Whole-body insulin sensitivity,low-density lipoprotein (LDL) particle size,and oxidized LDL in overweight,nondiabetic men

Insulin resistance is often accompanied by elevated plasma triglycerides (TG) and a preponderance of small, dense low-density lipoprotein (LDL) particles. However, it remains unclear whether or not insulin resistance is related to LDL particle size, independent of plasma TG. We sought to determine the strength of the relationships among these variables in a group of overweight, nondiabetic men (N = 34; body mass index [BMI], 25 to 35 kg/m(2); age, 50 to 75 years), as well as to examine the possible relation between insulin sensitivity and oxidized LDL (oxLDL). We also examined the strength of the relationships between these lipid variables and estimates of insulin sensitivity using calculated indices based on fasting insulin and glucose concentrations. Insulin sensitivity (Si) was significantly associated with total TG (r = -0.61, P <.001), very-low-density lipoprotein (VLDL)-TG (r = -0.60, P <.001), and LDL size (r =.414, P <.05). LDL size was also significantly associated with TG (r = -0.73, P <.001), VLDL-TG (r = -0.73, P <.001), high-density lipoprotein-cholesterol (HDL-C) (r = 0.65, P <.001), the quantitative insulin sensitivity check index (QUICKI) (rho = 0.46, P <.01), and the homeostatic model for the assessment of insulin resistance (HOMA-IR) (rho = -0.45, P <.01). Si was a significant predictor of LDL size, with age and BMI also independent contributors to the variance in LDL size (R(2) = 0.172). However, when TG and HDL-C were added to the model, Si was no longer a significant predictor of LDL size. The correlation between Si and oxLDL was weak, but stastically significant (rho = -0.40, P =.02). These data suggest that the relation between Si and LDL size is largely mediated by plasma TG, and that Si is only weakly related to oxLDL in overweight, nondiabetic men.     

Longitudinal changes in risk variables of insulin resistance syndrome from childhood to young adulthood in offspring of parents with type 2 diabetes: the Bogalusa Heart Study

The occurrence of metabolic abnormalities related to insulin resistance syndrome in nondiabetic offspring of type 2 diabetic parents is known. However, information is lacking on the timing and the course of development of the components of this syndrome from childhood to adulthood in the offspring of parents with diabetes. This aspect was examined in a community-based cohort with (n = 303) and without (n = 1,136) a parental history of type 2 diabetes followed longitudinally since childhood (ages 4 to 17 years; mean follow-up period, 15 years) by repeated surveys. Offspring with parental diabetes versus those without such history had significantly excess generalized and truncal adiposity as measured by body mass index (BMI) and subscapular skinfold beginning in childhood, higher levels of fasting insulin and glucose and homeostasis model assessment index of insulin resistance (HOMA-IR) from adolescence, and higher levels of low-density lipoprotein (LDL) cholesterol and triglycerides and lower levels of high-density lipoprotein (HDL) cholesterol in adulthood. Many of these risk variables changed adversely at an increased rate in offspring of diabetic parents. In a multivariate analysis, parental diabetes was an independent predictor of longitudinal changes in adiposity, glucose, insulin, HOM-IR, systolic and diastolic blood pressure, and LDL cholesterol in the offspring, regardless of race and gender. As young adults, the offspring of diabetic parents had a higher prevalence of generalized (BMI > 30, 36% v 16%, P =.0001) and visceral (waist > 100 cm, 15% v 6%, P =.0001) obesity, hyperinsulinemia indicative of insulin resistance (insulin > 18 microU/mL, 15% v 8%, P =.0001), hyperglycemia (>or=110 mg/dL, 2% v 0.5%, P =.02), high LDL cholesterol (>or=160 mg/dL, 11% v 7%, P =.02), low HDL cholesterol (<40 mg/dL for males and <50 mg/dL for females, 40% v 31%, P =.004), high triglycerides (>or=150 mg/dL, 23% v 15%, P =.0001), and hypertension (>140/90 mm Hg, 11% v 6%, P =.004). Thus, the offspring of diabetic parents displayed excess body fatness beginning in childhood and accelerated progression of adverse risk profile characteristics of insulin resistance syndrome from childhood to young adulthood. These observations have important implications for early prevention and intervention.     

