Greater Omentectomy Improves Insulin Sensitivity in Nonobese Dogs

Visceral adiposity is strongly associated with insulin resistance; however, little evidence directly demonstrates that visceral fat per se impairs insulin action. Here, we examine the effects of the surgical removal of the greater omentum and its occupying visceral fat, an omentectomy (OM), on insulin sensitivity (S_I) and β‐cell function in nonobese dogs. Thirteen male mongrel dogs were used in this research study; animals were randomly assigned to surgical treatment with either OM (n = 7), or sham‐surgery (SHAM) (n = 6). OM failed to generate measurable changes in body weight (+2%; P = 0.1), or subcutaneous adiposity (+3%; P = 0.83) as assessed by magnetic resonance imaging (MRI). The removal of the greater omentum did not significantly reduce total visceral adipose volume (?7.3 ± 6.4%; P = 0.29); although primary analysis showed a trend for OM to increase S_I when compared to sham operated animals (P = 0.078), further statistical analysis revealed that this minor reduction in visceral fat alleviated insulin resistance by augmenting S_I of the periphery (+67.7 ± 35.2%; P = 0.03), as determined by the euglycemic‐hyperinsulinemic clamp. Insulin secretory response during the hyperglycemic step clamp was not directly influenced by omental fat removal (presurgery 6.82 ± 1.4 vs. postsurgery: 6.7 ± 1.2 pmol/l/mg/dl, P = 0.9). These findings provide new evidence for the deleterious role of visceral fat in insulin resistance, and suggest that a greater OM procedure may effectively improve insulin sensitivity.     

Effects of gastric bypass and gastric banding on glucose kinetics and gut hormone release

Background: Bariatric surgery markedly improves glucose homeostasis in patients with type 2 diabetes even before any significant weight loss is achieved. Procedures that involve bypassing the proximal small bowel, such as Roux‐en‐Y gastric bypass (RYGBP), are more efficient than gastric restriction procedures such as gastric banding (GB). Objective: To evaluate the effects of RYGBP and GB on postprandial glucose kinetics and gastro‐intestinal hormone secretion after an oral glucose load. Methods and Procedures: This study was a cross‐sectional comparison among non‐diabetic, weight‐stable women who had undergone RYGBP (n = 8) between 9 and 48 months earlier or GB (n = 6) from 25 to 85 months earlier, and weight‐ and age‐matched control subjects (n = 8). The women were studied over 4 h following ingestion of an oral glucose load. Total glucose and meal glucose kinetics were assessed using glucose tracers and plasma insulin, and gut hormone concentrations were simultaneously monitored. Results: Patients who had undergone RYGBP showed a a more rapid appearance of exogenous glucose in the systemic circulation and a shorter duration of postprandial hyperglycemia than patients who had undergone GB and C. The response in RYGBP patients was characterized by early and accentuated insulin response, enhanced postprandial levels of glucagon‐like peptide‐1 (GLP‐1) and polypeptide YY (PYY), and greater postprandial suppression of ghrelin. Discussion: These findings indicate that RYGBP is associated with alterations in glucose kinetics and glucoregulatory hormone secretion. These alterations are probably secondary to the anatomic rearrangement of the foregut, given the fact that they are not observed after GB. Increased PYY and GLP‐1 concentrations and enhanced ghrelin suppression are compatible with reduced food intake after RYGBP.     

Effect of Obesity on Growth‐related Oncogene Factor‐α, Thrombopoietin,and Tissue Inhibitor Metalloproteinase‐1 Serum Levels

