Management Of The

The use of insulin sensitizers and lifestyle modifications to improve insulin resistance in the treatment of type 2 diabetes is discussed elsewhere in the book. Any therapeutic maneuver that improves insulin sensitivity should also have beneficial effects on all the metabolic and CV abnormalities associated with the IRS. In this section we will concentrate on management of the syndrome as a whole particularly its link with CVD.

Lifestyle Changes

Since obesity and physical activity are important precursors of the syndrome, lifestyle change may be critical in its prevention and treatment. The NCEP has strongly endorsed the concept of "total lifestyle change" in the prevention of CVD due to the syndrome. Recent clinical trials have demonstrated that modest reductions in calorie and fat intake and a small increase in physical activity can prevent the development of type 2 diabetes (100). While a reduction in CV events has not yet been documented, lifestyle changes significantly improve CV risk factors such as HDL, LDL and blood pressure.

Since many individuals with the metabolic syndrome are overweight, dietary treatment should be primarily focused on weight reduction. While the effect of weight reduction on the components of the IRS are widely accepted, there remains some controversy about specific diets to achieve weight loss.

Insulin sensitivity can also be influenced by diet composition (101,102). There is evidence that a higher saturated fat intake is associated with impaired insulin action, some of which may be mediated by changes in body weight. In contrast, a high-monounsaturated-fat diet significantly improves insulin sensitivity compared to a high-saturated-fat diet. Independent of its effects on insulin sensitivity, diet composition can influence the factors clustering in the metabolic syndrome. Dietary carbohydrate increases blood glucose levels, particularly in the post-prandial period, and consequently also insulin levels and plasma triglycerides. The detrimental effects of a high-carbohydrate diet on plasma glucose/insulin, triglyceride/HDL or fibrinolysis occur only when carbohydrate foods with a high glycemic index are consumed, while they are abolished if the diet is based largely on fiber-rich, low-glycemic-index foods. Mono-unsaturated fats and ro-3 fatty acids can reduce plasma triglycerides. Such diets may also improve endothelial function.

Moderate physical activity (brisk walking for at least 30 min/day) should be feasible for most patients. One of the major anticipated benefits of an active lifestyle is a reduction in CV mortality. Exercise improves insulin sensitivity and glucose tolerance rapidly and independently of weight loss. Exercise training results in preferential loss of fat stores from central regions of the body (103). Aerobic exercise training has been shown to lower systolic and diastolic blood pressure, and plasma triglycerides and increase HDL cholesterol.

Pharmacological Therapy

Unfortunately, no clinical trial data is available to show a reduction in CV events with pharmacological treatment of the IRS per se. However, current pharmacological strategies for established risk factors such as hyperglycemia, hypertension, dyslipidemia and platelet aggregation have been shown to mitigate many of the consequences of the syndrome. Nevertheless, this leads to the prescription of complex multidrug regimens and there is a need for therapy that will directly treat the syndrome. Insulin sensitizers are approved for treatment of hyperglycemia in type 2 diabetes (discussed elsewhere). We will consider their role in the IRS and its vascular complications. The effects of pharmacological therapy on some components of the IRS are summarized in Table 5.

Metformin

Metformin is a biguanide that has been approved for the treatment of type 2 diabetes and has also been shown to prevent diabetes in obese subjects with impaired glucose tolerance. The primary glucose lowering effect of metformin results from a decrease in hepatic gluco-neogenesis with some effect on peripheral glucose disposal (104). The mechanism of action is different from and complementary to that of the thiazolidinediones (TZDs).

Obese patients in the United Kingdom Prospective Diabetes Study (UKPDS) treated with metformin had a 36% lower risk of all cause mortality and a 39% lower risk of myocardial infarction (105). Since there was no difference in glycemic control in subjects treated with Metformin compared to that achieved with other treatment modalities, it is possible that other effects of the drug, including its effects on the IRS may have decreased CV events. Most importantly, patients in the UKPDS gained less weight compared to those treated with other agents (105). Potential mechanisms by which metformin may decrease CV events, include reduced plasma triglycerides, LDL cholesterol concentration, postprandial lipemia, and plasma free fatty acid concentration (106,107) In addition metformin has a favorable effect on several nontraditional CV risk factors including plasminogen activator inhibitor-1, fibrinogen and endothelial function (106,107) (Table 5).

Thiazolidinediones

TZDs are oral anti-diabetic agents developed to improve insulin sensitivity. TZDs primarily exert their insulin sensitizing effect by increasing peripheral uptake of glucose especially at the skeletal muscles (108). Drugs of this class act as ligands for PPARy, which functions as a transcription factor involved in the regulation of genes involved in glucose homeostasis and lipid metabolism. These receptors have several potential effects in different tissues, including the vasculature. Since PPARy plays a role endothelial and vascular smooth muscle cells, ligands of these receptors, such as TZDs may play a role in atherosclerosis. For example, the TZDs inhibit vascular smooth muscle cell proliferation and migration (90).

TZDs have been shown to have many other effects other than reduction of hyperglycemia, some of which are summarized in Table 5 (109) They decrease plasma free fatty acid concentrations and the associated inhibition of free fatty acid oxidation. They decrease the release of cytokines and peptides such as TNF-a from adipose tissue that are associated with insulin resistance and vascular inflammation. TZDs have been shown to improve endothelial function and inflammation and have been shown to have an inhibitory effect on carotid artery IMT in patients with type 2 diabetes (110). However, TZDs cause weight gain, although a decrease in visceral fat may help explain the concomitant decrease in insulin resistance (109). They also increase plasma LDL concentration although studies suggest that they change LDL particle size to the less atherogenic large buoyant LDL cholesterol (109). Thus, TZDs may have beneficial effects against CVD, although reductions in CV events have not yet been demonstrated. Clinical trials are in progress to determine whether they will prevent CV events.

TABLE 5 Effect of Pharmacological Therapy on CV Risk Factors and Markers in the Insulin Resistance Syndrome

Drug type

Drug class

Body weight

Blood pressure

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