Insulin Resistance Concepts

ZACHARY T. BLOOMGARDEN 0 0 Zachary T. Bloomgarden, MD, is a practicing endocrinologist in New York, New York, and is affiliated with the Division of Endocrinology, Mount Sinai School of Medicine , New York, New York. Abbreviations: 11HSD, 11 OH steroid dehydrogenase; AgRP, Agouti-related peptide; AICAR, 5-ami- noimidazole-4-carboxamide-1- - R e v i e w s / C o m m e n t a r i e s / A D A O N - T cles on presentations given at the his is the first in a series of four arti World Congress on the insulin resistance syndrome (IRS), reviewing concepts pertaining to insulin resistance. Clinical aspects of insulin resistance Yehuda Handelsman (Tarzana, CA) discussed the clinical implications of insulin resistance. He reminded listeners that Gerald Reaven introduced the concept of Syndrome X with his 1988 Banting Lecture, leading to increasing recognition of the importance of the IRS by the World Health Organization (WHO), the American College of Endocrinology, the International Diabetes Federation (IDF), and the American Heart Association. With new definitions, there have been new approaches to treatment, and areas of controversy as well, with the IDF and American Heart Association suggesting that the syndrome exists and is clinically important, while the American Diabetes Association and European Association for the Study of Diabetes have suggested this not to be the case. Handelsman offered a synthesis of the apparently opposing positions. The syndrome, he said, is not a disease. It is distinguished from type 2 diabetes and CVD [cardiovascular disease]. The concept [of an IRS] is designed to predict and prevent [the development of illness]. In this context, it may be particularly important to redefine the metabolic syndrome as the insulin resistance syndrome, allowing one to group together the multitude of seemingly diverse conditions, affecting skin, the reproductive system, liver, cancer, the brain, breathing/ sleeping disorders, coagulation disorders, hypertension, and atherosclerosis, with abnormality in one of these areas suggesting the need to look in others. Increased alanine transaminase (ALT) may, for example, predict the development of CVD. Handelsman pointed out that among individuals with breast and prostate cancer, the second leading cause of death, after the malignancies themselves, is CVD. Insulin resistance increases the likelihood of microalbuminuria in individuals with hypertension, further increasing CVD risk. Sleep apnea increases insulin resistance and continuous positive airway pressure treatment reduces it, further evidence of the bidirectional links between all these conditions. Insulin resistance is linked to CVD by dyslipidemia, with elevated triglyceride and small LDL particles and low HDL cholesterol, and by direct interactions between insulin resistance and atherosclerotic end points, with evidence that the insulin sensitizer pioglitazone may reduce CVD as suggested by the PROactive Study. The DREAM Study, among others, suggests improvement of liver function with rosiglitazone and shows marked reduction with this agent in the development of diabetes among individuals with impaired glucose tolerance (IGT). Handelsman concluded that we need to develop new clinical diagnostic algorithms, being particularly careful to screen individuals with some manifestations of the IRS for the myriad of other associated conditions. Gerald Reaven (Stanford, CA) offered a reappraisal of aspects of the relationship between insulin resistance and the insulin resistance syndrome. Early studies of insulin resistance were carried out by Himsworth in the 1930s (1), and Reavens original studies characterizing insulin sensitivity with the steady-state plasma glucose methodology were carried out more than three decades ago (2). He described a study of 490 apparently healthy individuals with up to eightfold variability in insulin sensitivity, of which, he suggested, approximately half is likely genetic, and one quarter each related to the presence or absence of obesity and of regular physical activity. Insulin resistance should, he suggested, be distinguished from hyperinsulinemia, which causes many of the manifestations of the IRS in tissues that remain responsive to insulin. As an example, he pointed out that hypertension in insulin resistant individuals in part reflects the occurrence of this phenomenon in the kidney and in the sympathetic nervous system. Discussing three popular definitions of the metabolic syndrome, those of the WHO, Adult Treatment Panel III, and IDF, he pointed out that they all use criteria and cut points that are essentially arbitrary, including the WHO requirement of a glycemic marker, the Adult Treatment Panel III requirement for three of five criteria, and the IDF ethnic-specific waist circumference criteria. Insulin acts on the liver to set the level of triglyceride production from free fatty acid (FFA). Among insulin-resistant individuals with hypertriglyceridemia, these lipid levels progressively increase during the day with accumulation of remnant lipoproteins, leading to the clustering of high insulin and high triglyceride, along with low HDL cholesterol, elevated blood pressure, and multiple additional abnormalities characterizing those at greatest risk of developing CVD. Reaven referred to excess adiposity as the most confusing component of the IRS, as obesity modulates insulin action. The degree of insulin resistance and BMI vary independently as well: for a given degree of insulin resistance, BMI predicts, while for a given BMI the degree of insulin resistance predicts CVD risk factors. Considering total versus abdominal adiposity, Reaven noted that BMI correlates with waist circumference and that neither is particularly more useful in predicting insulin sensitivity. He further put forward the concept that in many studies the correlations of visceral, subcutaneous, and total fat with clamp insulin sensitivity are similar, suggesting that the concept of visceral adiposity may be overstated and that the simple calculation of BMI is as likely to be helpful. Addressing the assessment of inflammation, he showed data suggesting that the measurement of the leukocyte count is as useful as that of C-reactive protein. Finally, he questioned whether there is a benefit to making the diagnosis of the metabolic syndrome, suggesting rather that one should simply treat all CVD risk factors. Mechanisms of insulin resistance Neil Ruderman (Boston, MA) reviewed the role of AMP-activated protein kinase (AMPK) in the development of insulin resistance and its complications. He defined the IRS as a disorder in which a group of genetic factors, inactivity, diet, and obesity lead to a set of metabolic disregulatory conditions, causing conditions including diabetes, hypertension, malignancies, atherosclerosis, dyslipidemia, nonalcoholic steatohepatitis, and polycystic ovarian syndrome. AMPK was discovere (...truncated)