Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats

To determine the influence of dietary fructose and glucose on circulating leptin levels in lean and obese rats, plasma leptin concentrations were measured in ventromedial hypothalamic (VMH)-lesioned obese and sham-operated lean rats fed either normal chow or fructose- or glucose-enriched diets (60% by calories) for 2 wk. Insulin resistance was evaluated by the steady-state plasma glucose method and intravenous glucose tolerance test. In lean rats, glucose-enriched diet significantly increased plasma leptin with enlarged parametrial fat pad, whereas neither leptin nor fat-pad weight was altered by fructose. Two weeks after the lesions, the rats fed normal chow had marked greater body weight gain, enlarged fat pads, and higher insulin and leptin compared with sham-operated rats. Despite a marked adiposity and hyperinsulinemia, insulin resistance was not increased in VMH-lesioned rats. Fructose brought about substantial insulin resistance and hyperinsulinemia in both lean and obese rats, whereas glucose led to rather enhanced insulin sensitivity. Leptin, body weight, and fat pad were not significantly altered by either fructose or glucose in the obese rats. These results suggest that dietary glucose stimulates leptin production by increasing adipose tissue or stimulating glucose metabolism in lean rats. Hyperleptinemia in VMH-lesioned rats is associated with both increased adiposity and hyperinsulinemia but not with insulin resistance. Dietary fructose does not alter leptin levels, although this sugar brings about hyperinsulinemia and insulin resistance, suggesting that hyperinsulinemia compensated for insulin resistance does not stimulate leptin production.     

Insulin secretion in metabolically obese, but normal weight, and in metabolically healthy but obese individuals

Metabolically obese but normal-weight (MONW) individuals present metabolic disturbances typical of obese individuals. Additionally, metabolically healthy but obese (MHO) individuals have been identified who are relatively insulin sensitive and have a favorable cardiovascular risk profile. We compared insulin secretion patterns of MONW and MHO with those of two age-matched groups comprising nonobese individuals or obese insulin-resistant subjects, respectively. To this end, 110 nonobese subjects and 87 obese subjects were stratified into quartile based on their insulin-stimulated glucose disposal (M(FFM)). Insulin secretion was estimated by acute insulin response (AIR) during an intravenous glucose-tolerance test (IVGTT), and the disposition index was calculated as AIR x M(FFM). We found that, as defined, M(FFM) was lower in MONW, who exhibited higher triglycerides, free-fatty acid (FFA), and 2-h postchallenge glucose levels compared to normal nonobese group. Insulin secretion was higher in MONW than in normal nonobese subjects, but disposition index was lower in MONW. Disposition index did not differ between MONW and insulin-resistant obese. M(FFM) was higher in MHO who exhibited lower waist circumference, blood pressure (BP), triglycerides, FFA, insulin levels, and higher high-density lipoprotein (HDL) cholesterol compared to insulin-resistant obese. Insulin secretion did not differ between insulin-resistant obese and MHO, but disposition index was lower in the former group. In conclusion, MONW and insulin-resistant obese showed decreased compensatory insulin secretion compared to normal nonobese and MHO subjects, respectively. Because these subjects also exhibited a worse metabolic risk profile, these findings may account for their increased risk for type 2 diabetes.     

Invited review: Effects of acute exercise and exercise training on insulin resistance.

Insulin resistance of skeletal muscle glucose transport is a key defect in the development of impaired glucose tolerance and Type 2 diabetes. It is well established that both an acute bout of exercise and chronic endurance exercise training can have beneficial effects on insulin action in insulin-resistant states. This review summarizes the present state of knowledge regarding these effects in the obese Zucker rat, a widely used rodent model of obesity-associated insulin resistance, and in insulin-resistant humans with impaired glucose tolerance or Type 2 diabetes. A single bout of prolonged aerobic exercise (30-60 min at approximately 60-70% of maximal oxygen consumption) can significantly lower plasma glucose levels, owing to normal contraction-induced stimulation of GLUT-4 glucose transporter translocation and glucose transport activity in insulin-resistant skeletal muscle. However, little is currently known about the effects of acute exercise on muscle insulin signaling in the postexercise state in insulin-resistant individuals. A well-established adaptive response to exercise training in conditions of insulin resistance is improved glucose tolerance and enhanced skeletal muscle insulin sensitivity of glucose transport. This training-induced enhancement of insulin action is associated with upregulation of specific components of the glucose transport system in insulin-resistant muscle and includes increased protein expression of GLUT-4 and insulin receptor substrate-1. It is clear that further investigations are needed to further elucidate the specific molecular mechanisms underlying the beneficial effects of acute exercise and exercise training on the glucose transport system in insulin-resistant mammalian skeletal muscle.     

