Hereditary predisposition to diet-induced type 2 diabetes has not yet been fully elucidated. We recently established 2 mouse lines with different susceptibilities (resistant and prone) to high-fat diet (HFD)-induced glucose intolerance by selective breeding (designated selectively bred diet-induced glucose intolerance-resistant [SDG-R] and -prone [SDG-P], respectively). To investigate the predisposition to HFD-induced glucose intolerance in pancreatic islets, we examined the islet morphological features and functions in these novel mouse lines. Male SDG-P and SDG-R mice were fed a HFD for 5 weeks. Before and after HFD feeding, glucose tolerance was evaluated by oral glucose tolerance test (OGTT). Morphometry and functional analyses of the pancreatic islets were also performed before and after the feeding period. Before HFD feeding, SDG-P mice showed modestly higher postchallenge blood glucose levels and lower insulin increments in OGTT than SDG-R mice. Although SDG-P mice showed greater β cell proliferation than SDG-R mice under HFD feeding, SDG-P mice developed overt glucose intolerance, whereas SDG-R mice maintained normal glucose tolerance. Regardless of whether it was before or after HFD feeding, the isolated islets from SDG-P mice showed impaired glucose- and KCl-stimulated insulin secretion relative to those from SDG-R mice; accordingly, the expression levels of the insulin secretion-related genes in SDG-P islets were significantly lower than those in SDG-R islets. These findings suggest that the innate predispositions in pancreatic islets may determine the susceptibility to diet-induced diabetes. SDG-R and SDG-P mice may therefore be useful polygenic animal models to study the gene–environment interactions in the development of type 2 diabetes.
Ktorza A, Bernard C, Parent V, Penicaud L, Froguel P, et al. (1997) Are animal models of diabetes relevant to the study of the genetics of non-insulin-dependent diabetes in humans? Diabetes Metab 23 Suppl 238–46.
DeFronzo RA, Ferrannini E (1991) Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 14: 173–194.
Nagao M, Asai A, Kawahara M, Nakajima Y, Sato Y, et al. (2012) Selective breeding of mice for different susceptibilities to high fat diet-induced glucose intolerance: Development of two novel mouse lines, Selectively bred Diet-induced Glucose intolerance-Prone and -Resistant. J Diabetes Invest 3: 245–251.
Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, et al. (2010) Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Model Mech 3: 525–534.
Koyama M, Wada R, Sakuraba H, Mizukami H, Yagihashi S (1998) Accelerated loss of islet beta cells in sucrose-fed Goto-Kakizaki rats, a genetic model of non-insulin-dependent diabetes mellitus. Am J Pathol 153: 537–545.
Koyama M, Wada R, Mizukami H, Sakuraba H, Odaka H, et al. (2000) Inhibition of progressive reduction of islet beta-cell mass in spontaneously diabetic Goto-Kakizaki rats by alpha-glucosidase inhibitor. Metab Clin Exp 49: 347–352.
Nesher R, Gross DJ, Donath MY, Cerasi E, Kaiser N (1999) Interaction between genetic and dietary factors determines beta-cell function in Psammomys obesus, an animal model of type 2 diabetes. Diabetes 48: 731–737.
Chen KW, Boyko EJ, Bergstrom RW, Leonetti DL, Newell-Morris L, et al. (1995) Earlier appearance of impaired insulin secretion than of visceral adiposity in the pathogenesis of NIDDM: 5-year follow-up of initially nondiabetic Japanese-American men. Diabetes Care 18: 747–753.
Ishida H, Takizawa M, Ozawa S, Nakamichi Y, Yamaguchi S, et al. (2004) Pioglitazone improves insulin secretory capacity and prevents the loss of β-cell mass in obese diabetic db/db mice: possible protection of β cells from oxidative stress. Metabolism 53: 488–494.
Wallin T, Ma Z, Ogata H, J？rgensen IH, Iezzi M, et al. (2010) Facilitation of fatty acid uptake by CD36 in insulin-producing cells reduces fatty-acid-induced insulin secretion and glucose regulation of fatty acid oxidation. Biochim Biophys Acta 1801: 191–197.
Noushmehr H, D'Amico E, Farilla L, Hui H, Wawrowsky KA, et al. (2005) Fatty acid translocase (FAT/CD36) is localized on insulin-containing granules in human pancreatic beta-cells and mediates fatty acid effects on insulin secretion. Diabetes 54: 472–481.
Bollheimer LC, Skelly RH, Chester MW, McGarry JD, Rhodes CJ (1998) Chronic exposure to free fatty acid reduces pancreatic beta cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation. J Clin Invest 101: 1094–1101.
Jacqueminet S, Briaud I, Rouault C, Reach G, Poitout V (2000) Inhibition of insulin gene expression by long-term exposure of pancreatic beta cells to palmitate is dependent on the presence of a stimulatory glucose concentration. Metabolism 49: 532–536.
Leahy JL, Cooper HE, Deal DA, Weir GC (1986) Chronic hyperglycemia is associated with impaired glucose influence on insulin secretion. A study in normal rats using chronic in vivo glucose infusions. J Clin Invest 77: 908–915.
Permutt MA, Kakita K, Malinas P, Karl I, Bonner-Weir S, et al. (1984) An in vivo analysis of pancreatic protein and insulin biosynthesis in a rat model for non-insulin-dependent diabetes. J Clin Invest 73: 1344–1350.
Asai A, Nagao M, Kawahara M, Shuto Y, Sugihara H, et al. (2013) Effect of impaired glucose tolerance on atherosclerotic lesion formation: An evaluation in selectively bred mice with different susceptibilities to glucose intolerance. Atherosclerosis 231: 421–426.