Objective To determine the effects of diet-induced obesity and caloric restriction on blood glucose, insulin secretion, and islet β-cell morphology in mice. Methods Eight-week-old male C57BL/6 mice were randomly allocated to control, high-fat diet-fed obese, and calorie restriction groups. Their body masses and blood glucose concentrations were measured over a 12-week period. In addition, insulin tolerance testing (ITT), intraperitoneal glucose tolerance testing (IPGTT), and pathological examination using hematoxylin and eosin-staining of the pancreas were used to evaluate the glucose and insulin tolerance, and islet β-cell function and morphology. Glucose-stimulated insulin secretion (GSIS) was also assessed in isolated islets. Results The body mass gain in the high-fat group was 55. 7%, higher than in the control group ( P <0. 05), but that of the caloric restriction group was 12. 8% less ( P <0. 05). Insulin sensitivity and GSIS were lower in the high-fat diet-fed than in control mice. In contrast, fasting insulin was lower in the caloric restriction group, and early phase insulin secretion and GSIS were normal. Conclusions Obese mice exhibit an insulin-secretory deficit and insulin resistance, whereas caloric restriction is associated with normal insulin secretion and a low fasting insulin concentration.