Obese Normal Glucose Tolerance Research Articles

Nuclear Magnetic Resonance Derived Biomarkers for Evaluating Cardiometabolic Risk in Youth and Young Adults Across the Spectrum of Glucose Tolerance.

Youth with obesity have an increased risk for cardiometabolic disease, but identifying those at highest risk remains a challenge. Four biomarkers that might serve this purpose are “by products” of clinical NMR LipoProfile® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance and type 2 diabetes (T2DM) in adults (glycine inversely) and are independent of biological and methodological variations in insulin assays. However, their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 186 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT, 23 with prediabetes (PreDM), and 33 with T2DM. All four biomarkers were associated with obesity and glycemia in youth. LPIR and GlycA were highest in youth with PreDM and T2DM, whereas glycine was lowest in youth with T2DM. While all four were correlated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LPIR had the strongest correlation (LPIR: r = 0.6; GlycA: r = 0.4, glycine: r = −0.4, BCAA: r = 0.2, all P < 0.01). All four markers correlated with HbA1c (LPIR, GlycA, BCAA: r ≥ 0.3 and glycine: r = −0.3, all P < 0.001). In multi-variable regression models, LPIR, GlycA, and glycine were independently associated with HOMA-IR (Adjusted R2 = 0.473, P < 0.001) and LPIR, glycine, and BCAA were independently associated with HbA1c (Adjusted R2 = 0.33, P < 0.001). An LPIR index of >44 was associated with elevated blood pressure, BMI, and dyslipidemia. Plasma NMR-derived markers were related to adverse markers of cardiometabolic risk in youth. LPIR, either alone or in combination with GlycA, should be explored as a non-insulin dependent predictive tool for development of insulin resistance and diabetes in youth.Clinical Trial Registration Clinicaltrials.gov, identifier NCT:02960659

1243-P: NMR-Derived Biomarkers Identify Cardiometabolic Disease Risk in Youth

Youth with obesity have increased risk for cardiometabolic (CM) disease but identifying those at highest risk remains a challenge. 4 potential biomarkers are “byproducts” of clinical NMR LipoProfile® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance (IR) and type 2 diabetes (T2D) in adults (glycine inversely), but their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 184 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT and 54 obese with abnormal glucose tolerance (AGT; 20 with T2D and 34 with prediabetes) and determined their relationships with HOMA-IR (homeostatic model of IR) and hemoglobin A1c (HbA1c). Compared to lean and obese NGT, AGT youth had higher systolic blood pressure and HbA1c (Table). All 4 biomarkers were higher in youth with obesity vs. lean, while only LPIR was higher in AGT youth vs. obese NGT (Table). While all 4 were correlated with HOMA-IR, LPIR had the strongest correlation (LPIR: r=0.6; GlycA: r=0.4, glycine: r=-0.4, BCAA: r=0.2, all P&amp;lt;0.01). All 4 correlated with HbA1c (GlycA, LPIR, BCAA: r≥0.3 and glycine: r=-0.3, all P&amp;lt;0.001). Plasma NMR-derived markers were related to CM risk in youth, with LPIR distinguishing between obese NGT and AGT. These biomarkers should be explored as predictive tools for development of IR and T2DM. Disclosure S.T. Chung: None. S. Matta: None. A. Meyers: None. C.K. Cravalho: None. A. Villalobos-Perez: None. L. Mabundo: None. A.B. Courville: None. M.L. Sampson: None. J.D. Otvos: Employee; Self; LabCorp. S.N. Magge: None. Funding National Institutes of Health (to S.T.C., L.M., A.B.C.)

1703-P: Altered UCP1 Expression in ADSC-Derived Beige Adipocytes Determines Mitochondrial ROS Production in T2DM Patients