Relationship of regional adiposity to insulin resistance and serum triglyceride levels in nonobese Japanese type 2 diabetic patients

The aim of this study was to investigate the relationships between insulin resistance and regional abdominal fat area, body mass index (BMI), and serum lipid profile in nonobese Japanese type 2 diabetic patients. A total of 63 nonobese Japanese type 2 diabetic patients aged 45 to 83 years were examined. The duration of diabetes was 8.4 +/- 0.8 years. BMI, glycosylated hemoglobin (HbA(1c)) levels, and fasting concentrations of plasma glucose, serum lipids (total cholesterol, high-density lipoprotein [HDL] cholesterol, and triglycerides), and serum insulin were measured. The low-density lipoprotein (LDL) cholesterol level was calculated using the Friedewald formula (LDL cholesterol = total cholesterol - HDL cholesterol - 1/5 triglycerides). Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). Computed tomography (CT) was used to measure cross-sectional abdominal subcutaneous and visceral fat areas in all the patients. Adipose tissue areas were determined at the umbilical level. Subcutaneous and visceral abdominal fat areas were 136.5 +/- 6.0 and 86.0 +/- 4.1 cm(2), respectively. Univariate regression analysis showed that insulin resistance was positively correlated with subcutaneous (r =.544, P <.001) and visceral (r =.408, P =.001) fat areas, BMI (r =.324, P =.009), HbA(1c) (r =.254, P =.001), serum triglycerides (r =.419, P <.001), and serum LDL cholesterol (r =.290, P =.019) levels and was negatively correlated with serum HDL cholesterol level (r =.254, P =.041). Multiple regression analyses showed that insulin resistance was independently predicted by the areas of subcutaneous (F = 6.76, P <.001) and visceral (F = 4.61, P <.001) abdominal fat and serum triglycerides (F = 8.88, P <.001) level, which explained 36.9% of the variability of insulin resistance. Moreover, the present study demonstrated that whereas BMI was positively correlated with visceral (r =.510, P <.001) and subcutaneous (r =.553, P <.001) fat areas, serum triglyceride level was positively associated with visceral (r =.302, P =.015), but not with subcutaneous (r =.222, P =.074) fat area. From these results, it can be suggested that (1) both subcutaneous and visceral abdominal fat areas are independently associated with insulin resistance and (2) visceral fat area, but not the subcutaneous one, is associated with serum triglyceride levels in our nonobese Japanese type 2 diabetic patients.     

Study of the effect of changing glucose, insulin, and insulin-like growth factor-I levels on serum corticosteroid binding globulin in lean, obese, and obese subjects with glucose intolerance

We have previously described that serum corticosteroid binding globulin (CBG) concentrations are associated with insulin secretion. The present study was designed to evaluate the effects of changing insulin concentrations, both endogenous and after exogenous insulin administration, on circulating CBG levels in vivo. Serum CBG concentrations were measured during an insulin-modified frequently sampled intravenous (IV) glucose tolerance test (FSIVGT) in 14 lean and 19 obese otherwise healthy subjects with varying degrees of glucose tolerance. Acute insulin response to glucose (AIRg) correlated significantly with serum CBG concentrations at time 0 (r = -.38, P =.029), 22 minutes (r = -.41, P =.01), 50 minutes (r = -.41, P =.01), and 180 minutes (r = -.39, P =.02). Insulin sensitivity (S(I)) was not associated with serum CBG concentration at time 0 (r = -.16, P = not significant [NS]), but correlated significantly with CBG concentration at 22 minutes (r = -.41, P =.02) and 50 minutes (r = -.35, P =.048) of the FSIVGT. In lean subjects, serum CBG concentration decreased significantly after IV insulin from 37.9 +/- 5.4 to 35.4 +/- 3 mg/L (P =.02) and returned to basal levels thereafter. In contrast, obese, glucose-tolerant subjects had lower CBG levels than lean and obese glucose intolerant subjects (33.8 +/- 3.0 v 37.9 +/- 5.4 and 39.8 +/- 4.4 mg/L, respectively), and their serum CBG concentrations remained unchanged during FSIVGT. Mean serum-free insulin-like growth factor-I (IGF-I) concentrations steadily declined from 1.21 +/- 0.81 to 0.8 +/- 0.36 microg/L during the FSIVGT, and this effect was restricted to lean subjects. Basal serum-free IGF-I did not correlate with CBG levels at time 0, but correlated inversely with the serum CBG concentrations at 22 minutes (r = -.36, P =.04). Stepwise multivariant analysis showed that AIRg (P =.035) and S(I) (P =.046), but not free IGF-I levels, independently contributed to 28% of CBG variance at 22 minutes. These results suggest that insulin, but not IGF-I, constitutes an important negative regulator of CBG liver synthesis. Endogenous and exogenous insulin do not affect serum CBG concentrations in insulin-resistant obese subjects with preserved or decreased insulin secretion. Obese glucose-tolerant subjects are hypothesized to exhibit tonically inhibited serum CBG levels. In contrast, in lean subjects, the higher the insulin secretion the lower the serum CBG concentration. The mechanisms of this CBG inhibitory effect exerted by insulin and its implication on cortisol homeostasis and fat distribution in humans await further investigations.     

