Water intake, thirst, and copeptin responses to two dehydrating stimuli in lean men and men with obesity.

OBJECTIVE: Physiological systems responsible for water homeostasis and energy metabolism are interconnected. This study hypothesized altered responses to dehydration including thirst, ad libitum water intake, and copeptin in men with obesity. METHODS: Forty-two men (22 lean and 20 with obesity) were stimulated by a 2-hour hypertonic saline infusion and a 24-hour water deprivation. In each dehydrating condition, thirst, ad libitum water intake after dehydration, and urinary and hormonal responses including copeptin were assessed. RESULTS: After each dehydration condition, ad libitum water intake was similar between both groups (p > 0.05); however, those with obesity reported feeling less thirsty (p < 0.05) and had decreased copeptin response and higher urinary sodium concentrations when stressed (p < 0.05). Angiotensin II, aldosterone, atrial and brain natriuretic peptides, and apelin concentrations did not differ by adiposity group and did not explain the different thirst or copeptin responses in men with obesity. However, leptin was associated with copeptin response in lean individuals during the hypertonic saline infusion (p < 0.05), but the relationship was diminished in those with obesity. CONCLUSIONS: Diminished thirst and copeptin responses are part of the obesity phenotype and may be influenced by leptin. Adiposity may impact pathways regulating thirst and vasopressin release, warranting further investigation.

Type 2 diabetes after gastric bypass: remission in five models using HbA1c, fasting blood glucose, and medication status.

BACKGROUND: The remission rates of type 2 diabetes mellitus (T2DM) after Roux-en-Y gastric bypass (RYGB) vary according to the glycosylated hemoglobin A1c (HbA1c), fasting blood glucose (FG), and medication status. Our objectives were to describe remission using the American Diabetes Association standards for defining normoglycemia and to identify the factors related to the preoperative severity of T2DM that predict remission to normoglycemia, independent of weight loss, after RYGB. The setting was an urban not-for-profit community hospital. METHODS: We performed a retrospective analysis of prospectively collected data from a cohort of 2275 patients who qualified for bariatric surgery (2001-2008). Five different models for defining remission (no diabetes medication and a FG <100 mg/dL; no diabetes medication and HbA1c <6.0; no diabetes medication and HbA1c <5.7%; no diabetes medication, FG <100 mg/dL, and HbA1c <6.0%; and no diabetes medication, FG <100 mg/dL, and HbA1c <5.7%) were compared in 505 obese patients with T2DM 14 months after RYGB. The secondary aims were to determine the effects of preoperative insulin therapy and the duration of known T2DM on remission. RESULTS: Of the 505 patients, 43.2% achieved remission using the most stringent criteria (no diabetes medication, HbA1c <5.7%, and FG <100 mg/dL) compared with 59.4% using the most liberal definition (no diabetes medication and FG <100 mg/dL; P < .001). The remission rates were greater for patients not taking insulin preoperatively (53.8% versus 13.5%, P < .001) and for patients with a more recent preoperative T2DM diagnosis (8.9 versus 3.7 yr, P < .001). CONCLUSION: Remission, defined at a threshold less than what would be expected to result in microvascular damage, was achieved in 43.2% of diabetic patients by 14 months after RYGB. A more recent diagnosis of T2DM and the absence of preoperative insulin therapy were significant predictors, regardless of how remission was defined, independent of the percentage of excess weight loss.

Short-term isocaloric manipulation of carbohydrate intake: effect on subsequent ad libitum energy intake.

