First described by Reaven in 1988 as “Syndrome-X” [1], the constellation of obesity (particularly central or abdominal obesity), high triglycerides, low high density lipoprotein (HDL), elevated blood pressure, and elevated plasma glucose has been variously described as “insulin resistance syndrome”, “metabolic syndrome” and “cardiometabolic risk” (CMR). We use the latter term in this paper to describe the cluster of risk factors. Although the American Diabetes Association, the American Heart Association, and the National Heart, Lung, and Blood Institute at the National Institutes of Health do not recognize the group of risk factors as a syndrome, the organizations all acknowledge that the individual risk factors are causally related to diabetes, heart disease, stroke, and renal failure [2,3]. It is important to understand the origins of CMR and develop appropriate intervention strategies because CMR costs the United States nearly $500 billion a year in health care and lost wages [4,5] and is an emerging problem worldwide.

Along the path from health to disease, abdominal obesity and insulin resistance are precursors to elevated blood glucose, dyslipidemia and, possibly, systemic inflammation and hypofibrinolysis [6–14]. When abdominal obesity is present, excess release of circulating free fatty acids and a variety of cytokines that may contribute to inflammation and/or oxidative stress, may cause or exacerbate peripheral insulin resistance [7,8,15–17]. Evidence from cross-sectional and longitudinal studies demonstrates higher risk of morbidity and mortality among individuals with disproportionately high visceral abdominal fat when accounting for total body weight or total body fat [17–19]. Indeed, there is evidence for an association of excess abdominal fat and chronic disease risk across a wide range of BMI values [20–22], and the prevalence of CMR begins to rise well below the cutoff for overweight status (BMI 25 kg/m²) [21].

The experimental evidence that exercise modulates insulin resistance and lowers risk factor levels for type 2 diabetes and cardiovascular disease is substantial [23–29]. Well-conducted experiments in men and women of varying race/ethnic groups have clearly demonstrated improvements in insulin sensitivity as a result of single exercise bouts or brief training periods with no change in body weight [24,25,27–37].

Although the precise mechanisms whereby physical activity may have a direct effect on insulin sensitivity are not completely understood, there appears to be support from animal and human studies for mechanisms that involve enhanced insulin receptor and post-receptor function, increased skeletal muscle insulin-sensitive glucose transporter proteins, increased skeletal muscle capillary density, and, over longer time periods, changes in body composition [38–51]. Some of these responses to exercise may also occur in the liver and adipose tissue [36]. Exercise also reduces levels of inflammatory markers, raises high density lipoprotein cholesterol (HDL) and lowers triglycerides.

Through a variety of mechanisms, including those independent of energy balance and weight change, endurance training has been shown to reduce visceral abdominal fat deposition and improve insulin sensitivity [52–55]. Endurance training, such as brisk walking, has been shown to increase HDL [53]. Independent of weight loss, physical activity may reduce blood pressure through a variety of mechanisms, including an attenuation of adrenergic sympathetic activity and a reduction in total peripheral resistance [25,56,57]. Additionally, the reductions in hyperinsulinemia and abdominal fat associated with exercise may reduce blood pressure through decreased sodium retention and reduced sympathetic nervous system stimulation [58–61]. This strong negative association between physical activity and risk of coronary heart disease biologically underscore the plausible effects of physical activity on CMR [30,62].

As with exercise, the literature is rich with experimental evidence supporting direct effects of a variety of dietary components on insulin sensitivity and risk factors for cardiovascular disease and diabetes. The results appear to be independent of weight loss. Clinically important effects have appeared within four weeks of intervention in controlled studies [63–65]. It is clear from experimental and observational studies that intake of saturated and trans-fatty acids promote insulin resistance, whereas monounsaturated, polyunsaturated, and longer chain n-3 fatty acids appear to improve insulin sensitivity [66–69]. Evidence has emerged over the past decade from experimental studies that less refined and less-starchy carbohydrates, such as fresh fruit, whole grains, green leafy vegetables, nuts, legumes, in contrast to fruit juice, refined grains, and starchy vegetables, have direct and independent beneficial effects on both glucose and insulin metabolism [63,70–95]. Several studies have demonstrated, over the short term, that changing dietary composition without changing calories may improve insulin sensitivity [63,93–97]. There are many plausible physiological explanations for these observations including attenuation of postprandial glycemia, reduced demand for insulin, and direct effects of dietary constituents on beta cells and peripheral insulin receptors [75–81,84,98–103].

The dietary fatty acids that promote insulin sensitivity are the same as those that lower triglycerides and raise HDL. Conversely, low-fat diets that are high in low-quality carbohydrates lower HDL and raise triglycerides. Long-chain fatty acids, such as the n-3 (omega-3) fatty acids found in certain fish, nuts, and seeds, may reduce blood triglyceride concentrations [104–111]. Replacing dietary saturated fat with monounsaturated fat also improves blood lipid profiles [106,112–114]. Controlled feeding studies demonstrate that these dietary effects are independent of changes in body weight [104,112–118].

