Discrepancy between predicted and measured exercise intensity for eliciting the maximal rate of lipid oxidation.

BACKGROUND AND AIMS: Ectopic lipid storage is implicated in type 2 diabetes pathogenesis; hence, exercise to deplete stores (i.e., at the intensity that allows for maximal rate of lipid oxidation; MLO) might be optimal for restoring metabolic health. This intensity ("Fatmax") is estimated during incremental exercise ("Fatmax test"). However, in "the field" general recommendations exist regarding a range of percentages of maximal heart rate (HR) to elicit MLO. The degree to which this range is aligned with measured Fatmax has not been investigated. We compared measured HR at Fatmax, with maximal HR percentages within the typically recommended range in a sample of 26 individuals (Female: n = 11, European ancestry: n = 17). METHODS AND RESULTS: Subjects completed a modified Fatmax test with a 5-min warmup, followed by incremental stages starting at 15 W with work rate increased by 15 W every 5 min until termination criteria were reached. Pulmonary gas exchange was recorded and average values for V˙ o2 and V˙ co2 for the final minute of each stage were used to estimate substrate-oxidation rates. We modeled lipid-oxidation kinetics using a sinusoidal model and expressed MLO relative to peak V˙ o2 and HR. Bland-Altman analysis demonstrated lack of concordance between HR at Fatmax and at 50%, 70%, and 80% of age-predicted maximum with a mean difference of 23 b·min-1. CONCLUSION: Our results indicate that estimated "fat-burning" heart rate zones are inappropriate for prescribing exercise to elicit MLO and we recommend direct individual exercise lipid oxidation measurements to elicit these values.

Whole body lipid oxidation during exercise is impaired with poor insulin sensitivity but not with obesity per se.

Equivocal findings regarding the influence of overweight/obesity on exercise lipid-oxidizing capacity (EX-LIPOX) might reflect inadequate control of 1) acute energy balance/macronutrient composition of diet; 2) intensity/duration of exercise; and/or 3) insulin sensitivity (IS) of participant. To assess independent/combined influences of IS and overweight/obesity with other factors controlled, we recruited sedentary adults with normal weight (NW; n = 15) or overweight/obesity (O; n = 15) subdivided into metabolically healthy (MH; n = 8) and unhealthy (MU; n = 7) groups (IS; MH > MU). Participants completed a 9-day, weight-stabilizing, controlled-feeding protocol comprising measurements of resting metabolism, body composition, oral glucose tolerance, and maximal exercise capacity. We measured EX-LIPOX during the initial 45 min of "steady state" during constant-work-rate cycling at 70% and 100% of participant gas-exchange threshold (GET). At 70%, average EX-LIPOX in absolute (0.11 ± 0.02 g·min-1) and relative (2.4 ± 0.3 mg·kgFFM-1·min-1) terms was lower for NW-MU than MH regardless of body composition (NW-MH, 0.19 ± 0.02 g·min-1/3.9 ± 0.3 mg·kgFFM-1·min-1; O-MH, 0.19 ± 0.02 g·min-1/3.7 ± 0.3 mg·kgFFM-1·min-1), whereas no difference was present for NW-MU and O-MU (0.15 ± 0.02 g·min-1/2.8 ± 0.3 mg·kgFFM-1·min-1). Multiple regression confirmed that with IS-controlled, overweight/obesity was not associated with decreased EX-LIPOX, whereas decreased EX-LIPOX was associated with decreased IS independent of overweight/obesity. Overweight/obesity also did not influence EX-LIPOX across MH groups or with cohort divided by body-composition classification alone (P > 0.05). Exercise lipid-oxidizing capacity is impaired with poor IS regardless of body composition, but not with overweight/obesity per se.NEW & NOTEWORTHY In this study, we have shown that the capacity to oxidize lipid during exercise is influenced by metabolic health of the exerciser regardless of body composition, but not by body composition per se. This observation refutes the belief that a reduced capacity to oxidize lipid is an obligatory characteristic of the overweight/obese condition while supporting the contention that exercise should be prescribed with specificity based on both absence/presence of overweight/obesity and compromise/lack thereof in metabolic health.

OPPORTUNISTIC SCREENING FOR DIABETES AND PREDIABETES USING HEMOGLOBIN A1C IN AN URBAN PRIMARY CARE SETTING.