BACKGROUND: Isocaloric manipulation of carbohydrate or fat intake could alter subsequent ad libitum food intake. METHODS: In a controlled inpatient study, we investigated whether isocaloric manipulation of carbohydrate or fat would alter subsequent ad libitum energy intake. Eighteen non-diabetic subjects (age range 19-53 years.; 15 M/3F; % body fat 38.5 ± 9.1 (mean ± SD)) were fed for 3 days an isocaloric high-carbohydrate diet (HC; 60% carbohydrate, 20% fat, 20% protein) and a high-fat diet (HF; 50% fat, 30% carbohydrate, 20% protein) in random order each followed by 3 days of ad libitum food intake. RESULTS: There were no differences in mean daily energy intake (EI) following each diet (HC vs. HF: 4,811 ± 1,190 vs. 4,823 ± 1,238 kcal/d; P = 0.7) or in the percent of weight maintenance energy needs (%EN-WM; 173 ± 41 vs. 173 ± 46%, P = 0.5). However, the individual difference in EI between the HF versus HC diet (ΔEI) both on day one and over the 3 days of each ad libitum period was negatively associated with % body fat (%BF) and waist circumference (day 1: ΔEI vs. %BF, r = -0.49, P = 0.04; mean day 1-3 kcal ΔEI vs. %BF, r = -0.66, P = 0.003, and ΔEI vs. waist, r = -0.65, P = 0.004). CONCLUSIONS: A short-term isocaloric HC diet did not result in overall lower EI compared with a HF diet in the same individuals. However, we did find that increasing body fat was associated with less decline in EI following the HC versus HF diet indicating that increasing adiposity is associated with altered regulation of EI in response to macronutrient changes.

Effect of paternal diabetes on pre-diabetic phenotypes in adult offspring.

OBJECTIVE: Paternal and maternal type 2 diabetes, exclusive of gestational diabetes, may influence risk factors in the offspring differently (through possible epigenetic effects of parental diabetes) and are difficult to identify without accurate dates of diagnosis. We aimed to examine a metabolic phenotype in three different groups of offspring to see distinct paternal versus maternal effects. RESEARCH DESIGN AND METHODS: We examined body composition and insulin action (M) in nondiabetic subjects and insulin secretion tested via acute insulin response (AIR) in normal glucose-tolerant full-heritage Pima Indian adults categorized by disparate parental diabetes status: 1) offspring of fathers with early-onset diabetes (age <35 years) and nondiabetic mothers (ODF; n = 10), 2) offspring of mothers with early-onset diabetes (age <35 years), not exposed to diabetes in utero with nondiabetic fathers (OMED; n = 11), and 3) a control group of offspring of parents without diabetes until >50 years of age (CON; n = 15). RESULTS: ODFs were leaner than CONs and OMEDs (percent of body fat [%BF]: least-squares means adjusted for age and sex [95% CI]: 27.3 [23.3-31.3] in ODFs vs. 35.4 [32.2-38.5] in CONs and 32.4 [28.8-36.1] in OMEDs, P = 0.04). ODFs were more insulin sensitive (had a higher M) than OMEDs or CONs, but not after adjustment for age, sex, and %BF. AIR adjusted for M, age, sex, and %BF was lower in ODFs versus CONs and OMEDs (P < 0.05). CONCLUSIONS: Adult ODFs were leaner and had lower early insulin secretion, despite being equally insulin sensitive after adjustment for body fat compared to the other groups, indicating a paternal imprinted effect.

Assessment of non-insulin-mediated glucose uptake: association with body fat and glycemic status.

