The conundrum of whole foods versus macronutrient composition in assessing effects on insulin sensitivity

See corresponding article on page 1173.

Cardiometabolic disease encompasses a spectrum of clinical manifestations, beginning early in life with relative insulin resistance, progressing to clinically identifiable states of high risk (i.e., prediabetes and metabolic syndrome), and culminating in type 2 diabetes (T2D), cardiovascular disease events, or both in single patients (1, 2). This spectrum of disease is driven by a common pathophysiologic process that involves the accumulation of intra-abdominal fat, dysregulated secretion of adipocytokines, and systemic inflammation (3, 4). Generalized obesity can exacerbate insulin resistance and impel progression to T2D; however, obesity alone is neither necessary nor sufficient because even lean individuals can be insulin resistant, and obese individuals can be insulin sensitive with low diabetes risk (1). Nevertheless, it is clear that weight loss in overweight/obese individuals with insulin resistance and cardiometabolic disease prevents progression to T2D. In addition, alterations in the macronutrient composition of diets may also modulate insulin resistance and diabetes risk independent of weight loss (5). Given the increasing prevalence of T2D, together with its burden of patient suffering and social costs, it is critical that we identify effective strategies for prevention.

In this issue of the Journal, Turner et al. (6) compared the relative ability of diets enriched in red meat, dairy products, or white meat (referred to as the control group) to affect insulin sensitivity in 47 overweight/obese middle-aged men and women. This randomized crossover study featured 4 wk of isocaloric feeding with each of the 3 diets separated by 2-wk washout periods, with oral-glucose-tolerance tests performed at the beginning and end of each diet period to assess insulin sensitivity. An effort was made to ensure that all diets were isocaloric, which is valuable because overweight/obese patients with cardiometabolic disease will be isocaloric most of their lives, whether or not they have attempted weight loss or after a period of weight loss when the goal is to maintain body weight at the reduced level. The authors observed that subjects consuming the red meat diet were relatively insulin sensitive and those consuming the dairy product diet were more insulin resistant. The implications of the study are important because a diet that promotes insulin sensitivity would predictably decrease risk of future diabetes. However, there are few data available with regard to long-term effects of dietary macronutrient composition on clinical outcomes such as diabetes, cardiovascular disease events, and mortality. The current study used isocaloric substitution of red meat vs. dairy products as a source of protein to assess effects on insulin sensitivity as a surrogate for longer term outcomes, namely progression to T2D. In the absence of clinical outcome data, effects on insulin sensitivity constitute the best evidence available on which to base the dietary prescription for patients with cardiometabolic disease.

There are limitations to the study, including the following: 1) the small numbers of research subjects; 2) the fact that the diets were not truly isocaloric, resulting in small but clinically significant differences in body weight (loss of 0.4 ± 1.1 kg with the red meat diet and gain of 0.1 ± 1.2 kg with dairy products); 3) the use of suboptimal measures of insulin sensitivity (i.e., indexes based on fasting and post–oral-glucose-tolerance test glucose and insulin concentrations (7); and 4) the fact that the differences in insulin sensitivity were quite small, necessitating the need for cautious interpretation of the data. Moreover, the authors emphasized different foods as sources of protein, but it may be differences in fat content and quality of fat in the foods that explain the data. In their Table 4, it is clear that the dairy product diet is characterized by higher total and saturated fat content and, by subtraction, lower amounts of poly- and monounsaturated fats. There is a large body of data indicating that the amount and composition of dietary fatty acids can modulate insulin sensitivity and cardiovascular disease risk factors independent of total caloric intake (5). Specifically, many cross-sectional studies and interventional trials showed that isocaloric enrichment with saturated and trans fatty acids is associated with hyperinsulinemia and greater risk of T2D, independent of body adiposity (8, 9), and that substitution of MUFAs for saturated fat, or even substituting MUFAs for carbohydrates, can have positive effects on insulin sensitivity, lipids, and cardiometabolic health (10–12). Along these same lines, the dairy product diet contained more carbohydrate and less fiber than the other diets, which could have increased insulin secretion, thus affecting the indexes used as measures of insulin sensitivity.

Therefore, the macronutrient composition may be the primary determinant of insulin sensitivity rather than the selection of whole foods per se (e.g., meat or dairy) or the meal plan. For example, the same experiment performed with low-fat dairy products, which resulted in decreased intake of saturated fat, could have produced entirely different results. In fact, this could explain the discrepancy between the current results and other studies cited by the authors as showing that consumption of dairy products could be beneficial in patients with insulin resistance and cardiometabolic disease.

Overall, these considerations point to the need for well-controlled studies that take into account multiple variables in assessing the impact of diet on cardiometabolic health. In particular, it will be important to address the variable macronutrient composition of foods and meal plans as a determinant of insulin sensitivity and design larger and longer-term studies that address the impact on clinical outcomes, such as progression to diabetes, while ensuring isocaloric weight neutrality. In the meantime, given the central role of insulin resistance in the pathophysiology of cardiometabolic disease, it is reasonable to emphasize macronutrients that enhance insulin sensitivity and to reduce nutrients that promote insulin resistance in formulating dietary therapy (5). The authors interpret their data to suggest that overweight/obese patients should consume a diet enriched in red meat rather than high-fat dairy products. However, improvements in insulin sensitivity might also be accomplished by a diet enriched in low-fat dairy products in persons who do not prefer a high intake of red meat.