Obesity is associated with insulin resistance, particularly when body fat has a central distribution. However, insulin resistance also frequently occurs in apparently lean individuals. It has been proposed that these lean insulin-resistant individuals have greater amounts of body fat than lean insulin-sensitive subjects. Alternatively, their body fat distribution may be different. Obesity is associated with elevated plasma leptin levels, but some studies have suggested that insulin sensitivity is an additional determinant of circulating leptin concentrations. To examine how body fat distribution contributes to insulin sensitivity and how these variables are related to leptin levels, we studied 174 individuals (73 men, 101 women), a priori classified as lean insulinsensitive (LIS, n ‫؍‬ 56), lean insulin-resistant (LIR, n ‫؍‬ 61), and obese insulin-resistant (OIR, n ‫؍‬ 57) based on their BMI and insulin sensitivity index (S I ). Whereas the BMI of the two lean groups did not differ, the S I of the LIR subjects was less than half that of the LIS group. The subcutaneous and intra-abdominal fat areas, determined by computed tomography, were 45 and 70% greater in the LIR subjects (P < 0.001) and 2.5-and 3-fold greater in the OIR group, as compared with the LIS group. Fasting plasma leptin levels were moderately increased in LIR subjects (10.8 ؎ 7.1 vs. 8.1 ؎ 6.4 ng/ml in LIS subjects; P < 0.001) and doubled in OIR subjects (21.9 ؎ 15.5 ng/ml; P < 0.001). Because of the confounding effect of body fat, we examined the relationships between adiposity, insulin sensitivity, and leptin concentrations by multiple regression analysis. Intraabdominal fat was the best variable predicting insulin sensitivity in both genders and explained 54% of the variance in S I . This inverse relationship was nonlinear (r ‫؍‬ ؊0.688). On the other hand, in both genders, fasting leptin levels were strongly associated with subcutaneous fat area (r ‫؍‬ 0.760) but not with intraabdominal fat. In line with these analyses, when LIS and LIR subjects were matched for subcutaneous fat area, age, and gender, they had similar leptin levels, whereas their intra-abdominal fat and insulin sensitivity remained different. Thus, accumulation of intra-abdominal fat correlates with insulin resistance, whereas subcutaneous fat deposition correlates with circulating leptin levels. We conclude that the concurrent increase in these two metabolically distinct fat compartments is a major explanation for the association between insulin resistance and elevated circulating leptin concentrations in lean and obese subjects. Diabetes 51: 1005-1015, 2002

Obesity and insulin resistance are both associated with an atherogenic lipoprotein profile. We examined the effect of insulin sensitivity and central adiposity on lipoproteins in 196 individuals (75 men and 121 women) with an average age of 52.7 years. Subjects were subdivided into three groups based on BMI and their insulin sensitivity index (S I ): lean insulin sensitive (n ‫؍‬ 65), lean insulin resistant (n ‫؍‬ 73), and obese insulin resistant (n ‫؍‬ 58). This categorization revealed that both obesity and insulin resistance determined the lipoprotein profile. In addition, the insulin-resistant groups had increased central adiposity. Increasing intra-abdominal fat (IAF) area, quantified by computed tomography scan and decreasing S I , were important determinants of an atherogenic profile, marked by increased triglycerides, LDL cholesterol, and apolipoprotein B and decreased HDL cholesterol and LDL buoyancy (Rf). Density gradient ultracentrifugation (DGUC) revealed that in subjects who had more IAF and were more insulin resistant, the cholesterol content was increased in VLDL, intermediate-density lipoprotein (IDL), and dense LDL fractions whereas it was reduced in HDL fractions. Multiple linear regression analysis of the relation between the cholesterol content of each DGUC fraction as the dependent variable and IAF and S I as independent variables revealed that the cholesterol concentration in the fractions corresponding to VLDL, IDL, dense LDL, and HDL was associated with IAF, and that S I additionally contributed independently to VLDL, but not to IDL, LDL, or HDL. Thus an atherogenic lipoprotein profile appears to be the result primarily of an increase in IAF, perhaps via insulin resistance.

We studied sex differences in the serum lipid abnormalities associated with diabetes mellitus in 111 patients with insulin-dependent diabetes and 270 patients with non-insulin-dependent diabetes, who were compared with 586 nondiabetic controls. Relative to control levels, the increases in triglycerides were 17 to 34 mg per deciliter greater in diabetic women than in diabetic men. The median low-density-lipoprotein cholesterol concentration in non-insulin-dependent diabetics was 1 to 4 mg per deciliter lower than the control level in women and 16 to 22 mg per deciliter lower in men, and was 30 mg per deciliter higher than control in insulin-dependent diabetic women and similar to control in insulin-dependent diabetic men. The decrease in median high-density-lipoprotein cholesterol in non-insulin-dependent diabetics was 2 to 7 mg per deciliter greater in women than in men, and the increase in high-density-lipoprotein cholesterol in insulin-dependent diabetics was 3 mg per deciliter less in women than in men. We conclude that diabetes has a greater adverse effect on triglyceride and lipoprotein cholesterol concentrations in diabetic women than in diabetic men, and that this may explain the greater increase in risk of arteriosclerosis in diabetic women.