Beta cell function, insulin resistance and plasma adiponectin concentrations are predictors for the change of postprandial glucose in non-diabetic subjects at risk for type 2 diabetes.

Insulin resistance, impaired insulin secretion, and low adiponectin levels have been shown to be predictors for type 2 diabetes. However, it is not yet clear whether these associations (1) are independent of changes in body weight, or (2) are valid for changes in glucose tolerance in the prediabetic state. Sixty-two non-diabetics (50 with normal glucose tolerance) aged 41 +/- 11 years, BMI 30.5 +/- 5.3 kg/m2 (mean +/- SD) were studied twice with a standard oral glucose tolerance test (oGTT, mean follow-up time 3.0 +/- 1.8 years (mean +/- SD) [range 0.5-6.5 years]). Insulin sensitivity and insulin secretion were estimated from oGTT using validated indices. Two-hour blood glucose during oGTT deteriorated over time (baseline 2 h glucose 6.32 +/- 0.21 VS. follow-up 2 h glucose 7.14 +/- 0.22 mM, p < 0.001) while the percentage body fat did not change (32.7 +/- 1.2 VS. 32.6 +/- 1.2%, p = 0.46). Follow-up 2 h blood glucose was predicted by adiponectin (p = 0.01), baseline insulin sensitivity (p = 0.02) and baseline insulin secretion relative to insulin sensitivity (p = 0.03) independent of sex, age, baseline 2 h blood glucose or change in percentage body fat. Our results suggest that low adiponectin levels, insulin resistance and low beta cell function predict the continuous deterioration of glucose tolerance in early prediabetic states, independent of changes in adiposity. Therefore, the early influence of these parameters should be the subject of future prevention programs to prevent deterioration of glucose tolerance.     

Effects of vanadate on glucose production in cultured hepatocytes isolated from rats on high saturated fat diet

Insulin resistance is a common phenomenon in obesity and Type 2 diabetes. Common factor important for development of diabetes and insulin resistance is intake of saturated fat. Vanadate treatment improves glucose homeostasis in vivo. The aim of this study was to find out changing of hepatic glucose output in dependence of saturated fat diet and possible direct action of vanadate in cultured hepatocytes. Hepatocytes were isolated by a collagenase perfusion technique and cultured for 24 h in M 199 serum-free medium. The glucose production in hepatocytes isolated from rats on high saturated fat diet was significantly 139% higher comparable to standard controls. Glucagon 100% increased glucose production in hepatocytes from rats on standard diet and 200% in hepatocytes on saturated high fat diet. The addition vanadate significantly decreased basic glucose production and did not influence glucagon stimulated glucose production. Presence of insulin did not influence either glucagon or vanadate effect. High saturated fat diet not only increases insulin resistance but also decreases chances of successful therapy of diabetes.     

