Rapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolism

Abstract

Rapamycin, an immunosuppressant used in human transplantation, impairs b-cell function, but the mechanism is unclear. Chronic (24 h) exposure to rapamycin concentration dependently suppressed 16 . 7 mM glucose-induced insulin release from islets (1 . 65G0 . 06 2G3 . 3 pmol/islet per 90 min, control, nZ9, P!0 . 01). Immunoblotting revealed that the expression of complex I, III, IV, and V was not affected by rapamycin. Mitochondrial ATP production indicated that the respiratory chain downstream of complex II was not affected, but that carbohydrate metabolism in the Krebs cycle was reduced by rapamycin. Analysis of enzymes in the Krebs cycle revealed that activity of a-ketoglutarate dehydrogenase (KGDH), which catalyzes one of the slowest reactions in the Krebs cycle, was reduced by rapamycin (10 . 08G0 . 82, rapamycin versus 13 . 82 G0 . 84 nmol/mg mitochondrial protein per min, control, nZ5, P!0 . 01). Considered together, these findings indicate that rapamycin suppresses high glucose-induced insulin secretion from pancreatic islets by reducing mitochondrial ATP production through suppression of carbohydrate metabolism in the Krebs cycle, together with reduced KGDH activity.

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

“…32,33 Recently, the suppression of carbohydrate metabolism by rapamycin was suggested as a candidate mechanism for the inhibition of insulin secretion. 34 However, the mechanism of action of rapamycin in the insulin secretory pathway is largely unknown. Susceptibility of cells expressing ZnT-8 W325 to rapamycin but not to tacrolimus supports the tolerance of the W325 variant to calcineurin activity.…”

mTORC1 signaling and regulation of pancreatic β-cell mass

“…Rapamycin treatment has been shown to have mixed effects on insulin secretion, depending on the experimental conditions. [56][57][58][59] The role of mTORC1 in β-cell proliferation using rapamycin has been explored in multiple studies, which have resulted in five important observations. (1) Rapamycin treatment blocks β-cell expansion, cell size and proliferation induced by an activation of AKT in β cells.…”

Leucine Stimulates Insulin Secretion via Down-regulation of Surface Expression of Adrenergic α2A Receptor through the mTOR (Mammalian Target of Rapamycin) Pathway

“…In pancreatic ␤-cells, the mTOR pathway mediates nutrient sensing and regulates protein synthesis (15,16). Recent studies demonstrated that inhibition of mTOR by rapamycin impairs glucose-induced insulin secretion in pancreatic ␤-cells (17,18), and the use of rapamycin has been identified as a risk factor for new onset of diabetes in organ transplant patients (19). However, the downstream target of mTOR on insulin secretion in pancreatic islets remains enigmatic.…”