The Potential Protective Action of Vitamin D in Hepatic Insulin Resistance and Pancreatic Islet Dysfunction in Type 2 Diabetes Mellitus

Vitamin D deficiency (i.e., hypovitaminosis D) is associated with increased insulin resistance, impaired insulin secretion, and poorly controlled glucose homeostasis, and thus is correlated with the risk of metabolic diseases, including type 2 diabetes mellitus (T2DM). The liver plays key roles in glucose and lipid metabolism, and its dysregulation leads to abnormalities in hepatic glucose output and triglyceride accumulation. Meanwhile, the pancreatic islets are constituted in large part by insulin-secreting β cells. Consequently, islet dysfunction, such as occurs in T2DM, produces hyperglycemia. In this review, we provide a critical appraisal of the modulatory actions of vitamin D in hepatic insulin sensitivity and islet insulin secretion, and we discuss the potential roles of a local vitamin D signaling in regulating hepatic and pancreatic islet functions. This information provides a scientific basis for establishing the benefits of the maintenance, or dietary manipulation, of adequate vitamin D status in the prevention and management of obesity-induced T2DM and non-alcoholic fatty liver disease.

[1]  Bess Dawson-Hughes,et al.  The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. , 2007, The Journal of clinical endocrinology and metabolism.

[2]  S. Ringquist,et al.  FoxO1 links hepatic insulin action to endoplasmic reticulum stress. , 2010, Endocrinology.

[3]  S. Tangye,et al.  Inflammatory Mechanisms in Obesity , 2013 .

[4]  F. Tang,et al.  Inducing Embryonic Stem Cells to Differentiate into Pancreatic β Cells by a Novel Three‐Step Approach with Activin A and All‐Trans Retinoic Acid , 2005, Stem cells.

[5]  L. Harrison,et al.  A randomised controlled trial of high dose vitamin D in recent-onset type 2 diabetes. , 2014, Diabetes research and clinical practice.

[6]  P. Leung,et al.  Current progress in stem cell research and its potential for islet cell transplantation. , 2012, Current molecular medicine.

[7]  C. Kampf,et al.  Angiotensin II type 1 receptor inhibition markedly improves the blood perfusion, oxygen tension and first phase of glucose-stimulated insulin secretion in revascularised syngeneic mouse islet grafts , 2005, Diabetologia.

[8]  P. Leung,et al.  The novel roles of glucagon-like peptide-1, angiotensin II, and vitamin D in islet function. , 2010, Advances in experimental medicine and biology.

[9]  P. Leung,et al.  Involvement of the Niacin Receptor GPR109a in the Local Control of Glucose Uptake in Small Intestine of Type 2 Diabetic Mice , 2015, Nutrients.

[10]  F. Foufelle,et al.  New insights into ER stress-induced insulin resistance , 2012, Trends in Endocrinology & Metabolism.

[11]  E. Henriksen,et al.  The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle , 2013, Molecular and Cellular Endocrinology.

[12]  Guido Gerken,et al.  The interaction of hepatic lipid and glucose metabolism in liver diseases. , 2012, Journal of hepatology.

[13]  S. Uchida,et al.  Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase , 2002, Nature Medicine.

[14]  P. Leung,et al.  Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. , 2006, Diabetes.

[15]  C. Mathieu.  Vitamin D and diabetes: Where do we stand? , 2015, Diabetes research and clinical practice.

[16]  J. Kouba,et al.  Vitamin D and Diabetes , 2008, The Diabetes educator.

[17]  P. Leung,et al.  Human Fetal Liver Stromal Cell Co-Culture Enhances the Differentiation of Pancreatic Progenitor Cells into Islet-Like Cell Clusters , 2014, Stem Cell Reviews and Reports.

