Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport

Abstract

A connection between diet, obesity and diabetes exists in multiple species and is the basis of an escalating human health problem. The factors responsible provoke both insulin resistance and pancreatic beta cell dysfunction but remain to be fully identified. We report a combination of molecular events in human and mouse pancreatic beta cells, induced by elevated levels of free fatty acids or by administration of a high-fat diet with associated obesity, that comprise a pathogenic pathway to diabetes. Elevated concentrations of free fatty acids caused nuclear exclusion and reduced expression of the transcription factors FOXA2 and HNF1A in beta cells. This resulted in a deficit of GnT-4a glycosyltransferase expression in beta cells that produced signs of metabolic disease, including hyperglycemia, impaired glucose tolerance, hyperinsulinemia, hepatic steatosis and diminished insulin action in muscle and adipose tissues. Protection from disease was conferred by enforced beta cell–specific GnT-4a protein glycosylation and involved the maintenance of glucose transporter expression and the preservation of glucose transport. We observed that this pathogenic process was active in human islet cells obtained from donors with type 2 diabetes; thus, illuminating a pathway to disease implicated in the diet- and obesity-associated component of type 2 diabetes mellitus.

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Figure 1: Dietary regulation of Mgat4a and Slc2a2 gene expression by Foxa2 and Hnf1a in mouse pancreatic islet cells.
Figure 2: Effect of palmitic acid on normal mouse and human islet cells.
Figure 3: Analyses of human islets from normal donors and donors with type 2 diabetes.
Figure 4: Enforced beta cell–specific GnT-4a glycosylation prevents loss of Glut-2 expression and inhibits onset of disease signs including hyperglycemia and failure of GSIS.
Figure 5: Beta cell–specific GnT-4a protein glycosylation promotes systemic insulin sensitivity and inhibits development of hepatic steatosis.
Figure 6: Enforced beta cell–specific expression of GnT-4a substrate GLUT-2 mitigates diet- and obesity-induced diabetes.

References

  1. 1

    Olefsky, J.M. & Courtney, C.H. Type 2 diabetes mellitus: etiology, pathogenesis and natural history. in Endocrinology 5th edn (eds. DeGroot, L.J. et al.) 1093–1117 (W.B. Saunders, 2005).

    Google Scholar 

  2. 2

    Weir, G.C. & Leahy, J.L. Pathogenesis of non-insulin dependent (type II) diabetes mellitus. in Joslin's Diabetes Mellitus (eds. Joslin, E.P., Kahn, C.R. & Weir, G.C.), Ch. 14, 240–264 (Lea and Febiger, 1994).

  3. 3

    Smyth, S. & Heron, A. Diabetes and obesity: the twin epidemics. Nat. Med. 12, 75–80 (2006).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Korner, J., Woods, S.C. & Woodworth, K.A. Regulation of energy homeostasis and heath consequences in obesity. Am. J. Med. 122, S12–S18 (2009).

    Article  PubMed  Google Scholar 

  5. 5

    Parillo, M. & Ricardi, G. Diet composition and the risk of type 2 diabetes: epidemiological and clinical evidence. Br. J. Nutr. 92, 7–19 (2004).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Surwit, R.S., Kuhn, C.M., Cochrane, C., McCubbin, J.A. & Feinglos, M.N. Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37, 1163–1167 (1988).

    CAS  Article  PubMed  Google Scholar 

  7. 7

    Kahn, S.E. The relative contribution of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46, 3–19 (2003).

    CAS  Article  PubMed  Google Scholar 

  8. 8

    Winzell, M.S. & Ahren, B. The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 53 (suppl. 3) S215–S219 (2004).

    Article  PubMed  Google Scholar 

  9. 9

    Leroith, D. & Accili, D. Mechanisms of disease: using genetically altered mice to study concepts of type 2 diabetes. Nat. Clin. Pract. Endocrinol. Metab. 4, 164–172 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Saltiel, A.R. & Kahn, C.R. Insulin signaling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Schenk, S., Saberi, M. & Olefsky, J.M. Insulin sensitivity: modulation by nutrients and inflammation. J. Clin. Invest. 118, 2992–3002 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Reaven, G.M. The insulin resistance syndrome: definition and dietary approaches to treatment. Annu. Rev. Nutr. 25, 391–406 (2005).