We have recently identified several adipokines as oversecreted by omental adipose tissue (AT) of obese subjects: two chemokines (growth‐related oncogene factor‐α (GRO‐α), macrophage inflammatory protein‐1β (MIP‐1β)), a tissue inhibitor of metalloproteinases‐1 (TIMP‐1), an interleukin‐7 (IL‐7) and a megakaryocytic growth‐factor (thrombopoietin (TPO)). These adipokines are involved in insulin resistance and atherosclerosis. The objectives of this study were to determine whether the circulating levels of these adipokines were increased in obesity and to identify the responsible factors. A cross‐sectional study including 32 lean (BMI (kg/m²) <25), 15 overweight (BMI: 25–29.9), 11 obese (BMI: 30–39.9), and 17 severely obese (BMI >40) age‐matched women was carried out. Serum adipokine levels, insulin sensitivity, and substrate oxidation were measured by ELISA, euglycemic–hyperinsulinemic clamp, and indirect calorimetry, respectively. Circulating levels of GRO‐α, TPO, and TIMP‐1 were higher in obese and/or severely obese women than in lean ones (+30, 55, and 20%, respectively). Serum levels of these adipokines positively correlated with insulinemia or glycemia, and negatively with insulin sensitivity. TIMP‐1 also positively correlated with blood pressure, and TPO with triglyceride levels. Multiple regression analysis showed that fat mass per se was an independent determinant of GRO‐α, TPO, and TIMP‐1 levels, suggesting that hypertrophied adipocytes and recruited macrophages in expanded AT mainly contribute to this hyperadipokinemia. Insulinemia, glycemia and resistance of glucose oxidation to insulin were additional predictors for TPO. Circulating GRO‐α, TPO, and TIMP‐1 levels are increased in obesity. This may be partially due to augmented adiposity per se and to hyperinsulinemia/insulin resistance. These high systemic levels may in turn worsen/promote insulin resistance and cardiovascular disease.     

Differential effects of gastric bypass and banding on circulating gut hormone and leptin levels

Objective: To quantify plasma concentrations of hormones that regulate energy homeostasis in order to establish possible mechanisms for greater weight loss after Roux‐en‐Y gastric bypass (RYGBP) compared with gastric banding (BND). Research Methods and Procedures: Four groups of women were studied: lean (n = 8; mean BMI, 21.6 kg/m²); BND (n = 9; BMI, 35.8; 25% weight loss), RYGBP (n = 9; BMI, 34.2; 36% weight loss), and controls matched for BMI to the surgical groups (n = 11; BMI, 34.4). Results: Fasting total peptide YY (PYY) and PYY_(3–36) immunoreactivity were similar among all groups, but the postprandial response in the RYGBP group was exaggerated, such that 30 minutes after the meal, total and PYY_(3–36) levels were 2‐ to 4‐fold greater compared with all other groups. Maximal postprandial suppression of total ghrelin was blunted in the BND group (13%) compared with RYGBP (27%). Postprandial suppression of octanoylated ghrelin was also less in BND (29%) compared with RYGBP (56%). Fasting insulin was lower in RYGBP (6.6 μU/mL) compared with BND (10.0 μU/mL). Compared with lean controls, leptin concentrations were significantly higher in BND but not in RYGBP. There was a greater increase in post‐meal satiety in the RYGBP group compared with BND and overweight controls. Discussion: The differences between RYGBP and BND subjects in postprandial concentrations of PYY and ghrelin would be expected to promote increased satiety and earlier meal termination in RYGBP and may aid in greater weight loss. The differences in insulin and leptin concentrations associated with these procedures may also reflect differences in insulin sensitivity and energy partitioning.     

Elevated Insulin Sensitivity in Low‐protein Offspring Rats Is Prevented by a High‐fat Diet and Is Associated With Visceral Fat

