The Insulin Tolerance Test in Morbidly Obese Patients Undergoing Bariatric Surgery

Objective: To assess the effect of massive weight loss in relation to insulin resistance and its correlation to changes in glycemic homeostasis and lipid profile in severely obese patients. Research Methods and Procedures: A prospective clinical intervention study was carried out with 31 morbidly obese women (body mass index: 54.2 ± 8.8 kg/m²) divided into three groups according to their glucose tolerance test: 14 normal, 8 impaired glucose tolerance, and 9 type 2 diabetes. All subjects underwent an insulin tolerance test with intravenous bolus of 0.1 U insulin/kg body weight before silastic ring vertical gastroplasty Roux‐en‐Y gastric bypass surgery, and again at 2, 4, 6, and 12 months postoperatively. Fasting plasma glucose, hemoglobin A1c, and lipid profile were also evaluated. Results: A reduction of 68 ± 15% in initial excess body weight was evident within 1 year. Along with weight loss, the following statistically significant changes were found: an increase in the insulin‐sensitivity index (Kitt) and a decrease in fasting plasma glucose and hemoglobin A1c, most notably in the type 2 diabetes group. An overall improvement in lipid profile was observed in all three groups. Discussion: Bariatric surgery was an effective therapeutic approach for these obese patients because it reduced both weight and insulin resistance, along with improving metabolic parameters. Significant correlations were found between insulin resistance and metabolic improvements. Weight loss after bariatric surgery induced an improvement in metabolic fitness, related to the reduction in insulin resistance over a range of glucose tolerance statuses from normal to diabetic.     

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.     

Fasting-based estimates of insulin sensitivity in overweight and obesity: a critical appraisal

Objective: To identify simple methods to estimate the degree of insulin resistance. Research Methods and Procedures: The performance of a wide range of fasting‐based index estimates of insulin sensitivity was compared by receiver operating characteristic analysis (area under curves and their 95% confidence intervals) against the M value from euglycemic insulin clamp studies collected in the San Antonio (non‐Hispanic whites and Hispanic residents of San Antonio, TX) and European Group for the Study of Insulin Resistance (non‐diabetic white Europeans) databases (n = 638). Results: Insulin resistance differed substantially between lean (BMI < 25 kg/m²), overweight or obese (BMI ≥ 25 kg/m²), and type 2 diabetic individuals. Estimates of insulin resistance were, therefore, assessed in each group separately. In the overweight and obese subgroup (n = 302), the receiver operating characteristic performance of fasting‐based indices varied from 0.72 (0.62 to 0.82), in the case of the insulin/glucose ratio, to 0.80 (0.72 to 0.88) in the case of Belfiore free fatty acids. One superior method could not be identified; the confidence intervals overlapped, and no statistically significant differences emerged. All indices performed better when using the whole study population, with fasting plasma insulin, homeostatic model assessment, insulin/glucose ratio, quantitative insulin sensitivity check index, glucose/insulin ratio, Belfiore glycemia, revised quantitative insulin sensitivity check index, McAuley index, and Belfiore free fatty acids showing area under curves of 0.83, 0.90, 0.66, 0.90, 0.66, 0.90, 0.85, 0.83, and 0.86, respectively, because of the inclusion of very insulin sensitive (lean) and very insulin resistant cases (diabetic subjects). Discussion: In conclusion, a superior fasting‐based index estimate to distinguish between the presence and absence of insulin resistance in overweight and obesity could not be identified despite the use of the large datasets.     

Insulin‐ and Exercise‐Stimulated Skeletal Muscle Blood Flow and Glucose Uptake in Obese Men

