Gene expression profiling of islets from pre-diabetic male Zucker diabetic fatty (ZDF) rats showed increased expression of hypoxia-related genes, prompting investigation of the vascular integrity of the islets. The islet microvasculature was increased approximately twofold in young male ZDF rats by both morphometric analysis and quantifying mRNA levels of endothelial markers. ZDF rats at 12 weeks of age showed a significant reduction in the number of endothelial cells, which was prevented by pretreatment with pioglitazone. Light and electron microscopy of normoglycemic 7-week-old ZDF rats showed thickened endothelial cells with loss of endothelial fenestrations. By 12 weeks of age, there was disruption of the endothelium and intra-islet hemorrhage. Islets from 7-and 12-week-old ZDF rats showed an approximate three-and twofold increase in vascular endothelial growth factor (VEGF)-A mRNA and VEGF protein secretion, respectively, compared with lean controls. Thrombospondin-1 mRNA increased in 7-and 12-week-old rats by 2-and 10-fold, respectively, and was reduced by 50% in 12-week-old rats pretreated with pioglitazone. Islets from young male control rats induced migration of endothelial cells in a collagen matrix only after pretreatment with matrix metalloproteinase (MMP)-9. Islets from 7-week-old ZDF rats showed a fivefold increase in migration score compared with wild-type controls, even without MMP-9 treatment. Islets from 15-week-old ZDF rats did not induce migration; rather, they caused a significant rounding up of the duct-derived cells, suggesting a toxic effect. These data suggest that in the ZDF rat model of type 2 diabetes, an inability of the islet to maintain vascular integrity may contribute to ␤-cell failure.

BackgroundThe molecular mechanisms underlying the sex differences in human muscle morphology and function remain to be elucidated. The sex differences in the skeletal muscle transcriptome in both the resting state and following anabolic stimuli, such as resistance exercise (RE), might provide insight to the contributors of sexual dimorphism of muscle phenotypes. We used microarrays to profile the transcriptome of the biceps brachii of young men and women who underwent an acute unilateral RE session following 12 weeks of progressive training. Bilateral muscle biopsies were obtained either at an early (4 h post-exercise) or late recovery (24 h post-exercise) time point. Muscle transcription profiles were compared in the resting state between men (n = 6) and women (n = 8), and in response to acute RE in trained exercised vs. untrained non-exercised control muscle for each sex and time point separately (4 h post-exercise, n = 3 males, n = 4 females; 24 h post-exercise, n = 3 males, n = 4 females). A logistic regression-based method (LRpath), following Bayesian moderated t-statistic (IMBT), was used to test gene functional groups and biological pathways enriched with differentially expressed genes.ResultsThis investigation identified extensive sex differences present in the muscle transcriptome at baseline and following acute RE. In the resting state, female muscle had a greater transcript abundance of genes involved in fatty acid oxidation and gene transcription/translation processes. After strenuous RE at the same relative intensity, the time course of the transcriptional modulation was sex-dependent. Males experienced prolonged changes while females exhibited a rapid restoration. Most of the biological processes involved in the RE-induced transcriptional regulation were observed in both males and females, but sex specificity was suggested for several signaling pathways including activation of notch signaling and TGF-beta signaling in females. Sex differences in skeletal muscle transcriptional regulation might implicate a mechanism behind disproportional muscle growth in males as compared with female counterparts after RE training at the same relative intensity.ConclusionsSex differences exist in skeletal muscle gene transcription both at rest and following acute RE, suggesting that sex is a significant modifier of the transcriptional regulation in skeletal muscle. The findings from the present study provide insight into the molecular mechanisms for sex differences in muscle phenotypes and for muscle transcriptional regulation associated with training adaptations to resistance exercise.

To clarify the lineage relationship between cells that express the neural stem cell marker nestin and endocrine cells of the pancreas, we analyzed offspring of a cross between mice carrying a nestin promoter/enhancer-driven cre-recombinase (Nestin-cre) and C57BL/ 6J-Gtrosa26 tm1Sor mice that carry a loxP-disrupted ␤-galactosidase gene (Rosa26). In nestin-cre ؉/tg ;R26R

The effect of short-term denervation on the response to insulin was studied in isolated rat soleus and extensor digitorum longus (EDL) muscles 6 and 24 h after severing one sciatic nerve. Impaired insulin sensitivity and response occurred within 6 h postdenervation in solei. After 24 h, EDL of fed and fasted rats and solei of fed rats showed no stimulation of glycogen synthesis even with supraphysiological doses, whereas solei of fasted rats showed markedly decreased sensitivity and response to insulin. Insulin resistance of glycogen synthesis represented impaired stimulation of glucose transport and impaired glucose-independent activation of glycogen synthase by insulin. Changes in initial glycogen content of muscles did not correlate with insulin resistance. Insulin binding after denervation showed only minimum impairment and did not account for the marked insulin resistance. The response of denervated solei to epinephrine was unimpaired. Insulin resistance, which develops early after denervation in red and white muscles, represents primarily a defect in receptor-function coupling, suggesting that in muscle, nervous stimuli and/or contractile activity modulate signal transmission by the occupied insulin receptor.

Background: Pathways underlying fatty acid potentiation of glucose-stimulated insulin secretion have not been fully elucidated.Results: In INS-1 cells, fatty acids increase de novo production of glycerolipids and simultaneously increase glucose utilization. GPR40 receptor activation increases these activities. Conclusion: Fatty acids enhance the production of multiple signals supporting glucose-stimulated insulin secretion. Significance: The studies clarify the effects of fatty acids and GPR40 activity in ␤ cell insulin secretion.