OBJECTIVE: In 2010, the American Diabetes Association (ADA) endorsed hemoglobin A1c (HbA1c) as 1 of 3 tests for diabetes and prediabetes screening. We describe the use of HbA1c testing for screening during routine visits in primary care clinics of an urban health care system in the U.S. METHODS: In 2013 to 2014, retrospective analyses of deidentified electronic health records over a 2-year period, January 2010 to December 2011, for academic private practices (clinic group 1) and federally-qualified Community Health Centers (clinic group 2) identified 11,885 adults without prior diabetes or recent HbA1c testing. We estimated the proportion of patients eligible for screening according to ADA and U.S. Preventative Services Task Force (USPSTF) guidelines and calculated the potential yield of previously undiagnosed diabetes or prediabetes among those who received at least 1 HbA1c test. RESULTS: Overall, 3,316 and 5,613 patients of clinic groups 1 and 2 (75.2% of each) were eligible for screening by ADA guidelines, while only 1,764 (39.9%) of clinic group 1 and 3,799 (50.9%) of clinic group 2 were eligible by USPSTF guidelines. In those eligible by either guideline, 731 (21.4%) patients of clinic group 1 and 1,293 (21.5%) of clinic group 2 received HbA1c testing; among these, in 71 (9.7%) and 121 (9.4%) patients from clinic groups 1 and 2, respectively, HbA1c results were in the diabetes range, and in 330 (45.2%) and 733 (56.7%), results were in the prediabetes range. CONCLUSION: In urban primary care settings, appropriate HbA1c testing could result in the detection of a substantial number of previously undiagnosed diabetes and prediabetes cases needing treatment.

Responsiveness and Reliability of a Sipping Device to Measure Motivation in Normal-Weight Individuals and Bariatric Surgery Patients.

There is an urgent need to measure the motivation to taste a sweet fluid in order to determine the influence of sweet tastes on the potential choices and consumption of beverages in patients with obesity. Current methods utilize either survey instruments or arbitrary operant tasks. The sipometer enables the participant to utilize an actual ingestive behavioral response to measure motivation during access to beverages on either ad libitum (AL) or progressive time ratio (PR) schedules. We determined the sipometer's responsiveness and reliability as a test of change in motivation for sweet tastes after bariatric surgery. Participants (58 patients and 28 controls, BMI: 18.5-24.9 kg/m2) sham-consumed an aspartame-sweetened (S) and non-sweetened (N) beverage under AL and PR schedules at a pre-surgery/baseline and a 3-month and 24-month visit (patients only). Cumulative pressure (CumPres), a measure of effort, was the sum of the pressures exerted during sipping under each condition. Baseline CumPres for PRS was higher than ALS and ALN in patients (p < 0.03) and higher than PRN in controls (p = 0.009). At 3 months, CumPres did not differ amongst conditions in patients, but CumPres for PRS was higher than all other conditions in controls (p < 0.0005). There were no baseline group differences; however, patients' CumPres for PRS was lower than controls' at 3 months (p = 0.002). Patients' CumPres for PRS decreased non-significantly between the baseline and 3 months but increased at 24 months compared to 3 months (p = 0.025) and was no different from baseline. Controls' CumPres for PRS increased at 3 months (p = 0.0359), but CumPres for all conditions was correlated between visits (p's < 0.038). The sipometer is a reliable and sensitive measure of motivation to consume sweet beverages and may reflect changes in post-operative energy intake.

Effect of angiotensin receptor blockade on insulin sensitivity and endothelial function in abdominally obese hypertensive patients with impaired fasting glucose.

AngII (angiotensin II) may contribute to cardiovascular risk in obesity via adverse effects on insulin sensitivity and endothelial function. In the present study, we examined the effects of ARB (angiotensin receptor blocker) therapy (losartan, 100 mg/day) on insulin sensitivity and endothelial function in 53 subjects with stage I hypertension, abdominal obesity and impaired fasting glucose. The study design was a randomized double-blinded parallel design placebo-controlled multi-centre trial of 8 weeks duration. We used the hyperinsulinaemic-euglycaemic clamp technique to measure insulin sensitivity (expressed as the 'M/I' value) and RH-PAT (reactive hyperaemia-peripheral arterial tonometry) to measure endothelial function. Additional measures included HOMA (homoeostasis model assessment)-B, an index of pancreatic ß-cell function, and markers of inflammation [e.g. CRP (C-reactive protein)] and oxidative stress (e.g. F2-isoprostanes). ARB therapy did not alter insulin sensitivity [5.2 (2.7) pre-treatment and 4.6 (1.6) post-treatment] compared with placebo therapy [6.1 (2.9) pre-treatment and 5.3 (2.7) post-treatment; P value not significant], but did improve the HOMA-B compared with placebo therapy (P=0.05). ARB therapy also did not change endothelial function [RH-PAT, 2.15 (0.7) pre-treatment and 2.11 (0.7) post-treatment] compared with placebo therapy [RH-PAT, 1.81 (0.5) pre-treatment and 1.76 (0.7) post-treatment; P value not significant]. Markers of inflammation and oxidative stress were not significantly changed by ARB therapy. In conclusion, ARB therapy did not alter peripheral insulin sensitivity or endothelial function in this cohort of patients with essential hypertension, abdominal obesity and impaired fasting glucose, but did improve pancreatic ß-cell function.