    CAS  Article  Google Scholar 

  13. 13

    Johnson, J.H. et al. Underexpression of beta cell high Km glucose transporters in noninsulin-dependent diabetes. Science 250, 546–549 (1990).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Orci, L. et al. Evidence that down-regulation of β-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia. Proc. Natl. Acad. Sci. USA 87, 9953–9957 (1990).

    CAS  Article  PubMed  Google Scholar 

  15. 15

    Orci, L. et al. Reduced β-cell glucose transporter in new onset diabetic rats. J. Clin. Invest. 86, 1615–1622 (1990).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    Thorens, B., Weir, G., Leahy, J.L., Lodish, H.F. & Bonner-Weir, S. Reduced expression of the liver/beta-cell glucose transporter isoform in glucose-insensitive pancreatic beta cells of diabetic rats. Proc. Natl. Acad. Sci. USA 87, 6492–6496 (1990).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Unger, R.H. Diabetic hyperglycemia: link to impaired glucose transport in pancreatic beta cells. Science 251, 1200–1205 (1991).

    CAS  Article  PubMed  Google Scholar 

  18. 18

    Valera, A. et al. Expression of GLUT2 antisense RNA in β cells of transgenic mice leads to diabetes. J. Biol. Chem. 269, 28543–28546 (1994).

    CAS  PubMed  Google Scholar 

  19. 19

    Gremlich, S., Roduit, R. & Thorens, B. Dexamethasone induces posttranslational degradation of GLUT2 and inhibition of insulin secretion in isolated pancreatic β cells. J. Biol. Chem. 272, 3216–3222 (1997).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Guillam, M.T. et al. Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat. Genet. 17, 327–330 (1997).

    CAS  Article  PubMed  Google Scholar 

  21. 21

    Guillam, M.-T., Dupraz, P. & Thorens, B. Glucose uptake, utilization, and signaling in GLUT2-null islets. Diabetes 49, 1485–1491 (2000).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Reimer, M.K. & Ahrén, B. Altered β-cell distribution of pdx-1 and GLUT2 after a short-term challenge with a high-fat diet in C57BL/6J mice. Diabetes 51, S138–S143 (2002).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Del Guerra, S. et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54, 727–735 (2005).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Kahn, S.E., Hull, R.L. & Utzschneider, K.M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Ohtsubo, K. et al. Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes. Cell 123, 1307–1321 (2005).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Minowa, M.T. et al. cDNA cloning and expression of bovine UDP-N-acetylglucosamine:α1,3-D-mannoside β1,4-N-acetylglucosaminyltransferase IV. J. Biol. Chem. 273, 11556–11562 (1998).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    De Vos, A. et al. Human and rat beta cells differ in glucose transporter but not glucokinase gene expression. J. Clin. Invest. 96, 2489–2495 (1995).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    Thorens, B., Guillam, M.T., Beermann, F., Burcelin, R. & Jaqueet, M. Transgenic overexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion. J. Biol. Chem. 275, 23751–23758 (2000).

    CAS  Article  PubMed  Google Scholar 

  29. 29

    Alessi, D.R. & Cohen, P. Mechanism of activation and function of protein kinase B. Curr. Opin. Genet. Dev. 8, 55–62 (1998).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    White, M.F. IRS proteins and the common path to diabetes. Am. J. Physiol. Endocrinol. Metab. 283, E413–E422 (2002).

    CAS  Article  PubMed  Google Scholar 

  31. 31

    Rossmeisl, M., Rim, J.S., Koza, R.A. & Kozak, L.P. Variation in type 2 diabetes-related traits in mouse strains susceptible to diet-induced obesity. Diabetes 52, 1958–1966 (2003).

