Ghrelin is produced by stomach oxyntic cells and thought to be involved in the regulation of body weight and food intake. We demonstrate here that the peptide inhibits insulin secretion from overnight-incubated mouse islets in the presence of 8.3, 11.1, and 22.2 mmol/liter glucose. Ghrelin was most efficient at 1 nmol/liter and its effect disappeared by raising the dose more than 25 nmol/liter. Also, insulin secretion in the presence of high K(+) concentrations (20 mmol/liter) was inhibited by ghrelin. Furthermore, when administered iv to mice together with glucose (1 g/kg), ghrelin (50 nmol/kg) inhibited both the rapid 1-min insulin response (364 +/- 90 vs. 985 +/- 114 pmol/liter in controls, P < 0.001) and the area under the 50 min curve of insulin concentration (12.6 +/- 1.2 vs. 15.6 +/- 1.2 nmol/liter x 50 min; P = 0.046) without affecting the glucose disposal rate, insulin sensitivity or glucose effectiveness, i.e. glucose disposal independent from any dynamic change in insulin. The insulinostatic effect of ghrelin was inversely related to insulin sensitivity. In contrast, ghrelin had no influence at the lower dose of 5 nmol/kg and only slightly inhibited insulin secretion at the higher dose of 150 nmol/kg. These findings therefore show that ghrelin inhibits glucose-stimulated insulin secretion in the mouse. The effect is dependent on the dose and elicited on distal signaling steps in islet cells. The results suggest that the islet beta-cells are targets for ghrelin.

Objectives: Inhibitors of the glucagon-like peptide-1 (GLP-1)-degrading enzyme, dipeptidyl peptidase IV (DPPIV), are being explored in the treatment of diabetes. We examined the long-term influence of a selective, orally active inhibitor of DPPIV (NVP DPP728), in normal female C57BL/6J mice and such mice rendered glucose-intolerant and insulin-resistant by feeding a high-fat diet. Design: In mice fed a standard diet (11% fat) or a high-fat diet (58% fat), NVP DPP728 (0.12 mmol/g body weight) was administered in the drinking water for an 8 week period. Results: DPPIV inhibition reduced plasma DPPIV activity to 0:01^0:03 mU=ml vs 3:26^0:19 mU=ml in controls ðP , 0:001Þ: Glucose tolerance after gastric glucose gavage, as judged by the area under the curve for plasma glucose levels over the 120 min study period, was increased after 8 weeks by NVP DPP728 in mice fed normal diet ðP ¼ 0:029Þ and in mice fed a high-fat diet ðP ¼ 0:036Þ: This was accompanied by increased plasma levels of insulin and intact GLP-1. Glucose-stimulated insulin secretion from islets isolated from NVP DPP728-treated animals after 8 weeks of treatment was increased as compared with islets from control animals at 5.6, 8.3 and 11.1 mmol/l glucose both in mice fed normal diet and in mice fed a high-fat diet (both P , 0:05). Islet insulin and glucagon immunocytochemistry revealed that NVP DPP728 did not affect the islet architecture. However, the expression of immunoreactive glucose transporter isoform-2 (GLUT-2) was increased by DPPIV inhibition, and in mice fed a high-fat diet, islet size was reduced after treatment with NVP DPP728 from 16:7^2:6 £ 10 3 mm 2 in controls to 7:6^1:0 £ 10 3 mm 2 ðP ¼ 0:0019Þ: Conclusion: Long-term DPPIV inhibition improves glucose tolerance in both normal and glucose-intolerant mice through improved islet function as judged by increased GLUT-2 expression, increased insulin secretion and protection from increased islet size in insulin resistance.

Mechanisms involved in the islet adaptation to insulin resistance were examined in mice of the C57BL/6J strain challenged with a high-fat (58%) diet for 8 weeks. Basal hyperglycemia commenced after 1 week, whereas hyperinsulinemia evolved after 8 weeks. Glucose elimination after an intravenous glucose challenge (1 g/kg) was significantly delayed after 1, 4, and 8 weeks on the high-fat diet compared with normal-diet-fed mice. This result was associated with unchanged insulin responses. However, glucose-stimulated insulin secretion from isolated islets was increased in a compensatory fashion at all glucose levels over a wide range (3.3-22 mmol/l) after 8 weeks on the high-fat diet, whereas no compensatory hypersecretion of insulin was evident after 1 or 4 weeks, except at 22 mmol/l glucose. Immunohistochemistry revealed that the islet architecture of insulin and glucagon cells remained intact in islets from mice fed a high-fat diet. However, the nuclear translocation of the homeobox transcription factor, pdx-1, and the plasma membrane translocation of GLUT2 were both impaired in high-fat-fed animals after 1 week. In contrast, the expression of the full-length leptin receptor (ObRb) was not affected by high-fat feeding. The study thus shows that 8 weeks are required for the development of a compensatory hypersecretion of insulin after high-fat feeding in mice, and even then the in vivo insulin secretion is insufficient to normalize impaired glucose tolerance. The early-onset islet dysfunction is accompanied by impaired ␤-cell trafficking of two factors, pdx-1 and GLUT-2, which are involved in ␤-cell proliferation and glucose recognition. The mechanisms compromising this ␤-cell trafficking remain to be established. Diabetes 51 (Suppl. 1):S138 -S143, 2002 I nsulin resistance is associated with islet adaptation ensuring adequate hyperinsulinemia to maintain normoglycemia. However, if the islet adaptation is impaired, hyperinsulinemia is inadequate and metabolic perturbations such as hyperglycemia might ensue (1). A model to study the mechanisms of impaired islet adaptation in insulin resistance is the high-fat feeding of C57BL/6J mice, which are especially susceptible to highfat treatment with regard to the development of glucose intolerance compared with other strains (2,3). We have previously shown that this model is associated with obesity, hyperglycemia, hyperinsulinemia, and hyperlipidemia (4); increased insulin mRNA expression in islets (5); and exaggerated insulin response to challenges with ␤-cell secretagogues (6,7). In contrast, the early islet changes after feeding these mice a high-fat diet are less well studied. Therefore, we have explored whether the development of glucose intolerance provoked by short-term feeding of a high-fat diet in C57BL/6J mice is associated with changes in insulin secretion, islet architecture of insulin and glucagon cells, and islet localization of factors thought to be of particular relevance for ␤-cell adaptation to insulin resistance. One such factor is the homeobox transcript...

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Purpose:To evaluate whether MRI signal and T2* measurements of lung tissue acquired at ultrashort detection times (tds) can detect emphysematous changes in lungs. Materials and Methods:MR signal intensity of in vivo mouse lungs was measured at 4.7 T at tds of 0.2 and 0.4 msec using single-point imaging (SPI). T2* was calculated from the measurements obtained at the two tds. Two groups of 8-and 30-week-old Tight Skin (TS) and agedmatched CB57BL/6 mice were examined. The TS mice spontaneously developed emphysema-like alveolar enlargement. In vivo micro-computed tomography (CT) scanning and histology were used as reference methods.Results: MR signal and T2* were significantly lower in the lungs of TS mice than in controls. There were no significant differences between the different age groups. MR signal in lung parenchyma correlated linearly (P Ͻ 0.0001, r ϭ 0.89) with CT mass density, and T2* correlated linearly (P Ͻ 0.0001, r ϭ -0.91) with the alveoli size (mean linear intercept [MLI]). Conclusion:The MR signal intensity and T2* measured at short tds can be used as imaging biomarkers to characterize parenchyma density and alveolar size, respectively.