This study tests the hypothesis that a high‐fat postnatal diet increases fat mass and reduces improved insulin sensitivity (IS) found in the low‐protein model of maternal undernutrition. Offspring from Wistar dams fed either a 20% (control (CON)) or 8% (low protein (LP)) protein diet during gestation and lactation were randomly assigned to a control (con) or cafeteria (caf) diet at weaning (21 days) until 3 months of age at which point IS was measured (hyperinsulinemic–euglycemic clamp). Fat mass, growth, energy intake (EI) and expenditure (EE), fuel utilization, insulin secretion, and leptin and adiponectin levels were measured to identify a possible role in any changes in IS. IS was increased in LP‐con in comparison to CON‐con animals. Cafeteria feeding prevented this increase in LP animals but had no effect in CON animals (insulin‐stimulated glucose infusion rates (GIRs; mg/min/kg); CON‐con: 13.9 ± 1.0, CON caf: 12.1 ± 2.1, LP‐con: 25.4 ± 2.0, LP‐caf: 13.7 ± 3.7, P < 0.05). CON‐caf animals had similar percent epididymal white adipose tissue (%EWAT; CON‐con: 1.71 ± 0.09 vs. CON‐caf: 1.66 ± 0.08) and adiponectin (µg/ml: CON‐con: 4.61 ± 0.34 vs. CON‐caf: 3.67 ± 0.18) except hyperinsulinemia and relative hyperleptinemia in comparison to CON‐con. Differently, LP‐caf animals had increased %EWAT (LP‐con: 1.11 ± 0.06 vs. LP‐caf: 1.44 ± 0.08, P < 0.05) and adiponectin (µg/ml: LP‐con: 5.38 ± 0.39 vs. LP‐caf: 3.75 ± 0.35, P < 0.05) but did not show cafeteria‐induced hyperinsulinemia or relative hyperleptinemia. An increased propensity to store visceral fat in LP animals may prevent the elevated IS in LP offspring.     

Urinary C‐Peptide Excretion: A Novel Alternate Measure of Insulin Sensitivity in Physiological Conditions

Insulin sensitivity (IS) is measured by the euglycemic–hyperinsulinemic clamp under a nonphysiological condition. Daily C‐peptide urinary excretion may be a physiological index of IS, because C‐peptide is co‐secreted with insulin as a function of nutrient intake and IS. The amount of ²H₂O released from glycolytic glucose metabolism after [6,6‐²H₂]‐glucose ingestion was recently proposed as a physiological measure of IS. We compared these IS surrogates to the gold standard (euglycemic–hyperinsulinemic clamp). Thirty (15 male/15 female) sedentary, nondiabetic participants (27.2 ± 4.0 (s.d.) kg/m², 35 ± 12 years) were admitted for 3 days to our in‐patient unit. After a 10‐h fast, they received 60 g of glucose and 15 g of [6,6‐²H₂]‐glucose. Before glucose ingestion and hourly thereafter for 4 h, plasma glucose and insulin concentrations, and plasma deuterium enrichment were determined. Plasma ²H₂O production divided by insulin response was used as the glycolytic index. On day 2, subjects spent 23 h in a metabolic chamber (eucaloric diet, 50% carbohydrate, 30% fat). Urinary C‐peptide excretion was divided by energy intake yielding the C‐peptide to energy intake ratio (CPEP/EI). After leaving the chamber (day 3, 10‐h fast), IS was measured by a 2‐h clamp (120 mU/m²/min). Average IS (clamp) was 7.3 ± 2.6 mg glucose/kg estimated metabolic body size/min (range: 3.6–13.2). These values were inversely correlated with CPEP/EI (r = ?0.62; P < 0.01) and positively with the glycolytic rate (r = 0.60; P < 0.01). In nondiabetic subjects, two novel estimates of IS—daily urinary C‐peptide urinary excretion and glycolytic rate during an oral glucose tolerance test —were related to IS by a clamp.     

Cardiorespiratory fitness in youth: relationship to insulin sensitivity and beta-cell function