Objective: Insulin resistance in obese subjects results in the impaired use of glucose by insulin‐sensitive tissues, e.g., skeletal muscle. In the present study, we determined whether insulin resistance in obesity is associated with an impaired ability of exercise to stimulate muscle blood flow, oxygen delivery, or glucose uptake. Research Methods and Procedures: Nine obese (body mass index = 36 ± 2 kg/m²) and 11 age‐matched nonobese men (body mass index = 22 ± 1 kg/m²) performed one‐legged isometric exercise during hyperinsulinemia. Rates of femoral muscle blood flow, oxygen consumption, and glucose uptake were measured simultaneously in both legs using [¹⁵O]H₂O, [¹⁵O]O₂, [¹⁸F]fluoro‐deoxy‐glucose, and positron emission tomography. Results: The obese subjects exhibited resistance to insulin stimulation of glucose uptake in resting muscle, regardless of whether glucose uptake was expressed per kilogram of femoral muscle mass (p = 0.001) or per the total mass of quadriceps femoris muscle. At similar workloads, oxygen consumption, blood flow, and glucose uptake were lower in the obese than the nonobese subjects when expressed per kilogram of muscle, but similar when expressed per quadriceps femoris muscle mass. Discussion: We conclude that obesity is characterized by insulin resistance of glucose uptake in resting skeletal muscle regardless of how glucose uptake is expressed. When compared with nonobese individuals at similar absolute workloads and under identical hyperinsulinemic conditions, the ability of exercise to increase muscle oxygen uptake, blood flow, and glucose uptake per muscle mass is blunted in obese insulin‐resistant subjects. However, these defects are compensated for by an increase in muscle mass.     

Liver steatosis in obese prepubertal children: a possible role of insulin resistance

Objective: To determine whether in obese prepubertal children insulin resistance (IR) is associated with the development of liver steatosis. Methods and Procedures: Cross‐sectional study evaluating the prevalence of liver steatosis in 100 severely obese prepubertal children and comparing IR indexes between children with (group 1) and without steatosis (group 2). Furthermore, IR indexes were compared to values of 50 normal weight children. Fasting blood samples were collected for the evaluation of liver function tests, lipid profile, plasma glucose, and insulin levels. All children underwent an oral glucose tolerance test and anthropometric measurements. Hepatic ultrasound was performed according to international criteria and by one single operator. Analysis was performed by Mann–Whitney U‐test, Pearson correlation, and logistic regression. Results: Liver steatosis was found in 52% obese children and was equally distributed between the two sexes. Obese children were more insulin resistant when compared to controls (homeostasis model assessment of IR (HOMA‐IR): P = 0.0001; whole body insulin sensitivity index (WBISI): P = 0.0005; fasting glucose/fasting insulin ratio (G/I): P = 0.0001), and group 1 presented an even higher degree of IR when compared to group 2 (HOMA‐IR P = 0.0001; WBISI P = 0.0004; G/I P = 0.0001). The area under the curve (AUC) for insulin was significantly higher in group 1 when compared to group 2, while no difference was found in the AUC for glucose. There was no association between IR and adiposity indexes (P >0.05). The role of IR as a predictor for the development of steatosis was analyzed by multiple logistic regression, which documented that IR indexes were significantly related to steatosis independently of BMI‐SDS. Discussion: Liver steatosis is an emerging problem in prepubertal severely obese children, and it appears to be an association between liver steatosis and IR in these subjects.     

Tissue specificity in fasting glucose utilization in slightly obese diabetic patients submitted to bariatric surgery

Objective:

The present study was planned to investigate, by means of quantitative FDG‐PET, how bariatric surgery (BS) modifies the metabolic pattern of the whole body and different tissues in slightly obese patients with type 2 diabetes mellitus (T2DM).

Design and Methods:

Before, 1 and 4 months after BS, 21 consecutive slightly obese T2DM patients underwent blood sampling to estimate plasma levels of glucose, insulin, glycosylated hemoglobin. At the same time points, these patients underwent a dynamic ¹⁸F‐FDG PET study of thorax and upper abdomen in fasting state and after washout of T2DM therapy. Gjedde‐Patlak analysis was applied to estimate glucose uptake in the whole body and in different tissues (myocardium, skeletal back muscle, adipose tissue, and liver).

Results:

Surgical intervention quickly lowered levels of both insulin and glucose documenting an amelioration of glucose tolerance. Similarly, skeletal muscle and myocardial glucose uptake significantly increased soon after surgery (P < 0.001 and P < 0.01 at 1 month versus baseline, respectively) and remained substantially stable thereafter. By contrast, glucose uptake slightly decreased from its baseline values in the liver (P < 0.01 at 4 months) while no response could be documented over time in the adipose tissue.