Familial type C syndrome of insulin resistance and short stature with possible autosomal dominant transmission

We describe a 17-yr-old girl with insulin resistant diabetes, acanthosis nigricans, hirsutism and short stature. At the age of 14 she was found to have glycosuria and diagnosed as diabetes mellitus. No endocrinological abnormality except transient amenorrhea and exaggerated LH response to LHRH was found. Insulin resistance was demonstrated by fasting hyperinsulinemia, insulin tolerance test and euglycemic glucose clamp test, and large doses of insulin with CSII were not effective in controlling blood glucose. Insulin binding to erythrocytes was normal, suggesting a postbinding defect. The same phenotype of insulin resistant diabetes and short stature was found in her mother who was diagnosed as diabetes mellitus at the age of 31 and died of diabetic nephropathy at the age of 41. Her maternal grandfather and uncle were reportedly affected with the same phenotype. Her father had impaired glucose tolerance, but no hyperinsulinemia. Two sisters had essentially normal glucose tolerance. Insulin binding to erythrocytes of her father and mother was also in the normal range. These results suggest that the present case may be a rare syndrome present together with type C syndrome of insulin resistance, and with short stature which was inherited autosomal dominantly.     

Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.     

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.     

Lipoprotein metabolism mediates the association of MTP polymorphism with β-cell dysfunction in healthy subjects and in nondiabetic normolipidemic patients with nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) predicts incident diabetes independently of insulin resistance, adiposity and metabolic syndrome through unclear mechanisms. Dietary fat consumption and lipoperoxidative stress predispose to diabetes in the general population and to liver injury in NASH. Microsomal triglyceride transfer protein (MTP) polymorphism modulates lipoprotein metabolism in the general population and liver disease in NASH; a functional MTP polymorphism recently predicted incident diabetes independently of insulin resistance in the general population. We simultaneously assessed the impact of MTP polymorphism, diet, adipokines and lipoprotein metabolism, on glucose homeostasis in NASH.MTP ?493G/T polymorphism, dietary habits, adipokines and postprandial triglyceride-rich lipoproteins, high-density lipoprotein cholesterol (HDL-C) and oxidized low-density lipoprotein (oxLDL) responses to an oral fat load, were cross-sectionally correlated to oral glucose tolerance test- and frequently sampled intravenous glucose tolerance test-derived Minimal Model indexes of glucose homeostasis in 40 nondiabetic normolipidemic patients with NASH and 40 age-,sex- and body mass index-matched healthy controls.Despite comparable insulin resistance, fasting lipids, adipokines and dietary habits, MTP GG genotype had significantly more severe β-cell dysfunction; higher plasma Tg, FFA, intestinal and hepatic very low-density lipoprotein 1 subfractions and oxLDL responses and deeper HDL-C fall than GT/TT carriers in patients and controls.Postprandial HDL-C and oxLDL responses independently predicted β-cell dysfunction and mediated the effect of MTP polymorphism on β-cell function.In nondiabetic normolipidemic NASH, MTP ?493G/T polymorphism modulates β-cell function, an effect mediated by postprandial HDL-C and oxLDL metabolism. The impact of this polymorphism on the risk of diabetes and the efficacy of lipid-lowering therapies in restoring β-cell function in NASH, even with normal fasting lipid values, warrant further investigation.     

Reversal of the sex difference in plasma leptin levels in obese children with impaired glucose tolerance

INTRODUCTION: Basal leptin level has been demonstrated to correlate positively with many indices of obesity, as well as insulin resistance. However, to date, little is known about regulation of leptin in obese children with incipient glucose metabolic disorders. OBJECTIVE: The aim of this study was to define the precise influence of the glucose tolerance status on plasma leptin in obese boys and girls separately. MATERIAL AND METHODS: 70 obese children with impaired glucose tolerance (IGT) and well-matched 70 normal glucose-tolerant (NGT) subjects were examined. Fasting and 2-h post glucose load plasma glucose and insulin levels as well as fasting leptin levels were determined, apart from anthropometric measurements. RESULTS: Leptin levels were significantly lower in girls with IGT compared to NGT girl (17.7+/-6.5 microg/L vs. 23.1+/-7.7 microg/L; p<.001). No such difference was observed in boys. In a multiple regression analysis adjusting for age and adiposity, in the female group plasma glucose and insulin levels 2-h after glucose load were the best predictors of fasting plasma leptin (r=-0.49, p<.005 and r=0.34, p<.05; respectively). In boys, plasma insulin level 2-h after glucose load was the independent determinant of leptin (r=0.36, p<.05). CONCLUSION: The differences between regulation of leptin synthesis in girls and boys with simple obesity were found. The stimulatory effect of insulin on leptin synthesis was greater in girls with normoglycemia than in girls with impaired glucose tolerance.     