Objective: We examined whether the relationship between cardiorespiratory fitness (CRF) and insulin sensitivity (IS)/secretion is independent of adiposity in healthy African‐American (n = 65) and white (n = 57) youth. Research Methods and Procedures: IS and β‐cell function were evaluated by a 3‐hour hyperinsulinemic‐euglycemic and a 2‐hour hyperglycemic (12.5 mM) clamp, respectively. Total fat was measured by DXA and abdominal fat with computed tomography. CRF (peak volume of oxygen) was measured using a graded maximal treadmill test. Results: Independent of race, CRF was inversely (p < 0.05) related to total and abdominal fat, fasting insulin and first phase insulin secretion, and positively (p < 0.05) related to IS. When subjects were categorized into low (≤50th) and high (>50th) CRF groups, IS was significantly (p < 0.05) higher in the high compared with the low CRF group independently of race. Furthermore, first and second phase insulin secretion were lower (p < 0.05) in the high CRF group in comparison with the low CRF group in both races. However, in multiple regression analyses CRF was not (p > 0.05) an independent predictor of IS and acute insulin secretion after accounting for total adiposity. Discussion: Our findings demonstrate that low CRF is associated with decreased IS compensated by higher insulin secretion in both African‐American and white youth. However, this relationship disappears after adjusting for differences in adiposity, suggesting that the association between fitness and IS is mediated, at least in part, through fatness.     

Pioglitazone Improves Fat Distribution,the Adipokine Profile and Hepatic Insulin Sensitivity in Non-Diabetic End-Stage Renal Disease Subjects on Maintenance Dialysis: A Randomized Cross-Over Pilot Study

Background

Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity.

Trial Design

This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects.

Methods

At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored.

Results

Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10⁻³ to 0.76×10⁻³. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP.

Conclusions/Limitations

Pioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation.

Trial Registration

ClinicalTrial.gov {"type":"clinical-trial","attrs":{"text":"NCT01253928","term_id":"NCT01253928"}}NCT01253928     

Effect of gastric bypass on spontaneous growth hormone and ghrelin release profiles

Objective : The purpose of this study was to analyze growth hormone (GH) concentrations in obese women before and after Roux‐en‐Y gastric bypass (RYGBP) and how resulting changes in weight, fat mass, ghrelin levels, and insulin sensitivity affect GH secretion. Research Methods and Procedures : Blood was sampled at 20‐minute intervals for 24 hours in 10 non‐diabetic premenopausal severely obese women before and 6 months after RYGBP. GH concentrations were measured in all samples, and serum ghrelin was collected at five time‐points. Results : After a 27% BMI drop (55.9 ± 6.2 to 40.7 ± 5.8 kg/m²), blunted GH profiles underwent partial recovery. Basal, postprandial, and mean ghrelin concentrations were not changed. A negative correlation was found between mean GH levels and insulin and homeostasis model assessment (p < 0.01). BMI accounted for 54% of GH variation. Discussion : Partial recovery of GH secretion after RYGBP‐induced weight loss suggests that a blunted secretion is not a causal factor of obesity but a consequence of the obese state and does not seem to be ghrelin‐level dependent.     

Proinflammatory Markers,Insulin Sensitivity,and Cardiometabolic Risk Factors in Treated HIV Infection

Treated HIV infection and HIV‐lipoatrophy increases risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Circulating inflammatory molecules may, in part, explain this increased risk. This study examined circulating inflammatory molecules in treated HIV infection in relation to insulin sensitivity, lipids total body, and intramyocellular fat, compared to insulin‐resistant obesity (an index group at high risk of diabetes). Detailed metabolic phenotypes were measured in 20 treated HIV‐infected men (with and without subcutaneous lipoatrophy) vs. 26 insulin‐resistant obese men (IR‐O, n = 26), including inflammatory molecules, insulin sensitivity, total body fat (TBF), visceral fat (visceral adipose tissue (VAT)), and intramyocellular lipid (IMCL). C‐reactive protein (CRP) levels in treated HIV were similar to those in IR‐O, despite lower TBF and greater insulin sensitivity in treated HIV. In HIV‐lipoatrophy, CRP was higher than that found in IR‐O. Adiponectin was similar between treated HIV and IR‐O, but significantly lower in those with HIV‐lipoatrophy. In treated HIV, subjects with higher CRP had significantly higher total cholesterol, VAT, and IMCL. In treated HIV, subjects with lower adiponectin had significantly lower HDL and higher triglycerides, glucose, VAT, and IMCL. In conclusion, a proinflammatory milieu equivalent to that of insulin‐resistant obesity characterizes lean men with treated HIV infection, worse in those with subcutaneous lipoatrophy. These factors may contribute to the accelerated diabetogenesis and cardiac risk observed in treated HIV infection.     

