Welcome!
To use the personalized features of this site, please log in or register.
If you have forgotten your username or password, we can help.
|
 |
Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction
| Journal | Diabetologia |
| Publisher | Springer Berlin / Heidelberg |
| ISSN | 0012-186X (Print) 1432-0428 (Online) |
| Issue | Volume 50, Number 7 / July, 2007 |
| Category | Article |
| DOI | 10.1007/s00125-007-0662-8 |
| Pages | 1481-1489 |
| Subject Collection | Medicine |
| SpringerLink Date | Tuesday, April 17, 2007 |
| |
|
Article
Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction
H. S. Jürgens1, S. Neschen1, S. Ortmann2, S. Scherneck1, K. Schmolz1, G. Schüler1, S. Schmidt1, M. Blüher3, S. Klaus1, D. Perez-Tilve4, M. H. Tschöp4, A. Schürmann1  and H.-G. Joost1
| (1) |
Department of Pharmacology, German Institute of Human Nutrition, Potsdam Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany |
| (2) |
Institute for Zoo and Wildlife Research, Berlin, Germany |
| (3) |
Internal Medicine III, University Hospital Leipzig, Leipzig, Germany |
| (4) |
Obesity Research Centre, Department of Psychiatry, University of Cincinnati, Cincinnati, OH, USA |
Received: 17 October 2006 Accepted: 31 January 2007 Published online: 17 April 2007
Abstract
Aims/hypothesis The role of dietary carbohydrate in the pathogenesis of type 2 diabetes is still a subject of controversial debate. Here we
analysed the effects of diets with and without carbohydrate on obesity, insulin resistance and development of beta cell failure
in the obese, diabetes-prone New Zealand Obese (NZO) mouse.
Materials and methods NZO mice were kept on a standard diet (4% [w/w] fat, 51% carbohydrate, 19% protein), a high-fat diet (15, 47 and 17%, respectively)
and a carbohydrate-free diet in which carbohydrate was exchanged for fat (68 and 20%, respectively). Body composition and
blood glucose were measured over a period of 22 weeks. Glucose tolerance tests and euglycaemic-hyperinsulinaemic clamps were
performed to analyse insulin sensitivity. Islet morphology was assessed by immunohistochemistry.
Results Mice on carbohydrate-containing standard or high-fat diets developed severe diabetes (blood glucose >16.6 mmol/l, glucosuria)
due to selective destruction of pancreatic beta cells associated with severe loss of immunoreactivity of insulin, glucose
transporter 2 (GLUT2) and musculoaponeurotic fibrosarcoma oncogene homologue A (MafA). In contrast, mice on the carbohydrate-free
diet remained normoglycaemic and exhibited hyperplastic islets in spite of a morbid obesity associated with severe insulin
resistance and a massive accumulation of macrophages in adipose tissue.
Conclusions/interpretation These data indicate that the combination of obesity, insulin resistance and the inflammatory response of adipose tissue are
insufficient to cause beta cell destruction in the absence of dietary carbohydrate.
Electronic supplementary material The online version of this article (doi:10.1007/s00125-007-0662-8) contains supplementary material, which is available to authorised users.
Keywords Beta cell failure - Carbohydrate - Euglycaemic-hyperinsulinaemic clamps - Inflammation - Insulin sensitivity - Insulin - New Zealand obese mouse - Obesity - Pancreas - White adipose tissue
H. S. Jurgens and S. Neschen contributed equally to this paper.
References
| 1. |
Leahy JL, Bonner-Weir S, Weir G (1992) Beta-cell dysfunction induced by chronic hyperglycemia. Current ideas on mechanism
of impaired glucose-induced insulin secretion. Diabetes Care 15:442–455
|
| |
| 2. |
Yki-Jarvinen H (1992) Glucose toxicity. Endocr Rev 13:415–431
|
| |
| 3. |
Weir GC, Laybutt DR, Kaneto H, Bonner-Weir S, Sharma A (2001) Beta-cell adaptation and decompensation during the progression
of diabetes. Diabetes 50(Suppl 1):S154–S159
|
| |
| 4. |
Lee Y, Hirose H, Ohneda M, Johnson JH, McGarry JD, Unger RH (1994) Beta-cell lipotoxicity in the pathogenesis of non-insulin-dependent
diabetes mellitus of obese rats: impairment in adipocyte-beta-cell relationships. Proc Natl Acad Sci USA 91:10878–10882
|
| |
| 5. |
Unger RH (2003) Minireview: weapons of lean body mass destruction: the role of ectopic lipids in the metabolic syndrome. Endocrinology
144:5159–5165
|
| |
| 6. |
Poitout V, Robertson RP (2002) Secondary beta-cell failure in type 2 diabetes—a convergence of glucotoxicity and lipotoxicity.
Endocrinology 143:339–342
|
| |
| 7. |
Leiter EH, Coleman DL, Ingram DK, Reynolds MA (1983) Influence of dietary carbohydrate on the induction of diabetes in C57BL/KsJ-db/db
diabetes mice. J Nutr 113:184–195
|
| |
| 8. |
Plum L, Giesen K, Kluge R et al (2002) Characterization of the diabetes susceptibility locus Nidd/SJL in the New Zealand obese
(NZO) mouse: islet cell destruction, interaction with the obesity QTL Nob1, and effect of dietary fat. Diabetologia 45:823–830
|
| |
| 9. |
Jürgens HS, Schürmann A, Kluge R et al (2006) Hyperphagia, lower body temperature, and reduced running wheel activity precede
development of morbid obesity in New Zealand obese mice. Physiol Genomics 13:234–241
|
| |
| 10. |
Crofford OB, Davis CK (1965) Growth characteristics, glucose tolerance and insulin sensitivity of New Zealand obese mice.