In the fasting state, approximately 83% of glucose uptake occurs via non-insulin-mediated mechanisms. A widely accepted static rate for NIMGU is 1.62 mg kg(-1)·min(-1). To investigate the variability of NIMGU, we examined differences by glucose tolerance, sex, age, race (American Indian/African American/Caucasian), and adiposity in 616 volunteers (including individuals with normal glucose regulation [NGR] and impaired glucose regulation [IGR] and diabetes mellitus [DM]) using data from euglycemic-hyperinsulinemic clamp experiments. NIMGU was determined by plotting basal glucose output and insulin action against fasting and steady-state clamp insulin. The intercept with the y-axis after extrapolation was interpreted as NIMGU at zero insulin. Body composition was determined by dual-energy x-ray absorptiometry; and glucose regulation, by a 75-g oral glucose tolerance test. Energy expenditure was measured by indirect calorimetry in a metabolic chamber. In individuals with NGR (n = 385), NIMGU was 1.63 mg kg(estimated metabolic body size (fat free mass + 17.7 kg))(-1) min(-1) (95% confidence interval, 1.59-1.66). NIMGU increased with IGR and DM (IGR: n = 189, 1.67 [1.62-1.72]; DM: n = 42, 2.39 [2.29-2.49]; P < .0001 across groups). NIMGU did not differ by sex (P = .13), age (P = .22), or race (P = .06); however, NIMGU was associated with percentage body fat (r(2) = 0.04, P < .0001). Furthermore, NIMGU was positively associated with 24-hour and sleep energy expenditure (r(2) = 0.002, P = .03; r(2) = 0.01, P < .01). Extrapolated NIMGU in individuals with NGR is remarkably consistent with previously published data. Our results indicate that NIMGU is associated with adiposity. NIMGU increases with declining glucose tolerance perhaps to preserve glucose uptake during increased insulin resistance.

Repeatability and reproducibility of the hyperinsulinemic-euglycemic clamp and the tracer dilution technique in a controlled inpatient setting.

The objective of the study was to evaluate the reproducibility and repeatability of the combined use of the hyperinsulinemic-euglycemic (H-E) clamp and tracer dilution techniques. Ten nondiabetic men underwent a low-dose (40 mU/[m(2) min]) H-E clamp that was repeated within 3 to 4 days using porcine or human insulin in a double-blinded, randomized, crossover design. Coefficients of variation (CVs) for intraindividual differences and repeatability coefficient were calculated to evaluate reproducibility and repeatability. The Bland and Altman method was used to quantify repeatability. The CVs for intraindividual differences were 5.7% +/- 3.5% for steady-state (SS) insulin; 6.7% +/- 6.2% and 54.2 +/- 38.3% for basal and SS endogenous glucose product (EGP), respectively; and 10.3% +/- 8.5% for total insulin-stimulated glucose disposal (M) values. Basal EGP, SS EGP, and SS glucose and insulin concentrations were similar for the 2 clamps; but glucose infusion rate (P = .02) and M (borderline significant, P = .06) were higher in the first clamp than the second clamp. No significant correlations between mean of differences and average of basal and SS EGP, SS insulin concentration, and M between the 2 clamps were observed. We also found that the different values were less than the repeatability coefficients of these parameters and that the 95% limits of agreement and the interval of repeatability coefficient of these parameters were similar. There were no differences in metabolic responses between clamps when compared by the type of insulin (porcine vs human) infused. Our findings indicate that, although SS EGP has a high CV, the clamp, which measures insulin action (ie, SS insulin, M), and the tracer dilution technique for assessing basal EGP are repeatable and reproducible. Decreased glucose infusion rate and M over a short period in the second clamp may reflect an accumulative effect of continued physical inactivity.

Childhood predictors of adult acute insulin response and insulin action.

OBJECTIVE: Because declines in acute insulin response (AIR) and insulin action (M) predict development of type 2 diabetes, we sought to determine childhood factors that predict insulin action and AIR using longitudinal data from young Pima Indian adults with normal glucose regulation. RESEARCH DESIGN AND METHODS: Predictors of adult M, measured by the euglycemic-hyperinsulinemic clamp, and AIR, measured after a 25-g glucose bolus, were assessed in 76 individuals from a set of childhood data (BMI, systolic blood pressure [sBP] and diastolic blood pressure, cholesterol, fasting and 2-h insulin, and glucose levels during an oral glucose tolerance test). RESULTS: After adjustment for sex, adult percent body fat, adult and childhood age, childhood BMI, and sBP were negative and independent predictors of adult M. A 5 kg/m(2) increase in childhood BMI was associated with a 7.4% decrease in adult insulin action (95% CI -12.7 to -1.8%, P = 0.01) and a 10-mmHg increase in childhood sBP with a 5.0% decrease in adult M (95% CI -8.4 to -1.4%, P = 0.007). After a similar adjustment with M as an additional covariate, childhood 2-h insulin was a positive predictor of adult AIR such that a 25% increase predicted a 7.3% increase in adult AIR (95% CI 1.5-13.5%, P = 0.014). CONCLUSIONS: Childhood insulin response during an oral glucose challenge predicts adult AIR, indicating that beta-cell capacity may be set early in life. Childhood measures related to adiposity predict adult insulin action, which may reflect common underlying mechanisms that may be amenable to modification through programs targeting prevention or treatment of childhood obesity.