Lifestyle variables, non-traditional cardiovascular risk factors, and the metabolic syndrome in an Aboriginal Canadian population

Objective : To examine lifestyle factors associated with metabolic syndrome (MetS) and to explore the relationships between MetS and non‐traditional cardiovascular disease risk factors [adiponectin, leptin, C‐reactive protein (CRP), interleukin‐6 (IL‐6), and serum amyloid A (SAA)] in an isolated Aboriginal Canadian community. Research Methods and Procedures : Data were obtained from 360 non‐diabetic adults participating in a population‐based study of Aboriginal Canadians. Fasting samples were drawn for glucose, insulin, lipids, adiponectin, leptin, CRP, IL‐6, and SAA. Percentage body fat was measured using bioelectrical impedance analysis. Past year physical activity and fitness level were assessed. MetS was diagnosed according to the criteria of the National Cholesterol Education Program, the World Health Organization, and the International Diabetes Federation. Results : The results showed that older age, higher percentage body fat, and lower fitness levels were associated with increased odds of MetS regardless of MetS definition and subject gender. Past year physical activity was independently related with the World Health Organization‐MetS in male subjects. Subjects with MetS had significantly higher leptin, CRP, IL‐6, and SAA levels and lower adiponectin levels; however, only adiponectin remained significantly low after adjustment for age and percentage body fat. Discussion : The study showed that higher percentage body fat and lower physical activity and fitness were associated with a higher prevalence of MetS in this Aboriginal community and that hypoadiponectinemia was independently associated with MetS.     

Restoration of acute insulin response in T2DM subjects 1 month after biliopancreatic diversion

Objective: Biliopancreatic diversion (BPD) restores normal glucose tolerance in a few weeks in morbid obese subjects with type 2 diabetes, improving insulin sensitivity. However, there is less known about the effects of BPD on insulin secretion. We tested the early effects of BPD on insulin secretion in obese subjects with and without type 2 diabetes. Methods and Procedures: Twenty‐one consecutive morbid obese subjects, 9 with type 2 diabetes (T2DM) and 12 with normal fasting glucose (NFG) were evaluated, just before and 1 month after BPD, by measuring body weight (BW), glucose, adipocitokines, homeostasis model assessment of insulin resistance (HOMA‐IR), acute insulin response (AIR) to e.v. glucose and the insulinogenic index adjusted for insulin resistance ([ΔI5/ΔG5]/HOMA‐IR). Results: Preoperatively, those with T2DM differed from those with NFG in showing higher levels of fasting glucose, reduced AIR (57.9 ± 29.5 vs. 644.9 ± 143.1 pmol/l, P < 0.01) and reduced adjusted insulinogenic index (1.0 ± 0.5 vs. 17.6 ± 3.9 1/mmol², P < 0.001). One month following BPD, in both groups BW was reduced (by ～11%), but all subjects were still severely obese; HOMA‐IR and leptin decreased significanlty, while high‐molecular weight (HMW) adiponectin and adjusted insulinogenic index increased. In the T2DM group, fasting glucose returned to non‐diabetic values. AIR did not change in the NFG group, while in the T2DM group it showed a significant increase (from 58.0 ± 29.5 to 273.8 ± 47.2 pmol/l, P < 0.01). In the T2DM group, the AIR percentage variation from baseline was significantly related to changes in fasting glucose (r = 0.70, P = 0.02), suggesting an important relationship exists between impaired AIR and hyperglycaemia. Discussion: BPD is able to restore AIR in T2DM even just 1 month after surgery. AIR restoration is associated with normalization of fasting glucose concentrations.     