Associations of middle-aged mother's but not father's body mass index with 18-year-old son's waist circumferences, birth weight, and serum hepatic enzyme levels

Mitochondrial dysfunction has been reported to contribute to insulin resistance (IR) in the elderly and type 2 diabetes. To test this hypothesis, we examined relations of insulin resistance in young men to their mother's body mass index (BMI) and compared with those to their father's BMI, because as a rule, mitochondrial DNA is exclusively maternally inherited and because mitochondria are fundamental in mediating effects on energy dissipation. We measured heights, weights, waist circumference, systolic and diastolic blood pressure (BP), and biochemical variables in sera from 193 male college students aged 18 to 20 years after an overnight fast. Birth weight was available from 184 students. Self-reported heights and weights of their parents were obtained from 148 students. Insulin resistance and insulin secretion were estimated using homeostasis model assessment (HOMA-IR and HOMA-beta, respectively). Mother's BMI was associated with their son's birth weight (r=0.23, P=.008), BMI (r=0.37, P<.0001), waist circumference (r=0.42, P<.0001), fasting insulin (r=0.19, P=.02), and HOMA-IR (r=0.18, P=.03) but not with fasting glucose, HOMA-beta , and systolic and diastolic BP. In addition, high-density lipoprotein cholesterol and lipoprotein(a) [Lp(a)] were inversely associated with mother's BMI (r=-0.21, P=.01 and r=-0.17, P=.03, respectively). Furthermore, there were significant associations with aspartate (r=0.20, P=.01) and alanine (r=0.28, P=.0008) aminotransferase and gamma-glutamyl transpeptidase (r=0.30, P=.0003), all of which are associated with mitochondrial function. In contrast, none of those variables were associated with father's BMI, except for Lp(a), which showed a significant and inverse association (r=-0.17, P=.05). After adjustment for sons' BMI, waist circumference and 3 hepatic enzymes were associated with mother's BMI, whereas Lp(a) was associated with both mother's and father's BMI. In multiple regression analysis for HOMA-IR as a dependent variable, BMI of their own (beta=.10, P<.0001) and of their mothers (beta=.04, P=10) and birth weight (beta=-.27, P=.10) emerged as determinants of HOMA-IR of the students(R2=0.30). Our results are consistent with clinical observations of a greater risk of transmission of type 2 diabetes from the mother than the father and suggest that son's IR may be influenced by maternal effect as well as their adiposity.     

Regional abdominal fat distribution in lean and obese Thai type 2 diabetic women: relationships with insulin sensitivity and cardiovascular risk factors

To determine the relationships of body fat distribution and insulin sensitivity and cardiovascular risk factors in lean and obese Thai type 2 diabetic women, 9 lean and 11 obese subjects, with respective mean age 41.7 +/- 6.3 (SD) and 48.0 +/- 8.5 years, and mean body mass index (BMI) 23.5 +/- 1.8 and 30.3 +/- 3.7 kg/m2, were studied. The amount of total body fat (TBF) and total abdominal fat (AF) were measured by dual-energy x-ray absorptiometer, whereas subcutaneous (SAF) and visceral abdominal fat areas (VAF) were measured by computerized tomography (CT) of the abdomen at the L4-L5 level. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp. Cardiovascular risk factors, which included fasting and post-glucose challenged plasma glucose and insulin, systolic (SBP) and diastolic blood pressure (DBP), lipid profile, fibrinogen, and uric acid, were also determined. VAF was inversely correlated with insulin sensitivity as determined by glucose infusion rate (GIR) during the clamp, in both lean (r=-0.8821; P=.009) and obese subjects (r=-0.582; P=.078) independent of percent TBF. SAF and TBF were not correlated with GIR. With regards to cardiovascular risk factors, VAF was correlated with SBP (r=0.5279; P=.024) and DBP (r=0.6492; P=.004), fasting insulin (r=0.7256; P=.001) and uric acid (r=0.4963; P=.036) after adjustment for percent TBF. In contrast, TBF was correlated with fasting insulin (r=0.517; P=.023), area under the curve (AUC) of insulin (r=0.625; P=.004), triglyceride (TG) (r=0.668; P=.002), and uric acid (r=0.49; P=.033). GIR was not correlated with any of cardiovascular risk factors independent of VAF. In conclusion, VAF was a strong determinant of insulin sensitivity and several cardiovascular risk factors in both lean and obese Thai type 2 diabetic women.     