Reversal of the sex difference in plasma leptin levels in obese children with impaired glucose tolerance

INTRODUCTION: Basal leptin level has been demonstrated to correlate positively with many indices of obesity, as well as insulin resistance. However, to date, little is known about regulation of leptin in obese children with incipient glucose metabolic disorders. OBJECTIVE: The aim of this study was to define the precise influence of the glucose tolerance status on plasma leptin in obese boys and girls separately. MATERIAL AND METHODS: 70 obese children with impaired glucose tolerance (IGT) and well-matched 70 normal glucose-tolerant (NGT) subjects were examined. Fasting and 2-h post glucose load plasma glucose and insulin levels as well as fasting leptin levels were determined, apart from anthropometric measurements. RESULTS: Leptin levels were significantly lower in girls with IGT compared to NGT girl (17.7+/-6.5 microg/L vs. 23.1+/-7.7 microg/L; p<.001). No such difference was observed in boys. In a multiple regression analysis adjusting for age and adiposity, in the female group plasma glucose and insulin levels 2-h after glucose load were the best predictors of fasting plasma leptin (r=-0.49, p<.005 and r=0.34, p<.05; respectively). In boys, plasma insulin level 2-h after glucose load was the independent determinant of leptin (r=0.36, p<.05). CONCLUSION: The differences between regulation of leptin synthesis in girls and boys with simple obesity were found. The stimulatory effect of insulin on leptin synthesis was greater in girls with normoglycemia than in girls with impaired glucose tolerance.     

Adropin deficiency is associated with increased adiposity and insulin resistance

Adropin is a secreted peptide that improves hepatic steatosis and glucose homeostasis when administered to diet-induced obese mice. It is not clear if adropin is a peptide hormone regulated by signals of metabolic state. Moreover, the significance of a decline in adropin expression with obesity with respect to metabolic disease is also not clear. We investigated the regulation of serum adropin by metabolic status and diet. Serum adropin levels were high in chow-fed conditions and were suppressed by fasting and diet-induced obesity (DIO). High adropin levels were observed in mice fed a high-fat low carbohydrate diet, whereas lower levels were observed in mice fed a low-fat high carbohydrate diet. To investigate the role of adropin deficiency in metabolic homeostasis, we generated adropin knockout mice (AdrKO) on the C57BL/6J background. AdrKO displayed a 50%-increase in increase in adiposity, although food intake and energy expenditure were normal. AdrKO also exhibited dyslipidemia and impaired suppression of endogenous glucose production (EndoR(a)) in hyperinsulinemic-euglycemic clamp conditions, suggesting insulin resistance. While homo- and heterozygous carriers of the null adropin allele exhibited normal DIO relative to controls, impaired glucose tolerance associated with weight gain was more severe in both groups. In summary, adropin is a peptide hormone regulated by fasting and feeding. In fed conditions, adropin levels are regulated dietary macronutrients, and increase with dietary fat content. Adropin is not required for regulating food intake, however, its functions impact on adiposity and are involved in preventing insulin resistance, dyslipidemia, and impaired glucose tolerance.     

ADRB2 Haplotype Is Associated With Glucose Tolerance and Insulin Sensitivity in Obese Postmenopausal Women