Conclusions:

These findings document that BS‐induced modification of glucose homeostasis in slightly obese T2DM patients is mostly due to an increase in muscle glucose consumption. The surgically modified metabolic pattern of these patients might be of interest as a new model to investigate mechanism underlying insulin resistance.     

Use of Glucose,Insulin, and C‐Reactive Protein to Determine Need for Glucose Tolerance Testing

Objective: Glucose intolerance has been shown to be a better predictor of morbidity and mortality than impaired fasting glucose. However, glucose tolerance tests are inconvenient and expensive. This study evaluated the relative frequencies of glucose intolerance and impaired fasting glucose and sought to determine if 2‐hour glucose could be predicted from simple demographic and laboratory data in an obese population. Research Methods and Procedures: Eighty‐nine obese subjects (median BMI 35 kg/m², range 30 to 40 kg/m²) underwent glucose tolerance testing. Using step‐wise linear and logistic regression analysis, fasting glucose, high‐sensitivity C‐reactive protein (hsCRP), fasting insulin, high‐density lipoprotein cholesterol, triglycerides, weight, height, BMI, waist circumference, hip circumference, waist‐to‐hip ratio, sex, and age were assessed as predictors of glucose intolerance. Results: Impaired glucose tolerance was more prevalent (27%) than impaired fasting glucose (5.6%). Only fasting glucose and hsCRP were significant (p < 0.05) independent predictors of impaired 2‐hour glucose (>140 mg/dL). A fasting glucose ≥ 100 mg/dL or an hsCRP > 0.32 mg/dL (upper quartile of the normal range) detected 81% (sensitivity) of obese subjects with impaired glucose tolerance; however, specificity was poor (46%). Fasting insulin ≥ 6 μU/mL had better sensitivity (92%) but poorer specificity (30%). Discussion: Impaired glucose tolerance is more common than impaired fasting glucose in an obese population. Possible strategies to avoid doing glucose tolerance tests in all obese patients would be to do glucose tolerance testing only in those whose fasting glucose is ≥ 100 mg/dL or whose hsCRP exceeds 0.32 mg/dL or those whose fasting insulin is ≥ 6 μU/mL.     

Consequences of obstructive sleep apnea on metabolic profile: A Population‐Based Survey

Objective:

Epidemiologic studies that control for potential confounders are needed to assess the independent associations of obstructive sleep apnea (OSA) with metabolic abnormalities. The aim of our study was to evaluate the associations of OSA with metabolic abnormalities among the adult population of Sao Paulo, Brazil.

Design and Methods:

Questionnaires were applied face‐to‐face, full night polysomnography (PSG) was performed, and blood samples were collected in a population‐based survey in Sao Paulo, Brazil, adopting a probabilistic three‐stage cluster sample method. The metabolic profile included fasting glucose, insulin, and lipid levels. The hepatic insulin resistance index was assessed by the homeostasis model assessment‐estimated insulin resistance (HOMA_IR).

Results:

A total of 1,042 volunteers underwent PSG. Mild OSA and moderate to severe OSA comprised 21.2% and 16.7% of the population, respectively. Subjects with severe to moderate OSA were older, more obese, had higher fasting glucose, HOMA_IR, and triglycerides (TG) levels than did the mild and non‐OSA group (P < 0.001). Multivariate regression analyses showed that an apnea‐hypopnea index (AHI) ≥15 and a time of oxy‐hemoglobin saturation <90% were independently associated with impaired fasting glucose, elevated TG, and HOMA_IR.

Conclusions:

The results of this large cross‐sectional epidemiological study showed that the associations of OSA and metabolic abnormalities were independent of other risk factors.     