Relationship of dietary fat and serum cholesterol ester and phospholipid fatty acids to markers of insulin resistance in men and women with a range of glucose tolerance

High-fat diets are associated with insulin resistance, however, this effect may vary depending on the type of fat consumed. The purpose of this study was to determine the relationship between intakes of specific dietary fatty acids (assessed by 3-day diet records and fatty acid composition of serum cholesterol esters [CEs] and phospholipids [PLs]) and glucose and insulin concentrations during an oral glucose tolerance test (OGTT). Nineteen men and 19 women completed the study. Nine subjects had type 2 diabetes or impaired glucose tolerance. Fasting insulin correlated with reported intakes of total fat (r = .50, P < .01), monounsaturated fat (r = .44, P < .01), and saturated fat (r = .49, P < .01), but not with trans fatty acid intake (r = .11, not significant [NS]). Fasting glucose also correlated with total (r = .39, P < .05) and monounsaturated fat intakes (r = .37, P < .05). In multivariate analysis, both total and saturated fat intake were strong single predictors of fasting insulin (R2 approximately .25), and a model combining dietary and anthropometric measures accounted for 47% of the variance in fasting insulin. Significant relationships were observed between fasting insulin and the serum CE enrichments of myristic (C14:0), palmitoleic (C16:1), and dihomo-gamma-linolenic (C20:3n-6) acids. In multivariate analysis, a model containing CE 14:0 and percent body fat explained 45% of the variance in fasting insulin, and C14:0 and age explained 30% of the variance in fasting glucose. PL C20:3n-6 explained 30% of the variance in fasting insulin, and a model including PL C18:1n-11 cis, C20:3n-6, age and body fat had an R2 of .58. In conclusion, self-reported intake of saturated and monounsaturated fats, but not trans fatty acids, are associated with markers of insulin resistance. Furthermore, enhancement of dihomo-gamma-linolenic and myristic acids in serum CE and PL, presumably markers for dietary intake, predicted insulin resistance.     

Relationship between lipoprotein levels and in vivo insulin action in normal young white men

In epidemiologic studies, hyperinsulinemia has been found to be an independent risk factor for coronary heart disease (CHD). However, the mechanisms responsible for its role in atherogenesis remain unclear. We studied the relationship of in vivo insulin action and plasma lipids and lipoproteins in 44 normotriglyceridemic white men (aged 18 to 34 years). The euglycemic, hyperinsulinemic glucose clamp technique was used to quantitate insulin-mediated glucose disposal (M/I value) at a plasma insulin concentration of approximately 100 microU/mL. The M/I value correlated negatively with plasma triglycerides (r = -0.553, P less than .0001), as well as with fasting plasma insulin levels (r = -0.483, P less than .001), independent of age, body mass index, and fasting plasma glucose levels. A negative correlation of the M/I value was also observed with very low density lipoprotein (VLDL)-cholesterol (r = -0.347, P less than .05), VLDL-triglycerides (r = -0.474, P less than 0.005), and total cholesterol/high density lipoprotein (HDL)-cholesterol ratio (r = -0.431, P less than .01). The relationship between the M/I value and the total cholesterol/HDL-cholesterol ratio was independent of VLDL-cholesterol and VLDL-triglycerides, however, not independent of plasma triglycerides. No relationship was observed between insulin-mediated glucose uptake and total cholesterol, low density lipoprotein (LDL)-cholesterol, and HDL-cholesterol values. Individual differences in plasma triglycerides, fasting insulin concentration, and the total cholesterol/HDL-cholesterol ratio accounted for about half the variance observed in the M/I value.(ABSTRACT TRUNCATED AT 250 WORDS)     

C-reactive protein in young, apparently healthy men: associations with serum leptin, QTc interval, and high-density lipoprotein-cholesterol

To determine which anthropometric, biochemical, and cardiovascular variables are associated with serum levels of C-reactive protein (CRP) in young, apparently healthy men, a cross-sectional study of 179 male college students aged 18 to 22 years was performed. Multiple regression analysis was used to derive models for serum CRP concentrations in terms of the other variables measured. Although CRP was positively correlated with body mass index (BMI), percent fat mass, and serum leptin, correlations with BMI (r = 0.15, P =.05) and percent body fat (r = 0.16, P =.003) were not as strong as the correlation with leptin (r = 0.28, P =.0002). CRP was also associated with resting heart rate (r = 0.14, P =.05), heart-rate corrected QT (QTc) interval (r = 0.22, P =.003) and several components of the insulin resistance (IR) syndrome. CRP showed a strong and negative association with high-density lipoprotein (HDL)-cholesterol (r = -0.26, P =.0005) and a marginal and positive association with triglyceride (r = 0.14, P =.05). Although CRP was associated with fasting insulin (r = 0.15, P =.04), it was not related to serum adiponectin or IR index estimated using homeostasis model assessment (HOMA). Multiple regression analysis indicated that serum CRP was positively related to serum leptin (P =.003) and QTc interval (P =.01), and negatively correlated with HDL-cholesterol (P =.01, R(2) = 0.15). In young, apparently healthy men, serum leptin but not BMI was independently associated with serum CRP, suggesting that amount of body fat may be the most significant predictor of CRP. Although low-grade inflammation was associated with long QTc interval and low HDL-cholesterol, the mechanism underlying these associations is an important question to be addressed.     