Distribution of subcutaneous fat predicts insulin action in obesity in sex-specific manner.

The pattern of adipose tissue (AT) distribution is an important predictor of metabolic risk. The aim of this study was to analyze the association of peripheral (insulin-mediated glucose disposal--M) and hepatic (suppression of endogenous glucose production--EGP) insulin action with abdominal (subcutaneous abdominal AT-SAAT intraabdominal AT-IAAT) and thigh AT depots in obese individuals. Fifty-seven Pima Indians with normal glucose tolerance underwent magnetic resonance imaging (MRI) and euglycemic-hyperinsulinemic clamp. M was negatively related to intraperitoneal IAAT (P = 0.02) and deep SAAT (P = 0.03). Suppression of EGP was negatively related to total (P < 0.05) or deep SAAT (P < 0.05 and P = 0.01, respectively), and total or intraperitoneal IAAT (P = 0.009 and P = 0.002, respectively). A significant interaction with sex was found in the association between superficial SAAT and M, so that in women, but not men, M negatively correlated with superficial SAAT (P = 0.02). In stepwise regression analysis, both M (r2 = 0.09) and EGP suppression (r2 = 0.17) were associated only with intraperitoneal IAAT in the whole group. In the sex-specific analysis (because of the significant interaction), lower M was associated with higher deep SAAT (r2 = 0.15) in combination with lower superficial SAAT (r2 = 0.09) in men, and with higher superficial SAAT (r2 = 0.29) in combination with lower thigh subcutaneous AT (r2 = 0.16) in women. Although intraperitoneal IAAT and deep SAAT were major predictors of peripheral and hepatic insulin action in obese Pima Indians, the largest variance in M rate was explained in a sex-specific manner by relative size of subcutaneous AT depots.

Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals.

BACKGROUND: Enlargement of adipocytes from subcutaneous abdominal adipose tissue (SAT), increased intrahepatic lipid content (IHL), intramyocellular lipid content (IMCL), and low circulating adiponectin concentrations are associated with insulin resistance. OBJECTIVE: Because adiponectin increases fat oxidation in skeletal muscle and liver, and the expression of the adiponectin gene in SAT is inversely associated with adipocyte size, we hypothesized that hypoadiponectinemia links hypertrophic obesity with insulin resistance via increased IMCL and IHL. DESIGN: Fifty-three obese Pima Indians with a mean (+/-SD) age of 27 +/- 8 y, body fat of 35 +/- 5%, and normal glucose regulation (normal fasting and 2-h glucose concentration per WHO 1999 criteria) underwent euglycemic-hyperinsulinemic clamp, biopsies of SAT and vastus lateralis muscle, and magnetic resonance imaging of the abdomen. RESULTS: Adipocyte diameter (AD) correlated positively with body fat (P < 0.0001) and IHL (estimated from magnetic resonance imaging intensity of liver; P = 0.047). No association was found between AD and plasma adiponectin or IMCL. Plasma adiponectin negatively correlated with type II IMCL (IIA, P = 0.004; IIX, P = 0.009) or IHL (P = 0.02). In a multivariate analysis, plasma adiponectin, AD, and visceral adipose tissue (VAT) independently predicted IHL. Low insulin-mediated glucose disposal was associated with low plasma adiponectin (P = 0.02) and high IHL (P = 0.0003), SAT (P = 0.02), and VAT (P = 0.04). High IHL was the only predictor of reduced insulin-mediated suppression of hepatic glucose production (P = 0.02) and the only independent predictor of insulin-mediated glucose disposal in a multivariate analysis. CONCLUSIONS: Increased lipid content in the liver may independently link hypoadiponectinemia, hypertrophic obesity, and increased visceral adiposity with peripheral and hepatic insulin resistance.

Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals.

BACKGROUND: Thyroid hormones (TH) may influence glucose metabolism. Hyperthyroid subjects have higher insulin secretion rates when compared with euthyroid individuals. OBJECTIVE: To evaluate the association between TH concentrations and insulin secretion in euthyroid, healthy Pima Indian adults (n=55, 29+/-7 years, females/males 36/19) with normal glucose tolerance (NGT) admitted to a Clinical Research Unit. METHODS: TSH, free thyroxine (FT4), 3,5,3'-L-tri-iodothyronine (FT3), and fasting plasma insulin (FPI) concentrations were measured in fasting plasma samples, percentage of body fat (%BF) by dual energy x-ray absorptiometry (DXA), acute insulin response (AIR), and incremental area under the curve (AUC) of insulin in response to a 25 g intravenous glucose tolerance test (IVGTT) and 75 g oral glucose tolerance test (OGTT) respectively and insulin action (M) during an euglycemic clamp. RESULTS: FT3 concentrations were associated with FPI, AIR, and insulin AUC both before (r=0.33, P=0.01; r=0.29, P=0.03; and r=0.35, P=0.008 respectively) and after adjustment for age, sex, %BF, glucose (fasting concentrations or glucose AUC), and M (beta=0.09, P=0.01; beta=0.16, P=0.03; and beta=0.24, P=0.0007 respectively). No associations were found for TSH or FT4. CONCLUSION: FT3 was associated with several measurements of insulin secretion in euthyroid individuals with NGT. T3 concentrations may play a role in the regulation of insulin secretion.

Palmitate action to inhibit glycogen synthase and stimulate protein phosphatase 2A increases with risk factors for type 2 diabetes.

Recent studies have suggested that abnormal regulation of protein phosphatase 2A (PP2A) is associated with Type 2 diabetes in rodent and human tissues. Results with cultured mouse myotubes support a mechanism for palmitate activation of PP2A, leading to activation of glycogen synthase kinase 3. Phosphorylation and inactivation of glycogen synthase by glycogen synthase kinase 3 could be the mechanism for long-chain fatty acid inhibition of insulin-mediated carbohydrate storage in insulin-resistant subjects. Here, we test the effects of palmitic acid on cultured muscle glycogen synthase and PP2A activities. Palmitate inhibition of glycogen synthase fractional activity is increased in subjects with high body mass index compared with subjects with lower body mass index (r = -0.43, P = 0.03). Palmitate action on PP2A varies from inhibition in subjects with decreased 2-h plasma glucose concentration to activation in subjects with increased 2-h plasma glucose concentration (r = 0.45, P < 0.03) during oral glucose tolerance tests. The results do not show an association between palmitate effects on PP2A and glycogen synthase fractional activity. We conclude that subjects at risk for Type 2 diabetes have intrinsic differences in palmitate regulation of at least two enzymes (PP2A and glycogen synthase), contributing to abnormal insulin regulation of glucose metabolism.

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

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

Glucose response to an oral glucose tolerance test predicts weight change in non-diabetic subjects.

