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.

Aims/Introduction:  The development of type 2 diabetes is primarily due to lifestyle and environmental factors, as well as genetics, as shown by familial clustering. To establish mouse lines for evaluating heritable factors determining susceptibility to diet‐induced diabetes, we performed selective breeding for differences in high fat diet (HFD)‐induced glucose intolerance.Materials and Methods:  Selective breeding was performed using hybrid mice of C57BL/6J, C3H/HeJ and AKR/N backgrounds. After 5‐week HFD feeding, mice showing high and low 2‐h blood glucose levels in an oral glucose tolerance test (OGTT) were selected and bred over 14 generations to produce lines prone and resistant to diet‐induced glucose intolerance (designated Selectively bred Diet‐induced Glucose intolerance‐Prone [SDG‐P] and ‐Resistant [SDG‐R]).Results:  At 5 weeks of age (pre HFD feeding), SDG‐P mice showed higher blood glucose levels both in the OGTT and insulin tolerance test as compared to SDG‐R mice. After receiving HFD, the glucose intolerance of SDG‐P mice became more evident without hyper insulin secretion. In addition, SDG‐P mice had greater body weight gain and lower HDL‐cholesterol levels as compared to SDG‐R mice. In comparison with C57BL/6J, a well‐known strain prone to HFD‐induced glucose intolerance, SDG‐P mice showed significantly higher glucose levels in OGTT after the 5‐week HFD feeding.Conclusions:  Susceptibility to HFD‐induced glucose intolerance was transmitted over generations and was intensified by selective breeding. The newly established mouse lines, SDG‐P and SDG‐R, may be useful in investigating the pathophysiology of type 2 diabetes through elucidating the crucial factors for determining the susceptibility to HFD‐induced glucose intolerance. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00175.x, 2011)

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Aim: Although metformin treatment has been reported to reduce the risk of cardiovascular events in patients with type 2 diabetes, the underlying mechanisms have not been elucidated fully. Here we assessed atherosclerotic lesion formation in newly established 2 mouse lines with different blood glucose levels (Oikawa-Nagao Diabetes-Prone [ON-DP] and -Resistant [ON-DR]) to evaluate the effect of metformin on early-stage atherosclerosis.Methods: Mildly hyperglycemic ON-DP and normoglycemic ON-DR female mice fed an atherogenic diet for 20 weeks (8–28 weeks of age). During the feeding period, one group of each mouse line received metformin in drinking water (0.1%), while another group received water alone as control. Atherosclerotic lesion formation in the aortic sinus was quantitively analyzed from the oil red O-stained area of the serial sections.Results: Metformin treatment did not affect food intake, body weight, and casual blood glucose levels within each mouse line during the 20-week feeding period. Nevertheless, metformin treatment significantly reduced atherosclerotic lesion formation in the ON-DP mice (59% of control), whereas no significant effect of metformin was observed in the lesion size of the ON-DR mice.Conclusion: Metformin can attenuate early-stage atherogenesis in mildly hyperglycemic ON-DP mice. Pleiotropic effects of metformin, beyond its glucose-lowering action, may contribute to the antiatherogenic property in the early-stage atherosclerosis.