Lipid Profile in the Severely Obese: Changes with Weight Loss after Lap‐Band Surgery

Objective: To characterize dyslipidemia before and after weight loss in the severely obese. Research Methods and Procedures: Five hundred fifteen subjects who had Lap‐Band surgery were followed with yearly conventional lipid profiles for up to 4 years. Preoperative data were collected from the most recent 381 subjects, and predictors of dyslipidemia were sought. One hundred seventy‐one subjects completed a 1‐year review, providing data to assess predictors of change in lipids. Results: Favorable changes in fasting triglycerides (TG), high‐density lipoprotein‐cholesterol (HDL‐C), and total cholesterol (TC):HDL‐C ratio occurred within 1 year. All improvements were maintained up to 4 years. Male gender, central obesity, elevated fasting glucose, and insulin resistance were associated with less favorable lipid levels. Fasting plasma glucose best predicted TG (r = 0.46, p < 0.001), whereas insulin sensitivity using the homeostatic model assessment (HOMA %S) correlated best with the HDL‐C (r =0.34, p < 0.001). Higher preoperative fasting glucose best predicted the decrease in TG; improved HOMA %S with weight loss correlated best with HDL‐C. The extent of weight loss had limited influence on lipid changes. However, low preoperative HOMA %S was associated with lower weight loss. Greater weight loss was associated with more favorable lipid measures after controlling for preoperative HOMA %S. Discussion: Dyslipidemia of obesity is related to weight distribution, insulin sensitivity, and impaired glucose tolerance. Improvement with weight loss is related to the decrease in fasting glucose, improvement in insulin sensitivity, and the extent of weight lost. Improvement in dyslipidemia is sustained with long‐term weight loss.     

Retinol‐binding Protein 4 (RBP4) Protein Expression Is Increased in Omental Adipose Tissue of Severely Obese Patients

Visceral fat has been linked to insulin resistance and type 2 diabetes mellitus (T2DM); and emerging data links RBP4 gene expression in adipose tissue with insulin resistance. In this study, we examined RBP4 protein expression in omental adipose tissue obtained from 24 severely obese patients undergoing bariatric surgery, and 10 lean controls (4 males/6 females, BMI = 23.2 ± 1.5 kg/m²) undergoing elective abdominal surgeries. Twelve of the obese patients had T2DM (2 males/10 females, BMI: 44.7 ± 1.5 kg/m²) and 12 had normal glucose tolerance (NGT: 4 males/8 females, BMI: 47.6 ± 1.9 kg/m²). Adipose RBP4, glucose transport protein‐4 (GLUT4), and p85 protein expression were determined by western blot. Blood samples from the bariatric patients were analyzed for serum RBP4, total cholesterol, triglycerides, and glucose. Adipose RBP4 protein expression (NGT: 11.0 ± 0.6; T2DM: 11.8 ± 0.7; lean: 8.7 ± 0.8 arbitrary units) was significantly increased in both NGT (P = 0.03) and T2DM (P = 0.005), compared to lean controls. GLUT4 protein was decreased in both NGT (P = 0.02) and T2DM (P = 0.03), and p85 expression was increased in T2DM subjects, compared to NGT (P = 0.03) and lean controls (P = 0.003). Regression analysis showed a strong correlation between adipose RBP4 protein and BMI for all subjects, as well as between adipose RBP4 and fasting glucose levels in T2DM subjects (r = 0.76, P = 0.004). Further, in T2DM, serum RBP4 was correlated with p85 expression (r = 0.68, P = 0.01), and adipose RBP4 protein trended toward an association with p85 protein (r = 0.55, P = 0.06). These data suggest that RBP4 may regulate adiposity, and p85 expression in obese‐T2DM, thus providing a link to impaired insulin signaling and diabetes in severely obese patients.     

Changes in Insulin Secretion and Glucose Metabolism Induced by Dexamethasone in Lean and Obese Females

Objective: In healthy lean individuals, changes in insulin sensitivity occurring as a consequence of a 2‐day dexamethasone administration are compensated for by changes in insulin secretion, allowing glucose homeostasis to be maintained. This study evaluated the changes in glucose metabolism and insulin secretion induced by short‐term dexamethasone administration in obese women. Research Methods and Procedures: Eleven obese women with normal glucose tolerance were studied on two occasions, without and after 2 days of low‐dose dexamethasone administration. A two‐step hyperglycemic clamp (7.5 and 10 mM glucose) with 6, 6 ²H₂ glucose was used to assess insulin secretion and whole body glucose metabolism. Results were compared with those obtained in a group of eight lean women. Results: Without dexamethasone, obese women had higher plasma insulin concentrations in the fasting state, during the first phase of insulin secretion, and at the two hyperglycemic plateaus. However, they had normal whole body glucose metabolism compared with lean women, indicating adequate compensation. After dexamethasone, obese women had a 66% to 92% increase in plasma insulin concentrations but a 15.4% decrease in whole body glucose disposal. This contrasted with lean women, who had a 91% to 113% increase in plasma insulin concentrations, with no change in whole body glucose disposal. Discussion: Dexamethasone administration led to a significant reduction in whole body glucose disposal at fixed glycemia in obese but not lean women. This indicates that obese women are unable to increase their insulin secretion appropriately.     

