Recent studies have demonstrated the importance of insulin or insulin-like growth factor 1 (IGF-1) for regulation of pancreatic -cell mass. Given the role of tuberous sclerosis complex 2 (TSC2) as an upstream molecule of mTOR (mammalian target of rapamycin), we examined the effect of TSC2 deficiency on -cell function. Here, we show that mice deficient in TSC2, specifically in pancreatic  cells (TSC2 ؊/؊ mice), manifest increased IGF-1-dependent phosphorylation of p70 S6 kinase and 4E-BP1 in islets as well as an initial increased islet mass attributable in large part to increases in the sizes of individual  cells. These mice also exhibit hypoglycemia and hyperinsulinemia at young ages (4 to 28 weeks). After 40 weeks of age, however, the TSC2 ؊/؊ mice develop progressive hyperglycemia and hypoinsulinemia accompanied by a reduction in islet mass due predominantly to a decrease in the number of  cells. These results thus indicate that TSC2 regulates pancreatic -cell mass in a biphasic manner.
Pancreatic β cell failure is thought to underlie the progression from glucose intolerance to overt diabetes, and ER stress is implicated in such β cell dysfunction. We have now shown that the transcription factor CCAAT/ enhancer-binding protein β (C/EBPβ) accumulated in the islets of diabetic animal models as a result of ER stress before the onset of hyperglycemia. Transgenic overexpression of C/EBPβ specifically in β cells of mice reduced β cell mass and lowered plasma insulin levels, resulting in the development of diabetes. Conversely, genetic ablation of C/EBPβ in the β cells of mouse models of diabetes, including Akita mice, which harbor a heterozygous mutation in Ins2 (Ins2 WT/C96Y ), and leptin receptor-deficient (Lepr -/-) mice, resulted in an increase in β cell mass and ameliorated hyperglycemia. The accumulation of C/EBPβ in pancreatic β cells reduced the abundance of the molecular chaperone glucose-regulated protein of 78 kDa (GRP78) as a result of suppression of the transactivation activity of the transcription factor ATF6α, thereby increasing the vulnerability of these cells to excess ER stress. Our results thus indicate that the accumulation of C/EBPβ in pancreatic β cells contributes to β cell failure in mice by enhancing susceptibility to ER stress.
This article describes second-look arthroscopic evaluation of the transplanted grafts after anatomical two-bundle ACL reconstruction, which had been performed between December 2000 and March 2004. Using two double-looped semitendinosus tendon grafts via separate femoral and tibial tunnels in the anatomical ACL footprints, 65 patients (mean age of 24 years) underwent anatomical two-bundle ACL reconstruction. The evaluation was performed for those who had undergone the procedure 5-29 months (mean 16.5) previously, with emphasis on graft tension and the presence of graft damage by meticulous probing. None of the anteromedial (AM) grafts showed rupture, while 11% of the posterolateral (PL) grafts showed substantial damage around the femoral tunnel aperture. Both the AM and PL grafts were evaluated as lax without apparent graft rupture in 9% of the knees. These results suggest that the currently performed anatomical two-bundle ACL reconstruction and postoperative regimen still remain to be improved to achieve better postoperative graft morphology.
AimWe previously found that chronic tuberous sclerosis protein 2 (TSC2) deletion induces activation of mammalian target of rapamycin Complex 1 (mTORC1) and leads to hypertrophy of pancreatic beta cells from pancreatic beta cell-specific TSC2 knockout (βTSC2−/−) mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells.MethodsIsolated islets from βTSC2−/− mice and TSC2 knockdown insulin 1 (INS-1) insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes.ResultsActivation of mTORC1 increased mitochondrial DNA expression, mitochondrial density and ATP production in pancreatic beta cells of βTSC2−/− mice. In TSC2 knockdown INS-1 cells, mitochondrial DNA expression, mitochondrial density and ATP production were increased compared with those in control INS-1 cells, consistent with the phenotype of βTSC2−/− mice. TSC2 knockdown INS-1 cells also exhibited augmented insulin secretory response to glucose. Rapamycin inhibited mitochondrial DNA expression and ATP production as well as insulin secretion in response to glucose. Thus, βTSC2−/− mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1.ConclusionActivation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells.
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