 2010;16:600–8.

    Article  PubMed  Google Scholar 

  137. Heshmat R, Tabatabaei-Malazy O, Abbaszadeh-Ahranjani S, et al. Effect of vitamin D on insulin resistance and anthropometric parameters in Type 2 diabetes; a randomized double-blind clinical trial. Daru: journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 2012; 20:10.

  138. Kampmann U, Mosekilde L, Juhl C, Moller N, Christensen B, Rejnmark L, Wamberg L, Orskov L. Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency - a double-blind, randomized, placebo-controlled trial. Metabolism. 2014;63:1115–24.

    Article  CAS  PubMed  Google Scholar 

  139. Tepper S, Shahar DR, Geva D, Ish-Shalom S. Differences in homeostatic model assessment (HOMA) values and insulin levels after vitamin D supplementation in healthy men: a double-blind randomized controlled trial. Diabetes Obes Metab. 2016;18:633–7.

    Article  CAS  PubMed  Google Scholar 

  140. Von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in south Asian women living in New Zealand who are insulin resistant and vitamin D deficient-a randomised, placebo-controlled trial. Br J Nutr. 2010;103:549–55.

    Article  CAS  PubMed  Google Scholar 

  141. Nazarian S, St Peter JV, Boston RC, et al. Vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucose. Transl Res. 2011;158:276–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Davidson MB, Duran P, Martin LL, Friedman TC. High-DoseVitaminDSupplementation inPeopleWithPrediabetesand Hypovitaminosis. Diabetes Care. 2013;36:260–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Ljunghall S, Lind L, Lithell H, et al. Treatment with one-alpha-hydroxycholecalciferol in middle-aged men with impaired glucose tolerance - a prospective randomized double-blind study. Acta Med Scand. 1987;222:361–7.

    Article  CAS  PubMed  Google Scholar 

  144. Tai K, Need AG, Horowitz CIM. Glucose tolerance and vitamin D: effects of treating vitamin D deficiency. Nutrition. 2008;24:950–6.

    Article  CAS  PubMed  Google Scholar 

  145. George PS, Pearson ER, Witham MD. Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic reviewand meta-analysis. Diabet Med. 2012;29:e142–50.

    Article  CAS  PubMed  Google Scholar 

  146. Seida JC, Mitri J, Colmers IN, Majumdar SR, Davidson MB, Edwards AL, Hanley DA, Pittas AG, Tjosvold L, Johnson JA. Clinical review: effect of vitamin D3 supplementation on improving glucose homeostasis and preventing diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99:3551–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Daniele G, Winnier D, Mari A, Bruder J, Fourcaudot M, Pengou Z, Tripathy D, Jenkinson C, Folli F. Sclerostin and insulin resistance in Prediabetes: evidence of a cross talk between bone and glucose metabolism. Diabetes Care. 2015;38:1509–17.

    Article  CAS  PubMed  Google Scholar 

  148. Wei J, Ferron M, Clarke CJ, Hannun YA, Jiang H, Blaner WS, Karsenty G. Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. J Clin Invest. 2014;124:1–13.

    Article  PubMed  CAS  Google Scholar 

  149. Palsgaard J, Emanuelli B, Winnay JN, Sumara G, Karsenty G, Kahn CR. Cross-talk between insulin and Wnt signaling in preadipocytes. Role of Wnt co-receptor LDL receptor-related protein-5 (LRP5). J Biol Chem. 2016;291:16878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Franco Folli.

Ethics declarations

Conflict of interest

The authors declare no conflict of interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garbossa, S.G., Folli, F. Vitamin D, sub-inflammation and insulin resistance. A window on a potential role for the interaction between bone and glucose metabolism. Rev Endocr Metab Disord 18, 243–258 (2017). https://doi.org/10.1007/s11154-017-9423-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-017-9423-2

Keywords

Navigation