Body mass index and all-cause mortality in a large Chinese cohort.

BACKGROUND: Obesity is known to be associated with an increased risk of death, but current definitions of obesity are based on data from white populations. We examined the association between body mass index (BMI) and the risk of death in a large population of adult Chinese people. METHODS: We examined the association between body mass index (BMI) and all-cause mortality prospectively among 58,738 men and 65,718 women aged 20 years and older enrolled in 1998-1999 from four national health screening centres in Taiwan. We used Cox proportional hazards regression analyses to estimate the relative risks of all-cause mortality for different BMI categories during a maximum follow-up of 10 years. RESULTS: A total of 3947 participants died during the follow-up period. The lowest risk of death was observed among men and women who had a BMI of 24.0-25.9 (mean 24.9). After adjustment for age, smoking status, alcohol intake, betel-nut chewing, level of physical activity, income level and education level, we observed a U-shaped association between BMI and all-cause mortality. Similar U-shaped associations were observed when we analyzed data by age (20-64 or ≥ 65 years), smoking (never, < 10 pack-years or ≥ 10 pack-years) and presence of a pre-existing chronic disease, and after we excluded deaths that occurred in the first three years of follow-up. INTERPRETATION: BMI and all-cause mortality had a U-shaped association among adult Chinese people in our study. The lowest risk of death was among adults who had a BMI of 24.0-25.9 (mean 24.9). Our findings do not support the use of a lower cutoff value for overweight and obesity in the adult Chinese population.

Longitudinal associations of blood markers of insulin and glucose metabolism and cancer mortality in the third National Health and Nutrition Examination Survey.

Insulin and glucose may influence cancer mortality via their proliferative and anti-apoptotic properties. Using longitudinal data from the nationally representative Third National Health and Nutrition Examination Survey (NHANES III; 1988-1994), with an average follow-up of 8.5 years to death, we evaluated markers of glucose and insulin metabolism, with cancer mortality, ascertained using death certificates or the National Death Index. Plasma glucose, insulin, C-peptide, and lipid concentrations were measured. Anthropometrics, lifestyle, medical, and demographic information was obtained during in-person interviews. After adjusting for age, race, sex, smoking status, physical activity, and body mass index, for every 50 mg/dl increase in plasma glucose, there was a 22% increased risk of overall cancer mortality. Insulin resistance was associated with a 41% (95% confidence interval (CI) (1.07-1.87; p = 0.01) increased risk of overall cancer mortality. These associations were stronger after excluding lung cancer deaths for insulin-resistant individuals (HR: 1.67; 95% CI: 1.15-2.42; p = 0.01), specifically among those with lower levels of physical activity (HR: 2.06; 95% CI: 1.4-3.0; p = 0.0001). Similar associations were observed for other blood markers of glucose and insulin, albeit not statistically significant. In conclusion, hyperglycemia and insulin resistance may be 'high-risk' conditions for cancer mortality. Managing these conditions may be effective cancer control tools.

Feasibility of a progressive protocol of high-intensity interval training for overweight/obese, sedentary African American women: a retrospective analysis.