Normal Insulin Sensitivity in Lean Offspring of Obese Parents

Objective: Offspring of diabetic or hypertensive patients are insulin resistant at a prediabetic/prehypertensive stage. We tested the hypothesis that insulin action may be impaired in the offspring of obese nondiabetic parents. Research Methods and Procedures: Twenty‐one lean offspring of nonobese subjects [(OL) 22 ± 3 years of age] were matched to 23 lean offspring of obese subjects (OOb) by gender distribution, age, BMI, and waist circumference. Anthropometry, oral glucose tolerance, in vivo insulin sensitivity [by a euglycemic insulin clamp (6 pmol/min per kilogram_FFM; where FFM represents fat‐free mass)], and thermogenesis (by indirect calorimetry) were measured in each subject. The study subjects were from a population of 267 nuclear families (one offspring and both his/her parents) in which there was statistically significant (χ² = 30.2, p = 0.001) concordance of BMI between parents and offspring. Results: In comparing OOb with OL, no statistically significant difference or trend toward a difference was detected in fasting plasma glucose and insulin concentrations, glucose and insulin responses to oral glucose, insulin sensitivity [metabolism value = 45 ± 12 (OOb) vs. 47 ± 17 μmol/min per kilogram_FFM (OL)], insulin‐induced inhibition of protein and lipid oxidation, stimulation of glucose oxidation and nonoxidative glucose disposal, respiratory quotient, resting energy expenditure, and glucose‐induced thermogenesis. Discussion: The metabolic similarity between lean offspring of obese parents and those of nonobese parents suggests that insulin resistance and its correlates are not co‐inherited with the predisposition to develop obesity.     

Effect of Family History of Type 2 Diabetes on White Blood Cell Count in Adult Women

Objective: To evaluate the effect of a first‐degree family history of type 2 diabetes on white blood cell (WBC) count, a risk factor for atherosclerotic vascular disease, in glucose‐tolerant adult women Research Methods and Procedures: WBC count was measured in 174 normal weight, overweight, and obese female offspring of type 2 diabetic patients (FH⁺) and 174 age‐ and BMI‐matched female controls with no family history of type 2 diabetes (FH^?). Other measurements included fat mass (FM), measured by body impedance analysis; central fat accumulation, evaluated by waist circumference; insulin resistance, estimated by homeostatic model assessment for insulin resistance (HOMA_IR); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. Results: WBC count, waist circumference, systolic blood pressure, and fasting levels of glucose, insulin, and triglycerides were significantly higher in FH⁺ than in FH^? subjects. In FH⁺ individuals, WBC count was positively associated with BMI, FM, waist circumference, HOMA_IR, and triglyceride and insulin concentrations, and negatively correlated with age and high‐density lipoprotein‐cholesterol. In FH^? subjects, WBC count was directly associated with BMI, FM, waist circumference, and triglyceride and insulin concentrations, and inversely correlated with age and high‐density lipoprotein‐cholesterol. After multivariate analyses, WBC count maintained a significant association with age, systolic blood pressure, and HOMA_IR in FH⁺ subjects and with age, BMI, FM, and triglycerides in FH^? individuals. Discussion: This study indicates that WBC count is increased in adult women with genetic predisposition to type 2 diabetes, and its main correlates are insulin resistance in FH⁺ and adiposity in FH^? individuals.     