[18]  P. Leung,et al.  Combination of the Dipeptidyl Peptidase IV Inhibitor LAF237 [(S)-1-[(3-Hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] with the Angiotensin II Type 1 Receptor Antagonist Valsartan [N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl]methyl]-l-valine] Enhances Pancreatic Islet Morpholo , 2008, Journal of Pharmacology and Experimental Therapeutics.

[19]  O. Ryu,et al.  A prospective randomized controlled trial of the effects of vitamin D supplementation on long-term glycemic control in type 2 diabetes mellitus of Korea. , 2014, Endocrine journal.

[20]  G. Hotamisligil,et al.  Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease , 2010, Cell.

[21]  J. Leahy,et al.  Mechanisms of compensatory beta-cell growth in insulin-resistant rats: roles of Akt kinase. , 2005, Diabetes.

[22]  P. Leung.  Current research of the RAS in diabetes mellitus. , 2010, Advances in experimental medicine and biology.

[23]  James D. Johnson,et al.  Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet beta cells. , 2004, The Journal of clinical investigation.

[24]  D. Torres,et al.  Vitamin D and nonalcoholic fatty liver disease (NAFLD): Is it more than just an association? , 2013, Hepatology.

[25]  S. Sharp,et al.  Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study , 2015, The lancet. Diabetes & endocrinology.

[26]  L. Groop,et al.  Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion. , 2000, International journal of clinical practice. Supplement.

[27]  D. Accili,et al.  The new biology of diabetes , 2015, Diabetologia.

[28]  K. Yao,et al.  PDZ-domain containing-2 (PDZD2) is a novel factor that affects the growth and differentiation of human fetal pancreatic progenitor cells. , 2008, The international journal of biochemistry & cell biology.

[29]  J. Alvarez,et al.  Role of Vitamin D in Insulin Secretion and Insulin Sensitivity for Glucose Homeostasis , 2009, International journal of endocrinology.

[30]  D. Onichtchouk,et al.  Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells* , 2007, Journal of Biological Chemistry.

[31]  M. Nakazato,et al.  Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic β-cells. , 2011, Metabolism: clinical and experimental.

[32]  S. Summers,et al.  Sphingolipids and insulin resistance: the five Ws , 2010, Current opinion in lipidology.

[33]  Robert V Farese,et al.  The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance. , 2012, Cell metabolism.

[34]  M. Bashyam,et al.  Hormonal regulation of gluconeogenic gene transcription in the liver , 2010, Journal of Biosciences.

[35]  F. Dudbridge,et al.  Functional genetic polymorphisms in cytokines and metabolic genes as additional genetic markers for susceptibility to develop type 1 diabetes , 2004, Genes and Immunity.

[36]  P. Leung,et al.  Niacin-induced hyperglycemia is partially mediated via niacin receptor GPR109a in pancreatic islets , 2015, Molecular and Cellular Endocrinology.

[37]  A. Pontecorvi,et al.  Vitamin D Deficiency: A New Risk Factor for Type 2 Diabetes , 2012, Annals of Nutrition and Metabolism.

[38]  P. Leung,et al.  “Maternal High-Fat-Diet Programs Rat Offspring Liver Fatty Acid Metabolism”: Might Reduced Vitamin D Availability Due to Increases in Maternal Body Fat Contribute to This Effect? , 2015, Lipids.

[39]  P. Leung,et al.  An update on the islet renin–angiotensin system , 2011, Peptides.

[40]  J. Zierath,et al.  AMP-activated protein kinase signaling in metabolic regulation. , 2006, The Journal of clinical investigation.

[41]  M. Permutt,et al.  Endoplasmic reticulum stress-induced apoptosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3beta in mouse insulinoma cells. , 2005, Diabetes.

[42]  P. Dollé,et al.  Retinoic acid in development: towards an integrated view , 2008, Nature Reviews Genetics.

[43]  M. Holick.  Sunlight, UV-radiation, vitamin D and skin cancer: how much sunlight do we need? , 2008, Advances in experimental medicine and biology.