BACKGROUND: African American (AA) women have a higher prevalence of obesity and related metabolic dysfunction and lower level of physical activity compared to white counterparts. Determining feasible exercise alternatives for AA women is, therefore, paramount. Time-efficient high-intensity interval training (HIIT) might be particularly suited for AA women who cite time constraints as a frequent barrier to exercise adherence. The purpose of this study was to assess the feasibility of a 14-week progressive HIIT protocol for previously-sedentary overweight/obese AA women. METHODS: Twenty-eight healthy, premenopausal (age, 20-40 yr), sedentary, nondiabetic, overweight/obese AA women volunteered to participate in the randomized controlled clinical trial from which these data were retrospectively analysed. After assessment, participants were randomly allocated to a HIIT group (n = 14) or a no-exercise control group. The HIIT intervention consisted of 24-min sessions performed three times per week for 14 weeks during which work-interval intensity (75 to 90% of heart rate reserve; HRR) and duration (30 to 60 s) and work/recovery ratio (1:7 to 1:3) were progressed in four stages. Feasibility was assessed based on adherence (attrition rate), perceptual response (RPE) and success rate, which was calculated based on the degree to which target intensities for work intervals were achieved/maintained. RESULTS: Five of 14 participants (35%) in the HIIT group dropped out during the intervention. One-way repeated-measures ANOVA revealed a significant difference across stages for success rate (p = 0.018) with post-hoc analysis indicating a significant difference between stage 1 and the other stages and stage 4 and the other stages. There was no significant difference in RPE across stages (p = 0.057). CONCLUSION: Albeit based on a limited number of participants, we found an attrition rate that was higher than what has been reported previously for HIIT (~ 17.6%) when previously-sedentary overweight/obese AA women performed a protocol with work-interval intensity progressed from 75 to 90% HRR during a 14-week intervention. With respect to intensity, the precipitous drop for achievement of the target HR during the fourth stage (weeks 8-14) for those who did complete the protocol implies that it might be advisable to restrict work-interval intensity to < 90% HRR. TRIAL REGISTRATION: ClinicalTrials.gov. (NCT04293367). Registered 03 March 2020 - Retrospectively registered.

Severe-intensity constant-work-rate cycling indicates that ramp incremental cycling underestimates ⩒o2max in a heterogeneous cohort of sedentary individuals.

In the absence of a ⩒o2-work-rate plateau, debate continues regarding the best way to verify that the peak ⩒o2 achieved during incremental exercise (⩒o2peak) is the "true ⩒o2max." Oft-used "secondary criteria" have been questioned in conjunction with the contention that a severe-intensity constant-work-rate "verification bout" should be considered the "gold standard." The purpose of this study was to compare the ⩒o2peak during ramp incremental cycling (RAMP-INC) by a heterogeneous (with respect to body composition and sex) cohort of sedentary individuals with the ⩒o2peak during severe-intensity constant-work-rate cycling (CWR) performed after RAMP-INC at the highest work rate achieved. A secondary purpose was to determine the degree to which traditional and newly-proposed age-dependent secondary criteria (RER, HR) identified RAMP-INC which CWR confirmed were characterized by a submaximal ⩒o2peak. Thirty-five healthy male (n = 19: 33.4 ± 6.3 yrs) and female (26.8 ± 3.6 yrs) sedentary participants performed RAMP-INC followed by CWR. The ⩒o2peak values from the two tests were correlated (r = 0.96; p < 0.01; mean CV = 24%); however, ⩒o2peak for CWR was significantly greater (29.6 ± 7.2 v. 28.6 ± 6.8 mL∙min-1∙kg-1; p < 0.01) with a mean bias of 0.98 mL∙min-1∙kg-1 (z = -2.9, p < 0.01). Both traditional and newly-proposed criterion values for RER were achieved during RAMP-INC by 33 of 35 participants (including 21 of 23 who registered a higher ⩒o2peak on CWR). The traditional HR criterion value was achieved on only seven tests (three of which were confirmed to be characterized by a submaximal ⩒o2peak) while use of less stringent newly-proposed criteria resulted in acceptance of an additional seven tests of which five were confirmed to be submaximal. Severe-intensity CWR to limit of tolerance indicates that RAMP-INC underestimates ⩒o2max in sedentary individuals and both traditional and newly-proposed secondary criteria are ineffective for identifying such tests.

Insulin resistance, hepatic lipid and adipose tissue distribution in HIV-infected men.

BACKGROUND: A large proportion of HIV-infected patients on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. METHODS: We performed a cross-sectional analysis of baseline data from 23 HIV-infected participants in three prospective clinical studies. Magnetic resonance spectroscopy was used to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole-body adipose tissue compartments: that is, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes, as well as the intermuscular adipose tissue (IMAT) subcompartment and the omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. The homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. RESULTS: Hepatic lipid content correlated significantly with total VAT (r = 0.62, P = 0.0014), but not with SAT (r = 0.053, P = 0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r = 0.67, P = 0.0004) and RPAT (r = 0.53, P = 0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r = 0.61, P = 0.057 and r = 0.68, P = 0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. CONCLUSION: Hepatic lipid content is associated with VAT volume, especially the OMAT subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.