OBJECTIVE: Glucose exerts a dual action in the regulation of energy balance, consisting of inhibition of energy intake and stimulation of energy expenditure. Whether blood glucose affects long-term regulation of body weight in humans remains to be established. We sought to test the hypothesis that the post-challenge glucose response is a predictor of weight change. RESEARCH METHODS AND PROCEDURES: We performed a prospective analysis of the impact of glucose response to an oral glucose tolerance test (OGTT) and a mixed-meal test (MT) on subsequent changes in body weight (BW) on 253 Pima Indians (166 men and 87 women) with normal glucose regulation at baseline and follow-up (follow-up: 7 +/- 4 years). Main outcome measures included BW change (total, percent, and annual), plasma glucose and insulin concentrations during OGTT and MT [total and incremental areas under the curve (AUCs)], resting metabolic rate (RMR; indirect calorimetry), and insulin action (euglycemic-hyperinsulinemic clamp). RESULTS: Total and incremental glucose AUCs during the OGTT (but not the MT) were negatively associated with BW change (total, percent, and annual), both before and after adjusting for sex, age, initial BW, follow-up time, insulin action, RMR, fasting plasma glucose and insulin concentrations, and insulin response. Total and incremental glucose AUCs during the OGTT were independent determinants of final BW with age, initial BW, follow-up time, fasting plasma insulin concentrations, and RMR. DISCUSSION: Higher post-challenge glucose response protects against BW gain in subjects with normal glucose regulation. We propose that this action may be because of the effect of glucose on food intake and/or thermogenesis.

Acute insulin response is an independent predictor of type 2 diabetes mellitus in individuals with both normal fasting and 2-h plasma glucose concentrations.

BACKGROUND: Earlier prospective studies have identified insulin action and secretion as predictors of T2DM in populations with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) (2-h OGTT < 7.8 and 7.8-11 mmol/L, respectively). Fasting plasma glucose (FPG), an additional and recently modified (normal <5.6 mmol/L) diagnostic criterion is associated with insulin secretion. We wanted to establish whether insulin secretion persists as an independent predictor of T2DM in individuals with no clinical evidence of impaired glucose regulation based on FPG and 2-h plasma glucose concentrations. METHODS: Insulin action (M, euglycemic-hyperinsulinemic clamp), insulin secretion (acute insulin response (AIR), IVGTT), and adiposity (%Fat, DXA or densitometry) were compared at baseline in 358 Pima Indians (232M/126F, 18-44 years old) with normal glucose regulation of whom 61 (35M/26F) developed diabetes (DIAB) during a median follow-up time of 7.6 years. RESULTS: In proportional-hazard analysis, % Fat (HR = 1.52, p = 0.03), M (HR = 0.51, p = 0.04) and AIR (HR = 0.64, p = 0.003) predicted the development of diabetes after adjustment for age and sex. In regression analysis adjusting for age, sex, %Fat and M at baseline, the non-diabetic group (NON-DM) had a higher AIR (p = 0.0002) than the DIAB group; the positive association of AIR with adiposity observed in the NON-DM group was absent in the DIAB group. Cumulative incidence rates (12y) for diabetes were highest (48%) in subjects with both M and AIR below the population median and lowest (11%) in subjects with both M and AIR above the population median. CONCLUSION: AIR can predict diabetes prior to the current clinical indicators of impaired glucose regulation.

11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue and prospective changes in body weight and insulin resistance.

OBJECTIVE: Increased mRNA and activity levels of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in human adipose tissue (AT) are associated with obesity and insulin resistance. The aim of our study was to investigate whether 11betaHSD1 expression or activity in abdominal subcutaneous AT of non-diabetic subjects are associated with subsequent changes in body weight and insulin resistance [homeostasis model assessment of insulin resistance (HOMA-IR)]. RESEARCH METHODS AND PROCEDURES: Prospective analyses were performed in 20 subjects (two whites and 18 Pima Indians) who had baseline measurements of 11betaHSD1 mRNA and activity in whole AT (follow-up, 0.3 to 4.9 years) and in 47 Pima Indians who had baseline assessments of 11betaHSD1 mRNA in isolated adipocytes (follow-up, 0.8 to 5.3 years). RESULTS: In whole AT, although 11betaHSD1 mRNA levels showed positive associations with changes in weight and HOMA-IR, 11betaHSD1 activity was associated with changes in HOMA-IR but not in body weight. 11betaHSD1 mRNA levels in isolated adipocytes were not associated with follow-up changes in any of the anthropometric or metabolic variables. DISCUSSION: Our results indicate that increased expression of 11betaHSD1 in subcutaneous abdominal AT may contribute to risk of worsening obesity and insulin resistance. This prospective relationship does not seem to be mediated by increased 11betaHSD1 expression in adipocytes.

