PATHOGENESIS OF THE METABOLIC SYNDROME AND TYPE 2 DIABETES

11.3 PATHOGENESIS OF THE METABOLIC SYNDROME AND TYPE 2 DIABETES

Type 2 diabetes not only is a manifestation of the metabolic syndrome, but also, in most cases, is preceded by the metabolic syndrome. 19 The metabolic syndrome is a concurrence of disturbed glucose and insulin metabolism, overweight and abdominal fat distribution, dyslipidemia, and hypertension. The hallmark of the syndrome is resistance to the biological effects of insulin in target tissues, thus why it is also known as the insulin resistance syndrome. The metabolic syndrome as defined by

Functional Food Carbohydrates

the National Cholesterol Education Program Expert Panel (2001) and the World Health Organization 20 is common, present in about 24% of all adults in the U.S., and in somewhat smaller proportions in most European countries. The metabolic syndrome constitutes a major threat to public health because of its association with a 5- to 10-fold increased risk of type 2 diabetes mellitus and a

2- to 3-fold higher risk of cardiovascular disease. 19,21–23 Cardiovascular risk factors such as dyslipidemia, hypertension, endothelial dysfunction, inflammation, hyper-

coagulability and impaired fibrinolysis, obesity, and abnormal insulin and glucose metabolism, all of which are part of or closely associated with the metabolic syn-

drome, contribute to this increased risk. The pathogenesis of the metabolic syndrome is poorly understood. Skeletal muscle is a major determinant of whole-body glucose disposal. Defects in insulin signaling in muscle tissue contribute to lowered insulin-stimulated glucose uptake. 24 Furthermore, an abdominal distribution of fat is particularly deleterious. Abdominal obesity has been hypothesized to mediate its deleterious effects on carbohydrate and lipid metabolism through the increased lipolytic activity of especially omental fat,

which drains directly into the portal-venous system. 25 This, in turn, results in higher nonesterified fatty acid concentrations, with consequent insulin resistance in the liver

and skeletal muscle. In addition to abdominal subcutaneous and visceral fat, lipid accumulation in skeletal muscle and the liver has also been shown to be a powerful determinant of insulin sensitivity. 26

As the metabolic syndrome becomes more severe, interplay among genetic susceptibility, insulin resistance, and dietary patterns may lead to progressive β-cell failure and impaired insulin secretion capacity. As β-cell function declines, impaired

glucose tolerance (IGT) develops. 27 At this point, pulsatile and first-phase insulin secretion, essential for normal glucose tolerance, is impaired, and an exaggerated longer-lasting second phase occurs in compensation. On a yearly basis, in roughly

5 to 10% of persons with IGT, it converts to type 2 diabetes. 28 Type 2 diabetes is a heterogeneous clinical entity, however, and not all patients have features of metabolic syndrome; about 10 to 20% have insulin secretion deficiency as the major contributor to hyperglycemia.

Hyperglycemia begets further loss of pancreatic β-cell function. It has not been fully resolved whether this loss of pancreatic function results primarily from exces- sive secretion of insulin (i.e., β-cell exhaustion) or toxicity to β-cells because of hyperglycemia. By definition, high intake of carbohydrates with a high glycemic index (GI) produces high concentrations of plasma glucose and increased insulin

demand, and may therefore hypothetically contribute to an increased risk of type 2 diabetes. The individual response to a given carbohydrate load is influenced by the degree of underlying insulin resistance and impaired insulin secretion, which is, in turn, determined primarily by the degree and type of adiposity, physical activity,

genetics, and diet. Thus, it might be expected that the adverse metabolic effects of high-GI, low-fiber foods would be pronounced in sedentary, overweight, or geneti-

cally susceptible persons and be quite modest in the healthy university students that frequently participate in metabolic studies.

The Role of Carbohydrates