Highlights From The First World Congress on the Insulin Resistance Syndrome

Zachary T. Bloomgarden, MD


January 29, 2004

In This Article

Lifestyle Approaches to the IRS

John P. Foreyt, PhD, Baylor College of Medicine, Houston, Texas, presented evidence that body weight has increased approximately 15% over the past century among the US population.[9] In 1980, 46% of the US population had a BMI > 25 kg/m2 and 14% had a BMI > 30 kg/m2. In 2000, these figures were 65% and 31% of the population, respectively.[10]

A 5% to 10% weight loss is a realistic goal, and the focus should be on health, energy, fitness, well-being, and self-esteem. Food diaries encourage adherence. The "100/100 plan," in which 100 fewer calories are consumed each day and 100 more calories are burned each day through exercise, establishes realistic expectations by starting with small changes. This plan should lead to a 20-pound annual weight loss. A US national weight control registry has demonstrated that persons who have been able to lose weight and maintain their weight loss follow a low-fat diet, exercise for 60-90 minutes per day, and eat regular meals.[11] Eating breakfast every day was an important characteristic of persons who were able to maintain their weight loss.[12]

Ronald Krauss, MD, from the Lawrence Berkeley National Laboratory and the University of California, Berkeley, discussed dietary approaches to the elimination of the atherogenic lipoprotein phenotype that characterizes the IRS: increased triglyceride, low HDL cholesterol, and increased small dense LDL particles. [13] As dietary carbohydrate (CHO) increases, LDL pattern B increases, suggesting that reducing CHO might improve the lipid pattern. Dr. Krauss randomized 178 men to 1 of 4 diets: an ATP III diet (30% fat, 55% CHO); a 40% CHO, 30% fat diet; and a 25% CHO, 45% fat diet, either with high saturated or high monounsaturated fat. After 3 weeks on the diets, calories were decreased by 1000/day for 5 weeks, followed by a 4-week stabilization period. The ATP III diet led to no change in pattern B frequency, while there was a significant decrease in pattern B with the 40% CHO diet, and a further decrease with the 25% CHO diet.

During the weight-loss phase of the diet, all groups had similar weight loss, despite differences in diet composition. Pattern B prevalence decreased on the ATP diet but to a more modest extent than with the low CHO diets. Apolipoprotein B decreased by 4, 10, 13, and 16 mg/dL, respectively, during the initial phase of the diets. After 3 weeks, when calories were decreased by 1000 per day, apolipoprotein B decreased further, but only in the 55% CHO diet group. Dr. Krauss suggested that either weight loss or CHO restriction can be effective in improving the atherogenic lipid phenotype.

Tracey McLaughlin, MD, Stanford Medical Center, Stanford, California, discussed the linear relationship between insulin resistance and BMI,[14] although there is wide scatter at any given level, so that 25% to 30% of the variance in insulin sensitivity is explained by BMI. Insulin sensitivity is clinically important because persons in the most insulin-resistant tertile have a 14% 5-year CVD event frequency, compared with 2% in the middle tertile, and none in the most insulin-sensitive group.[15]

In a study of 50 obese persons, 29 of whom were insulin resistant and 21 of whom were insulin sensitive, the 2-hour glucose was 144 vs 112 mg/dL, triglyceride 199 vs 125 mg/dL, HDL 42 vs 54 mg/dL, and triglyceride/HDL ratio 5.4 vs 2.5, suggesting that insulin resistance contributes to CVD risk independent of obesity.

Dr. McLaughlin noted that fasting and, to an even greater degree, 2-hour post-glucose load insulin levels, give optimal discrimination between insulin sensitivity and insulin resistance. In a study[16] of weight loss with a 4-month hypocaloric diet and sibutramine in 13 insulin-resistant and 11 insulin-sensitive healthy obese women, the 2 groups lost similar amounts of weight, while insulin sensitivity improved in the insulin-resistant group but not in the insulin-sensitive group (although insulin sensitivity was better in the insulin-sensitive group before weight loss than in the insulin-resistant group after weight loss). The women whose insulin sensitivity improved also experienced lowered blood glucose, insulin, triglyceride,[16] and C-reactive protein (CRP).[17]

Peter J. Havel, DVM, PhD, University of California at Davis, discussed the important role that adipose tissue plays in whole-body energy homeostasis -- both in terms of fat storage and release and with regard to the effects of adipocyte cytokines.[18] Leptin has major effects on food intake; leptin deficiency is associated with hyperphagia,[19] suggesting a lack of a satiety response; and partial leptin deficiency is also associated with increased body fat.[20] Infusion of insulin and glucose to maintain euglycemia in humans increases circulating leptin levels after approximately 3 hours and decreases adiponectin.[21] In streptozotocin diabetic rats, leptin levels fall and can be restored by insulin in a dose-dependent fashion. Comparing high-CHO and high-fat meals, the latter lead to smaller increases in insulin and to decreased levels of leptin.

Comparing glucose with fructose, the postprandial glycemia and insulin increase is lower with fructose, in association with a 35% lower overall leptin production. Plasma ghrelin, which increases food intake and sensation of hunger, decreases with glucose ingestion, while fat and fructose do not stimulate insulin and leptin. In a study of 11 overweight postmenopausal women consuming a high-fructose vs a high-glucose diet for 10 weeks, triglyceride and ApoB levels increased with fructose.

Adiponectin, which has insulin-sensitizing actions, anti-inflammatory effects on vascular endothelium,[22,23] and is associated with increased HDL cholesterol,[24] is produced by adipocytes, with levels inversely proportional to the degree of obesity. Adiponectin levels increase with weight loss following gastric bypass surgery[25] and also with the administration of thiazolidinedione (TZD) drugs.[26] Dr. Havel speculated that adiponectin, its receptors, and the subsequent metabolic steps may be targets for the treatment of obesity and diabetes.

Peter Reaven, MD, University of Arizona, Phoenix, discussed the association of both obesity and insulin resistance with systemic inflammation, suggesting a link with the chronic inflammation now known to be associated with atherosclerosis.[27] CRP activates complement, stimulates cytokine secretion, increases endothelial cell adhesion molecule expression, decreases NO, increases PAI-1 levels and activity, increases LDL uptake by macrophages, increases monocyte chemoattraction, increases expression of the angiotensin II type 1 receptor, and has many additional inflammatory effects. CRP is strongly associated with obesity, and may be directly secreted by adipocytes, which also produce interleukin-6, stimulating further hepatic CRP secretion. CRP elevation predicts future cardiovascular events in studies of both high- and low-risk populations.[28] In the Cholesterol and Recurrent Events Study, persons with low CRP levels had less than half the risk of myocardial infarction compared with persons with higher levels.[29] Studies of persons with unstable angina show that CRP may offer more information than the exercise electrocardiogram[30] and may improve risk assessment over that available from troponin measurement.[31] No studies of this marker have adjusted for insulin resistance status, so it is unclear whether the measure should be considered a risk marker or a risk factor.

CRP levels increase with age, are higher in women, and are associated with coronary disease and type 2 diabetes.[32] Modifiable causes of CRP elevation include obesity, cigarette smoking,[33] estrogen treatment, and chronic bronchial or periodontal inflammation. CRP decreases with alcohol ingestion[34] and during treatment with statins, fibrates, antibiotics, metformin, and TZDs.


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