Background: Under normal physiological conditions, adipose derived stem cells (ADSC) maintain adipose tissue homeostasis by responding to metabolic loading through proliferation and differentiation. Nevertheless, in T2DM their properties might be compromised. ADSC give rise to thermogenic beige adipocytes that make a significant contribution into excess energy utilization in obesity. We compared ADSC response to beiging inductors in obese patients with type 2 diabetes mellitus (T2DM) and with normal glucose tolerance (NGT). Methods: We collected subcutaneous fat biopsies from 5 obese NGT (BMI&amp;gt;35kg/m2) and 5 obese T2DM patients during bariatric surgery. ADSC were enzymatically isolated and underwent white and beige adipogenic differentiation. UCP-1 level was evaluated by RT-PCR and Western blot. Expression of lipid metabolism and electron transport chain (ETC) genes were analyzed by RT-PCR. ROS production was evaluated by fluorescent microscopy. Results: UCP-1 expression was decreased in beige adipocytes from T2DM patients in mRNA and protein levels. Nevertheless, expression and phosphorylation of lipolytic proteins were equal in beige adipocytes of NGT and T2DM groups. Expression analysis of ETC genes also has not shown any statistically significant differences. All the while, we revealed increased mitochondrial ROS production in T2DM beige adipocytes during beige differentiation. Conclusions: These results indicate association of ADSC thermogenic potential and T2DM development. Decreased UCP1 level in complex with normal lipolysis and ETC activity in beige adipocytes from T2DM patients may be liable to elevated ROS level, known to initiate mitochondria damage and insulin resistance. Disclosure S. Michurina: None. I. Stafeev: None. I. Sklyanik: None. E. Shestakova: Employee; Spouse/Partner; AstraZeneca. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis Pharma K.K., Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Yurasov: None. K. Yahyaev: None. E. Ratner: None. M. Menshikov: None. M.V. Shestakova: None. Y.V. Parfyonova: None. Funding Russian Science Foundation (17-15-01435)

Lower Insulin Clearance Parallels a Reduced Insulin Sensitivity in Obese Youths and Is Associated With a Decline in β-Cell Function Over Time.

We examined the relationship between insulin clearance, insulin sensitivity, and β-cell function and the longitudinal effect of insulin clearance on β-cell function in lean and obese insulin-sensitive and insulin-resistant adolescents. A hyperinsulinemic-euglycemic and a hyperglycemic clamp were performed in 110 youths to quantify hepatic and peripheral clearance, insulin sensitivity, and β-cell function (disposition index, DIh-clamp). Participants underwent an oral glucose tolerance test at baseline and after 2 years to assess glucose tolerance and oral β-cell function (oDIcpep) and were sorted into four groups (lean and obese normal glucose tolerance, insulin sensitive, insulin resistant, and impaired glucose tolerance). Insulin sensitivity was defined based on the median of insulin stimulated glucose disposal (M) measured during the hyperinsulinemic-euglycemic clamp. Lean and obese insulin-sensitive participants did not differ with respect to hepatic and peripheral clearance or for insulin sensitivity. Insulin sensitivity was linearly correlated with whole-body insulin clearance. Hepatic insulin extraction at baseline acted as an independent determinant of β-cell function at follow-up. The decline in insulin sensitivity, even in the absence of an impairment of glucose tolerance, is associated with lowering of hepatic insulin clearance in obese youth, which in turn may contribute to the decline in β-cell function over time.

Chronic inflammation and lipid profile parameters in obese subjects with normal and disturbed glucose metabolism

Introduction/Objective. In different states of increased chronic inflammation, like obesity and diabetes, early changes in lipid metabolism could represent an adaptive response aimed at diminishing the elevated inflammatory reaction. The aim of study was to investigate the impact of glucose tolerance status on relationship between chronic inflammation and lipid metabolism parameters. Methods. The study consisted of four groups (n = 30 for each group): obese individuals with disturbed glucose metabolism (subjects with newly diagnosed type 2 diabetes (T2DM)) before and after metformin treatment initiation, obese subjects with normal glucose tolerance (NGT) and a control group of healthy normal weight subjects. Appropriate anthropometric measurements and laboratory tests were carried out in all participants. Results. Among the sub-group of obese subjects, the association of highly sensitive C reactive protein (hsCRP) with triglycerides and lipoprotein (a) (Lp(a)) was especially pronounced in the group of T2DM subjects before treatment initiation. In this group, the level of inflammation was the highest and correlation coefficients of triglycerides and Lp(a) with hsCRP were significantly different compared with the group of obese without diabetes (r = 0.21 vs. r = -0.36; p = 0.0172) for triglycerides and (r = -0.17 vs. r = 0.36, p = 0.0324) for Lp(a). Correlations of hsCRP with triglycerides and Lp(a) in groups of NGT obese subjects and T2DM subjects after treatment initiation did not differ significantly. Treatment with metformin changed the relationship of hsCRP with triglycerides and Lp(a) to the one which is similar to the relationship observed in obese NGT subjects (r = 0.21 vs. r = 0.38; p = 0.2449) for triglycerides and (r = -0.17 vs. r = -0.27, p = 0.3562) for Lp(a). Conclusion. In subjects with newly diagnosed T2DM, who have the highest level of inflammation, it is probable that the increase in triglycerides is a part of the anti-inflammatory response, whereas Lp(a) is probably produced and used in the reduction of elevated inflammation.