Insulin Resistance in Nondiabetic Morbidly Obese Patients: Effect of Bariatric Surgery

Objective: To evaluate insulin action on substrate use and insulinemia in nondiabetic class III obese patients before and after weight loss induced by bariatric surgery. Research Methods and Procedures: Thirteen obese patients (four men/nine women; BMI = 56.3 ± 2.7 kg/m²) and 13 lean subjects (five men/eight women; BMI = 22.4 ± 0.5 kg/m²) underwent euglycemic clamp, oral glucose tolerance test, and indirect calorimetry. The study was carried out before (Study I) and after (～40% relative to initial body weight; Study II) weight loss induced by Roux‐en‐Y Gastric bypass with silastic ring surgery. Results: The obese patients were insulin resistant (whole‐body glucose use = 19.7 ± 1.5 vs. 51.5 ± 2.4 μmol/min per kilogram fat‐free mass, p < 0.0001) and hyperinsulinemic in the fasting state (332 ± 86 vs. 85 ± 5 pM, p < 0.0001) and during the oral glucose tolerance test compared with the lean subjects. Fasting plasma insulin normalized after weight loss, whereas whole‐body glucose use increased (35.5 ± 3.7 μmol/min per kilogram fat‐free mass, p < 0.05 vs. Study I). The higher insulin clearance of obese did not change during the follow‐up period. Insulin‐induced glucose oxidation and nonoxidative glucose disposal were lower in the obese compared with the lean group (all p < 0.05). In Study II, the former increased slightly, whereas nonoxidative glucose disposal reached values similar to those of the control group. Fasting lipid oxidation was higher in the obese than in the control group and did not change significantly in Study II. The insulin effect on lipid oxidation was slightly improved (p = 0.01 vs. Study I). Discussion: The rapid weight loss after surgery in obese class III patients normalized insulinemia and improved insulin sensitivity almost entirely due to glucose storage, whereas fasting lipid oxidation remained high.     

Beta and alpha cell function in metabolically healthy but obese subjects: Relationship with entero‐insular axis

Objective:

Obesity is widely acknowledged as a critical risk factor for metabolic complications. Among obese subjects, there is a phenotype of metabolically healthy but obese (MHO) individuals that shows a favorable cardiometabolic risk profile. We aimed to evaluate the potential mechanisms underlying the metabolic profile of this subset, including alpha and beta cell function and entero‐insular axis.

Design and Methods:

One hundred twenty‐nine obese and 24 nonobese subjects were studied. Obese participants were defined as MHO or at‐risk obese, according to the homeostasis model of assessment‐insulin resistance (HOMA‐IR) index (MHO: lower tertile of HOMA‐IR, n = 43; at‐risk: upper tertile of HOMA‐IR index, n = 41). Insulin, glucagon, and incretin responses after a 120′ oral glucose tolerance test (75‐g OGTT) were investigated.

Results:

During OGTT, MHO individuals showed in comparison with at‐risk subjects: lower fasting and afterloads plasma levels of glucose, insulin, and C‐peptide; higher disposition index; lower fasting (P = 0.004) and at 30′ (P = 0.01) plasma glucose‐dependent insulinotropic polypeptide (GIP) levels; lower area under the curve (AUC) (0‐30) for GIP (P = 0.008); higher glucagon‐like peptide‐1 (GLP‐1) plasma levels at 90′ (P = 0.02) and 120′ (P = 0.02); lower glucagon plasma levels at baseline (P = 0.04) and at 30′ (P = 0.03); and appropriate glucagon suppression after the oral glucose load.

Conclusions:

MHO subjects show, as well as normal‐weight individuals, a lower diabetogenic profile by virtue of higher disposition index and unaffected entero‐insular axis. At‐risk obese individuals present increased GIP levels that might play a role in determining increased glucagon secretion and inappropriate glucagon responses after glucose load, thus contributing to impaired glucose homeostasis.     

