Metabolic Clearance Rate Of Glucose Research Articles

Pioglitazone does not affect exogenous glucose oxidation or metabolic clearance rate during steady-state aerobic exercise at high altitude

Background: Hypoxia-induced insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR, proxy for peripheral glucose uptake) in native lowlanders exercising during the initial hours of high-altitude (HA) exposure compared sea level. These data suggest that administering an insulin sensitizing drug before HA exposure may increase exogenous glucose oxidation rate by stimulating peripheral glucose uptake. Objective: To compare the effects of pioglitazone (PIO) and placebo (PLA) on exogenous glucose oxidation and MCR during steady-state aerobic exercise at HA. We hypothesized that exogenous glucose oxidation and MCR would be higher with PIO than PLA. Methods: Using a randomized, crossover design, native lowlanders (n = 7 males, mean ± SD, age: 23 ± 6 y, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically-matched (1.43 ± 0.16 VȮ2 L/min) treadmill exercise at HA (460 mmHg) after being administered PIO (15 mg) or PLA (microcrystalline cellulose pill) daily for five days. Substrate oxidation and glucose turnover were determined using indirect calorimetry, oral 13C-glucose and [6,6-2H2]-glucose primed, continuous infusions. Results: Exogenous glucose oxidation rate was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation with PIO (1.65 ± 0.22 g/min) was the same as PLA (1.68 ± 0.32 g/min). There were no treatment effects on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min) disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), and MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Conclusion: These data do not support our hypothesis that exogenous glucose oxidation during exercise at HA can be restored through the short-term administration of PIO. Findings from this study may suggest that hypoxia-induced insulin resistance may be a symptom and not the primary etiology of dysregulated glucose metabolism during acute HA exposure. Supported by MOMRP; authors’ views not offcial US Army or DoD policy. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pioglitazone does not enhance exogenous glucose oxidation or metabolic clearance rate during aerobic exercise in men under acute high-altitude exposure.

Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer before acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared with placebo (PLA) during aerobic exercise at HA. With the use of a randomized crossover design, native lowlanders (n = 7 males, means ± SD, age: 23 ± 6 yr, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80 min of steady-state (1.43 ± 0.16 V̇o2 L/min) treadmill exercise at HA (460 mmHg; [Formula: see text] 96.6 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes ([13C]glucose and 6,6-[2H2]glucose). Exogenous glucose oxidation was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation (PIO: 1.65 ± 0.22 g/min, PLA: 1.68 ± 0.32 g/min) or fat oxidation (PIO: 0.10 ± 0.0.08 g/min, PLA: 0.09 ± 0.07 g/min) was not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min), disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests that the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues.NEW & NOTEWORTHY Short-term (5 days) use of the oral insulin sensitizer pioglitazone does not alter circulating glucose or insulin responses to enhance exogenous glucose oxidation during steady-state aerobic exercise in young healthy men under simulated acute (8 h) high-altitude (460 mmHg) conditions. These results indicate that dysregulations in glucose metabolism in native lowlanders sojourning at high altitude may not be due to insulin resistance at peripheral tissue.

β-Cell Function, Incretin Effect, and Glucose Kinetics in Response to a Mixed Meal in Patients With Type 2 Diabetes Treated With Dapagliflozin Plus Saxagliptin.

To explore the complementary effects of a combination of dipeptidyl peptidase 4 and sodium-glucose cotransporter 2 inhibitors added to metformin on hormonal and metabolic responses to meal ingestion. Forty-five patients (age 58 ± 8 years; HbA1c 58 ± 6 mmol/mol; BMI 30.7 ± 3.2 kg/m2) with type 2 diabetes uncontrolled with metformin were evaluated at baseline and 3 and 28 days after 5 mg saxagliptin (SAXA), 10 mg dapagliflozin (DAPA), or 5 mg saxagliptin plus 10 mg dapagliflozin (SAXA+DAPA) using a mixed-meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion, and sensitivity. At day 3, fasting and mean MMTT glucose levels were lower with SAXA+DAPA (-31.1 ± 1.6 and -91.5 ± 12.4 mg/dL) than with SAXA (-7.1 ± 2.1 and -53 ± 10.5 mg/dL) or DAPA (-17.0 ± 1.1 and -42.6 ± 10.0 mg/dL, respectively; P < 0.001). Insulin secretion rate (SAXA+DAPA +75%; SAXA +11%; DAPA +3%) and insulin sensitivity (+2.2 ± 1.7, +0.4 ± 0.7, and +0.4 ± 0.4 mg ⋅ kg-1⋅ min-1, respectively) improved with SAXA+DAPA (P < 0.007). Mean glucagon-like peptide 1 (GLP-1) was higher with SAXA+DAPA than with SAXA or DAPA. Fasting glucagon increased with DAPA and SAXA+DAPA but not with SAXA. Fasting endogenous glucose production (EGP) increased with SAXA+DAPA and DAPA. During MMTT, EGP suppression was greater (48%) with SAXA+DAPA (vs. SAXA 44%; P = 0.02 or DAPA 34%; P = 0.2). Metabolic clearance rate of glucose (MCRglu) increased more with SAXA+DAPA. At week 4, insulin secretion rate, β-cell glucose sensitivity, and insulin sensitivity had further increased in the SAXA+DAPA group (P = 0.02), with no additional changes in GLP-1, glucagon, fasting or MMTT EGP, or MCRglu. SAXA+DAPA provided superior glycemic control compared with DAPA or SAXA, with improved β-cell function, insulin sensitivity, GLP-1 availability, and glucose clearance.

