The Vascular Trigger of Type II Diabetes Mellitus

Abstract

Type II diabetes mellitus is associated with obesity and insulin resistance. However, many humans with these symptoms never develop diabetes. This raises the key question of the difference that determines why one obese individual develops diabetes, whereas another one does not. Here we review the experimental support for our hypothesis that mutual signaling between insulin producing beta cells and pancreatic endothelial cells determines whether a person develops type II diabetes. According to our hypothesis, a disturbance of this mutual signaling leads to diabetes in an insulin-resistant individual. We discuss that most type II diabetes-associated genes have a function in the vascular system, and that endoplasmic reticulum (ER) stress in beta cells can result from vascular defects in pancreatic islets. Whereas vascular complications have been widely accepted as a result of type II diabetes, we suggest that changes within the vascular system may act at an earlier stage and trigger the onset of type II diabetes.

Key words

diabetes - VEGF - pancreatic islet

References

• 1 Koning EJ de, Bonner-Weir S, Rabelink TJ. Preservation of beta-cell function by targeting beta-cell mass.  Trends Pharmacol Sci. 2008;  29 218-227
• 2 Nikolova G, Strilic B, Lammert E. The vascular niche and its basement membrane.  Trends Cell Biol. 2007;  17 19-25
• 3 Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels.  Science. 2001;  294 564-567
• 4 Yoshitomi H, Zaret KS. Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a.  Development. 2004;  131 807-817
• 5 Nikolova G, Jabs N, Konstantinova I. et al . The vascular basement membrane: a niche for insulin gene expression and beta cell proliferation.  Dev Cell. 2006;  10 397-405
• 6 Lammert E, Gu G, MacLaughlin M. et al . Role of VEGF-A in vascularization of pancreatic islets.  Curr Biol. 2003;  13 1070-1074
• 7 Iwashita N, Uchida T, Choi JB. et al . Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice.  Diabetologia. 2007;  50 380-389
• 8 Laurent G, Solari F, Mateescu B. et al . Oxidative stress contributes to aging by enhancing pancreatic angiogenesis and insulin signaling.  Cell Metab. 2008;  7 113-124
• 9 Brissova M, Shostak A, Shiota M. et al . Pancreatic islet production of vascular endothelial growth factor-a is essential for islet vascularization, revascularization, and function.  Diabetes. 2006;  55 2974-2985
• 10 Aronne LJ. Classification of obesity and assessment of obesity-related health risks.  Obes Res. 2002;  10 ((Suppl 2)) 105S-115S
• 11 Graham TE, Kahn BB. Tissue-specific alterations of glucose transport and molecular mechanisms of intertissue communication in obesity and type 2 diabetes.  Horm Metab Res. 2007;  39 717-721
• 12 Luca C de, Olefsky JM. Inflammation and insulin resistance.  FEBS Lett. 2008;  582 97-105
• 13 Muoio DM, Newgard CB. Mechanisms of disease: molecular and metabolic mechanisms of insulin resistance and beta-cell failure in type 2 diabetes.  Nat Rev Mol Cell Biol. 2008;  9 193-205
• 14 Poitout V, Robertson RP. Minireview: Secondary beta-cell failure in type 2 diabetes – a convergence of glucotoxicity and lipotoxicity.  Endocrinology. 2002;  143 339-342
• 15 Yamaguchi S, Ishihara H, Yamada T. et al . ATF4-Mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress.  Cell Metab. 2008;  7 269-276
• 16 Scheuner D, Vander Mierde D, Song B. et al . Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis.  Nat Med. 2005;  11 757-764
• 17 Harding HP, Zeng H, Zhang Y. et al . Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival.  Mol Cell. 2001;  7 1153-1163
• 18 Marchetti P, Bugliani M, Lupi R. et al . The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients.  Diabetologia. 2007;  50 2486-2494
• 19 Laybutt DR, Preston AM, Akerfeldt MC. et al . Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes.  Diabetologia. 2007;  50 752-763
• 20 Zhang W, Feng D, Li Y. et al . PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis.  Cell Metab. 2006;  4 491-497
• 21 Weber SM, Chambers KT, Bensch KG, Scarim AL, Corbett JA. PPARgamma ligands induce ER stress in pancreatic beta-cells: ER stress activation results in attenuation of cytokine signaling.  Am J Physiol Endocrinol Metab. 2004;  287 E1171-E1177
• 22 Han KL, Choi JS, Lee JY. et al . Therapeutic potential of peroxisome proliferators–activated receptor-alpha/gamma dual agonist with alleviation of endoplasmic reticulum stress for the treatment of diabetes.  Diabetes. 2008;  57 737-745
• 23 Yamada T, Ishihara H, Tamura A. et al . WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells.  Hum Mol Genet. 2006;  15 1600-1609
• 24 Frayling TM. Genome-wide association studies provide new insights into type 2 diabetes aetiology.  Nat Rev Genet. 2007;  8 657-662
• 25 Grant SF, Thorleifsson G, Reynisdottir I. et al . Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.  Nat Genet. 2006;  38 320-323
• 26 Cauchi S, Meyre D, Dina C. et al . Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes.  Diabetes. 2006;  55 2903-2908
• 27 Shu L, Sauter NS, Schulthess FT. et al . Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets.  Diabetes. 2008;  57 645-653
• 28 Lyssenko V, Lupi R, Marchetti P. et al . Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.  J Clin Invest. 2007;  117 2155-2163
