Methods for assessment, e.g., anthropometric indicators and imaging techniques, of several phenotypes of human obesity, with special reference to abdominal fat content, have been evaluated. The correlation of fat distribution with age, gender, total body fat, energy balance, adipose tissue lipoprotein lipase and lipolytic activity, adipose tissue receptors, and genetic characteristics are discussed. Several secreted or expressed factors in the adipocyte are evaluated in the context of fat tissue localization. The body fat distribution and the metabolic profile in nonobese and obese individuals is discussed relative to lipolysis, antilypolysis and lipogenesis, insulin sensitivity, and glucose, lipid, and protein metabolism. Finally, the endocrine regulation of abdominal visceral fat in comparison with the adipose tissue localized in other areas is presented.

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Subcutaneous and visceral adipose tissue : Their relation to the metabolic syndrome

It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.

The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes.

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The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes.

Hyperinsulinemia secondary to a poorly characterized disorder of insulin action is a feature of the polycystic ovary syndrome (PCO). However, controversy exists as to whether insulin resistance results from PCO or the obesity that is frequently associated with it. Thus, we determined in vivo insulin action on peripheral glucose utilization (M) and hepatic glucose production (HGP) with the euglycemic glucose-clamp technique in obese ( n = 19) and nonobese ( n = 10) PCO women and age- and body-composition-matched normal ovulatory women ( n = 11 obese and n = 8 nonobese women). None had fasting hyperglycemia. Two obese PCO women had diabetes mellitus, established with an oral glucose tolerance test; no other women had impairment of glucose tolerance. However, the obese PCO women had significantly increased fasting and 2-h glucose levels after an oral glucose load and increased basal HGP compared with their body-composition-matched control group. There were statistically significant interactions between obesity and PCO in fasting glucose levels and basal HGP ( P < .05). Steady-state insulin levels of ∼100 μU/ml were achieved during the clamp. Insulin-stimulated glucose utilization was significantly decreased in both PCO groups whether expressed per kilogram total weight ( P < .001) or per kilogram fat free mass ( P < .001) or when divided by the steady-state plasma insulin (I) level (M/I, P < .001). There was residual HGP in 4 of 15 obese PCO, 0 of 11 obese normal, 2 of 10 nonobese PCO, and 0 of 8 nonobese normal women. The metabolic clearance rate of insulin did not differ in the four groups. We conclude that 1 ) PCO women have significant insulin resistance that is independent of obesity, changes in body composition, and impairment of glucose tolerance, 2 ) PCO and obesity have a synergistic deleterious effect on glucose tolerance, 3 ) hyperinsulinemia in PCO is not the result of decreased insulin clearance, and 4 ) PCO is associated with a unique disorder of insulin action.

Profound Peripheral Insulin Resistance, Independent of Obesity, in Polycystic Ovary Syndrome

Evidence is reviewed that free fatty acids (FFAs) are one important link between obesity and insulin resistance and NIDDM. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations in plasma FFA concentrations inhibit insulin stimulated peripheral glucose uptake in a dose-dependent manner in normal controls and in patients with NIDDM. Two possible mechanisms are identified: 1) a fat-related inhibition of glucose transport or phosphorylation, which appears after 3-4 h of fat infusion, and 2) a decrease in muscle glycogen synthase activity, which appears after 4-6 h of fat infusion. Third, FFAs stimulate insulin secretion in nondiabetic individuals. Some of this insulin is transmitted in the peripheral circulation and is able to compensate for FFA-mediated peripheral insulin resistance. FFA-mediated portal hyperinsulinemia counteracts the stimulation of FFAs on hepatic glucose production (HGP) and thus prevents hepatic glucose overproduction. We speculate that, in obese individuals who are genetically predisposed to develop NIDDM, FFAs will eventually fail to promote insulin secretion. The stimulatory effect of FFAs on HGP would then become unchecked, resulting in hyperglycemia. Hence, continuously elevated levels of plasma FFAs may play a key role in the pathogenesis of NIDDM in predisposed individuals by impairing peripheral glucose utilization and by promoting hepatic glucose overproduction.

Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM

The effects of obesity and body fat distribution on splanchnic insulin metabolism and the relationship to peripheral insulin sensitivity were assessed in 6 nonobese and 16 obese premenopausal women. When compared with the nonobese women, obese women had significantly greater prehepatic production and portal vein levels of insulin both basally and following glucose stimulation. This increase correlated with the degree of adiposity but not with waist-to-hip girth ratio (WHR). WHR, however, correlated inversely with the hepatic extraction fraction and directly with the posthepatic delivery of insulin. The latter correlated with the degree of peripheral insulinemia. The decline in hepatic insulin extraction with increasing WHR also correlated with the accompanying diminution in peripheral insulin sensitivity. Increasing adiposity is thus associated with insulin hypersecretion. The pronounced hyperinsulinemia of upper body fat localization, however, is due to an additional defect in hepatic insulin extraction. This defect is closely allied with the decline in peripheral insulin sensitivity.

Splanchnic insulin metabolism in obesity. Influence of body fat distribution.