Serum homocysteine levels are increased in women with gestational diabetes mellitus

Serum homocysteine (sHcy) has been found to be elevated in patients with type 2 diabetes mellitus, as well as in other clinical conditions associated with insulin resistance and/or vascular diseases. The aims of this study were to measure the relationship between sHcy with biohumoral markers of insulin resistance in pregnant women affected with gestational diabetes mellitus (GDM). We studied 2 groups of pregnant women categorized, after a 100-g, 3-hour oral glucose tolerance test (OGTT) as nondiabetic (n = 78) or affected with GDM (n = 15), by measuring sHcy, serum folate, albumin, vitamin B(12), uric acid, and lipids. In both groups, peripheral insulin sensitivity was measured by using the OGTT-derived index of Matsuda and DeFronzo (ISI(OGTT)). Serum homocysteine was significantly higher in the group with GDM compared with nondiabetic women (5.88 +/- 2.26 micromol/L v 4.45 +/- 1.52 micromol/L; P =.003); was inversely related to serum folate (r = -.48; P =.0001), and was significantly related to serum albumin (r =.27; P =.009), 2-hour plasma glucose (r =.25; P =.01), as well as to serum uric acid (r =.23; P =.03). No relationship was observed between sHcy and serum vitamin B(12), serum triglycerides, total, or high-density lipoprotein (HDL) cholesterol, mean blood pressure and ISI(OGTT). Vitamin B(12) was correlated with ISI(OGTT) (r =.36; P =.0005) and inversely with mean blood pressure (r = -.24; P =.02). GDM remained significantly associated with higher sHcy concentrations also after adjusting for age, serum folate, albumin, uric acid, ISI(OGTT), and vitamin B(12) (P =.006). In conclusion, we found that sHcy is significantly increased in women with GDM, independently of other confounding variables, is significantly related to 2-hour OGTT plasma glucose, and seems unrelated to insulin resistance in these subjects.     

Hepatic fat content is a determinant of postprandial triglyceride levels in type 2 diabetes mellitus patients with normal fasting triglyceride

Postprandial hypertriglyceridemia is common in type 2 diabetes mellitus (T2D). Significant numbers of T2D patients who have normal fasting triglyceride (TG) have postprandial hypertriglyceridemia. The role of regional adipose tissue and adiponectin on postprandial TG responses in this group of T2D patients is unclear. This study aimed to examine the contribution of regional adipose tissue and adiponectin to the variation of postprandial TG responses in T2D patients who have normal fasting TG levels. Thirty-one Thai T2D patients who had fasting TG<1.7 mmol/L were studied. All were treated with diet control or sulphonylurea and/or metformin. None was treated with lipid-lowering agents. Mixed-meal test was performed after overnight fast. Plasma glucose, insulin, and TG were measured before and 1, 2, 3, and 4 hours after the test. Adiponectin was measured in fasting state. Visceral as well as superficial and deep subcutaneous abdominal adipose tissues were determined by magnetic resonance imaging, and hepatic fat content (HFC) was determined by magnetic resonance spectroscopy. Univariate and multivariate regression analyses of postprandial TG and regional adipose tissue and metabolic parameters were performed. The TG levels before and 1, 2, 3, and 4 hours after the mixed meal were 1.32+/-0.40 (SD), 1.40+/-0.41, 1.59+/-0.40, 1.77+/-0.57, and 1.80+/-0.66 mmol/L, respectively (P<.0001). The area under the curve (AUC) of postprandial TG was positively and significantly correlated with fasting TG (r=0.84, P<.0001) and log.HFC (r=0.456, P=.033) and was inclined to be correlated with log.deep subcutaneous adipose tissue (r=0.38, P=.05) and sex (r=0.326, P=.073). The AUC of postprandial TG was not correlated with age, body mass index, waist circumference, log.superficial subcutaneous adipose tissue, log.visceral adipose tissue, hemoglobin A1c, fasting glucose, AUC.glucose, log.fasting insulin, log.AUC.insulin, log.homeostasis model assessment%B, log.homeostasis model assessment of insulin resistance, and adiponectin. Only fasting TG (beta=.815, P<.0001) and log.HFC (beta=.249, P=.035) predicted AUC of postprandial TG in regression model (adjusted R2=0.84, P<.0001). In conclusion, in T2D patients with normal fasting TG, the increase of postprandial TG levels is directly determined by fasting TG level and the amount of hepatic fat.     