Adipose Tissue Insulin Resistance in Youth on the Spectrum From Normal Weight to Obese and From Normal Glucose Tolerance to Impaired Glucose Tolerance to Type 2 Diabetes.

Adipose tissue insulin resistance is one of the pathophysiological components of type 2 diabetes. Herein we investigated: 1) adipose insulin resistance index (Adipose-IR) (calculated as fasting insulin × free fatty acids [FFAs]) in youth across the spectrum of adiposity from normal weight to obese and the spectrum from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) to type 2 diabetes, 2) the relationship of Adipose-IR with physical and metabolic characteristics, and 3) the predictive power of Adipose-IR for determining dysglycemia in youth. A total of 205 youth had fasting glucose, insulin, FFA, Adipose-IR, body composition, visceral adipose tissue (VAT), leptin, and adiponectin evaluated. Adipose-IR was 2.2-fold higher in obese NGT, 4.3-fold higher in IGT, and 4.6-fold higher in type 2 diabetes compared with that in normal-weight peers (all P < 0.05). Females with dysglycemia (IGT and type 2 diabetes) had higher Adipose-IR than their male counterparts (P < 0.001). Adipose-IR correlated positively with total body and visceral adiposity, fasting glucose, HOMA-IR, and leptin and negatively with adiponectin. Receiver operating characteristic curve analysis yielded an optimal cutoff for Adipose-IR of 9.3 μU/mL × mmol/L for determining dysglycemia with 80% predictive power. Adipose-IR is a simple surrogate estimate that reflects pathophysiological alterations in adipose tissue insulin sensitivity in youth, with progressive deterioration from normal weight to obese and from NGT to IGT to type 2 diabetes. Adipose-IR can be applied in large-scale epidemiological/observational studies of the natural history of youth-onset type 2 diabetes and its progression or reversal with intervention strategies.

Adipocyte Insulin Resistance Index in Youth along the Span of Glycemia from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) to Type 2 Diabetes (T2D)

One of the pathophysiological components of T2D is adipocyte insulin resistance. We demonstrated diminished insulin suppression of lipolysis, using the hyperinsulinemic-euglycemic clamp combined with [2H5]glycerol tracer, in obese IGT vs. NGT youth (Diabetes 66: 2017). Herein we examined a surrogate index of adipose tissue insulin resistance (AT-IR= fasting insulin x FFA) to test the hypothesis that AT-IR increases from normal weight (NW) to obese NGT to IGT to T2D. A total of 2youth (70 M/135 F; Tanner IV-V) had body composition, visceral adipose tissue (VAT), fasting glucose, insulin and free fatty acids (FFA), and AT-IR evaluated. Despite hyperinsulinemia in obese IGT youth, fasting FFA was higher compared with NW and obese NGT peers (Table). AT-IR was 2.2 fold higher in obese NGT, 4.3 fold higher in IGT and 4.6 fold higher in T2D compared with NW before and after adjusting for sex, Tanner stage, BMI and VAT. In conclusion, the surrogate index of AT-IR reflects pathophysiological alterations in adipose tissue insulin sensitivity showing progressive increase in AT-IR in youth from normal weight to obese, and from NGT to IGT to T2D. This AT-IR, derived from fasting blood samples, could be used in epidemiological, observational and/or interventional studies investigating changes in adipocyte insulin sensitivity in obese youth with IGT and T2D. Variables, mean ± SEMNW (n=49)Obese-NGT (n=89)Obese-IGT (n=38)Obese-T2D (n=29)P, ANCOVAAge (years)14.4 ± 0.314.6 ± 0.214.9 ± 0.415.2 ± 0.3NSBMI (kg/m2)20.6 ± 0.333.9 ± 0.736.8 ± 1.036.8 ± 1.0&amp;lt;0.0001Visceral adipose tissue (cm2)24.4 ± 2.260.8 ± 4.185.1 ± 5.183.6 ± 7.7&amp;lt;0.0001Fasting glucose (mg/dL)95.1 ± 0.895.4 ± 0.696.8 ± 1.2121.5 ± 4.8&amp;lt;0.0001Fasting insulin (µU/mL)16.2 ± 0.831.3 ± 1.550.4 ± 4.957.6 ± 9.6&amp;lt;0.0001Fasting FFA (mmol/L)0.25 ± 0.020.28 ± 0.010.35 ± 0.020.32 ± 0.020.001AT-IR (µU/mL x mmol/L)4.± 0.388.98 ± 0.6917.51 ± 1.9918.59 ± 3.00&amp;lt;0.0001 Disclosure J. Kim: None. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. H. Tfayli: None. S. Michaliszyn: None. S.A. Arslanian: None.

