REGIONAL ADIPOSITY AND MORBIDITY

Abdominal-visceral fat has emerged as a significant correlate of hyperinsulinemia, increased plasma triglyceride levels, decreased HDL levels, and elevated blood pressure. Abdominal obesity is a phenotypic companion for a cluster of metabolic abnormalities characterized by decreased insulin sensitivity, which is compensated by increased insulin secretion and diminished hepatic insulin extraction, with resultant hyperinsulinemia. Hyperinsulinemia is the most significant metabolic variable in these associations. Abdominal obesity, on the other hand, results from interactions between genetic, environmental, and neuroendocrine mechanisms, and each of these can affect insulin dynamics and the metabolic profile independently. Abdominal obesity and its associated insulin resistance are predictive of a myriad of disorders, including glucose intolerance, NIDDM, salt-sensitive hypertension, hyperapobetalipoproteinemia, hypoalphalipoproteinemia, and coronary heart disease. Again, the etiology of these disorders is contingent on other factors, both genetic and environmental, and it is possible that abdominal obesity and/or insulin resistance operate as provocative or exacerbating factors. What is so peculiar about fat deposition around the waist? Its anatomic location and α/β-adrenoceptor sensitivity suggest that FFA flux from this tissue may play a major role in suppressing hepatic insulin clearance and creating peripheral insulin resistance. How visceral fat can mediate or exacerbate insulin resistance and the associated metabolic changes is still far from clear. Glucocorticoids and the sex hormones are both involved in directly influencing abdominal obesity. Glucocorticoids seem to act at the level of influencing preadipocyte recruitment and filling, while perinatal and peripubertal sex hormones play major roles in influencing both insulin dynamics and fat deposition. Whether these two types of hormones interact in some manner is uncertain. The existence of putative 'obesity genes' in inbred rodents suggests that such genes might be responsible for obesity in humans as well, and some of these genes may be responsible for regional fat deposition. Clearly, genes encoding for such proteins as LPL or the fat cell β-adrenergic receptor would play a role in regional adiposity. Glucokinase has emerged as an early candidate for NIDDM, and others are likely to follow. If such an obesity gene, or series of genes, responsible for the obesity phenotype exists, its identity, regulatory aspects, and interactions between the gene products in promoting obesity represent important areas for future research. The coexistence of hyperinsulinemia and impaired glucose tolerance in abdominal obesity suggests that insulin resistance is the underlying abnormality. Efforts to identify the exact locus of the insulin resistance have not been successful. It seems clear that neither decreased insulin receptor number nor alterations in glucose transporter number or structure can explain this insulin resistance. The mechanism connecting the regulation of hepatic insulin extraction to the compensatory peripheral hyperinsulinemia of insulin resistance is also another area for future investigation. The modes of insulin release and coupling of insulin secretion to insulin demand appear to be at fault. Might insulin secretion pulsatilities and response dynamics be early markers of β- cell secretory dysfunction in those abdominally obese individuals with a strong predisposition to NIDDM, and if so, what are the factors responsible for these responses? In abdominally obese women, the degree of capillary rarefaction is correlated with the decline in insulin-mediated peripheral glucose utilization. Increased androgenic activity has also been demonstrated, and this in turn is highly correlated with the reductions in capillarization and in insulin sensitivity. These relationships suggest potential roles for androgens in the pathogenesis of the reduced capillarization, in regulating muscle fiber metabolism, in influencing compositional features, and in the insulin resistance that characterizes abdominally obese women. Does capillary rarefaction influence in vivo insulin sensitivity, and if so, how might this be modulated by androgenization?