Obesity,Fasting Plasma Insulin,and C‐Reactive Protein Levels in Healthy Children

Objective: Obesity is associated with hyperinsulinemia and increased level of C‐reactive protein in older children and adults, but little is known about these relationships in very young children. We examined these relationships in healthy 2‐ to 3‐year‐old children. Research Methods and Procedures: Analyses were performed on data from 491 healthy 2‐ to 3‐year‐old Hispanic children enrolled in a dietary study conducted in New York City, 1992 to 1995. Results: Body mass index (BMI), ponderal index, and sum of four skinfolds were highly correlated (r > 0.75) in both boys and girls. Fasting insulin and glucose levels were only modestly correlated (r = 0.37 for boys and r = 0.28 for girls; p < 0.001 for both), but essentially all of the variability in a calculated index of insulin resistance was attributable to variability in fasting insulin level. The correlations of BMI with fasting insulin level were r = 0.16 (p < 0.05) in boys and r = 0.14 (p < 0.05) in girls. In separate multivariate regression analyses adjusting for age and sex, BMI and ponderal index were associated with fasting plasma insulin level (p < 0.001 for both obesity measures). In multivariate regression analyses adjusting simultaneously for age, sex, and either BMI or ponderal index, fasting insulin level, but not these obesity measures, was associated with C‐reactive protein level. Discussion: Obesity is associated with higher fasting insulin level, and fasting insulin is associated with C‐reactive protein level, in healthy 2‐ to 3‐year‐old children.     

Very low-carbohydrate versus isocaloric high-carbohydrate diet in dietary obese rats

Objective: The effects of a very low‐carbohydrate (VLC), high‐fat (HF) dietary regimen on metabolic syndrome were compared with those of an isocaloric high‐carbohydrate (HC), low‐fat (LF) regimen in dietary obese rats. Research Methods and Procedures: Male Sprague‐Dawley rats, made obese by 8 weeks ad libitum consumption of an HF diet, developed features of the metabolic syndrome vs. lean control (C) rats, including greater visceral, subcutaneous, and hepatic fat masses, elevated plasma cholesterol levels, impaired glucose tolerance, and fasting and post‐load insulin resistance. Half of the obese rats (VLC) were then fed a popular VLC‐HF diet (Weeks 9 and 10 at 5% and Weeks 11 to 14 at 15% carbohydrate), and one‐half (HC) were pair‐fed an HC‐LF diet (Weeks 9 to 14 at 60% carbohydrate). Results: Energy intakes of pair‐fed VLC and HC rats were less than C rats throughout Weeks 9 to 14. Compared with HC rats, VLC rats exhibited impaired insulin and glycemic responses to an intraperitoneal glucose load at Week 10 and lower plasma triacylglycerol levels but retarded loss of hepatic, retroperitoneal, and total body fat at Week 14. VLC, HC, and C rats no longer differed in body weight, plasma cholesterol, glucose tolerance, or fasting insulin resistance at Week 14. Progressive decreases in fasting insulin resistance in obese groups paralleled concomitant reductions in hepatic, retroperitoneal, and total body fat. Discussion: When energy intake was matched, the VLC‐HF diet provided no advantage in weight loss or in improving those components of the metabolic syndrome induced by dietary obesity and may delay loss of hepatic and visceral fat as compared with an HC‐LF diet.     

Effects of Insulin on Ketogenesis Following Fasting in Lean and Obese Men

The ketone bodies (KBs) D‐3‐hydroxybutyrate (D‐3HB) and acetoacetate (AcAc) play a role in starvation and have been associated with insulin resistance. The dose–response relationship between insulin and KBs was demonstrated to be shifted to the right in type 2 diabetes patients. However, KB levels have also been reported to be decreased in obesity. We investigated the metabolic adaptation to fasting with respect to glucose and KB metabolism in lean and obese men without type 2 diabetes using stable glucose and D‐3HB isotopes in a two‐step pancreatic clamp after 38 h of fasting. We found that D‐3HB fluxes in the basal state were higher in lean compared to obese men: 15.2 (10.7–27.1) vs. 7.0 (3.5–15.1) µmol/kg lean body mass (LBM)·min, respectively, P < 0.01. No differences were found in KB fluxes between lean and obese volunteers during the pancreatic clamp (step 1: 6.9 (1.8–12.0) vs. 7.4 (4.2–17.8) µmol/kg LBM·min, respectively; and step 2: 2.9 (0–7.2) vs. 3.4 (0.85–18.7) µmol/kg LBM·min, respectively), despite similar plasma insulin levels. Meanwhile, peripheral glucose uptake was higher in lean compared to obese men (step 1: 15.2 (12.3–25.6) vs. 14.7 (11.9–22.7) µmol/kg LBM·min, respectively, P ≤ 0.05; and step 2: 12.5 (7.0–17.3) vs. 10.8 (5.2–15.0) µmol/kg LBM·min, respectively, P ≤ 0.01). These data show that obese subjects who display insulin resistance on insulin‐mediated peripheral glucose uptake have the same sensitivity for the insulin‐mediated suppression of ketogenesis. This implies differential insulin sensitivity of intermediary metabolism in obesity.     