• 29 Li J, Mizukami Y, Zhang X, Jo WS, Chung DC. Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3beta.  Gastroenterology. 2005;  128 1907-1918
• 30 Giles RH, Lolkema MP, Snijckers CM. et al . Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis.  Oncogene. 2006;  25 3065-3070
• 31 Levy L, Neuveut C, Renard CA. et al . Transcriptional activation of interleukin-8 by beta-catenin-Tcf4.  J Biol Chem. 2002;  277 42386-42393
• 32 Lobov IB, Rao S, Carroll TJ. et al . WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature.  Nature. 2005;  437 417-421
• 33 Freedman DA, Folkman J. CDK2 translational down-regulation during endothelial senescence.  Exp Cell Res. 2005;  307 118-130
• 34 Yang DG, Liu L, Zheng XY. Cyclin-dependent kinase inhibitor p16(INK4a) and telomerase may co-modulate endothelial progenitor cells senescence.  Ageing Res Rev. 2008;  7 137-146
• 35 Song Z, Wang Y, Xie L, Zang X, Yin H. Expression of senescence-related genes in human corneal endothelial cells.  Mol Vis. 2008;  14 161-170
• 36 Krishnamurthy J, Ramsey MR, Ligon KL. et al . p16INK4a induces an age-dependent decline in islet regenerative potential.  Nature. 2006;  443 453-457
• 37 Bort R, Martinez-Barbera JP, Beddington RS, Zaret KS. Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas.  Development. 2004;  131 797-806
• 38 Hallaq H, Pinter E, Enciso J. et al . A null mutation of Hhex results in abnormal cardiac development, defective vasculogenesis and elevated Vegfa levels.  Development. 2004;  131 5197-5209
• 39 Kubo A, Chen V, Kennedy M. et al . The homeobox gene HEX regulates proliferation and differentiation of hemangioblasts and endothelial cells during ES cell differentiation.  Blood. 2005;  105 4590-4597
• 40 Duan SZ, Ivashchenko CY, Usher MG, Mortensen RM. PPAR-gamma in the Cardiovascular System.  PPAR Res. 2008;  2008 745-804
• 41 Biscetti F, Gaetani E, Flex A. et al . Selective activation of PPAR{alpha} and PPAR{gamma} induces neoangiogenesis through a VEGF-dependent mechanism.  Diabetes. 2008; 
• 42 Moibi JA, Gupta D, Jetton TL. et al . Peroxisome proliferator-activated receptor-gamma regulates expression of PDX-1 and NKX6.1 in INS-1 cells.  Diabetes. 2007;  56 88-95
• 43 Konstantinova I, Nikolova G, Ohara-Imaizumi M. et al . EphA-Ephrin-A-mediated beta cell communication regulates insulin secretion from pancreatic islets.  Cell. 2007;  129 359-370
• 44 Ahren B. Autonomic regulation of islet hormone secretion–implications for health and disease.  Diabetologia. 2000;  43 393-410
• 45 Gilon P, Henquin JC. Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function.  Endocr Rev. 2001;  22 565-604
• 46 Bonner-Weir S, Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat.  Diabetes. 1982;  31 883-889
• 47 Nikolova G, Lammert E. Interdependent development of blood vessels and organs.  Cell Tissue Res. 2003;  314 33-42
• 48 Normund Jabs IF, Martin BB, Gromada J, Ferrara N, Claes BW, Lammert E. Reduced insulin secretion and content in VEGF-A deficient mouse pancreatic islets.  Exp Clin Endocrinol & Diabetes. 2008;  in press
• 49 Cali AM, Caprio S. Prediabetes and type 2 diabetes in youth: an emerging epidemic disease?.  Curr Opin Endocrinol Diabetes Obes. 2008;  15 123-127
• 50 Gunton JE, Kulkarni RN, Yim S. et al . Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes.  Cell. 2005;  122 337-349
• 51 Harris AL. Hypoxia – a key regulatory factor in tumour growth.  Nat Rev Cancer. 2002;  2 38-47
• 52 Gerken T, Girard CA, Tung YC. et al . The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase.  Science. 2007;  318 1469-1472
• 53 Lynch JA, George AM, Eisenhauer PB. et al . Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures.  J Neurosci Res. 2006;  83 1262-1270
• 54 Bernstein HG, Lendeckel U, Bukowska A. et al . Regional and cellular distribution patterns of insulin-degrading enzyme in the adult human brain and pituitary.  J Chem Neuroanat. 2008;  35 216-224
• 55 Schnitzler MM, Derst C, Daut J, Preisig-Muller R. ATP-sensitive potassium channels in capillaries isolated from guinea-pig heart.  J Physiol. 2000;  525 ((Pt 2)) 307-317
• 56 Yoshida H, Feig JE, Morrissey A. et al . K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits.  J Mol Cell Cardiol. 2004;  37 857-869
• 57 Inoue H, Tanizawa Y, Wasson J. et al . A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome).  Nat Genet. 1998;  20 143-148
• 58 Strom TM, Hortnagel K, Hofmann S. et al . Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein.  Hum Mol Genet. 1998;  7 2021-2028
• 59 Sharma MR, Tuszynski GP, Sharma MC. Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5.  J Cell Biochem. 2004;  91 398-409
• 60 Mitsios N, Pennucci R, Krupinski J. et al . Expression of cyclin-dependent kinase 5 mRNA and protein in the human brain following acute ischemic stroke.  Brain Pathol. 2007;  17 11-23
• 61 Ager EI, Pask AJ, Shaw G, Renfree MB. Expression and protein localisation of IGF2 in the marsupial placenta.  BMC Dev Biol. 2008;  8 17
• 62 Chimienti F, Devergnas S, Favier A, Seve M. Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules.  Diabetes. 2004;  53 2330-2337
• 63 Baumhueter S, Mendel DB, Conley PB. et al . HNF-1 shares three sequence motifs with the POU domain proteins and is identical to LF-B1 and APF.  Genes Dev. 1990;  4 372-379

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