Androgenicity and obesity are independently associated with insulin sensitivity in postmenopausal women

An increase in androgenicity may contribute to the development of insulin resistance in postmenopausal women. Increased androgenicity in women has been found to be associated with the development of type 2 diabetes. In addition, obesity and central obesity are associated with greater androgenicity. Insulin sensitivity, androgenicity, and body composition were characterized in 34 nondiabetic postmenopausal women age 72 +/- 1 years (mean +/- SEM) to test the hypothesis that androgenicity is a predictor of insulin sensitivity independent of measures of obesity. Androgenicity was measured using levels of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and free androgen index (FAI). Insulin sensitivity (S(I)) was determined from a frequently sampled intravenous glucose tolerance test. Body composition measures included body mass index (BMI) and dual energy x-ray absorptiometry measurements of total and central fat mass. S(I) was found to be associated with total fat mass (r = -.51, P =.002), central fat mass (r = -.62, P =.0001), BMI (r = -.55, P =.0008), SHBG levels (r =.65, P =.0001), and FAI (r = -.41, P =.01). SHBG levels were inversely correlated with central fat mass (r = -.59, P =.0002). Using multiple regression, SHBG and central fat mass were the only significant independent predictors of S(I), accounting for 50% of its variance (r =.71, P =.0001); total fat mass, BMI, total and free testosterone, DHEA-S, androstenedione, and FAI did not enter the model. We conclude that there is a significant association between insulin sensitivity and androgenicity in postmenopausal women that is independent of obesity. Interventions to decrease androgenicity may therefore be useful in improving insulin sensitivity in postmenopausal women.     

Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30.

We studied 31 nondiabetic, habitually (> or =5 years) morbidly obese subjects (mean +/- SD body mass index [BMI] 43 +/- 8.7, median 43). Our specific aim was to determine whether metformin (2.55 g/d for 28 weeks) would ameliorate morbid obesity and reduce centripetal obesity; lipid and lipoprotein cholesterol, insulin, and leptin levels; and plasminogen activator inhibitor activity (PAI-Fx), risk factors for coronary heart disease (CHD). The patients were instructed to continue their prestudy dietary and exercise regimens without change. After 2 baseline visits 1 week apart, the 27 women and 4 men began receiving metformin, 2.55 g/d, which was continued for 28 weeks with follow-up visits at study weeks 5, 13, 21, and 29. Daily food intake was recorded by patients for 7 days before visits then reviewed with a dietitian. Kilocalories per day and per week were calculated. At each visit, fasting blood was obtained for measurement of lipid profile, insulin, leptin, and PAI-Fx. The mean +/- SD kilocalories consumed per day, 1,951 +/- 661 at entry, fell by week 29 to 1,719 +/- 493 (P =.014) but did not differ at weeks 5, 13, and 21 from that at week 29 (P >.2). Weight fell from 258 +/- 62 pounds at entry to 245 +/- 54 pounds at week 29 (P =.0001). Girth was reduced from 51.8 +/- 6.2 to 49.2 +/- 4.5 inches (P =.0001). Waist circumference fell from 44.0 +/- 6.4 inches to 41.3 +/- 5.9 (P =.0001). The waist/hip ratio fell from 0.85 +/- 0.09 to 0.84 +/- 0.09 (P =.04). Fasting serum insulin, 28 +/- 15 microU/mL at entry, fell to 21 +/- 11 microU/mL at week 29 (P =.0001), and leptin fell from 79 +/- 33 ng/mL to 55 +/- 27 ng/mL (P =.0001). On metformin, there were linear trends in decrements in weight, girth, waist circumference, waist/hip ratio, insulin, and leptin throughout the study period (P <.007). Low-density lipoprotein (LDL) cholesterol, 126 +/- 34 mg/dL at study entry, fell to 112 +/- 43 mg/dL at week 29 (P =.001), with a linear trend toward decreasing levels throughout (P =.036). By stepwise linear regression, the higher the entry weight, the larger the reduction in weight on metformin therapy (partial R(2) = 31%, P =.001). The greater the reduction in kilocalories consumed per day, the greater the decrease in weight on metformin therapy (partial R(2) = 15%, P =.011). The higher the waist/hip ratio at entry, the greater its reduction on metformin therapy (partial R(2) = 11%, P =.004). The higher the entry serum leptin, the greater its reduction on metformin therapy (partial R(2) = 29%, P =.002). The greater the reduction in insulin on metformin, the greater the reduction in leptin (partial R(2) = 8%, P =.03). The higher the entry PAI-Fx, the greater the reduction in PAI-Fx on metformin (partial R(2) = 43%, P =.0001). Metformin safely and effectively reduces CHD risk factors (weight, fasting insulin, leptin, LDL cholesterol, centripetal obesity) in morbidly obese, nondiabetic subjects with BMI > 30, probably by virtue of its insulin-sensitizing action.     

