The evolution of diabetes in the male leptin receptor؊deficient (fa/fa) Zucker diabetic fatty (ZDF) rat is associated with disruption of normal islet architecture, ␤-cell degranulation, and increased ␤-cell death. It is unknown whether these changes precede or develop as a result of the increasing plasma glucose, or whether the increased ␤-cell death can be prevented. Early intervention with thiazolidinediones prevents disruption of the islet architecture. To determine the specific effects of rosiglitazone (RSG) on ␤-cell mass dynamics, male fa/fa (obese) and ؉/fa or ؉/؉ (lean) rats age 6 weeks were fed either chow (control group [CN]) or chow mixed with rosiglitazone (RSG group) at a dosage of 10 mol ⅐ kg ؊1 body wt ⅐ day ؊1 . Rats were killed after 0, 2, 4, 6, or 10 weeks of treatment (at age 6, 8, 10, 12, or 16 weeks). Plasma glucose increased from 8.9 ؎ 0.4 mmol/l at 0 weeks to 34.2 ؎ 1.8 mmol/l (P ‫؍‬ 0.0001) at 6 weeks of treatment in obese CN rats and fell from 8.0 ؎ 0.3 to 6.3 ؎ 0.4 mmol/l in obese RSG rats (P ‫؍‬ 0.02). ␤-cell mass fell by 51% from 2 to 6 weeks of treatment (ages 8 -12 weeks) in obese CN rats (6.9 ؎ 0.9 to 3.4 ؎ 0.5 mg; P < 0.05), whereas ␤-cell mass was unchanged in obese RSG rats. At 10 weeks of treatment (age 16 weeks), ␤-cell mass in obese CN rats was only 56% of that of obese RSG rats (4.4 ؎ 0.4 vs. 7.8 ؎ 0.3 mg, respectively; P ‫؍‬ 0.0001). The ␤-cell replication rate fell from a baseline value of 0.95 ؎ 0.12% in lean rats and 0.94 ؎ 0.07% in obese rats (at 0 weeks) to ϳ0.3-0.5% in all groups by 6 weeks of treatment (age 12 weeks). After 10 weeks of treatment, ␤-cell replication was higher in obese RSG rats than in CN rats (0.59 ؎ 0.14 vs. 0.28 ؎ 0.05%, respectively; P < 0.02). Application of our mass balance model of ␤-cell turnover indicated that net ␤-cell death was fivefold higher in obese CN rats as compared with RSG rats after 6 weeks of treatment (age 12 weeks). The increase in ␤-cell death in obese CN rats during the 6-week observation period was well correlated with the increase in plasma glucose (r 2 ‫؍‬ 0.90, P < 0.0001). These results suggest that the development of hyperglycemia in ZDF rats is concomitant with increasing net ␤-cell death. ␤-cell proliferation compensates for the increased ␤-cell loss at a time when plasma glucose is moderately elevated, but compensation ultimately fails and the plasma glucose levels increase beyond ϳ20 mmol/l. Treatment with rosiglitazone, previously shown to reduce insulin resistance, prevents the loss of ␤-cell mass in obese ZDF rats by maintaining ␤-cell proliferation and preventing increased net ␤-cell death.

High-fat feeding induces insulin resistance and increases the risk for the development of diabetes and coronary artery disease. Glucocorticoids exacerbate this hyperinsulinemic state, rendering an individual at further risk for chronic disease. The present studies were undertaken to determine whether dietary fat-induced increases in corticosterone (B) reflect alterations in the regulatory components of the hypothalamic-pituitary-adrenal (HPA) axis. Adult male rats were maintained on a high-fat (20%) or control (4%) diet for varying periods of time. Marked elevations in light-phase spontaneous basal B levels were evident as early as 7 days after fat diet onset, and B concentrations remained significantly elevated up to 21 days after fat diet onset compared with controls. In contrast, there were no significant effects on any parameters of spontaneous growth hormone secretory profiles, thus providing support for the specificity of the effects on the HPA axis. In a second study, all groups of rats fed the high-fat diet for 1, 9, or 12 wk exhibited significantly elevated levels of plasma adrenocorticotropic hormone, B, fatty acid, and glucose before, during, and/or at 20, 60, and/or 120 min after the termination of a restraint stress. Furthermore, 12-wk fat-fed animals showed a significant resistance to insulin compared with normally fed controls. There were no differences in negative feedback efficacy in high-fat-fed rats vs. controls. Taken together, these results suggest that dietary fat intake acts as a background form of chronic stress, elevating basal B levels and enhancing HPA responses to stress.

Aims/hypothesis. Several studies have employed the chronic glucose infusion protocol to quantify the metabolic adaptations associated with a prolonged glucose challenge. However, the limited number of indices and time points reported by these studies has generated an incomplete picture of this process. In this study we aimed to generate an integrative and dynamic picture of the physiological adaptations that occur during chronic glucose infusion. Methods. Sprague-Dawley rats were infused with either 50% dextrose or saline (2 ml/h) for a period of between 0 and 6 days. Glucose, insulin and NEFA dynamics were determined from daily blood samples. Subsets of animals were killed daily for histological determination of beta cell mass, size and replication rates. The mathematical model of coupled beta cell mass, insulin and glucose (the βIG model) was used to estimate insulin sensitivity, beta cell function and net neogenesis from this data. Results. Glucose-infused rats displayed transient hyperglycaemia, persistent hyperinsulinaemia and unchanged NEFA levels. Insulin sensitivity decreased by approximately 80% during the first day of glucose infusion, but had returned to pre-infusion levels by Day 3. Beta cell function was four to six times higher than in control rats throughout the experiment. Beta cell mass doubled over the 6 days of glucose infusion due to three phases of adaptation: (i) neogenesis; (ii) hypertrophy and hyperplasia; and (iii) continued hyperplasia coupled to a second wave of neogenesis. Conclusions/interpretation. Contrary to the results reported for perfused pancreas and in vitro experiments, we found that chronic glucose infusion elevated beta cell function. The prediction of a second wave of beta cell neogenesis, coupled with our previous report of "focal areas" on Day 3, suggests the existence of delayed acinar-to-islet transdifferentiation.

No abstract