Higher fasting plasma concentrations of glucagon-like peptide 1 are associated with higher resting energy expenditure and fat oxidation rates in humans.

BACKGROUND: Glucagon-like peptide 1 (GLP-1) is a gut hormone that decreases appetite and promotes satiety. Its role in energy metabolism regulation is still poorly understood. OBJECTIVE: The aim of the study was to investigate the relation of fasting plasma GLP-1 concentrations to rates of energy expenditure (EE) and substrate oxidation-ie, respiratory quotient (RQ). DESIGN: Forty-six glucose-tolerant white subjects (22 men, 24 women) aged 18-49 y whose adiposity spanned a wide range [body mass index (in kg/m2): 18.5-50] were studied in an inpatient clinic. Main outcome measures included resting EE and RQ (ventilated hood technique), body composition (dual-energy X-ray absorptiometry), and fasting plasma concentrations of GLP-1, pancreatic polypeptide, glucose, and insulin. RESULTS: Fasting plasma GLP-1 concentrations were positively associated with resting EE (after adjustment for age, sex, and body composition) and negatively correlated with RQ (after adjustment for age, sex, and percentage body fat) and fasting plasma pancreatic polypeptide concentrations (both before and after adjustment for age, sex, percentage body fat, and fasting plasma glucose and insulin concentrations). Adjustment for fasting plasma pancreatic polypeptide concentrations, a marker of parasympathetic outflow to the gut, attenuated the strength of the association of fasting plasma GLP-1 concentrations with resting EE and RQ. CONCLUSIONS: Higher fasting plasma GLP-1 concentrations are associated with higher rates of EE and fat oxidation independent of age, sex, and body composition. The autonomic nervous system may have a role in this relation. This effect, along with the established role of GLP-1 in promoting satiety, may further foster its therapeutic potential in the treatment of obesity.

Lower total fasting plasma adiponectin concentrations are associated with higher metabolic rates.

CONTEXT: The possible role of adiponectin, a protein uniquely produced by the adipose tissue and significantly reduced in obesity and other insulin-resistant states, in the regulation of energy expenditure (EE) is still poorly understood. OBJECTIVE: The objective of the study was to investigate the relationship between total fasting plasma adiponectin concentrations and the various components of EE measured in a metabolic chamber in Pima Indians and to test whether body fat distribution may have a role in this association. DESIGN: This was a cross-sectional study. SETTING: The study was an inpatient clinical research unit. PARTICIPANTS: Sixty nondiabetic Pima Indians (45 males and 15 females), aged 18-45 yr, spanning a wide range of adiposity (body mass index 19.6-46.2 kg/m(2)) participated in the study. MAIN OUTCOME MEASURES: Total fasting plasma adiponectin concentrations, EE (24-h respiratory chamber), insulin sensitivity (euglycemic-hyperisulinemic clamp), body composition (dual-energy x-ray absorptiometry), and body fat distribution (waist to thigh ratio) were the main outcome measures. RESULTS: Total fasting plasma adiponectin concentrations are negatively associated with sleep EE adjusted for sex, age, fat-free mass, and fat mass. This correlation is still significant, although attenuated, after inclusion of insulin-stimulated glucose disposal among the regressors and further attenuated when adjusted also for waist to thigh ratio. CONCLUSIONS: The decrease in total fasting plasma adiponectin concentrations that accompanies fat accumulation may be a mechanism to prevent further weight gain by decreasing insulin sensitivity and increasing energy expenditure.