Serum fetuin-A levels in obese and non-obese subjects with and without type 2 diabetes mellitus

BackgroundHigher fetuin-A expression is linked to both obesity and type 2 diabetes mellitus (T2DM), However, studies in non-obese patients with T2DM are scarce. Methods345 newly diagnosed T2DM patients and 300 subjects with normal glucose tolerance (NGT) were divided into obese and non-obese subgroups, respectively. Serum fetuin-A and adiponectin levels and related parameters were measured. ResultsT2DM patients with obesity had higher fetuin-A levels compared with non-obese patients and obese NGT subjects (p<0.001). Significant correlations were observed between fetuin-A and most metabolic parameters in obese NGT and T2DM subjects, but which was not in non-obese patients with T2DM. The independent associations were found between fetuin-A and free fatty acids, HOMA-IR, C-reactive protein and adiponectin only in obese NGT and T2DM subjects (all p<0.05). The adjusted odds ratios for obesity were increased with increasing quartile of fetuin-A in both T2DM and NGT subjects in logistic regression models (p for trend<0.001), but which was more significant in T2DM patients. ConclusionHigher serum fetuin-A levels in obese T2DM patients compared with non-obese patients and obese NGT subjects supports the hypothesis that fetuin-A may be as a bridge connecting obesity and obesity-related T2DM.

Restoration of high-frequency glucose-entrained insulin oscillations in obese subjects with type 2 diabetes after biliopancreatic diversion

BackgroundMinimal glucose infusions are known to entrain insulin oscillations in patients with normal glucose tolerance (NGT) but not in patients with type 2 diabetes (T2D). ObjectivesTo investigate whether weight loss after a version of biliopancreatic diversion (BPD) can restore the glucose entrainment of high-frequency insulin oscillations in morbidly obese NGT or T2D patients. SettingUniversity Hospital, Greece. MethodsWe prospectively studied 9 NGT controls (body mass index [BMI] 23.3±1.6 kg/m2), 9 obese NGT patients (BMI 51.1±12.7 kg/m2), and 9 obese T2D patients (BMI 56.8±11.6 kg/m2). Patients were studied before and 1.5 years after BPD. Insulin was sampled every minute for 90 minutes. Glucose (6 mg/kg weight) was infused every 10 minutes for 1 minute. Regularity of insulin pulses was estimated by autocorrelation analysis, spectral analysis, approximate entropy/sample entropy (ApEn/SampEn), and insulin pulsatility by deconvolution analysis. ResultsPostoperatively, glucose and insulin concentrations of NGT and T2D patients decreased to control levels and BMI to 31.3±6.3 for NGT patients and 34.9±9.9 kg/m2 for T2D patients. Preoperatively, glucose entrainment was absent in all T2D and in 4 NGT patients as assessed with spectral analysis and in 8 and 4, respectively, as assessed with autocorrelation and deconvolution analysis. Postoperatively, it was restored to normal in all patients. ApEn/SampEn decreased significantly only in the T2D group postoperatively. ConclusionBPD restores the glucose entrainment of high-frequency insulin oscillations in obese NGT and T2D patients after marked weight loss and normalizes glucose levels and insulin sensitivity, thus demonstrating recovery of β-cell glucose sensing.

Relationship of Adipokines and Proinflammatory Cytokines Among Asian Indians With Obesity and Youth Onset Type 2 Diabetes