The β₂‐adrenergic receptor (ADRB2) mediates obesity, cardiorespiratory fitness, and insulin resistance. We examined the hypothesis that ADRB2 Arg16Gly‐Gln27Glu haplotype is associated with body composition, glucose tolerance, and insulin sensitivity in obese, postmenopausal women. Obese (>35% body fat), postmenopausal (age 45–75 years) women (n = 123) underwent genotyping, dual‐energy X‐ray absorptiometry, and computed tomography scans, exercise testing (VO_2max), 2‐h oral glucose tolerance tests (OGTTs), and hyperinsulinemic‐euglycemic clamps (80 mU/m²/min). Analysis of covariance (ANCOVA) tested for differences among haplotypes, with race, % body fat, and VO_2max as covariates. We found that ADRB2 haplotype was independently associated with % body fat, abdominal fat distribution, VO_2max, insulin sensitivity (M/ΔInsulin), and glucose tolerance (ANOVA, P < 0.05 for all). Women homozygous for Gly16–Gln27 haplotype had the highest % body fat (52.7 ± 1.9%), high abdominal fat, low M/ΔInsulin (0.49 ± 0.08 mg/kg/min/pmol/l/10²), and impaired glucose tolerance (IGT) during an OGTT (G₁₂₀ = 10.2 ± 0.9 mmol/l). Women homozygous for Gly16–Glu27 haplotype also had low M/ΔInsulin (0.51 ± 0.05 mg/kg/min/pmol/l/10²) and IGT (G₁₂₀ = 8.2 ± 0.7 mmol/l). Subjects with Arg16–Gln27/Gly16–Gln27 haplotype combination had the highest VO_2max (1.84 ± 0.07 l/min) and M/ΔInsulin (0.7 ± 0.04 mg/kg/min/pmol/l/10²), and normal glucose tolerance (G₁₂₀ = 6.4 ± 0.4 mmol/l), despite being obese. These data show associations of the ADRB2 Arg16Gly‐Gln27Glu haplotype with VO_2max and body composition, and an independent association with glucose metabolism, which persists after controlling for body composition and fitness. This suggests that ADRB2 haplotypes may mediate insulin action, glucose tolerance, and potentially risk for type 2 diabetes mellitus (T2DM) in obese, postmenopausal women.     

Insulin signaling and glucose transport in insulin resistant human skeletal muscle

Insulin increases glucose uptake and metabolism in skeletal muscle by signal transduction via protein phosphorylation cascades. Insulin action on signal transduction is impaired in skeletal muscle from Type 2 diabetic subjects, underscoring the contribution of molecular defects to the insulin resistant phenotype. This review summarizes recent work to identify downstream intermediates in the insulin signaling pathways governing glucose homeostasis, in an attempt to characterize the molecular mechanism accounting for skeletal muscle insulin resistance in Type 2 diabetes. Furthermore, the effects of pharmaceutical treatment of Type 2 diabetic patients on insulin signaling and glucose uptake are discussed. The identification and characterization of pathways governing insulin action on glucose metabolism will facilitate the development of strategies to improve insulin sensitivity in an effort to prevent and treat Type 2 diabetes mellitus.     

Effect of exercise training on insulin sensitivity and glucose metabolism in lean, obese, and diabetic men.

To clarify the impact of vigorous physical training on in vivo insulin action and glucose metabolism independent of the intervening effects of concomitant changes in body weight and composition and residual effects of an acute exercise session, 10 lean, 10 obese, and 6 diet-controlled type II diabetic men trained for 12 wk on a cycle ergometer 4 h/wk at approximately 70% of maximal O2 uptake (VO2max) while body composition and weight were maintained by refeeding the energy expended in each training session. Before and 4-5 days after the last training session, euglycemic hyperinsulinemic (40 mU.m2.min-1) clamps were performed at a plasma glucose of 90 mg/dl, combined with indirect calorimetry. Total insulin-stimulated glucose disposal (M) was corrected for residual hepatic glucose output. Body weight, fat, and fat-free mass (FFM) did not change with training, but cardiorespiratory fitness increased by 27% in all groups. Before and after training, M was lower for the obese (5.33 +/- 0.39 mg.kg FFM-1.min-1 pretraining; 5.33 +/- 0.46 posttraining) than for the lean men (9.07 +/- 0.49 and 8.91 +/- 0.60 mg.kg FFM-1.min-1 for pretraining and posttraining, respectively) and lower for the diabetic (3.86 +/- 0.44 and 3.49 +/- 0.21) than for the obese men (P less than 0.001). Insulin sensitivity was not significantly altered by training in any group, but basal hepatic glucose production was reduced by 22% in the diabetic men. Thus, when intervening effects of the last exercise bout or body composition changes were controlled, exercise training per se leading to increased cardiorespiratory fitness had no independent impact on insulin action and did not improve the insulin resistance in obese or diabetic men.     