Metabolism 14:271–280
|
| |
| 11. |
Ortlepp JR, Kluge R, Giesen K et al (2000) A metabolic syndrome of hypertension, hyperinsulinemia, and hypercholesterolemia
in the New Zealand Obese (NZO) mouse. Eur J Clin Invest 30:195–202
|
| |
| 12. |
Reifsnyder PC, Leiter EH (2002) Deconstructing and reconstructing obesity-induced diabetes (diabesity) in mice. Diabetes 51:825–832
|
| |
| 13. |
Junger E, Herberg L, Jeruschke K, Leiter EH (2002) The diabetes-prone NZO/Hl strain. II. Pancreatic immunopathology. Lab Invest
82:843–853
|
| |
| 14. |
Tinsley FC, Taicher GZ, Heiman ML (2004) Evaluation of a quantitative magnetic resonance method for mouse whole body composition
analysis. Obes Res 12:150–160
|
| |
| 15. |
Hellwig B, Brown FM, Schürmann A, Shanahan MF, Joost HG (1992) Localization of the binding domain of the inhibitory ligand
forskolin in the glucose transporter GLUT4 by photolabeling, proteolytic cleavage and a site-specific antiserum. Biochim Biophys
Acta 1111:178–184
|
| |
| 16. |
Kitamura YI, Kitamura T, Kruse JP et al (2005) FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA
induction. Cell Metab 2:153–163
|
| |
| 17. |
Ren JM, Marshall BA, Mueckler MM, McCaleb M, Amatruda JM, Shulman GI (1995) Overexpression of Glut4 protein in muscle increases
basal and insulin-stimulated whole body glucose disposal in conscious mice. J Clin Invest 95:429–432
|
| |
| 18. |
Carey DG (1998) Abdominal obesity. Curr Opin Lipidol 9:35–40
|
| |
| 19. |
Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked
insulin resistance. Science 259:87–91
|
| |
| 20. |
Greenberg AS, McDaniel ML (2002) Identifying the links between obesity, insulin resistance and beta-cell function: potential
role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest 32(Suppl 3):24–34
|
| |
| 21. |
Rajala MW, Scherer PE (2003) The adipocyte: at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology
144:3765–3773
|
| |
| 22. |
Xu H, Barnes GT, Yang Q et al (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related
insulin resistance. J Clin Invest 112:1821–1830
|
| |
| 23. |
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation
in adipose tissue. J Clin Invest 112:1796–1808
|
| |
| 24. |
Chankiewitz E, Peschke D, Herberg L et al (2006) Did the gradual loss of GLUT2 cause a shift to diabetic disorders in the
New Zealand obese mouse (NZO/Hl)? Exp Clin Endocrinol Diabetes 114:262–269
|
| |
| 25. |
Jörns A, Tiedge M, Sickel E, Lenzen S (1996) Loss of GLUT2 glucose transporter expression in pancreatic beta cells from diabetic
Chinese hamsters. Virchows Arch 428:177–185
|
| |
| 26. |
Jörns A, Tiedge M, Ziv E, Shafrir E, Lenzen S (2002) Gradual loss of pancreatic beta-cell insulin, glucokinase and GLUT2 glucose
transporter immunoreactivities during the time course of nutritionally induced type-2 diabetes in Psammomys obesus (sand rat).
Virchows Arch 440:63–69
|
| |
| 27. |
Harmon JS, Stein R, Robertson RP (2005) Oxidative stress-mediated, post-translational loss of MafA protein as a contributing
mechanism to loss of insulin gene expression in glucotoxic beta cells. J Biol Chem 280:11107–11113
|
| |
| 28. |
Leiter EH, Reifsnyder PC, Flurkey K, Partke HJ, Junger E, Herberg L (1998) NIDDM genes in mice. Deleterious synergism by both parental genomes contributes to diabetic thresholds. Diabetes 47:1287–1295
|
| |
| 29. |
Plum L, Kluge R, Giesen K, Altmüller J, Ortlepp JR, Joost HG (2000) Type-2-diabetes-like hyperglycaemia in a backcross model
of New Zealand obese (NZO) and SJL mice: Characterization of a susceptibility locus on chromosome 4 and its relation with
obesity. Diabetes 49:1590–1596
|
| |
| 30. |
Hu FB, Manson JE, Stampfer MJ et al (2001) Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med
345:790–797
|
| |
| 31. |
Schulze MB, Manson JE, Ludwig DS et al (2004) Sugar-sweetened beverages, weight gain, and incidence of type 2 diabetes in
young and middle-aged women. JAMA 292:927–934
|
| |
| 32. |
Heidemann C, Hoffmann K, Spranger J et al (2005) A dietary pattern protective against type 2 diabetes in the European Prospective
Investigation into Cancer and Nutrition (EPIC)–Potsdam Study cohort. Diabetologia 48:1126–1134
|
| |
| 33. |
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, STOP-NIDDM Trial Research Group (2002) Acarbose for prevention
of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359:2072–2077
|
| |
Supplemental Material
|
|
|
|
|
|