A diet rich in fruits, vegetables, whole grains, potassium, calcium, and magnesium, and low in sodium may also lower blood pressure [64,119,120]. Although not supported by all studies [121], evidence from observational studies suggests that systemic inflammation and hypofibrinolytic states, conditions known to cluster with the other components of CMR [10–13], can also be ameliorated by following a minimally processed plant-based diet and a physical activity program [81,82,122–124]. Recent cross sectional observations have suggested that certain dietary patterns, such as those including whole grains, fruits, vegetables, low-fat dairy products, and regular physical activity are inversely associated with the odds of having CMR [125–128]. Prospective observations also suggest that these dietary patterns are inversely associated with risk of developing CMR [82,126,129,130].

The Oslo Diet and Exercise Study compared the independent and joint effects of diet and exercise (aerobic training three times per week) on changes in CMR among 219 adults [131,132]. The goal of the dietary intervention was weight control, increased fish intake, and decreased fat intake. The exercise intervention included supervised endurance exercise three times per week. The group that received both the diet and physical activity intervention appeared to experience the greatest improvement in risk factors over a one-year period despite weight loss that was modest and no greater than that experienced in the diet only group [131,132]. In fact, the average BMI at follow-up remained in the overweight range (above 25 kg/m²). The correlations between changes in body weight and changes in insulin resistance and components of CMR were very weak [132].

Esposito et al. conducted a 2-year randomized trial of diet and exercise in 180 adults with CMR [133]. Although changes in activity and body weight (mean difference = −2.8 kg, p < 0.001) were modest over the 2-year intervention, the intervention group experienced significant improvements for all components of CMR. Based on regression analysis, these changes appeared to be largely independent of changes in weight. At the end of the trial, adjusted for weight changes, only 40 of the 90 intervention participants continued to have CMR, compared to 78 of the 90 control participants (p < 0.001).

Four large-scale randomized trials—one of them being the U.S. Diabetes Prevention Program--have examined the effect of diet and exercise in preventing type 2 diabetes among adults with glucose intolerance and high risk for type 2 diabetes [134–137]. These trials were conducted in four different populations—Sweden, China, Finland, and the United States. All found that lifestyle intervention significantly reduced the incidence of type 2 diabetes. These risk reductions were 25% in the Chinese study and 50 to 60% in the other trials. Weight loss was relatively modest across these studies, with means from −0.8% to +1.7% in the control groups and −1.8% to −6.0% in the intervention groups.

If reduction in CMR were dependent on magnitude of weight loss, one would expect correlations between changes in body weight and changes in CMR to be at least moderate in strength. However, all studies showed only weak or no correlations between changes in weight and changes in CMR. The relative risk reduction observed in the U.S. Diabetes Prevention Program for the diet and exercise intervention compared to usual care was ~55% with a mean weight loss of ~6% [135]. The intervention from Sweden and Finland achieved half of the weight loss of the U.S. study, but the relative risks for the diet and exercise intervention compared with usual care in those studies was very similar to the U.S. study. These data from well-conducted randomized trials with precise measures support the hypothesis that the behavioral components themselves, improved diet and increased physical activity, are the primary etiological factors driving the reduction in CMR and risk of diabetes, and that body weight changes may not be required for risk reduction to occur. Even if weight loss is relatively unimportant in the management of CMR, it can be important for other reasons. The same lifestyle behaviors that minimize CMR can aid in preventing weight gain over the long term because physical activity and the diet that prevents CMR also improves energy balance.

The data suggest that the emphasis in such interventions must include lifestyle changes for three reasons: 1) lifestyle changes have known direct effects on risk reduction through a variety of pathways, 2) while good nutrition and adequate physical activity have many benefits in addition to weight control, attempts to lose weight through fasting or unbalanced diets can increase risk of untoward events without the benefits of physical activity or good nutrition, and 3) diet and physical activity are behaviors that are under the direct and immediate control of the individual.

CMR arises from the constellation of obesity (particularly central or abdominal obesity), high triglycerides, low HDL, elevated blood pressure, and elevated plasma glucose. The mechanism of action appears to be a pathway that starts with a behavior pattern of inadequate physical activity and a diet high in saturated fat and added sugars, and inadequate in fruits, vegetables, and whole grains. These behaviors lead to insulin resistance as an intermediate state. Insulin resistance, appearing even within the “normal” range of BMI (<25 kg/m²), leads to the other risk factors in the cluster. These risk factors cause type 2 diabetes mellitus and cardiovascular disease. While maintaining or resuming ideal weight is beneficial for many reasons, experimental evidence demonstrates that improving diet and increasing physical activity reduces CMR independent of the degree of weight loss. These observations, and the fact that individuals can act directly to change their diet and increase their physical activity, suggest that the most effective intervention strategy to prevent and treat CMR is a universal intervention focusing on a healthy diet, adequate physical activity, and prevention of weight gain in adults and excess weight gain in youth.