Serum adiponectin is associated with high-density lipoprotein cholesterol, triglycerides, and low-density lipoprotein particle size in young healthy men

The chromosomal localization of adiponectin has been found to be mapped to human chromosome 1q21.4-1q23, a region that was identified as a susceptibility locus for familial combined hyperlipidemia and polygenic type 2 diabetes. As these 2 disorders are associated with low high-density lipoprotein (HDL)-cholesterol, high triglycerides, and insulin resistance (IR), we examined the relation of serum adiponectin concentrations to serum lipid and lipoprotein profiles as well as IR in young healthy men. Serum adiponectin levels were positively associated with HDL-cholesterol, apolipoprotein (apo) A1, and low-density lipoprotein (LDL) particle size, and negatively associated with triglycerides and apo B. Negative associations were also found between adiponectin and body mass index (BMI), percent body fat, and IR,as determined by homeostasis model assessment (HOMA). However, after adjustment for BMI, no significant associations were found between adiponectin and LDL particle size and apo B. In a multiple regression analysis including all variables that showed significant univariate associations with adiponectin, associations of adiponectin with HDL-cholesterol (beta = 0.079, P =.0009), percent body fat (beta = -0.165, P =.002), and serum leptin (beta = -0.291, P =.01) were statistically significant. HDL-cholesterol (beta = 0.077, P =.001), percent body fat (beta = -0.078, P =.03), and LDL size (beta = 0.092, P =.03) emerged as significant and independent determinants of adiponectin after HOMA IR, fasting glucose, triglycerides, and systolic blood pressure (BP) were taken into account. Together, these variables explained 19% of adiponectin variability in the 2 models. HOMA IR did not emerge as a determinant of adiponectin in both models. These findings suggest that in young healthy men hypoadiponectinemia is more closely related to adiposity and dyslipidemia than IR.     

Insulin resistance and adiposity influence lipoprotein size and subclass concentrations. Results from the Insulin Resistance Atherosclerosis Study

BACKGROUND: Insulin resistance and obesity are associated with a dyslipidemia composed of high levels of triglycerides (TG), low levels of high-density lipoprotein cholesterol (HDL-C), and no change in level of low-density lipoprotein cholesterol (LDL-C). We examined the association of insulin resistance and adiposity with lipoprotein particle size, concentration, and subclass concentrations. METHODS: The Insulin Resistance Atherosclerosis Study is a multicenter cohort study of middle-aged men and women. Lipoprotein lipid concentrations were determined using standard methods. Lipoprotein size, particle concentration, and subclass concentrations were determined using nuclear magnetic resonance technology. Insulin resistance (SI) was determined based on the frequently sampled intravenous glucose tolerance test and the MINMOD program. A higher SI represents less insulin resistance. Fasting insulin, body mass index, waist circumference, and waist/hip ratio were assessed. RESULTS: Among the 1371 participants were 754 women and 617 men; 459 Hispanics, 383 African Americans, and 529 non-Hispanic whites; 437 with type 2 diabetes, 301 with impaired glucose tolerance, and 633 with normal glucose tolerance. The mean (SD) age was 55.5 (8.5) years, body mass index was 29.3 (5.8) kg/m2 , and SI was 1.6 (1.8) units. Adjusted for age, sex, and ethnicity, SI was not associated with LDL-C (r = 0.01); however, S I was associated with LDL size (r = 0.34, P < .001), LDL particle concentration (r = -0.28, P < .001), small LDL (r = -0.34, P < .001), intermediate LDL (r = -0.37, P < .001), and large LDL (r = 0.21, P < .001). In addition, S I was associated with TG (r = -0.36, P < .001), VLDL particles (r = -0.08, P < .01), large VLDL (r = -0.32, P < .001), VLDL size (r = -0.38, P < .001), HDL-C (r = 0.37, P < .001), HDL particles (r = 0.09, P < .001), large HDL (r = 0.31, P < .001), and HDL size (r = 0.33, P < .001). A factor analysis revealed a factor that accounted for 41.4% of the variance across the lipoprotein measures and that was correlated with SI (r = -0.33, P < .001). Similar results of opposing direction were observed for analyses of lipoprotein measures with fasting insulin and adiposity. CONCLUSIONS: The dyslipidemia associated with insulin resistance and obesity includes effects on lipoprotein metabolism that are missed when traditional lipoprotein cholesterol and total TG are examined. Lipoprotein size and subclasses should be examined in studies investigating the roles of insulin resistance and obesity in the pathogenesis and prevention of atherosclerosis.     

