Highlights From The First World Congress on the Insulin Resistance Syndrome

Zachary T. Bloomgarden, MD

Disclosures

January 29, 2004

In This Article

Mechanisms of Insulin Resistance

Gerald I. Shulman, MD, PhD, Yale University School of Medicine, New Haven, Connecticut, showed evidence that elevations in free fatty acid (FFA) are an important mechanism of insulin resistance in muscle.[2,3] Peroxisome proliferator activated receptor (PPAR) gamma agonists may act in part by increasing adipose tissue fat stores and preventing the increase in fatty acid metabolites in liver and muscle.

John P. Cooke, MD, PhD, Stanford University School of Medicine, discussed the "tight coupling" between endothelial dysfunction and insulin resistance, with the potent endogenous vasodilator nitric oxide (NO) as an endothelial factor that maintains the balance between blood flow and vasoconstriction.[4] "The endothelium takes on a different phenotype" in the insulin-resistant state, he pointed out, producing vasoconstrictors and growth factors. Exercise increases NO synthase, improving vasodilation, while obesity and insulin resistance are associated with a deficiency of NO, leading to endothelial dysfunction.[5] Cardiovascular disease (CVD) risk factors that lower NO include hypertension and elevated cholesterol, glucose, triglyceride, and homocysteine.

Arun J. Sanyal, MD, Virginia Commonwealth University, Richmond, described nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), which are associated with obesity, increased triglyceride levels, diabetes, and hypertension, as "the hepatic manifestation of the IRS."[6,7] Given the high prevalence of IRS,[8] an increase in NAFLD is predictable. Approximately 40% of persons with NASH have diabetes, and an additional 20% have impaired glucose tolerance. Approximately 50% of persons with diabetes have NAFLD, of whom 20% also have NASH. Approximately 20% of these latter persons are ultimately expected to develop cirrhosis.

Treatment approaches for both NAFLD and NASH address insulin resistance, particularly obesity. Antiobesity medications and bariatric surgery are options. Treatment with insulin sensitizers is a consideration, and it should be recognized that insulin and insulin secretagogues have the potential to worsen the disease.

In a research presentation at the meeting, Diego Ardigo, MD, Parma, Italy, reported on the relationship between insulin resistance and liver fat content in 69 persons with normal serum transaminase levels, of whom 38% had a normal liver sonogram and 62% had evidence of some degree of abnormality. The plasma insulin level was directly correlated with the degree of hepatic steatosis, as were BMI, waist circumference, blood pressure, fasting glucose, HDL, triglyceride, and ALT (although not AST) concentration. In multivariate analysis, the fasting insulin level and BMI were the only independent predictors of the degree of steatosis, and fasting insulin was the only independent predictor of ALT, accounting for 20% of the variance of this measure.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....