Tackling the Multi-Organ Pathogenesis of Type 2 Diabetes Mellitus

Meredith Hawkins, MD, MS, FRCPC, FACP, Professor of Medicine

Director, Global Diabetes Initiative

Albert Einstein College of Medicine, New York City, USA

Given current projections that the number of people suffering from diabetes will increase from 246 million up to 366 million over the next 20 years, this is clearly a global health crisis. Despite a substantial increase in the availability of medications to treat type 2 diabetes, optimal blood glucose control remains elusive for most patients, and finding safe and effective medications is a great challenge. Contributing to this challenge is the fact that type 2 diabetes results from defects in many organ functions, including inadequate insulin secretion, inappropriately high rates of glucose production by the liver, and insulin resistance at the level of such insulin-responsive tissues as skeletal muscle and adipose tissue. Our research group has studied the pathogenesis of many of these metabolic defects, to aim for a better understanding of the causes of type 2 diabetes and to ultimately find new therapeutic approaches.

Glucose production (GP) is elevated in type 2 diabetes, and is the main cause of fasting hyperglycemia. Rising glucose levels rapidly suppress GP in nondiabetic individuals, which is very important for glucose homeostasis. Worsening hyperglycemia in type 2 diabetes is associated with loss of the suppressive effects of glucose on GP. Little is known about the pathogenesis of this loss of ‘glucose effectiveness’ in type 2 diabetes, despite its important contribution to hyperglycemia. We have been able to demonstrate several approaches that improve the regulation of glucose production in type 2 diabetes, which could potentially be of benefit in their management. In particular, we are excited by our recent data suggesting that glucose production is regulated by the brain, but this regulation is impaired in type 2 diabetes. This represents an important target for intervention in our current studies.

Additionally, obesity and type 2 diabetes mellitus are accompanied by increased circulating levels of various inflammatory mediators, particularly cytokines and acute phase reactants. Adipose tissue produces several pro-inflammatory factors in proportion to the degree of adiposity, and infiltration of adipose tissue macrophages appears to be responsible for most of the adipose tissue cytokine production. Ultimately, the inflammatory factors produced by adipose tissue macrophages contribute to systemic insulin resistance. Intriguingly, our studies have shown that secretory factors from adipocytes stimulate adipocyte macrophages to produce inflammatory factors, contributing to the whole vicious cycle of obesity, inflammation and insulin resistance.

Type 2 diabetes is also associated with skeletal muscle mitochondrial dysfunction and insulin resistance. We were able to demonstrate that the plant-derived substance resveratrol, which is abundant in red wine, improved insulin resistance and muscle mitochondrial function in human volunteers. This builds on very exciting previous studies in rodents, and suggests that resveratrol holds considerable promise for improving glucose metabolism in type 2 diabetes.