Association Between the 4 bp Proinsulin Gene Insertion Polymorphism (IVS‐69) and Body Composition in Black South African Women

The objective of the study was to examine the association between a functional 4 bp proinsulin gene insertion polymorphism (IVS‐69), fasting insulin concentrations, and body composition in black South African women. Body composition, body fat distribution, fasting glucose and insulin concentrations, and IVS‐69 genotype were measured in 115 normal‐weight (BMI <25 kg/m²) and 138 obese (BMI ≥30 kg/m²) premenopausal women. The frequency of the insertion allele was significantly higher in the class 2 obese (BMI ≥35kg/m²) compared with the normal‐weight group (P = 0.029). Obese subjects with the insertion allele had greater fat mass (42.3 ± 0.9 vs. 38.9 ± 0.9 kg, P = 0.034) and fat‐free soft tissue mass (47.4 ± 0.6 vs. 45.1 ± 0.6 kg, P = 0.014), and more abdominal subcutaneous adipose tissue (SAT, 595 ± 17 vs. 531 ± 17 cm², P = 0.025) but not visceral fat (P = 0.739), than obese homozygotes for the wild‐type allele. Only SAT was greater in normal‐weight subjects with the insertion allele (P = 0.048). There were no differences in fasting insulin or glucose levels between subjects with the insertion allele or homozygotes for the wild‐type allele in the normal‐weight or obese groups. In conclusion, the 4 bp proinsulin gene insertion allele is associated with extreme obesity, reflected by greater fat‐free soft tissue mass and fat mass, particularly SAT, in obese black South African women.     

Improvement of Insulin Resistance and Early Atherosclerosis in Patients after Gastric Banding

Objective: To evaluate the effect of massive weight loss on insulin sensitivity, soluble adhesion molecules, and markers of the insulin resistance syndrome (IRS). Research Methods and Procedures: Eighteen morbidly obese patients underwent gastric banding and were evaluated before and 6 and 12 months after surgery. Total insulin secretion, hepatic insulin extraction, and insulin sensitivity were analyzed by oral glucose‐tolerance test model analysis. In addition, soluble intercellular adhesion molecule‐1, vascular cell adhesion molecule‐1, E‐selectin, leptin, high‐sensitivity C‐reactive protein, plasminogen activating factor‐1 (PAI‐1), and tissue plasminogen activator were measured. Results: BMI dropped from 45.22 ± 5.62 to 36.99 ± 4.34 kg/m² after 6 months and 33.72 ± 5.55 kg/m² after 12 months (both p < 0.0001). This intervention resulted in a significant reduction of blood pressure (p < 0.00001), triglycerides (p < 0.01), fasting blood glucose (p = 0.03), basal insulin (p < 0.001), and basal C‐peptide (p = 0.008) levels. Total insulin secretion decreased (p < 0.05), whereas hepatic insulin extraction (p < 0.05) and oral glucose insulin sensitivity index (p < 0.0001) increased compared with baseline. Leptin (p < 0.0001) and E‐selectin levels decreased significantly after 6 and 12 months (p = 0.05), whereas significantly lower levels of intercellular adhesion molecule‐1 and PAI‐1 were only seen after 6 months. Subclinical inflammation, measured by high‐sensitivity C‐reactive protein, was lowered to normal ranges. No changes were observed in vascular cell adhesion molecule‐1 and tissue plasminogen activator levels. Discussion: Although gastric banding ameliorates several features of the IRS, including 29.05% improvement in insulin sensitivity and blood pressure and reduction of soluble adhesion molecules and PAI‐1, considerable weight loss did not normalize all components of the IRS in morbidly obese patients.