Insulin Sensitivity in African‐American and White Women: Association With Inflammation

Whether the contribution of inflammation to risk for chronic metabolic disease differs with ethnicity is not known. The objective of this study was to determine: (i) whether ethnic differences exist in markers of inflammation and (ii) whether lower insulin sensitivity among African Americans vs. whites is due to greater inflammatory status. Subjects were African‐American (n = 108) and white (n = 105) women, BMI 27–30 kg/m². Insulin sensitivity was assessed with intravenous glucose tolerance test and minimal modeling; fat distribution with computed tomography; body composition with dual‐energy X‐ray absorptiometry; markers of inflammation (tumor necrosis factor (TNF)‐α, soluble tumor necrosis factor receptor (sTNFR)‐1, sTNFR‐2, C‐reactive protein (CRP), and interleukin (IL)‐6) with enzyme‐linked immunosorbent assay (ELISA). Whites had greater intra‐abdominal adipose tissue (IAAT), insulin sensitivity, and concentrations of TNF‐α, sTNFR‐1, and sTNFR‐2 than African Americans. Greater TNF‐α in whites vs. African Americans was attributed to greater IAAT in whites. Among whites, but not African Americans, CRP was independently and inversely associated with insulin sensitivity, after adjusting for IAAT (r = ?0.29 P < 0.05, and r = ?0.13 P = 0.53, respectively). Insulin sensitivity remained lower in African Americans after adjusting for CRP (P < 0.001). In conclusion, greater IAAT among whites may be associated with greater inflammation. Insulin sensitivity was lower among African Americans, independent of obesity, fat distribution, and inflammation.     

Hepatic-dependent and -independent insulin actions are impaired in the obese Zucker rat model

Objective: Whole‐body insulin sensitivity (IS) depends on a hepatic pathway, involving parasympathetic activation and hepatic nitric oxide (NO) production. Both atropine and N‐monomethyl‐l ‐arginine (l ‐NMMA, NO synthase inhibitor) induce insulin resistance (IR). IR is associated with obesity. Because NO action was shown to be impaired in animal models of obesity, such as the obese Zucker rat (OZR), we tested the hypothesis that the hepatic‐dependent pathway is diminished in OZR, resulting in IR. Research Methods and Procedures: Lean Zucker rats (LZRs) were used as OZR controls. IS was evaluated in terms of glucose disposal [milligrams of glucose per kilogram of body weight (bw)]. Two groups were submitted to two protocols. First, a control clamp was followed by a post‐atropine (3 mg/kg intravenously) clamp. Second, after the control clamp, l ‐NMMA (0.73 mg/kg intraportally) was given, and a second clamp was performed. Hepatic‐dependent IS was assessed by subtracting the response after atropine or l ‐NMMA from the basal response. Results: In the first protocol, basal IS was lower in OZR than in LZR (OZR, 73.7 ± 14.2; LZR, 289.2 ± 24.7 mg glucose/kg bw; p < 0.001), and atropine decreased IS in the same proportion for both groups (OZR, 41.3 ± 8.0%; LZR, 40.1 ± 6.5%). Equally, in the second protocol, OZR presented lower IS (OZR, 79.3 ± 1.6; LZR, 287.4 ± 22.7 mg glucose/kg bw; p < 0.001). l ‐NMMA induced IS inhibition in both groups (OZR, 48.3 ± 6.6%; LZR, 46.4 ± 4.1%), similar to that after atropine. Discussion: We show that the IR in OZR is due to similar impairment of both hepatic‐dependent and ‐independent components of insulin action, suggesting the existence of a defect common to both pathways.     

The effect of insulin on net lipid oxidation predicts worsening of insulin resistance and development of type 2 diabetes mellitus

