mTOR Inhibition by Rapamycin Prevents β-Cell Adaptation to Hyperglycemia and Exacerbates the Metabolic State in Type 2 Diabetes

Abstract

OBJECTIVE-Mammalian target of rapamycin (mTOR) and its downstream target S6 kinase 1 (S6K1) mediate nutrient-induced insulin resistance by downregulating insulin receptor substrate proteins with subsequent reduced Akt phosphorylation. Therefore, mTOR/S6K1 inhibition could become a therapeutic strategy in insulin-resistant states, including type 2 diabetes. We tested this hypothesis in the Psammomys obesus (P. obesus) model of nutrition-dependent type 2 diabetes, using the mTOR inhibitor rapamycin.RESEARCH DESIGN AND METHODS-Normoglycemic and diabetic P. obesus were treated with 0.2 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 i.p. rapamycin or vehicle, and the effects on insulin signaling in muscle, liver and islets, and on different metabolic parameters were analyzed.RESULTS-Unexpectedly, rapamycin worsened hyperglycemia in diabetic P. obesus without affecting glycemia in normoglycemic controls. There was a 10-fold increase of serum insulin in diabetic P. obesus compared with controls; rapamycin completely abolished this increase. This was accompanied by weight loss and a robust increase of serum lipids and ketone bodies. Rapamycin decreased muscle insulin sensitivity paralleled by increased glycogen synthase kinase 3␤ activity. In diabetic animals, rapamycin reduced ␤-cell mass by 50% through increased apoptosis. Rapamycin increased the stress-responsive c-Jun NH 2 -terminal kinase pathway in muscle and islets, which could account for its effect on insulin resistance and ␤-cell apoptosis. Moreover, glucose-stimulated insulin secretion and biosynthesis were impaired in islets treated with rapamycin.CONCLUSIONS-Rapamycin induces fulminant diabetes by increasing insulin resistance and reducing ␤-cell function and mass. These findings emphasize the essential role of mTOR/S6K1 in orchestrating ␤-cell adaptation to hyperglycemia in type 2 diabetes. It is likely that treatments based on mTOR inhibition will cause exacerbation of diabetes. Diabetes 57:945-957, 2008

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

“…16 In contrast, rapamycin inhibits the mammalian target of rapamycin without affecting calcineurin activity as well as inhibiting GSIS in b-cells. 26,31 Although the therapeutic ranges of tacrolimus and rapamycin are comparable, the potency of rapamycin in inhibiting insulin secretion seemed to be much lower than that of tacrolimus in this study. This may partly explain why rapamycin has less diabetogenic activity.…”

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

“…Similarly, rapamycin alleviated stress in an autophagy-dependent manner in insulin-secretion deficient beta cells derived from fetal mice [94] and in beta cells exposed to lipotoxicity [81]. It is noteworthy that this apparent protection induced by rapamycin is contrary to the common view of this drug as being diabetogenic [88,95,96]. These findings may suggest that stimulating autophagy by rapamycin is protective to beta cells only under certain stressful conditions, such as proinsulin misfolding.…”

“…Yet, beyond the technicalities and interpretation of experimental results, it appears that opposing forces governing autophagy operate in beta cells in diabetes, similarly to adipose tissue, potentially leading to inconsistent modulation of autophagy depending on the metabolic and biological environment of the cell. As an example, hyperglycaemia stimulates mTORC1 in beta cells [88,89], which is expected to inhibit autophagy. By contrast, ER stress due to inflammation and accumulation of misfolded proinsulin may stimulate autophagy [90].…”

mTORC1 signaling in energy balance and metabolic disease

“…98,99 Conversely, rapamycin treatment leads to inhibition of b-cell proliferation and apoptosis, 100,101 and worsens hyperglycemia in obese animals by inhibiting glucose-stimulated insulin secretion. 102,103 mTORC1 in the liver As expected, once activated, mTORC1 signaling has a positive effect on hepatocyte growth, protein synthesis and cell cycle, and hence contributes to liver regeneration. 104 Furthermore, and as already reported for other tissues, either amino acids or insulin can stimulate hepatic mTORC1 signaling.…”

“…81 Conversely, S6K1 À/À mice show enhanced insulin sensitivity under HFD, which is accompanied by reduced IRS1 phosphorylation in the skeletal muscle. 82 Regulation of b-cell mass; regulation of glucose-stimulated insulin secretion [95][96][97][98][99][100][101][102][103] Regulation of hepatocytes growth and lipid metabolism [104][105][106][107][108][109] Abbreviation: mTORC1, mammalian target of rapamycin complex 1.…”