TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists

Abstract

This article is addressed to endocrinologists treating patients with diabetic complications as well as to basic scientists studying an elusive link between diseases and aging. It answers some challenging questions. What is the link between insulin resistance (IR), cellular aging and diseases? Why complications such as retinopathy may paradoxically precede the onset of type II diabetes. Why intensive insulin therapy may initially worsen retinopathy. How nutrient- and insulin-sensing mammalian target of rapamycin (mTOR) pathway can drive insulin resistance and diabetic complications. And how rapamycin, at rational doses and schedules, may prevent IR, retinopathy, nephropathy and beta-cell failure, without causing side effects.

Figure 1

mTOR and IR (via a feedback loop) in fat/muscle/liver cells. Insulin via insulin receptor substrate 1/2 (IRS1/2) activates the PI3K/Akt/mTOR/S6K pathway. The mTOR/S6K pathway is also activated by nutrients such as glucose, TNF and numerous other factors. The mTOR/S6K pathway in turn inactivates IRS1/2, thus causing IR

Figure 2

mTOR and retinopathy. See text for explanation

Figure 3

Pre-treatment with rapamycin may prevent negative effects of insulin therapy. (a) Insulin stimulates glucose uptake and metabolism. Simultaneously, insulin activates the mTOR/S6K pathway, causing induction of HIF-1, IR and cell senescence. (b) Acute treatment with rapamycin is expected to prevent negative side effects of insulin, while sparing most effects on glucose metabolism. Short-term courses of rapamycin are expected to restore insulin sensitivity

Figure 4

Consequences of sustained mTOR activation. In the liver, muscle and fat tissues, sustained mTOR activation causes systemic IR. In the beta cells, mTOR initially increases beta-cell function, causes beta-cell hypertrophy and adaptation to IR. Beta-cell hyperfunction and IR eventually may cause beta-cell failure and type II diabetes. In the retina and the kidney, hyperactivation of mTOR may lead to retinopathy and nephropathy, respectively