It is well known that inflammation is associated with diabetes, but it is unclear whether obesity mediates this association in individuals with youth-onset type 2 diabetes mellitus (T2DM-Y). We recruited individuals with T2DM-Y (age at onset <25 years) and age-matched normal glucose tolerance (NGT) subjects. Participants were further classified using Asia-Pacific body mass index cut-points for obesity and categorized as: nonobese NGT (n = 100), Obese NGT (n = 50), nonobese T2DM-Y (n = 50), and obese T2DM-Y (n = 50). We compared adipokines (adiponectin and leptin) and proinflammatory cytokines (tumor necrosis factor alpha [TNF-α] and monocyte chemotactic protein-1 [MCP-1]) across groups. Compared to nonobese NGT, the other 3 groups (obese NGT, nonobese T2DM-Y, and obese T2DM-Y) were found to have lower adiponectin (7.7 vs. 5.7, 4.2, 3.8 μg/mL, P<.01), and higher leptin (3.6 vs. 5.4, 5.7, 7.9 μg/mL, P<.001) and MCP 1 (186 vs. 272, 340, 473 pg/mL, P<.001) respectively. However, TNF-α levels were higher only among nonobese T2DM-Y (112 pg/mL) and obese T2DM-Y (141 pg/mL, P<.01 for each). After adjusting for age, sex, waist, hypertension, homeostatic model assessment of insulin resistance (HOMA-IR), serum cholesterol, triglycerides, and family history of diabetes, adiponectin was associated with 33% and 41% lower odds of being nonobese T2DM and obese T2DM, respectively. However, adjusted for same factors, leptin, TNF-α, and MCP-1 were associated with markedly higher odds (5- to 14-fold) of nonobese and obese T2DM. In young Asian Indians, leptin and proinflammatory cytokines are positively, and adiponectin negatively, associated with both nonobese and obese T2DM-Y compared to nonobese NGT individuals.

Effects of Roux-en-Y gastric bypass on fasting and postprandial inflammation-related parameters in obese subjects with normal glucose tolerance and in obese subjects with type 2 diabetes.

BackgroundObesity is characterized by low grade inflammation and an altered secretion of inflammatory cytokines from the adipose tissue. Weight loss has shown to reduce inflammation; however, changes in cytokine profiles during massive weight loss are not well described. The present study explored the hypothesis that Roux-en-Y gastric bypass (RYGB) reduces circulating levels of pro-inflammatory cytokines, while increasing anti-inflammatory cytokines in obese subjects with type 2 diabetes (T2D) and in obese normal glucose tolerant (NGT) subjects.MethodsThirteen obese subjects with T2D [weight; 129 ± 14 kg, glycated hemoglobin (HbA1c); 7.0 ± 0.9%, body mass index (BMI); 43.2 ± 5.3 kg/m2, mean ± SD] and twelve matched obese NGT subjects [weight; 127 ± 15 kg, HbA1c; 5.5 ± 0.4%, BMI; 41.5 ± 4.8 kg/m2, mean ± SD] were examined before, one week, three months, and one year after surgery. Interleukin (IL)-6, leptin, adiponectin, IL-8, transforming growth factor beta (TGF-β), and the incretin hormone glucagon-like peptide-1 (GLP-1) were measured in the fasting state and during a liquid meal. Insulin resistance was evaluated by HOMA-IR.ResultsWeight loss did not differ between the two groups. Before surgery, HbA1c was higher and HOMA-IR lower in T2D patients, however, converged to the values of NGT subjects one year after surgery. Circulating cytokine concentrations did not differ between the two groups at any time point. One week after surgery, circulating IL-6 and IL-8 were increased, while adiponectin and leptin were reduced compared with pre-surgical concentrations. Three months after surgery, IL-8 was increased, leptin was reduced, and no change was observed for IL-6, TGF-β, and adiponectin. One year after surgery, concentrations of IL-6, TGF-β, and leptin were significantly reduced compared to before surgery, while adiponectin was significantly increased.ConclusionsOne year after RYGB, fasting concentrations of IL-6 and leptin were reduced, while no changes were observed in IL-8. TGF-β was decreased and adiponectin increased in both T2D and NGT obese subjects. This study is the first to examine IL-8 and TGF-β in obese subject after RYGB. Resolution of inflammation could offer a potential explanation for the health improvement associated with major weight loss after bariatric surgery.Trial registrationhttp://www.clinicaltrials.gov (NCT01579981).

Myostatin in the placentae of pregnancies complicated with gestational diabetes mellitus

