mTORC1 at the Intersection of Aging and Type 2 Diabetes

For the vast majority of patients, type 2 diabetes is caused by the presence of excess visceral fat tissue, and can be reversed even at a late stage by losing that fat tissue. The degree to which one needs to abuse one's own body in order to become diabetic falls with advancing age, however. Aging makes type 2 diabetes more likely to occur, all other factors being equal. Looking at the relationship from the other direction, the chronic inflammation and other forms of metabolic dysfunction characteristic of type 2 diabetes accelerates the progression of aging. The condition shortens life expectancy and is associated with greater incidence of the other common age-related conditions.

Researchers here consider mTORC1 as an important regulator of this two-way relationship between aging and type 2 diabetes. The complexes of mTOR, mechanistic target of rapamycin, have become well studied in recent years as a result of research into calorie restriction. mTOR is a master regulator of metabolism, involved in nutrient sensing and most of the subsequent processes that must adapt to varying levels of calorie intake. Inhibition of mTOR, or preferentially only the mTORC1 complex, is a way to partially mimic some of the beneficial results of calorie restriction. It provokes increased activity in stress response mechanisms, and the outcome, in animal studies at least, is improved health and extended healthy life span. Both aging and type 2 diabetes give rise to greater mTORC1 activity, and thus move things in the opposite, undesirable direction.

It is well known that insulin signaling is involved in the control of longevity in a wide spectrum of organisms including worms, flies, and mice. In addition, the use of rapamycin or knocking down mTOR can promote life extension in several species. During aging or under a hypercaloric diet exists an mTORC1 hyperactivity, which derives into a disruption in autophagy and, concomitantly an increase in endoplasmic reticulum (ER) stress. The overactivation of mTORC1 signaling specifically in pancreatic β cells leads to an augmented in β cell mass, which are related to hyperinsulinemia and hypoglycemia. However, chronic overactivation of mTORC1 signaling pathway develops a progressive hyperglycemia and a diminished islet mass.

Type 2 diabetes mellitus (T2DM) is a very complicated disorder. It is a progressive disease including insulin resistance, β-cell hyperplasia and/or β cell hypertrophy, that mediates a compensatory insulin secretion and subsequently hyperinsulinemia and pancreatic β cell dysfunction. At the insulin resistant prediabetic stage, mTORC1 is a key effector for the growth and survival of pancreatic β cells. However, if mTORC1 remains chronically overactivated, pancreatic beta cell death occurs and the compensatory insulin secretion mechanism it is compromised. Then, mTORC1 is a double-edged sword in the progression to T2DM.

Diabetes is a multifactorial and progressive disease with two phases; firstly, a prediabetic stage, with an insulin resistance and hyperinsulinemia, and secondly as manifest diabetes associated with hypoinsulinemia and hyperglycemia. Then, it is crucial to understand the transition from prediabetes to type 2-diabetes status and the underlying molecular mechanisms of disease. At this stage, chronic overactivation of mTORC1 signaling pathway in β islets from prediabetic patients leads to on one hand to the expansion of the pancreatic beta cell mass and, on the other to the inhibition of autophagy as protective mechanism of beta cells against the attack of several stressors, making these cells more prone to trigger apoptosis. Thus, the maintenance of a functional autophagy it is an essential component to protect and prolong pancreatic β cell life span precluding chronic hyperglycemia.

Link: https://doi.org/10.3389/fendo.2018.00621

Comments

@Reason

Congrats reason, now the FA is popular enough to attract spammers. It is unfortunate that now you will have to spend much more effort curating the comments or even disallow posts without login...

Posted by: Cuberat at March 29th, 2019 6:20 AM

@Cuberat: There has long been an antispam system that gets rid of near all of it. Unfortunately near all is not all, and some manual cleanup is sometimes needed.

Posted by: Reason at March 29th, 2019 9:25 PM

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