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Poitout, V. & Robertson, R.P. Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr. Rev. 29, 351–366 (2008).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Kebede, M.A., Alquier, T., Latour, M.G. & Poitout, V. Lipid receptors and islet function: therapeutic implications? Diabetes Obes. Metab. 11 (suppl. 4) 10–20 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Unger, R.H. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44, 863–870 (1995).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Gremlich, S., Bonny, C., Waeber, G. & Thorens, B. Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J. Biol. Chem. 272, 30261–30269 (1997b).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Wolfrum, C., Asilmaz, E., Luca, E., Friedman, J.M. & Stoffel, M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432, 1027–1032 (2004).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Howell, J.J. & Stoffel, M. Nuclear export-independent inhibition of Foxa2 by insulin. J. Biol. Chem. 284, 24816–24824 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Chen, Y.W. et al. The role of phosphoinositide 3-kinase/Akt signaling in low-dose mercury-induced mouse pancreatic beta-cell dysfunction in vitro and in vivo. Diabetes 55, 1614–1624 (2006).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Lantz, K.A. et al. Foxa2 regulates multiple pathways of insulin secretion. J. Clin. Invest. 114, 512–520 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Gao, N. et al. Foxa1 and Foxa2 maintain the metabolic and secretory features of the mature beta-cell. Mol. Endocrinol. 24, 1594–1604 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    Mitchell, S.M. & Frayling, T.M. The role of transcription factors in maturity-onset diabetes of the young. Mol. Genet. Metab. 77, 35–43 (2002).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Fukui, K. et al. The HNF-1 target collection controls insulin exocytosis by SNARE complex formation. Cell Metab. 2, 373–384 (2005).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Gunton, J.E. et al. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122, 337–349 (2005).

    CAS  Article  PubMed  Google Scholar 

  44. 44

    Ohtsubo, K. & Marth, J.D. Glycosylation in cellular mechanisms of health and disease. Cell 126, 855–867 (2006).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Rapoport, E.M., Kurmyshkina, O.V. & Bovin, N.V. Mammalian galectins: structure, carbohydrate specificity, and functions. Biochemistry (Mosc.) 73, 393–405 (2008).

    CAS  Article  Google Scholar 

  46. 46

    Rabinovich, G.A., Toscano, M.A., Jackson, S.S. & Vasta, G.R. Functions of cell surface galectin-glycoprotein lattices. Curr. Opin. Struct. Biol. 17, 513–520 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Scarlett, J.A., Gray, R.S., Griffin, J., Olefsky, J.M. & Kolterman, O.G. Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care 5, 353–363 (1982).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Revers, R.R., Kolterman, O.G., Scarlett, J.A., Gray, R.S. & Olefsky, J.M. Lack of in vivo insulin resistance in controlled insulin-dependent, type I, diabetic patients. J. Clin. Endocrinol. Metab. 58, 353–358 (1984).

    CAS  Article  PubMed  Google Scholar 

  49. 49

    Garvey, W.T., Olefsky, J.M., Griffin, J., Hamman, R.F. & Kolterman, O.G. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34, 222–234 (1985).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Pillay, T.S., Xiao, S. & Olefsky, J.M. Glucose-induced phosphorylation of the insulin receptor. Functional effects and characterization of phosphorylation sites. J. Clin. Invest. 97, 613–620 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Shafi, R. et al. The O-GlcNAc transferase gene resides on the X chromosome and is essential for embryonic stem cell viability and mouse ontogeny. Proc. Natl. Acad. Sci. USA 97, 5735–5739 (2000).

    CAS  Article  PubMed  Google Scholar 

  52. 52

    Cousin, S.P. et al. Free fatty acid–induced inhibition of glucose and insulin-like growth factor I–induced deoxyribonucleic acid synthesis in the pancreatic β-cell line INS-1. Endocrinology 142, 229–240 (2001).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

This research was funded primarily by US National Institutes of Health (NIH) grant DK48247 with additional support from GM62116 and CA71932 (J.D.M.). Further funding was obtained from DK033651, DK074868, T32 DK007494, DK063491 and the Eunice Kennedy Shriver National Institute of Child Health and Human Development–NIH through cooperative agreement of U54 HD 012303-25 as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research (J.M.O.) and the Japan Diabetes Foundation and Suntory Institute for Bioorganic Research (SUNBOR grant; K.O.).

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K.O. conducted the majority of experiments and helped write the manuscript. M.Z.C. and J.M.O. carried out the hyperinsulinemic-euglycemic clamp studies and helped write the manuscript. J.D.M. conceived of and supervised the project and wrote the manuscript.

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Correspondence to Jamey D Marth.

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The authors declare no competing financial interests.

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Ohtsubo, K., Chen, M., Olefsky, J. et al. Pathway to diabetes through attenuation of pancreatic beta cell glycosylation and glucose transport. Nat Med 17, 1067–1075 (2011). https://doi.org/10.1038/nm.2414

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