IntroductionGestational diabetes mellitus (GDM) is characterised by maternal glucose intolerance and insulin resistance during pregnancy. Myostatin, initially identified as a negative regulator of muscle development may also function in the regulation of placental development and glucose uptake. Myostatin expression in placentae of GDM complicated pregnancies is unknown. However, higher myostatin levels occur in placentae of pregnancies complicated with preeclampsia. We hypothesise that myostatin will be differentially expressed in GDM complicated pregnancies. MethodsMyostatin concentrations (ELISA) were evaluated in plasma of presymptomatic women who later developed GDM and compared to plasma of normal glucose tolerant (NGT) women. Furthermore, myostatin protein expression (Western blot) was studied in placentae of pregnant women with GDM (treated with diet or insulin) compared to placentae of NGT women. ResultsNo significant difference in myostatin concentration was seen in plasma of pre-symptomatic GDM women compared to NGT women. In placenta significant differences in myostatin protein expressions (higher precursor; p < 0.05and lower dimer: p < 0.005) were observed in GDM complicated compared to NGT pregnancies. Furthermore, placentae of GDM women treated with insulin compared to diet have higher dimer (p < 0.005) and lower precursor (p < 0.05). Compared to lean women, placentae of obese NGT women were lower in myostatin dimer expression (p < 0.05). DiscussionMyostatin expression in placental tissue is altered under stress conditions (e.g. obesity and abnormal glucose metabolism) found in pregnancies complicated with GDM. We hypothesise that myostatin is active in these placentae and could affect glucose homoeostasis and/or cytokine production thereby altering the function of the placenta.

Chronic Reduction of Plasma Free Fatty Acid Improves Mitochondrial Function and Whole-Body Insulin Sensitivity in Obese and Type 2 Diabetic Individuals

Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) 1H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.

Autonomic nervous system activity in diabetic and healthy obese female subjects and the effect of distinct weight loss strategies

Obesity and type 2 diabetes mellitus (T2DM) are reported to be associated with relative overactivity of the sympathetic nervous system (SNS), which is reversible by weight loss. However, direct effects of weight loss by calorie restriction vs Roux-en-Y gastric bypass (RYGB) on SNS overactivity were not studied in parallel. This study compared the effects of RYGB vs restrictive weight loss in obese patients with normal glucose tolerance (NGT) and with T2DM on SNS function as measured by heart rate variability (HRV). Lean (n=12), obese NGT (n=27) and T2DM (n=27) subjects were included in this study. Weight reduction in NGT subjects was achieved by gastric banding (GB) or RYGB and in T2DM subjects by RYGB or high-protein very-low-calorie diet (VLCD). HRV analysis was performed and blood samples were taken at baseline, 3 weeks and 3 months after intervention. At baseline, T2DM subjects showed SNS overactivity and NGT subjects showed similar, but non-significant, findings when compared with lean controls. Weight loss after 3 weeks was comparable in all treatment groups, whereas after 3 months, weight loss was most in VLCD and RYGB subjects. RYGB and VLCD treatment reduced SNS activity within 3 weeks in T2DM patients. After 3 months, restoration to normal autonomic nervous system activity was evident for all groups, except for the NGT-GB group. We can conclude that SNS overactivity is more pronounced in obese T2DM subjects when compared with NGT subjects. Reduction of SNS overactivity coincides with weight loss with the time-course of reduction dependent on the type of intervention. Surgery or caloric restriction may transiently induce SNS overactivity but do not prevent a direct restoration of sympathovagal balance.

Genetic association of adrenergic receptor alpha 2A with obesity and type 2 diabetes

The sympathetic nervous system (SNS) is linked to glucose, lipid, and protein metabolism. The α2A -adrenergic receptor (ADRA2A) is involved in the SNS and mediates inhibition of insulin secretion and lipolysis. The association of ADRA2A single-nucleotide polymorphisms (SNPs) with obesity and/or type 2 diabetes (T2D) was investigated. Genotyping was performed in a case-control study of 1,177 Swedish individuals, including lean and obese subjects with normal glucose tolerance (NGT) and T2D patients. ADRA2A mRNA expression was measured in pancreatic islets isolated from T2D patients and nondiabetic subjects. SNP rs553668 was associated with T2D in men (odds ratio [OR] = 1.47; 95% confidence interval [CI] = 1.08-2.01; P = 0.015) but this association was lost after adjusting for age and for body mass index (BMI). Associations were also detected when comparing obese NGT and lean NGT subjects (OR = 1.49; 95% CI = 1.07-2.07; P = 0.017), and in obese (OR = 1.62; 95% CI = 1.06-2.49; P = 0.026), but not in lean T2D. In women, multiple logistic regression regarding SNP rs521674 demonstrated an increased OR of 7.61 (95% CI = 1.70-34.17; P = 0.008) for T2D when including age as a covariant. Correcting for BMI removed the significant association. When age was included in the model, association also found when obese T2D patients were compared with lean NGT subjects (P = 0.041). ADRA2A mRNA expression in human pancreatic islets was detectable, but with no statistically significant difference between the diabetic and the control groups. ADRA2A genetic polymorphisms are mainly associated with obesity and possibly with T2D in a Swedish population.