Potential role of increased matrix metalloproteinase-2 (MMP2) transcription in impaired adipogenesis in type 2 diabetes mellitus.

We measured gene expression of paracrine regulators involved in adipocyte differentiation within the stromovascular fraction of abdominal subcutaneous adipose tissue from obese individuals with (n=30) and without (n=18) type 2 diabetes mellitus (T2DM). Despite similar adiposity by design, subjects with T2DM had larger adipocytes (0.92+/-0.28 vs. 0.75+/-0.17 microl, p<0.05) than controls. Gene expression of the adipogenic marker aP2 was lower (0.35+/-0.16 vs. 0.58+/-0.27 arbitrary units, p<0.05) whereas the expression of matricellular peptidase, MMP2 was higher (1.65+/-0.17 vs. 1.27+/-0.21, p=0.02) in T2DM vs. controls. The gene expression levels between the aP2 and MMP2 were inversely correlated (r=-0.32, p=0.03). We conclude that early steps of adipogenesis may be impaired in T2DM independently of obesity due, in part, to an upregulation of the MMP2 transcription.

Femoral-gluteal subcutaneous and intermuscular adipose tissues have independent and opposing relationships with CVD risk.

Femoral-gluteal adipose tissue (AT) may be cardioprotective through fatty acids uptake. Femoral-gluteal AT has previously been defined as leg fat measured by dual energy x-ray absorptiometry (DXA); however, subcutaneous adipose tissue (SAT) and intermuscular adipose tissue (IMAT) are inseparable using DXA. This study investigated the independent relationships between femoral-gluteal SAT, femoral-gluteal IMAT, and cardiovascular disease (CVD) risk factors [fasting serum measures of glucose, total cholesterol (TC), high density lipoprotein cholesterol (HDLC), triglycerides (TG) and insulin] and whether race differences exist in femoral-gluteal AT distribution. Adult Caucasians (56 men and 104 women), African-Americans (37 men and 76 women), and Asians (11 men and 35 women) had total AT (TAT) including femoral-gluteal AT (upper leg SAT and IMAT) and visceral AT (VAT) by magnetic resonance imaging (MRI). General linear models identified the independent effects of femoral-gluteal SAT and femoral-gluteal IMAT on each risk factor after covarying for TAT, VAT, age, race, sex, and two-way interactions. Femoral-gluteal IMAT and glucose (P < 0.05) were positively associated independent of VAT. There were also significant inverse associations between femoral-gluteal SAT and insulin (P < 0.01) and TG (P < 0.05), although the addition of VAT rendered these effects nonsignificant, possibly due to collinearity. Asian women had less femoral-gluteal SAT and greater VAT than Caucasians and African-Americans (P < 0.05) and Asian and African-American men had greater femoral-gluteal IMAT than Caucasians, adjusted for age and TAT (P < 0.05 for both). Femoral-gluteal SAT and femoral-gluteal IMAT distribution varies by sex and race, and these two components have independent and opposing relationships with CVD risk factors.

Dual Paraneoplastic Endocrine Syndromes Heralding Onset of Extrapulmonary Small Cell Carcinoma: A Case Report and Narrative Review.

