Insulin sensitivity is a Rubik's Cube.

Insulin sensitivity is determined by complex metabolic interactions dictated by a multitude of inputs that include inherited genetic and epigenetic determinants as well as many varying modifiers such as diet, exercise, illness, age, socioeconomic status, and lifestyle. Imbalances in these modifiers may lead to insulin resistance, which, if it persists, can ultimately progress to type 2 diabetes with consequences that include hyperglycemia, obesity, hyperlipidemias, hypertension, myriad diabetic complications, and cardiovascular disease including strokes and heart attacks. This “metabolic syndrome” affects a substantial number of adults in this country, with insulin resistance present in a majority of overweight American adults and teenagers. The normal homeostatic interaction of these metabolic determinants is an essentially zero-sum game that results in the maintenance of body weight and metabolism. Like a Rubik’s Cube, any severe perturbation of a metabolic facet unveils a new dimension. Our role as clinicians is to restore normality. Because there are a multitude of still unknown possibilities, we have not been fully successful. In this issue of the Journal, de Courten et al. (1) evaluated the effect of isocaloric diets low and high in advanced glycation end products (AGEs) on insulin sensitivity in healthy overweight subjects in a double-blind randomized crossover study. AGEs are particularly enriched in processed foods, and the receptor for AGE (RAGE) interacts with many ligands linked to chronic inflammation and disease (2). Insulin sensitivity and insulin secretion were carefully measured at the beginning of each 2-wk diet period with a hyperinsulinemic-euglycemic clamp study and an oral-glucose-tolerance test, with a 4-wk washout period in between. The authors showed that the 20 participants in the study indeed consumed fewer AGEs during the low-AGE diet with lower plasma and urine AGE concentrations. Insulin sensitivity increased with the low-AGE diet and decreased with the highAGE diet. The authors proposed that long-term dietary AGE restriction may be an effective strategy to obviate the risk of diabetes and its cardiovascular complication risks. These results are not surprising [see references in (1)], and this careful study in humans eliminates some of the limitations of the previous studies. An earlier study by Turner et al. (3) and an accompanying editorial by Garvey on insulin sensitivity (4) published last year in the Journal reported a similar crossover study that addressed the ability of 4-wk feeding of diets enriched in red meat or dairy products to affect insulin sensitivity in 47 overweight/obese middle-aged men and women. The study found that the subjects who consumed the red meat diet had greater insulin sensitivity than when they consumed the dairy diet. The AGE contents of the 2 diets were not reported in that study. That a red meat diet (its exact macronutrient composition is unknown) enhances insulin sensitivity shows that a variety of diets can be engineered to exert similar effects to those observed in this study. The current study in these healthy overweight subjects by de Courten et al. confirms that insulin sensitivity correlates negatively with age and self-reported physical activity as well as with diet (in this study, to the AGE content of the diet), thus confirming some of themodifiers mentioned above in the first paragraph. But it remains to be shown that long-term alterations in lifestyles (diets with low or high AGE content or red meat or dairy products, etc.) can have lasting effects and/or result in improved insulin sensitivity and amelioration of the metabolic syndrome. Although we are cognizant of some of the factors that affect the metabolic balance, we still do not know enough of the genetic and epigenetic factors or how their interactions affect this balance. As the authors suggested, long-term studies would be required to show 1) the persistence of the effect, 2) arrest of progression to type 2 diabetes, and 3) consequent prevention of the metabolic syndrome and its sequelae. Such a study is currently not likely. Insulin resistance has long been known to be a risk factor for stroke and myocardial infarction (5). In addition to efforts to alter diet, exercise, and lifestyle, attempts have been underway to alter insulin sensitivity and glucose homeostasis by pharmacologic agents. For example, drugs such as the insulin-sensitizing thiazolidinediones that activate peroxisome proliferator-associated receptor (PPAR)-c nuclear receptors that control nutrient responses (PPARs) have been shown to reduce the rate of progression to type 2 diabetes. A recent study [IRIS (Insulin Resistance Intervention after Strokes)] in nondiabetic patients who had insulin resistance and a history of ischemic strokes and/or transient