Joy C. Bunt

Body weight gain in free-living Pima Indians: effect of energy intake vs expenditure.

BACKGROUND: Obesity results from a chronic imbalance between energy intake and energy expenditure. However, experimental evidence of the relative contribution of interindividual differences in energy intake and expenditure (resting or due to physical activity) to weight gain is limited.OBJECTIVE: To assess prospectively the association between baseline measurements of daily energy metabolism and weight changes by studying free-living adult Pima Indians, one of the most obese populations in the world.DESIGN: A study of the pathogenesis of obesity in the Pima Indians living in Southwestern Arizona. The participants were 92 nondiabetic Pima Indians (64M/28F, 35±12 y, 35±9% body fat; mean±s.d.). At baseline, free-living daily energy metabolism was assessed by doubly labeled water and resting metabolic rate (RMR) by indirect calorimetry. Data on changes in body weight (5.8±6.5 kg) over a follow-up period of 4±3 y were available in 74 (49M/25F) of the 92 subjects.RESULTS: The baseline calculated total energy intake (r=0.25, P=0.028) and RMR (r=−0.28, P=0.016) were significantly associated with changes in body weight. The baseline energy expenditure due to physical activity was not associated with changes in body weight.CONCLUSION: Using state-of-the-art methods to assess energy intake and expenditure in free-living conditions, we show for the first time that the baseline calculated total energy intake is a determinant of changes in body weight in Pima Indians. These data also confirm that a low RMR is a risk factor for weight gain in this population.

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.

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

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.

mRNA concentrations of MIF in subcutaneous abdominal adipose cells are associated with adipocyte size and insulin action

Objective:To determine whether the mRNA concentrations of inflammation response genes in isolated adipocytes and in cultured preadipocytes are related to adipocyte size and in vivo insulin action in obese individuals.Design:Cross-sectional inpatient study.Subjects:Obese Pima Indians with normal glucose tolerance.Measurements:Adipocyte diameter (by microscope technique; n=29), expression of candidate genes (by quantitative real-time PCR) in freshly isolated adipocytes (monocyte chemoattractant protein (MCP) 1 and MCP2, macrophage inflammatory protein (MIP) 1α, MIP1β and MIP2, macrophage migration inhibitory factor (MIF), tumor necrosis factor α, interleukin (IL) 6 and IL8; n=22) and cultured preadipocytes (MCP1, MIP1α, MIF, IL6 and matrix metalloproteinase 2; n=33) from subcutaneous abdominal adipose tissue (by aspiration biopsy, n=34), body fat by dual-energy X-ray absorptiometry, glucose tolerance by 75 g oral glucose tolerance test and insulin action by euglycemic-hyperinsulinemic clamp (insulin infusion rate 40 mU m−2 min−1) (all n=34).Results:MIF was the only gene whose expression in both freshly isolated adipocytes and cultured preadipocytes was positively associated with adipocytes diameter and negatively associated with peripheral and hepatic insulin action (all P<0.05). In multivariate analysis, the association between adipocyte MIF mRNA concentrations and adipocytes diameter was independent of the percentage of body fat (P=0.03), whereas adipocyte MIF mRNA concentrations, but not adipocyte diameter, independently predicted peripheral insulin action. The mRNA expression concentrations of the MIF gene in adipocytes were not associated with plasma concentrations of MIF, but were negatively associated with plasma adiponectin concentrations (P=0.004). In multivariate analysis, adipocyte MIF RNA concentrations (P=0.03) but not plasma adiponectin concentrations (P=0.4) remained a significant predictor of insulin action.Conclusions:Increased expression of MIF gene in adipose cells may be an important link between obesity characterized by enlarged adipocytes and insulin resistance in normal glucose tolerant people.

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.

11β-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue and Prospective Changes in Body Weight and Insulin Resistance

Objective: Increased mRNA and activity levels of 11β‐hydroxysteroid dehydrogenase type 1 (11βHSD1) in human adipose tissue (AT) are associated with obesity and insulin resistance. The aim of our study was to investigate whether 11βHSD1 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)].

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/m2 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 β-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.

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.

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.

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.