Suppression of lipid oxidation (L(ox)) by insulin is impaired in obesity and type 2 diabetes mellitus (T2DM). Here we tested whether high L(ox) represents a primary or acquired characteristic in the pathogenesis of T2DM. Hood-indirect calorimetry was performed under postabsorptive conditions and during a two-step hyperinsulinemic euglycemic clamp (insulin infusion rates in mU.m(-2).min(-1): 40 low and 400 high) in 465 Pima Indians: 317 with normal glucose tolerance (NGT), 117 with impaired glucose tolerance (IGT), and 31 with T2DM. The predictive effect of net lipid oxidation (L(ox)) on development of T2DM was assessed in 296 subjects (51 of whom developed T2DM), whereas the predictive effect of L(ox) on followup changes in insulin-mediated glucose disposal (M) and acute insulin response (AIR) was studied in 190 subjects with NGT at baseline. Cross-sectionally, after adjustment for age, sex, body fat (BF), and M low, L(ox) low was increased in T2DM compared with NGT and IGT subjects (P < 0.05). Prospectively, after adjustment for followup duration, age, sex, BF, M, and AIR, increased clamp L(ox) predicted T2DM [hazard rate ratios (95% CI): L(ox) low, 1.5 (1.1, 2.0), P < 0.01; L(ox) high, 1.3 (1.0, 1.8), P = 0.05]. High L(ox) low at baseline was also associated with subsequent worsening of M low (P = 0.04). These data indicate that the inability of insulin to suppress L(ox) may represent an early risk marker for insulin resistance and T2DM that is independent of adiposity, acute insulin secretion, and insulin action on glucose uptake.     

Racial Differences in Insulin Secretion and Sensitivity in Prepubertal Children: Role of Physical Fitness and Physical Activity

Objective: To investigate in prepubertal children whether physical fitness and/or physical activity are: 1) associated with insulin secretion and sensitivity and 2) account for racial differences in insulin secretion and sensitivity. Research Methods and Procedures: Subjects included 34 African American and 34 white nondiabetic children aged 5 to 11 years. Data were divided into two sets according to the availability of VO_2max and physical activity data. Body composition was measured by dual‐energy X‐ray absorptiometry. Subcutaneous abdominal adipose tissue and intra‐abdominal adipose tissue were examined by computed tomography. Insulin sensitivity (S_I) and acute insulin response (AIR) were determined by a frequently sampled intravenous glucose tolerance test. An all‐out, progressive treadmill exercise test was used for measuring VO_2max. Physical activity data were collected by questionnaire. Results: African American children had lower S_I and higher AIR than white children, after adjusting for total body fat mass. African Americans reported higher levels of physical activity (hours/wk) than whites, but had a lower VO_2max. In multiple linear regression analysis, hours/wk of activity and hours/wk of vigorous activity, but not moderate activity, were independently related to S_I and AIR after adjusting for race, total body fat mass or fat distribution, and total lean tissue mass. VO_2max was not related to AIR, and was inversely related to S_I, after adjusting for body composition. Race remained significantly associated with both S_I and AIR, even after adjusting for body composition, fat distribution, and hours/wk of activity or hours/wk of vigorous activity. Discussion: In summary, overall physical activity and, especially, vigorous activity were associated with insulin secretion and sensitivity. However, neither physical activity nor VO_2max explained the racial difference in insulin secretion (higher in African Americans) and sensitivity (lower in African Americans). Thus, racial (African American to white) differences in aspects of insulin action seem to be due to factors other than body composition, fat distribution, cardiovascular fitness, and amount of physical activity.     

Contribution of the lean body mass to insulin resistance in postmenopausal women with visceral obesity: a Monet study

Some insulin-resistant obese postmenopausal (PM) women are characterized by an android body fat distribution type and higher levels of lean body mass (LBM) compared to insulin-sensitive obese PM women. This study investigates the independent contribution of LBM to the detrimental effect of visceral fat (VF) levels on the metabolic profile. One hundred and three PM women (age: 58.0+/-4.9 years) were studied and categorized in four groups on the basis of their VF (higher vs. lower) and lean BMI (LBMI=LBM (kg)/height (m2); higher vs. lower). Measures included: fasting lipids, glucose homeostasis (by euglycemic/hyperinsulinemic clamp technique and 2-h oral glucose tolerance test (OGTT)), C-reactive protein (CRP) levels, fat distribution (by computed tomography (CT) scan), and body composition (by dual-energy X-ray absorptiometry). Women in the higher VF/higher LBMI group had lower glucose disposal and higher plasma insulin levels compared to the other groups. They also had higher plasma CRP levels than the women in the lower VF/lower LBMI group. VF was independently associated with insulin levels, measures of glucose disposal, and CRP levels (P<0.05). LBMI was also independently associated with insulin levels, glucose disposal, and CRP levels (P<0.05). Finally, significant interactions were observed between LBMI and VF levels for insulin levels during the OGTT and measures of glucose disposal (P<0.05). In conclusion, VF and LBMI are both independently associated with alterations in glucose homeostasis and CRP levels. The contribution of VF to insulin resistance seems to be exacerbated by increased LBM in PM women.     

