Reactive Species, Cellular Repair and Risk Factors in the Onset of Type 2 Diabetes Mellitus: Review and Hypothesis

Abstract

Insulin resistance (IRe) and a failure of insulin secretion are the major features of the early pathophysiology of type-2 diabetes mellitus (T2D) but the etiology is still not well understood. We suggest that: 1. The cellular mechanisms that protect against oxidative stress per se are capable of creating a reactive species-dependent IRe. 2. Reactive species-induced mitochondrial dysfunction can lead to disruption of lipid metabolism, increased intracellular lipid content, and can also contribute to lipid-dependent IRe in myocytes and adipocytes. 3. Metabolic secretagogues that stimulate insulin secretion by the activation of initial steps in the glucose-stimulated insulin secretion pathway can also lead to increased reactive species production and cellular destruction contributing to beta-cell damage and apoptosis. These events that underlie the repair mechanisms in beta-cells, muscle and adipocytes, are important factors in the early etiology of T2D, leading to both IRe and decreased insulin secretion. This hypothesis is supported by data from multiple disciplines and includes aging, obesity and genetic factors in promoting multiple failures in this system leading to the onset of T2D. On the basis of this hypothesis therapeutic strategies should be directed towards increasing insulin secretion and reducing IRe without increasing reactive species production or concentration. Pharmacological or other approaches that result in the activation of mitochondrial biogenesis could be beneficial for both IRe and T2D.

Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice

“…Oxidative and inflammatory stresses are both considered as important events that participate to the development of metabolic disorders associated with insulin resistance and obesity [1][2][3][4][5][6].…”

Mechanisms of glucose sensing in the pancreatic β-cell

“…Glucokinase catalyzed the rate-limiting step of glycolysis with a steep dependence on glucose concentration an understanding of β-cell glucose-sensing and mechanisms of dysfunction in type 2 diabetes. 5,14,16 For these reasons it is critical to develop a comprehensive understanding as to how cytoplasmic and intramitochondrial fuel metabolism is coupled to fuel availability and thereby "sensed" in the β-cell. We have performed a computational analysis of the main processes of β-cell fuel metabolism to quantitatively assess how cytoplasmic ATP/ADP ratio can be controlled by mitochondrial and cytoplasmic processes.…”

“…It has been proposed that a reduction in mitochondrial metabolism and/or cellular content (number or volume) can underlie progression to the decreased GSIS typical of type 2 diabetes. 11,15,16,49 For this reason, we employed our model to simulate the effect of changes in mitochondrial functional activity and/or content.…”

“…β-cell failure due to excess nutrients could play a critical role in the pathogenesis of type 2 diabetes. 16,45 Therefore, the existence of specific mechanisms for β-cell glucose sensitivity itself could underlie the increased sensitivity of these cells to injury. also modeled.…”

Establishment of inducible cAMP early repressor transgenic fibroblasts in a porcine model of human type 1 diabetes mellitus

“…These cells are capable of acting as a sensor of systemic glucose levels during the feeding state of the organism, and the transcription of genes associated with metabolism is induced by changing levels of the products of glucose catabolism; this represents specific regulation of the β cells in response to glucose concentrations in the body (20,21). The insulin promoter immediately regulates insulin gene transcription via glucose and the human promoter enables strongly regulated insulin production (22,23).…”