It is widely believed that overeating calorie-dense food, particularly a high-fat diet, together with an inactive lifestyle causes obesity. A consequence of obesity is increased circulating lipids and cytokines, indicators of inflammation and inducers of insulin resistance. Obesity and insulin resistance are believed to be the precursors of diabetes in about 20% of subjects. The current standard treatment for diabetes includes diet, exercise, and a biguanide together with agents that increase circulating insulin in an effort to overcome insulin resistance (5
The term Insulin Resistance Syndrome is used to describe the combination of insulin resistance and compensatory hyperinsulinemia (HI). It is assumed, without evidence, that insulin resistance precedes and causes HI. Insulin resistance purportedly stimulates increased insulin secretion, interpreted as the body’s attempt to overcome the resistance, however, there is no satisfactory explanation for how insulin resistance might stimulate insulin secretion. In addition, there are few naturally occurring or genetic models of primary insulin resistance and few diabetes genes are implicated in insulin resistance. Although this has been the prevalent model under investigation by basic scientists and a major focus for drug development, we have no viable drugs to improve long-term metabolic health. Perhaps the model is not viable and we need to look elsewhere.
It is well documented that average food consumption has increased and that activity has decreased and both correlate with insulin resistance, however, this does not prove or infer causation. There is no evidence that overeating and inactivity are the initiating causes of obesity and diabetes in our population. They may simply coexist or be caused by other yet unidentified factors. Where in the multiple tissue/metabolic interactions shown in does the trigger lie? Is there only one trigger?
Figure 1 Potential initiating defects and interactions in obesity/diabetes. Illustration of the interconnectedness among insulin secretion, fat mass, insulin resistance, and ingestive behavior such that a primary defect in any one could lead to the observed alterations (more ...)
Not all overweight/obese individuals are insulin resistant nor are all insulin resistant individuals overweight/obese (6
). Furthermore, there is evidence that alterations in food consumption do not cause sustained weight change. An elegant study by Sims et al. (7
) in the 1970s found that experimentally overfed volunteers required nearly 6,000 calories per day to maintain a 20% increase in their body weight and most of these subjects rapidly returned to their normal lower weight at the end of the study. Abundant evidence documents the failure of most dieters to sustain weight loss. In a review of studies of the long-term outcomes of diets to determine if dieting is an effective therapy for obesity, it was found that one-third to two-thirds of dieters regain more weight than they lost on their diets (8
). These studies also did not provide consistent evidence that dieting results in significant long-term health improvements (8
). Furthermore, the prevalent focus on the evils of dietary fat and their implied causative role in obesity are not well documented by scientific evidence. Indeed, the decrease in fat consumption that has resulted from abundant (nonevidence-based) medical and governmental advice against fat consumption has not decreased the burden of metabolic disease in our society (9
An alternative perspective is that insulin resistance is not the cause of diabetes, but is rather a beneficial adaptive mechanism to HI and/or hyperlipidemia. Insulin functions to store all fuels. Excess circulating lipids and amino acids can increase insulin secretion in the presence of normal circulating glucose levels. Thus, in the setting of normal blood glucose, insulin elevation caused by fat or amino acids would result in hypoglycemia. This does not happen because glucose transport into muscle and fat is diminished, because it is resistant to the normal ability of insulin to promote glucose transport.
Finding the right model is crucial to finding the right treatment. The therapeutic approach to further increase insulin, as often recommended to T2DM patients, may actually be exacerbating the disease. Resistance may prove to be secondary to another defect or even beneficial by facilitating excess fat storage without causing hypoglycemia that could ensue from “curing” resistance. Pharmacologic attempts to abolish this mechanism have largely failed as metabolic regulatory mechanisms appear able to overcome our efforts, suggesting that the body’s metabolic wisdom trumps ours.