Decreased Hepatic Insulin Extraction Precedes Overt Noninsulin Dependent (Type II) Diabetes in Obese Monkeys

Many obese middle-aged rhesus monkeys (Macaca mulatta) spontaneously develop noninsulin dependent diabetes mellitus (NIDDM). Basal hyperinsulinemia and increased stimulated plasma insulin levels are associated with this obesity and precede the onset of overt diabetes. The present studies sought to determine the relative contributions of enhanced insulin secretion and of reduced insulin clearance to this early obesity-associated hyperinsulinemia. Direct simultaneous measurement of portal and jugular vein insulin levels in two normal monkeys showed a constant rate of hepatic insulin extraction of 56±3% over the range of peripheral insulin levels from 351±113 to 625±118 pmol/L. In 33 additional monkeys ranging from normal to diabetic, basal C-peptide levels were examined as an indicator of β-cell secretion and the molar ratio of plasma C-peptide to insulin (C/I ratio) under basal steady state conditions calculated as an index of hepatic insulin extraction. Well in advance of overt diabetes, there was a progressive decline of 67% in the apparent hepatic insulin extraction rate in association with increased obesity and plasma insulin levels. Basal insulin levels and hepatic insulin extraction returned toward normal in monkeys with impaired glucose tolerance and in those with overt diabetes. We conclude that reduced insulin disposal, probably due to reduced hepatic extraction of insulin, in addition to increased β-cell activity, contributes to the development of basal hyperinsulinemia in obese rhesus monkeys progressing toward NIDDM. In addition, in overt diabetes, normal hepatic insulin extraction in the presence of limited β-cell secretion may exacerbate the hypoinsulinemic state. (OBESITY RESEARCH 1993; 1:252–260)     

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.     

实验性2型糖尿病恒河猴模型的构建及其部分临床特征分析

目的构建2型糖尿病（T2DM）恒河猴模型,使之成为研究人类T2DM的有效替身。方法以高糖高脂饮食为基础,在出现高脂血症和肥胖状态后注射35mg／kg的链脲佐菌素（STZ）,测定体重指数、血脂、空腹血糖、胰岛素、胰岛素抵抗指数、尿糖和口服葡萄糖耐量试验等,分析其部分临床特征。结果T2DM模型组体重指数（BMI）大于35达到重度肥胖,有高脂血症的特点,空腹血糖、胰岛素和胰岛素抵抗指数显著增高（P〈0．01）,尿糖检测呈阳性,葡萄糖耐量受损并且空腹血糖高于7mmol／L、2h的血糖水平高于11．Immol／L,胰岛有轻度损伤和病变。结论通过部分临床特征分析,T2DM模型组具有典型的T2DM临床特征,可成为T2DM研究的有效模型。     

Circulating Interleukin‐6 in Relation to Adiposity,Insulin Action,and Insulin Secretion

Objective: Plasma concentrations of interleukin‐6 (IL‐6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined whether circulating plasma IL‐6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes. Research Methods and Procedures: Fasting plasma IL‐6 concentrations (enzyme‐linked immunosorbent assay), body composition (DXA), insulin action (M; hyperinsulinemic euglycemic clamp), and acute insulin secretory responses to glucose (25 g intravenous glucose tolerance test) were measured in 58 Pima Indians without diabetes (24 women, 34 men). Results: Fasting plasma IL‐6 concentrations were positively correlated with percentage of body fat (r = 0.26, p = 0.049) and negatively correlated with M (r = ?0.28, p = 0.031), but were not related to acute insulin response (r = 0.13, p = 0.339). After adjusting for percentage of body fat, plasma IL‐6 was not related to M (partial r = ?0.23, p = 0.089). Discussion: Fasting plasma IL‐6 concentrations are positively related to adiposity and negatively related to insulin action in Pima Indians. The relationship between IL‐6 and insulin action seems to be mediated through adiposity.     

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.