Changes of blood glucose and gastrointestinal hormones 4months after Roux-en-Y gastric bypass surgery in Chinese obese type2 diabetes patients with lower body mass index.

The goal of this study was to evaluate the effect of Roux-en-Y gastric bypass (RYGB) on hyperglycemia and gastrointestinal hormones in Chinese obese type 2 diabetic patients with body mass index (BMI) between 28 and 35kg/m(2). A total of eight obese type 2 diabetes patients with BMI 28-35kg/m(2) who underwent RYGB and 10 obese normal glucose tolerance (NGT) patients with no surgery were identified. BMI and blood glucose on baseline, and 2-4months postoperative, changes of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), and oxyntomodulin (OXM) were recorded. Efficacy of RYGB was defined by the percentage of excess weight loss (%EWL) and amelioration of type 2 diabetes. The %EWL was 53.00±26.25% in 2month and 63.65±33.71% in 4month. Glycated hemoglobin changed from 7.2±1.0% preoperative to 6.2±0.9% in 2month and 6.3±1.2% in 4month postoperative. The improvement rate of type 2 diabetes 4 months after RYGB was 83.3%. After surgery, area under the curve (AUC) GLP-1 120 increased with no significance. AUC PYY 120 changed from 10.37±5.45pmol/L/min preoperative to 22.19±10.61pmol/L/min in 2month and 22.04±7.73pmol/L/min in 4month postoperative. Postoperative AUC OXM 120 was also higher than that of the preoperative level. AUC GIP 120 decreased from 13.06±8.45pg/mL/min preoperative to 8.71±3.28pg/ml/min in 2month and 6.88±2.33pg/mL/min in 4month postoperative. Roux-en-Y gastric bypass has a beneficial effect on weight loss and glucose metabolism in obese type 2 diabetes patients with lower BMI. Postoperative concentrations of GLP-1, PYY and OXM increased, whereas GIP decreased.

Retinol-binding protein 4 is associated with impaired glucose tolerance but not with whole body or hepatic insulin resistance in Mexican Americans

Retinol-binding protein-4 (RBP4), a novel protein secreted mainly by adipose tissue, has been associated with insulin resistance in obese subjects and in individuals with type 2 diabetes mellitus (T2DM). We examined the relationship between plasma RBP4 levels, expression of RBP4 in skeletal muscle and adipose tissue, and insulin sensitivity in Mexican Americans with varying degrees of obesity and glucose tolerance. Seventy-two subjects [16 lean normal-glucose-tolerant (NGT), 17 obese NGT, and 39 subjects with impaired fasting glucose/impaired glucose tolerance/T2DM] received an oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp. Insulin secretion was measured as insulinogenic index during OGTT. In a subset of subjects, hepatic glucose production was measured by 3-[3H]glucose infusion, biopsies of the vastus lateralis muscle and subcutaneous adipose tissue were obtained under basal conditions, and quantitative RT-PCR was performed to measure the RBP4 mRNA gene expression. Plasma RBP4 was significantly elevated in impaired glucose tolerance/T2DM compared with NGT lean or obese subjects. Plasma RBP4 levels correlated with 2-h glucose, triglycerides, and hemoglobin A1c. There was no association between RBP4 levels and whole body insulin sensitivity measured with either the euglycemic insulin clamp or OGTT, basal hepatic glucose production rates, and the hepatic insulin resistance index. There was no correlation between plasma RBP4 levels and indexes of insulin secretion. RBP4 mRNA expression in skeletal muscle was similar in lean NGT subjects, obese NGT subjects, and T2DM subjects. There was no difference in RBP4 mRNA expression in adipose tissue between lean and obese NGT subjects or between NGT and T2DM individuals. Plasma RBP4 levels are elevated in T2DM and associated with impaired glucose tolerance, but not associated with obesity or insulin resistance or impaired insulin secretion in Mexican Americans.

The Normal Glucose Tolerance Continuum in Obese Youth: Evidence for Impairment in β-Cell Function Independent of Insulin Resistance