The importance of androgenic activity in mediating the effects of obesity and body fat topography on splanchnic insulin metabolism and peripheral insulin sensitivity was studied in 19 nonhirsute premenopausal women with a wide range of ideal body weight [percent ideal body weight (% IBW), 78-202%] and body fat distribution pattern [waist to hip girth ratio (WHR), 0.67-0.91]. Turnover kinetics of peripheral plasma C-peptide and insulin were measured, and estimates of pancreatic insulin production (PIP) and the hepatic extraction fraction (HEF) were calculated. The peripheral insulin sensitivity index (M/I) was determined during an euglycemic insulin clamp study. Androgenic activity was assessed by estimating the plasma level of sex hormone-binding globulin (SHBG) and percentage of free testosterone (% FT). After iv glucose stimulation, PIP ranged from 40-254 mU/min X m2 and correlated highly with % IBW (r = 0.78; P less than 0.01). Insulin HEF ranged from 5-69% of the pancreatic production and was inversely proportional to WHR (r = -0.60; P less than 0.01). Increasing WHR also correlated with the diminution in M/I (r = -0.47; P less than 0.05), which, in turn, correlated with the decline in the HEF of insulin (r = 0.60; P less than 0.01). Since PIP, HEF, and M/I correlated with SHBG and % FT, and since the degree of androgenic activity correlated with % IBW and WHR, partial regression analysis was performed. After adjusting for the effects of SHBG and % FT, the relationship between % IBW and PIP remained unaltered, whereas the correlation between WHR and HEF or M/I and their relationship to each other were either markedly reduced or became insignificant. Thus, in premenopausal women, the increase in pancreatic insulin production with increasing weight is independent of the degree of androgenic activity. On the other hand, the decline in hepatic insulin extraction and diminution in peripheral insulin sensitivity with upper body fat localization are in part mediated by increased androgenic activity. This association may account for the pronounced hyperinsulinemia and insulin resistance characteristic of this form of obesity.

Relationship of Androgenic Activity to Splanchnic Insulin Metabolism and Peripheral Glucose Utilization in Premenopausal Women

The dose-response relationships between portal venous insulin concentrations and hepatic glucose production and between peripheral insulin concentrations and peripheral glucose utilization were determined in 8 nonobese and 17 obese premenopausal women with either upper or lower body fat localization. The glucose production dose-response curves for the two obese groups were shifted to the right at all levels of portal insulinemia. The upper body obese women had a greater rightward shift compared to the lower body obese women. The peripheral glucose utilization dose-response curve was shifted to the right in the lower body obese women, but maximal glucose utilization was normal. The upper body obese women had both a greater rightward shift and a marked reduction in maximal glucose utilization. The insulin concentrations that had halfmaximal effects on glucose production and utilization were similar in each group. These results indicate that the liver is not inherently more sensitive to insulin than peripher...

Glucose metabolism in obesity: influence of body fat distribution.

The effects of body fat distribution on the metabolic clearance rate of insulin (MCR) and its relationship to peripheral insulin sensitivity (M/I) and androgenic activity were assessed in six nonobese and 20 obese premenopausal women with varying waist-to-hip girth ratio (WHR). As an index of androgenic activity, plasma levels of the sex hormone binding globulin (SHBG) and percentage free testosterone (%FT) were determined. The mean MCR in the obese and nonobese groups were similar (571 +/- 29 vs 578 +/- 31 ml/min/m2). Within the obese group, MCR varied between 401 and 822 ml/min/m2 and was inversely correlated with the WHR (r = -0.50, P less than 0.05). The reduction in MCR with upper body fat localization was observed at both sub- and supra-maximal plasma insulin levels. MCR correlated negatively with fasting and postglucose challenge plasma insulin levels and positively with M/I. MCR also correlated with plasma SHBG and %FT levels. We conclude that upper body fat localization is associated with diminished insulin clearance. This diminution is closely aligned with the degree of peripheral insulinemia and insulin sensitivity. The increase in androgenic activity may contribute to the aberrant insulin clearance observed in upper body obese subjects.

Relationship of body fat distribution to the metabolic clearance of insulin in premenopausal women.

Neonates, having little or no pancreatic lipase, would have a compromised ability to digest lipids if not for lingual and gastric lipases. To document the postnatal developmental profile of preduodenal lipase activity, 350 premature infants who were at various gestational ages and who had an orogastric tube had their gastric aspirates collected. Two hundred one infants had their gastric aspirates collected within 12 h after delivery. Serial collections were performed in 25 infants at various postnatal ages. Gastric aspirates collected from premature infants had a pH activity profile similar to that of lingual and gastric lipase but different from that of pancreatic lipase, indicating that their origin was from the tongue and/or stomach. Lipolytic activity and pH of these aspirates were quite variable, but no correlation was found between pH and enzyme activity. At birth, lipase activity was lower in the younger infants ( or = 40 weeks, n = 40). Postnatally, a composite plot of the serially collected aspirates also showed a predominant peak at 28-33 weeks of age. Comparison among siblings in twins (n = 12 pairs) and triplets (n = 3) showed great variations in their lipolytic activities, suggesting that the hereditary factor is not a major determinant. Various combinations of antibiotic medications (ampicillin, cefotaxime, gentamicin, and vancomycin) and drugs (dexamethasone, heparin, furosemide, phenobarbital, albumin, and vitamin K) apparently had no effect on the level and development of gastric lipolytic activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Mark F. Struve

Papers

Splanchnic insulin metabolism in obesity. Influence of body fat distribution.

Relationship of Androgenic Activity to Splanchnic Insulin Metabolism and Peripheral Glucose Utilization in Premenopausal Women

Glucose metabolism in obesity: influence of body fat distribution.

Relationship of body fat distribution to the metabolic clearance of insulin in premenopausal women.

Development of lipolytic activity in gastric aspirates from premature infants.