Apolipoprotein A-IV, a putative satiety/antiatherogenic factor, rises after gastric bypass

Roux-en-Y gastric bypass surgery (RYGBP) leads to improvements in satiety and obesity-related comorbidities. The mechanism(s) underlying these improvements are not known but may be revealed in part by discovery proteomics. Therefore, fasting plasma was collected from 12 subjects (mean BMI >45) during RYGBP and during a second procedure approximately 17 months later. Body weight, obesity-related comorbidities, and medication use were decreased after RYGBP. Mass spectrometry-based proteomic analysis was performed on a subset of seven samples using isobaric isotope-coded affinity tags (four plex iTRAQ). Initial proteomic analysis (n = 7) quantified and identified hundreds of plasma proteins. Manual inspection of the data revealed a 2.6 +/- 0.5-fold increase in apolipoprotein A-IV (apo A-IV, gene designation: APOA4), a approximately 46-kDa glycoprotein synthesized mainly in the bypassed small bowel and liver after RYGBP. The change in apo A-IV was significantly greater than other apolipoproteins. Immunoblot analysis of the full longitudinal sample set (n = 12) indicated even higher increases (8.3 +/- 0.2 fold) in apo A-IV. Thus iTRAQ may underestimate the changes in protein concentrations compared to western blotting of apo A-IV. Apo A-IV inhibits gastric emptying and serves as a satiety factor whose synthesis and secretion are increased by the ingestion of dietary fat. It also possesses anti-inflammatory and antiatherogenic properties. Based on these functions, we speculate changes in apo A-IV may contribute to weight loss as well as the improvements in inflammation and cardiovascular disease after RYGBP. In addition, the findings provide evidence validating the use of iTRAQ proteomics in discovery-based studies of post-RYGBP improvements in obesity-related medical comorbidities.     

Body composition, insulin sensitivity, and cardiovascular disease profile in healthy Europeans

Objective: To assess whether insulin sensitivity can explain the associations of leg‐fat mass (LFM) and trunk‐fat mass (TFM) with the cardiovascular disease (CVD) risk profile in healthy European men and women. Methods and Procedures: We studied 142 healthy men and women of a multicenter European study on insulin sensitivity, aged 30–60 years, from the centres in Hoorn, the Netherlands and Rome, Italy. Whole‐body dual‐energy X‐ray absorptiometry (DXA) was used to determine fat and lean soft tissue mass in the trunk and legs. Fasting glucose, insulin, and lipid levels were measured. Insulin sensitivity (M/I‐ratio) was measured during a euglycemic‐hyperinsulinemic clamp. Associations between fat distribution and CVD risk factors were studied with linear regression analyses with adjustment for other body compartments, and subsequent adjustment for insulin sensitivity. Results: In men, larger LFM was significantly and independently associated with lower triglyceride levels (TGs) and higher high‐density lipoprotein (HDL) cholesterol (P < 0.10) and tended to be associated also with lower low‐density lipoprotein (LDL) cholesterol, and lower fasting insulin levels. In women, larger LFM was associated with favorable values of all CVD risk factors, although the associations were not statistically significant. In both sexes, larger TFM was independently and significantly associated with unfavorable values of most CVD risk factors, and most associations did not markedly change after adjustment for insulin sensitivity. Discussion: In a relatively young and healthy European population, larger LFM is associated with a lower and TFM with a higher cardiovascular and metabolic risk, which can not be explained by insulin sensitivity.