Serum gamma-glutamyl transpeptidase is a determinant of insulin resistance independently of adiposity in Pima Indian children.

CONTEXT: Elevated activities of serum enzymes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT), have been associated with obesity and insulin resistance (IR). ALT is an independent predictor of type 2 diabetes mellitus (T2DM) in adult Pima Indians, and GGT predicts T2DM in other adult populations. OBJECTIVE: Our aim was to establish whether independent relationships exist between either adiposity or IR and hepatic enzymes in a group of Pima Indian children. SUBJECTS AND METHODS: In a cross-sectional study, 44 children (22 males and 22 females; 7-11 yr old) were measured for weight (WT), height, percent body fat, and serum activities of ALT, AST, and GGT. Body mass index (kilograms per meter squared) was calculated. IR was calculated from fasting plasma concentrations of glucose and insulin using the homeostasis model assessment (HOMA-IR). RESULTS: Hepatic enzymes were positively associated with obesity measures, fasting insulin, and HOMA-IR. GGT was additionally associated with serum lipids and white blood cell count. GGT, but not AST or ALT, was a significant determinant of HOMA-IR independently of age, sex, and WT, body mass index, or percent body fat. The model that accounted for the largest portion of the variance in HOMA-IR included WT (beta = 0.004; P = 0.008) and GGT (beta = 0.20; P = 0.004; total R(2) = 0.62; P < 0.0001). CONCLUSION: Significant relationships between adiposity and hepatic enzyme activities exist during childhood in Pima Indians. Whether serum GGT activity predicts the development of T2DM in these children remains to be determined in follow-up studies.

Intrauterine exposure to diabetes is a determinant of hemoglobin A(1)c and systolic blood pressure in pima Indian children.

CONTEXT/OBJECTIVE: Given the increasing rates of both childhood obesity and type 2 diabetes (T2DM), we investigated whether maternal diabetes status during pregnancy is a determinant of risk factors associated with T2DM or cardiovascular disease in offspring during childhood. DESIGN/PARTICIPANTS: Forty-two Pima Indians, aged 7-11 yr, were identified retrospectively from maternal oral glucose tolerance tests as offspring of a diabetic pregnancy (22 ODM, eight males, 14 females) or offspring born before the mother developed diabetes (20 PRE, 12 males, eight females). SETTING/MAIN OUTCOME MEASURES: Weight, height, body mass index, percent body fat, blood pressure, and fasting concentrations of glucose, insulin, hemoglobin A1c (HbA1c), total cholesterol, triglycerides, and high-density lipoprotein-cholesterol were measured while staying in an in-patient clinical research unit and compared in cross-sectional analyses. RESULTS: After adjustment for age and gender, ODM had significantly higher concentrations of HbA1c (ODM = 5.7 +/- 0.4, PRE = 5.0 +/- 0.4%, P = 0.002), higher systolic (SBP) blood pressure (ODM = 118 +/- 13, PRE = 107 +/- 10 mm Hg; P = 0.02), and lower concentrations of high-density lipoprotein (ODM = 41 +/- 9, PRE = 48 +/- 6 mg/dl, P = 0.03) than PRE. Maternal diabetes status during pregnancy persisted as a significant determinant of SBP (beta = 7.50, P = 0.03) and HbA1c (beta = 0.43, P = 0.002), independent of age, gender, and percent body fat. CONCLUSION: Intrauterine exposure to diabetes is a significant determinant of higher SBP and HbA1c during childhood, independent of adiposity and a genetic predisposition to T2DM. These data suggest that in utero exposure to diabetes confers an additional independent risk for the development of T2DM and/or cardiovascular disease later in life.