Normal glucose tolerance is expressed over a wide range of glucose concentrations. Whether there is a continuum of risk for developing type 2 diabetes mellitus even when the 2-h plasma glucose is still within this normal range is uncertain. Oral glucose tolerance tests were performed in 407 obese normal glucose tolerance youth (4-20 yr) to examine the relationship between variations in 2-h plasma glucose levels and beta-cell responsiveness. Individuals were grouped by 2-h plasma glucose levels as follows: 1) less than 100 mg/dl, 2) 100-119 mg/dl, and 3) 120-139 mg/dl. Subsequent analysis stratified each 2-h plasma level by insulin sensitivity index. Increased 2-h glucose level was associated with a progressive increase in glucose between 0 and 30 min (P < 0.05). The Delta (0-30 min) insulin did not vary significantly across levels, thus resulting in a decreased insulinogenic index (P < 0.02). This pattern was observed at every level of insulin sensitivity (P < 0.02). These data translated to an unfavorable (leftward) shift in the insulin feedback system for increasing 2-h glucose level (P < 0.005). Increased 2-h plasma glucose within the range of normal glucose tolerance in obese youth is associated with a specific impairment of beta-cell responsiveness distinct from the deterioration of insulin sensitivity.

Beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis.

The nature of the progressive beta-cell failure occurring as normal glucose tolerant (NGT) individuals progress to type 2 diabetes (T2DM) is incompletely understood. We measured insulin sensitivity (by a euglycemic insulin clamp) and insulin secretion rate (by deconvolution of plasma C-peptide levels during an oral glucose tolerance test) in 188 subjects [19 lean NGT (body mass index [BMI] </= 25 kg/m(2)), 42 obese NGT, 22 BMI-matched impaired glucose tolerance [IGT], and 105 BMI-matched T2DM]. Main determinants of beta-cell function on the oral glucose tolerance test were derived from a mathematical model featuring the following: 1) glucose concentration-insulin secretion dose response (glucose sensitivity), 2) a secretion component proportional to the derivative of plasma glucose concentration (rate sensitivity); and 3) a potentiation factor. When NGT and T2DM were subgrouped by 2-h plasma glucose concentrations, insulin secretion rate revealed an inverted U-shaped pattern, rising through NGT up to IGT and falling off thereafter. In contrast, beta-cell glucose sensitivity dropped in a monophasic, curvilinear fashion throughout the range of 2-h plasma glucose. Within the NGT range (2-h glucose of 4.1-7.7 mmol/liter), beta-cell glucose sensitivity declined by 50-70% (P < 0.02). Insulin sensitivity decreased sharply in the transition from lean to obese NGT and then declined further in IGT and mild T2DM to level off in the higher three quartiles of diabetic hyperglycemia. In T2DM, defective beta-cell potentiation and rate sensitivity also emerged (P </= 0.05). In the whole data set, insulin sensitivity and the dynamic parameters of beta-cell function explained 89% of the variability of 2-h plasma glucose levels. The following conclusions were reached: 1) beta-cell glucose sensitivity falls already within the NGT range in association with rising 2-h plasma glucose concentrations, although absolute insulin secretion rates increase; and 2) throughout the glucose tolerance range, dynamic parameters of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) and insulin sensitivity are independent determinants of 2-h plasma glucose levels.

Specific insulin and proinsulin in normal glucose tolerant first-degree relatives of NIDDM patients.

In order to identify early abnormalities in non-insulin-dependent diabetes mellitus (NIDDM) we determined insulin (using an assay that does not cross-react with proinsulin) and proinsulin concentrations. The proinsulin/insulin ratio was used as an indicator of abnormal beta-cell function. The ratio of the first 30-min increase in insulin to glucose concentrations following the oral glucose tolerance test (OGTT; I30-0/G30-0) was taken as an indicator of insulin secretion. Insulin resistance (R) was evaluated by the homeostasis model assessment (HOMA) method. True insulin and proinsulin were measured during a 75-g OGTT in 35 individuals: 20 with normal glucose tolerance (NGT) and without diabetes among their first-degree relatives (FDR) served as controls, and 15 with NGT who were FDR of patients with NIDDM. The FDR group presented higher insulin (414 pmol/l vs 195 pmol/l; P = 0.04) and proinsulin levels (19.6 pmol/l vs 12.3 pmol/l; P = 0.03) post-glucose load than the control group. When these groups were stratified according to BMI, the obese FDR (N = 8) showed higher fasting and post-glucose insulin levels than the obese NGT (N = 9) (fasting: 64.8 pmol/l vs 7.8 pmol/l: P = 0.04, and 60 min post-glucose: 480.6 pmol/l vs 192 pmol/l: P = 0.01). Also, values for HOMA (R) were higher in the obese FDR compared to obese NGT (2.53 vs 0.30; P = 0.075). These results show that FDR of NIDDM patients have true hyperinsulinemia (which is not a consequence of cross-reactivity with proinsulin) and hyperproinsulinemia and no dysfunction of a qualitative nature in beta-cells.