OBJECTIVE: Extrapulmonary small cell carcinoma (EPSCC) is rare and frequent metastases at presentation can complicate efforts to identify a site of origin. In particular, SCC comprises <1% of prostate cancers and has been implicated in castration resistance. METHODS: Clinical, laboratory, imaging, and pathology data are presented. RESULTS: A 56-year-old man with locally advanced prostate adenocarcinoma on androgen deprivation therapy presented with a clogged nephrostomy tube. Laboratory results included calcium 13.8 mg/dL (8.5-10.5 mg/dL), albumin 3.6 g/dL (3.5-5 mg/dL), and potassium 2.8 mmol/L (3.5-5.2 mmol/L). Hypercalcemia investigation revealed intact PTH 19 pg/mL (16-87 pg/mL), 25-OH vitamin D 15.7 ng/mL (>30 ng/mL), and PTH-related peptide (PTHrP) 63.4 pmol/L (<2.3 pmol/L). Workup for hypokalemia yielded aldosterone 5.3 ng/dL (<31 ng/dL), renin 0.6 ng/mL/h (0.5-4 ng/mL/h), and 6:00 a.m. cortisol 82 µg/dL (6.7-22.6 µg/dL) with ACTH 147 pg/mL (no ref. range). High-dose Dexamethasone suppression testing suggested ACTH-dependent ectopic hypercortisolism. Contrast-enhanced CT findings included masses in the liver and right renal pelvis, a heterogeneous enlarged mass in the region of the prostate invading the bladder, bilateral adrenal thickening, and lytic lesions in the pelvis and spine. Liver biopsy identified epithelioid malignancy with Ki proliferation index 98% and immunohistochemical staining positive for synaptophysin and neuron-specific enolase, compatible with high-grade small cell carcinoma. Staining for ACTH was negative; no stain for CRH was available. Two weeks after chemotherapy, 6:00 a.m. cortisol normalized and CT scans showed universal improvement. CONCLUSION: Extensive literature details paraneoplastic syndromes associated with SCC, but we report the first case of EPSCC diagnosed due to onset of dual paraneoplastic syndromes.

Independent associations of insulin resistance with high whole-body intermuscular and low leg subcutaneous adipose tissue distribution in obese HIV-infected women.

BACKGROUND: Obesity and insulin resistance are growing problems in HIV-positive (HIV+) women receiving highly active antiretroviral therapy (HAART). OBJECTIVE: The objective was to determine the contribution of adipose tissue (AT) enlargement and distribution to the presence of insulin resistance in obese HIV+ women. DESIGN: Whole-body intermuscular AT (IMAT), visceral AT (VAT), subcutaneous AT (SAT), and SAT distribution (leg versus upper body) were measured by whole-body magnetic resonance imaging. Insulin sensitivity (S(I)) was measured with an intravenous glucose tolerance test in obese HIV+ women recruited because of their desire to lose weight (n=17) and in obese healthy controls (n=32). RESULTS: The HIV+ women had relatively less whole-body SAT and more VAT and IMAT than did the controls (P<0.05 for all). A significant interaction by HIV status was observed for the relation of total SAT with S(I) (P<0.001 for the regression's slope interactions after adjustment for age, height, and weight). However, relations of IMAT, VAT, and SAT distribution (leg SAT as a percentage of total SAT; leg SAT%) with S(I) did not differ significantly between groups. For both groups combined, the best model predicting a low S(I) included significant contributions by both high IMAT and low leg SAT%, independent of age, height, and weight, and no interaction between groups was observed (overall r(2)=0.44, P=0.0003). CONCLUSION: In obese HIV+ women, high whole-body IMAT and low leg SAT% distribution are independently associated with insulin resistance.

Energy expenditure, sex, and endogenous fuel availability in humans.

Adipose tissue lipolysis supplies circulating FFAs, which largely meet lipid fuel needs; however, excess FFAs, can contribute to the adverse health consequences of obesity. Because "normal" FFA release has not been well defined, average (mean of 4 days) basal FFA release and its potential regulation factors were measured in 50 lean and obese adults (25 women). Resting energy expenditure (REE), but not body composition, predicted most of the interindividual variation in FFA release. There was a significant, positive linear relationship between palmitate release and REE; however, women released approximately 40% more FFA than men relative to REE. Neither plasma palmitate concentrations nor respiratory quotient by indirect calorimetry differed between men and women. Glucose release rates were not different in men and women whether related to REE or fat free mass. These findings indicate that nonoxidative FFA clearance is greater in women than in men. This could be an advantage at times of increased fuel needs. We conclude that "normal" adipose tissue lipolysis is different in men and women and that the fuel export role of adipose tissue in obesity will need to be reassessed.

An Interrupted Time Series Analysis to Determine the Effect of an Electronic Health Record-Based Intervention on Appropriate Screening for Type 2 Diabetes in Urban Primary Care Clinics in New York City.

