The Role of Organelle Stresses in Diabetes Mellitus and Obesity: Implication for Treatment

Abstract

The type 2 diabetes pandemic in recent decades is a huge global health threat. This pandemic is primarily attributed to the surplus of nutrients and the increased prevalence of obesity worldwide. In contrast, calorie restriction and weight reduction can drastically prevent type 2 diabetes, indicating a central role of nutrient excess in the development of diabetes. Recently, the molecular links between excessive nutrients, organelle stress, and development of metabolic disease have been extensively studied. Specifically, excessive nutrients trigger endoplasmic reticulum stress and increase the production of mitochondrial reactive oxygen species, leading to activation of stress signaling pathway, inflammatory response, lipogenesis, and pancreatic beta-cell death. Autophagy is required for clearance of hepatic lipid clearance, alleviation of pancreatic beta-cell stress, and white adipocyte differentiation. ROS scavengers, chemical chaperones, and autophagy activators have demonstrated promising effects for the treatment of insulin resistance and diabetes in preclinical models. Further results from clinical trials are eagerly awaited.

Figure 1

(a) Endoplasmic reticulum (ER) stress response and unfolded protein response (UPR) are linked to insulin resistance, inflammation lipogenesis, and pancreatic beta-cell survival. (b) Defective mitochondrial function leads to inflammation, insulin resistance, and reduced insulin secretion. (c) Autophagy regulates hepatic lipogenesis, adipocyte physiology, pancreatic beta-cell function, and appetite control. UPR: unfolded protein response; ROS: reactive oxygen species; NAD: nicotinamide adenine dinucleotide; NADH: reduced nicotinamide adenine dinucleotide; ADP: adenosine diphosphate; ATP: adenosine triphosphate; TCA: tricarboxylic acid cycle; K_ATP: ATP-dependent potassium channel; UQ: ubiquinol; FGF21: fibroblast growth factor-21; AgRP: agouti-related peptide; POMC: proopiomelanocortin.

Figure 2

Interactions between endoplasmic reticulum (ER) stress, mitochondrial reactive oxygen species (ROS), and autophagy during nutrient deficiency and excess.