Of the five screening tests evaluated, all were elevated in GDM, but TG is the best discriminator of GDM from the GTT- group, and it is the only test significantly related to birth-weight ratio--and to glucose intolerance besides glucose itself. The TG association with birth weight is not explained fully by maternal weight. The results suggest that plasma TG may be a physiological contributor to infant birth weight. Further evaluation of plasma TG in GDM screening is justified, but GHb, GPro, and IRI appear to hold less promise.

Objective-This study was undertaken to determine if insulin resistance without and with obesity influences LDL response to dietary cholesterol and saturated fat. Methods and Results-We fed 0, 2, and 4 egg yolks per day to 197 healthy subjects in a 4-week, double-blind, randomized, crossover design. Subjects were dichotomized on body mass index (Ͻ27.5 and Ն27.5 kg/m 2 ) and insulin sensitivity (insulin-sensitivity index Ն4.2ϫ1.0 Ϫ4 and Ͻ4.2ϫ1.0 Ϫ4 min Ϫ1 U/mL), yielding insulin-sensitive (IS, nϭ65), insulinresistant (IR, nϭ75), and obese insulin-resistant (OIR, nϭ58) subjects. Mean fasting baseline LDL cholesterol (LDL-C) levels were higher in IR and OIR subjects (3.44Ϯ0.67 and 3.32Ϯ0.80 mol/L) than in IS subjects (2.84Ϯ0.75 mmol/L) (PϽ0.001). Progressive triglyceride elevations and HDL-C decreases were seen across the 3 groups. Ingesting 4 eggs daily yielded significant LDL-C increases of 7.8Ϯ13.7% (IS) and 3.3Ϯ13.2% (IR) (both PϽ0.05) compared with 2.4Ϯ12.6% for OIR (NS). HDL-C increases were 8.8Ϯ10.4%, 5.2Ϯ10.4%, and 3.6Ϯ9.4% in IS, IR, and OIR, respectively (all PϽ0.01). Conclusions-Insulin resistance without and with obesity is associated with elevated LDL-C as well as elevated triglyceride and low HDL-C. The elevated LDL-C cannot be explained by dietary sensitivity, because the LDL-C rise with egg feeding is less in IR persons regardless of obesity status, probably attributable to diminished cholesterol absorption. The results suggest that dietary management of insulin resistance and obesity can focus more on restricting calories and less on restricting dietary fat. (Arterioscler Thromb Vasc

Limb defects from 25 fetuses with limb-body wall (LBW) complex were evaluated to determine the mechanism of limb damage. The limb defects could be divided into 3 pathogenetic groups: (1) secondary to disruption of embryonic vessels and surrounding tissue (84%), (2) secondary to amniotic bands or adhesions (16%), and (3) deformation versus hemorrhage (44% with club feet), with some fetuses having more than one pathogenetic mechanism causing limb defects. The hypothesis that the majority of limb defects resulted from disruption of embryonic vessels was supported by the following findings: 96% of the LBW complex fetuses had limb defects; the lower limbs were at greater risk of damage than the upper limbs (28% rt arm, 52% lt arm, 60% rt leg, 72% lt leg); there was a distal to proximal progression of limb damage in 92% of the fetuses; statistical analysis of comparing the location of the most severe limb defect and the body wall defect did not find concordance between the side (p = 1.0) and the region (p = 0.18) of the body wall defect; and limb defects found in the human specimens were similar to those produced in experimental animals following disruption of embryonic vessels at a corresponding gestation. In the specimens with amniotic band related limb defects (16%), the most likely pathogenesis is mechanical rupture through the amnion in the presence of a persistent extraembryonic coelom or from adhesion of the amnion to necrotic embryonic tissue after the initial disruptive event. Club feet were present in 44% and may be due either to disruption of embryonic vessels or to deformation. Further studies are needed to resolve this question.

The transport of fat in the blood stream is approximately twice as fast in women as men. Disease states such as obesity and diabetes are associated with greater lipoprotein abnormalities in women compared with men. A greater increment in cardiovascular disease risk in women is linked to these abnormalities. A greater change in triglyceride level and a lesser change in low-density lipoprotein are observed in women than men with high-carbohydrate or high-fat feeding. Most consistent are greater changes in high-density lipoprotein (HDL), HDL2, and apolipoprotein A-I levels in women compared with men with high-carbohydrate or high-fat feeding. Dietary fat restriction in women appears to have a less beneficial lipoprotein effect than in men. Dietary fat restriction for heart disease prevention may be less ideal in women than in men.

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