OBJECTIVE: To determine the impact of a health system-wide primary care diabetes management system, which included targeted guidelines for type 2 diabetes (T2DM) and prediabetes (dysglycemia) screening, on detection of previously undiagnosed dysglycemia cases. RESEARCH DESIGN AND METHODS: Intervention included electronic health record (EHR)-based decision support and standardized providers and staff training for using the American Diabetes Association guidelines for dysglycemia screening. Using EHR data, we identified 40,456 adults without T2DM or recent screening with a face-to-face visit (March 2011-December 2013) in five urban clinics. Interrupted time series analyses examined the impact of the intervention on trends in three outcomes: 1) monthly proportion of eligible patients receiving dysglycemia testing, 2) two negative comparison conditions (dysglycemia testing among ineligible patients and cholesterol screening), and 3) yield of undiagnosed dysglycemia among those tested. RESULTS: Baseline monthly proportion of eligible patients receiving testing was 7.4-10.4%. After the intervention, screening doubled (mean increase + 11.0% [95% CI 9.0, 13.0], proportion range 18.6-25.3%). The proportion of ineligible patients tested also increased (+5.0% [95% CI 3.0, 8.0]) with no concurrent change in cholesterol testing (+0% [95% CI -0.02, 0.05]). About 59% of test results in eligible patients showed dysglycemia both before and after the intervention. CONCLUSIONS: Implementation of a policy for systematic dysglycemia screening including formal training and EHR templates in urban academic primary care clinics resulted in a doubling of appropriate testing and the number of patients who could be targeted for treatment to prevent or delay T2DM.

Metabolic inflexibility in substrate use is present in African-American but not Caucasian healthy, premenopausal, nondiabetic women.

CONTEXT: There is an increased prevalence of obesity and insulin resistance in African-American compared with Caucasian females. Metabolic inflexibility (MI) is the inability to switch the use of lipids and carbohydrates in the peripheral tissue (i.e. muscle) based upon substrate availability. OBJECTIVE: We examined whether MI exists in African-American females. MAIN OUTCOME MEASURES AND DESIGN: We measured substrate use differences during eucaloric, macronutrient-manipulated diets [high fat (50% fat, 35% carbohydrate, 15% protein) vs. low fat (30% fat, 55% carbohydrate, 15% protein)] between Caucasian and African-American women. We also compared differences in substrate use in response to insulin infusion during two-step pancreatic-euglycemic clamps and epinephrine infusion during lipolysis studies. In each study, similar groups of Caucasian and African-American women were compared. RESULTS: Caucasians had significantly higher fat oxidation (FO) (P = 0.01) and lower carbohydrate oxidation (P < 0.01) during the high-fat vs. low-fat diet, whereas no significant differences were observed in African-Americans. The African-American women also failed to significantly suppress FO during the second step of the pancreatic-euglycemic clamp despite a doubling of their fasting plasma insulin and failed to increase their FO or decrease their carbohydrate oxidation in response to epinephrine infusion as much as Caucasian women did. The response of free fatty acid turnover rates to insulin and epinephrine stimulation was similar between races. CONCLUSION: The impaired substrate use observed in African-American women during these three studies demonstrates the existence of MI and may contribute to their greater prevalence of obesity and insulin resistance.

Body composition and metabolic effects of a diet and exercise weight loss regimen on obese, HIV-infected women.

HIV has classically been a wasting disease. However, in the United States, obesity is increasingly common among HIV-infected individuals receiving effective antiviral treatment. The risks of obesity are unclear in HIV, although the increased prevalence of diabetes and cardiovascular disease in the presence or absence of obesity causes growing concern. This study aimed to assess the effects of weight loss (through energy restriction combined with aerobic and resistance exercise) on body composition, body fat distribution, resting energy expenditure, quality of life (QOL), strength and fitness, and metabolic risk factors in obese, HIV-infected women. Eighteen HIV-infected women with a body mass index of 30 or more completed a 12-week weight loss program. Before and after the intervention, body composition and fat distribution by dual energy x-ray absorptiometry and whole-body magnetic resonance imaging, resting energy expenditure by indirect calorimetry, QOL, strength, and fitness were measured. Insulin sensitivity by intravenous glucose tolerance test and circulating cardiovascular risk factors (including lipids, tissue plasminogen activator, and plasminogen activator inhibitor 1) were measured in a subset (n = 9). Daily food intake and total body weight decreased (mean +/- SD) by 3195 +/- 477 kJ and 6.7 +/- 4.2 kg, respectively. Weight lost was 95.5% fat by dual energy x-ray absorptiometry or 6.2 L of subcutaneous adipose tissue, 0.7 L visceral adipose tissue, and 0.8 L skeletal muscle by magnetic resonance imaging. Resting energy expenditure fell approximately 419 kJ, strength and fitness increased by 28.9% +/- 18.5% and 36.8% +/- 41.6%, respectively, and QOL improved in 11 of 13 dimensions. There was significant insulin resistance in the subset with metabolic measurements at baseline, and at follow-up there was no improvement in fasting glucose, insulin, or insulin sensitivity, nor was there any change in fasting lipids, tissue plasminogen activator, or plasminogen activator inhibitor 1. There was no significant change in CD4 count or HIV viral load. In conclusion, moderate weight loss achieved by a short-term program of diet and exercise in obese HIV-positive women appears safe and induces loss of adiposity in both the subcutaneous adipose tissue and visceral adipose tissue regions. Despite reduced food intake, weight and fat loss, as well as improvements in strength, fitness, and QOL, the lack of improvement in metabolic parameters suggests that additional interventions may be necessary to reduce the risk of diabetes and cardiovascular disease in this population.