[44]  B. Zinman,et al.  Association of Vitamin D With Insulin Resistance and β-Cell Dysfunction in Subjects at Risk for Type 2 Diabetes , 2010, Diabetes Care.

[45]  Guilin Qiao,et al.  Vitamin D: a negative endocrine regulator of the renin–angiotensin system and blood pressure , 2004, The Journal of Steroid Biochemistry and Molecular Biology.

[46]  Changhao Sun,et al.  Association between vitamin D receptor gene polymorphism (TaqI) and obesity in Chinese population , 2015, Journal of Genetics.

[47]  Li Yuan,et al.  Ang (1–7) Protects Islet Endothelial Cells from Palmitate-Induced Apoptosis by AKT, eNOS, p38 MAPK, and JNK Pathways , 2014, Journal of diabetes research.

[48]  P. Graves,et al.  Glycogen metabolism and signal transduction in mammals and yeast. , 1991, Advances in enzyme regulation.

[49]  K. Petersen,et al.  Lipid-induced insulin resistance: unravelling the mechanism , 2010, The Lancet.

[50]  M. Holick,et al.  Decreased bioavailability of vitamin D in obesity. , 2000, The American journal of clinical nutrition.

[51]  D. Carling,et al.  The regulation of AMP-activated protein kinase by upstream kinases , 2008, International Journal of Obesity.

[52]  P. Leung,et al.  Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. , 2006, Diabetes.

[53]  J. Gerich,et al.  The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. , 1998, Endocrine reviews.

[54]  J. Manson,et al.  Vitamin D and calcium intake in relation to type 2 diabetes in women. , 2006, Diabetes care.

[55]  R. Heshmat,et al.  Effect of vitamin D on insulin resistance and anthropometric parameters in Type 2 diabetes; a randomized double-blind clinical trial , 2012, DARU Journal of Pharmaceutical Sciences.

[56]  R. Coleman,et al.  Hepatic triacylglycerol accumulation and insulin resistance This work was supported by National Institutes of Health Grants DK56598, DK59935, and DK56350. Published, JLR Papers in Press, November 6, 2008. , 2009, Journal of Lipid Research.

[57]  R. Takayanagi,et al.  Dietary vitamin D3 improves postprandial hyperglycemia in aged mice. , 2015, Biochemical and biophysical research communications.

[58]  P. Leung,et al.  Angiotensin II Type 1 Receptor Antagonism Mediates Uncoupling Protein 2-Driven Oxidative Stress and Ameliorates Pancreatic Islet β-Cell Function in Young Type 2 Diabetic Mice , 2007 .

[59]  C. Wrede,et al.  Protein Kinase B/Akt Prevents Fatty Acid-induced Apoptosis in Pancreatic β-Cells (INS-1)* , 2002, The Journal of Biological Chemistry.

[60]  A. Barthel,et al.  Regulation of the forkhead transcription factor FKHR (FOXO1a) by glucose starvation and AICAR, an activator of AMP-activated protein kinase. , 2002, Endocrinology.

[61]  K. Petersen,et al.  Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance , 2013, Diabetes.

[62]  P. Leung,et al.  Vitamin D and Vitamin A Receptor Expression and the Proliferative Effects of Ligand Activation of These Receptors on the Development of Pancreatic Progenitor Cells Derived from Human Fetal Pancreas , 2011, Stem Cell Reviews and Reports.

[63]  Margaret S. Wu,et al.  Role of AMP-activated protein kinase in mechanism of metformin action. , 2001, The Journal of clinical investigation.

[64]  M. McKinley,et al.  Vitamin D and insulin resistance , 2016, Clinical endocrinology.

[65]  M. Ross,et al.  Maternal High-Fat-Diet Programs Rat Offspring Liver Fatty Acid Metabolism , 2015, Lipids.

[66]  P. Leung,et al.  Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets , 2004, Diabetologia.