C-reactive protein and insulin resistance in non-obese Japanese type 2 diabetic patients

The aim of the present study was to investigate the relationship between C-reactive protein (CRP) and insulin resistance in non-obese Japanese type 2 diabetic patients. A total of 135 non-obese Japanese type 2 diabetic patients (96 men and 39 women, aged 36 to 83 years, with a body mass index [BMI] of 16.2 to 26.8 kg/m2) were studied. BMI, glycosylated hemoglobin (HbA(1c)), fasting concentrations of plasma glucose, serum lipids (triglycerides, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and total cholesterol), CRP, and fibrinogen were measured. LDL cholesterol was calculated using the Friedewald formula. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Univariate regression analysis showed that CRP value was positively correlated to age (r = 0.218, P =.012), BMI (r = 0.239, P =.006), HOMA-IR (r = 0.397, P <.0001), triglycerides (r= 0.310, P <.005), LDL cholesterol (r= 0.179, P =.038), and fibrinogen (r = 0.371, P <.0001) levels and inversely correlated to HDL cholesterol (r = 0.174, P =.044) level in our diabetic patients. Multiple regression analysis showed that CRP was independently predicted by HOMA-IR (P<.0001, F = 11.6) and fibrinogen (P<.0001, F = 34.2), which explained 23.5% of the variability of CRP in our non-obese Japanese type 2 diabetic patients. These results indicate that insulin resistance and fibrinogen level are independent predictors of CRP in non-obese Japanese type 2 diabetic patients.     

Plasma cholesteryl ester fatty acid composition, insulin sensitivity, the menopause and hormone replacement therapy

This study was designed to determine the effect of menopause and hormone replacement therapy (HRT) on plasma cholesteryl ester fatty acid (CEFA) composition and insulin sensitivity and the relationships between these variables in perimenopausal women (aged 40-55 years) including 49 who were premenopausal and 32 who were postmenopausal. Plasma cholesteryl ester proportions of dihomo-gamma-linolenic acid (20:3 n-6) were correlated significantly with insulin sensitivity index (r=-0.319, P=0.005), fasting serum insulin levels (r=0.230, P=0.038), body mass index (r=0.242, P=0.03) and per cent body fat (r=0.329, P=0.003) in perimenopausal women (n=81). Similar associations were observed in premenopausal women. Regression analysis suggested the relationships between 20:3 n-6 proportions and indices of insulin action may be partly mediated by levels of adiposity. In postmenopausal women, 6 months of HRT significantly (P=0.008) increased the ratio of arachidonic acid (20:4 n-6) to linoleic acid (18:2 n-6), which is an indicator of activity in the pathway of 20:4 n-6 synthesis, compared with placebo. These findings suggest that the type of fat in the diet indicated by plasma CEFA composition is linked to adiposity and insulin action. They also suggest that in postmenopausal women, HRT may increase the synthesis of 20:4 n-6, which is the precursor for eicosanoids with important cardiovascular functions.     

Platelet count is independently associated with insulin resistance in non-obese Japanese type 2 diabetic patients

The aim of the present study was to investigate the relationship between platelet count and insulin resistance in non-obese Japanese type 2 diabetic patients. A total of 163 non-obese Japanese type 2 diabetic patients (112 men and 51 women, aged 36 to 84 years, body mass index [BMI] 16.2 to 26.9 kg/m(2)) were studied. In conjunction with BMI, glycosylated hemoglobin (HbA(1c)), fasting concentrations of plasma glucose and serum lipids (triglycerides, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and total cholesterol), and hematological parameters (platelets, white blood cell count, red blood cell count, hematocrit, hemoglobin) were measured. LDL cholesterol was calculated using the Friedewald formula. Insulin resistance was estimated by the insulin resistance index of homeostasis model assessment (HOMA-IR). Univariate regression analysis showed that HOMA-IR was positively correlated to BMI (r = 0.465, P <.0001), HbA(1c) (r = 0.423, P <.0001), platelet count (r = 0.310, P <.0001), triglycerides (r = 0.277, P <.0005), white blood cell count (r =.222, P =.005), red blood cell count (r = 0.210, P =.008), hematocrit (r = 0.156, P =.047), total cholesterol (r = 0.178, P =.023), and systolic (r = 0.216, P =.011) and diastolic (r = 0.263, P =.002) blood pressure, and inversely correlated to HDL cholesterol (r = -0.312, P <.0001) level in our diabetic patients. Multiple regression analysis showed that HOMA-IR was independently predicted by BMI (P <.0001, F = 22.45), HbA(1c) (P <.0001, F = 16.15), platelet count (P <.0001, F = 10.75), and serum triglycerides (P <.0001, F = 10.47) levels, which explained 34% of the variability of HOMA-IR in non-obese Japanese type 2 diabetic patients. These results indicate that not only BMI, HbA(1c), and triglycerides levels but also platelet counts are independent predictor of insulin resistance in non-obese Japanese type 2 diabetic patients.