The effect of recombinant human growth hormone with or without rosiglitazone on hepatic fat content in HIV-1-infected individuals: a randomized clinical trial.

BACKGROUND: Hepatic fat is related to insulin resistance (IR) and visceral adipose tissue (VAT) in HIV+ and uninfected individuals. Growth hormone (GH) reduces VAT but increases IR. We evaluated the effects of recombinant human GH (rhGH) and rosiglitazone (Rosi) on hepatic fat in a substudy of a randomized controlled trial. METHODS: HIV+ subjects with abdominal obesity and IR (QUICKI≤0.33) were randomized to rhGH 3 mg daily, Rosi 4 mg twice daily, the combination or double placebo. Hepatic fat was measured by magnetic resonance spectroscopy, visceral fat by MRI and IR by frequently sampled intravenous glucose tolerance tests at baseline and week 12. RESULTS: 31 subjects were studied at both time points. Significant correlations between hepatic fat and VAT (r=0.41; P=0.02) and QUICKI (r=0.39; P<0.05) were seen at baseline. IR rose with rhGH but not Rosi. When rhGH treatment groups were combined, hepatic fat expressed as percentage change decreased significantly (P<0.05) but did not change in Rosi (P=0.71). There were no correlations between changes in hepatic fat and VAT (P=0.4) or QUICKI (P=0.6). In a substudy of 21 subjects, a trend was noticed between changes in hepatic fat and serum insulin-like growth factor-1 (IGF-1; P=0.09). CONCLUSIONS: Hepatic fat correlates significantly with both VAT and IR, but changes in hepatic fat do not correlate with changes in VAT and glucose metabolism. Hepatic fat content is reduced by rhGH but Rosi has no effect. These results suggest an independent effect of GH or IGF-1 on hepatic fat. The study was registered at Clinicaltrials.gov (NCT00130286).

Independent association of insulin resistance with larger amounts of intermuscular adipose tissue and a greater acute insulin response to glucose in African American than in white nondiabetic women.

BACKGROUND: African Americans (AAs) have a higher prevalence of obesity and type 2 diabetes than do whites. Higher insulin resistance and hyperinsulinemia have been reported in adult AAs than in whites. Differences in adipose tissue and its distribution may account for these findings. OBJECTIVE: The objective was to ascertain whether differences between AA and white women in adipose tissue (AT) and skeletal muscle (SM) volumes account for ethnic differences in insulin resistance. DESIGN: We used whole-body magnetic resonance imaging to measure AT and SM volumes and used the intravenous-glucose-tolerance test to measure insulin resistance. RESULTS: AAs (n = 32) were 29-42% more insulin resistant than were whites (n = 28) after adjustment for weight and height or any AT volumes (P < 0.05). After adjustment for SM volume, the difference decreased to 19% and became nonsignificant. AAs had a 163% greater acute insulin response to glucose than did whites; this difference was significant even after adjustment for insulin sensivitity index, weight, height, and any magnetic resonance imaging measures. With respect to regional AT volumes, an association independent of race, weight, height, and SM volume was found only between increased intermuscular AT and lower insulin sensitivity index. CONCLUSIONS: Premenopausal AA women had significantly higher insulin resistance and acute insulin response to glucose than did their white counterparts. Whereas the difference in insulin resistance was partially accounted for by a greater SM volume in the AAs than in the whites, the difference in the acute insulin response to glucose was independent of any AT and SM measures and was disproportionately larger than expected according to the difference in insulin resistance. In addition, whole-body intermuscular AT was an important independent correlate of insulin resistance.