[67]  P. Leung,et al.  A novel role for vitamin D: modulation of expression and function of the local renin–angiotensin system in mouse pancreatic islets , 2011, Diabetologia.

[68]  Graeme I. Bell,et al.  Diabetes mellitus and genetically programmed defects in β-cell function , 2001, Nature.

[69]  S. Morini,et al.  Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes , 2011, BMC medicine.

[70]  C. Hales,et al.  Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in East London Asians , 1995, Diabetologia.

[71]  P. Lips,et al.  Effect of Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial , 2015, Diabetes Care.

[72]  A. de Leiva,et al.  Hypovitaminosis D in type 2 diabetes: relation with features of the metabolic syndrome and glycemic control , 2015, Endocrine research.

[73]  P. Leung.  Physiology of the pancreas. , 2010, Advances in experimental medicine and biology.

[74]  P. Leung,et al.  Angiotensin II Type 2 Receptor Is Critical for the Development of Human Fetal Pancreatic Progenitor Cells into Islet‐like Cell Clusters and Their Potential for Transplantation , 2012, Stem cells.

[75]  M. Permutt,et al.  Inhibition of Foxo1 Protects Pancreatic Islet β-Cells Against Fatty Acid and Endoplasmic Reticulum Stress–Induced Apoptosis , 2008, Diabetes.

[76]  P. Leung.  The Renin-Angiotensin System: Current Research Progress in The Pancreas , 2010 .

[77]  Lars Selander,et al.  Retinoic Acid Promotes the Generation of Pancreatic Endocrine Progenitor Cells and Their Further Differentiation into β-Cells , 2008, PloS one.

[78]  E. Furth,et al.  Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα , 2001, Nature Medicine.

[79]  G I Bell,et al.  Diabetes mellitus and genetically programmed defects in beta-cell function. , 2001, Nature.

[80]  N. Dávila,et al.  Identification of a Vitamin D response element in the human insulin receptor gene promoter , 2003, The Journal of Steroid Biochemistry and Molecular Biology.

[81]  A. Pittas,et al.  Vitamin D as a potential modifier of diabetes risk , 2008, Nature Clinical Practice Endocrinology &Metabolism.

[82]  Chilakamarti V. Ramana,et al.  Stat1-Vitamin D Receptor Interactions Antagonize 1,25-Dihydroxyvitamin D Transcriptional Activity and Enhance Stat1-Mediated Transcription , 2002, Molecular and Cellular Biology.

[83]  L. Guarente,et al.  Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[84]  K. Yao,et al.  PDZ-domain containing-2 (PDZD2) drives the maturity of human fetal pancreatic progenitor-derived islet-like cell clusters with functional responsiveness against membrane depolarization. , 2009, Stem cells and development.

[85]  Xianlin Han,et al.  Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease , 2011, Proceedings of the National Academy of Sciences.

[86]  P. Leung,et al.  Modulation of hypovitaminosis D-induced islet dysfunction and insulin resistance through direct suppression of the pancreatic islet renin–angiotensin system in mice , 2013, Diabetologia.

[87]  Shu Q. Liu,et al.  1,25-Dihydroxyvitamin D3 is a negative endocrine regulator of the renin-angiotensin system , 2002 .

[88]  P. Leung,et al.  Angiotensin II Type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet beta-cell function in young Type 2 diabetic mice. , 2007, Antioxidants & redox signaling.

[89]  S Del Prato,et al.  Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies , 2009, Diabetic medicine : a journal of the British Diabetic Association.

[90]  M. Prentki,et al.  Islet beta cell failure in type 2 diabetes. , 2006, The Journal of clinical investigation.

[91]  L. Maranda,et al.  The Effects of Vitamin D Supplementation on Hepatic Dysfunction, Vitamin D Status, and Glycemic Control in Children and Adolescents with Vitamin D Deficiency and Either Type 1 or Type 2 Diabetes Mellitus , 2014, PloS one.