Abstract P429: Coffee Intake is Associated With Enhanced Insulin Sensitivity, Lower Post-Load Glucose Responses, and Lower Truncal Adiposity

Higher coffee consumption has been associated with lower type 2 diabetes (T2D) risk, but the underlying mechanisms remain unclear. We tested the hypothesis that coffee intake is associated with improved glycemia insulin sensitivity, and reduced adiposity. We leveraged data in the VITamin D and OmegA-3 Trial (VITAL), a completed placebo-controlled 5-year trial including 25871 participants. Coffee intake was assessed by a diet questionnaire at baseline and year 2. In the VITAL clinical subcohort (n= 1054), glucose metabolism and insulin resistance were assessed by a 2-hr oral glucose tolerance test, body composition was measured by the dual X-ray absorptiometry, at baseline and year 2. We analyzed the association of coffee intake with glycemic traits and body composition, leveraging repeated assessments using multivariable-adjusted linear mixed models. Secondarily, we tested associations between coffee intake and T2D risk, in 22327 initially T2D-free individuals (482 cases in 5 years of follow-up) using multivariable-adjusted Cox regression. While coffee intake was not associated with fasting glucose or insulin levels, it was significantly associated with lower levels of 2-hr post-load glucose (SD difference per cup increment β = -0.062, P = 0.04) and insulin (β = -0.064, P = 0.02), and a higher metabolic clearance rate of glucose (β= 0.057, P = 0.007) and insulin sensitivity index (β= 0.059, P = 0.02). The associations were consistent for caffeinated and decaffeinated coffee. Further, caffeinated coffee intake was associated with higher body weight (β= 0.018, P = 0.02), but total coffee intake was associated with a lower truncal to limb fat ratio before and after adjusting for BMI (β= -0.057, P = 0.03). We did not observe evidence of association with incident T2D (HR =0.63; 95% CI 0.15-2.50). Higher coffee intake was associated with improved post-load glucose metabolism and insulin sensitivity, and lower truncal adiposity. The figure displays result estimates of linear mixed models. Asterisks represent associations P &lt; 0.05.

Effect of different levels of acute hypoxia on subsequent oral glucose tolerance in males with overweight: A balanced cross-over pilot feasibility study.

Previous research has shown that ≤60 min hypoxic exposure improves subsequent glycaemic control, but the optimal level of hypoxia is unknown and data are lacking from individuals with overweight. We undertook a cross-over pilot feasibility study investigating the effect of 60-min prior resting exposure to different inspired oxygen fractions (CON FI O2 =0.209; HIGH FI O2 =0.155; VHIGH FI O2 =0.125) on glycaemic control, insulin sensitivity, and oxidative stress during a subsequent oral glucose tolerance test (OGTT) in males with overweight (mean (SD) BMI=27.6 (1.3) kg/m2 ; n=12). Feasibility was defined by exceeding predefined withdrawal criteria for peripheral blood oxygen saturation (SpO2 ), partial pressure of end-tidal oxygen or carbon dioxide and acute mountain sickness (AMS), and dyspnoea symptomology. Hypoxia reduced SpO2 in a stepwise manner (CON=97(1)%; HIGH=91(1)%; VHIGH=81(3)%, p < 0.001), but did not affect peak plasma glucose concentration (CON=7.5(1.8) mmol∙L-1 ; HIGH=7.7(1.1) mmol∙L-1 ; VHIGH=7.7(1.1) mmol∙L-1 ; p=0.777; η2 =0.013), plasma glucose area under the curve, insulin sensitivity, or metabolic clearance rate of glucose (p > 0.05). We observed no between-conditions differences in oxidative stress (p > 0.05), but dyspnoea and AMS symptoms increased in VHIGH (p < 0.05), with one participant meeting the withdrawal criteria. Acute HIGH or VHIGH exposure prior to an OGTT does not influence glucose homeostasis in males with overweight, but VHIGH is associated with adverse symptomology and reduced feasibility.

Ketone Monoester Plus Carbohydrate Supplementation Does Not Alter Exogenous and Plasma Glucose Oxidation or Metabolic Clearance Rate During Exercise in Men Compared with Carbohydrate Alone

BackgroundIncreasing β-hydroxybutyrate (βHB) availability through ketone monoester (KE) plus carbohydrate supplementation is suggested to enhance physical performance by sparing glucose use during exercise. However, no studies have examined the effect of ketone supplementation on glucose kinetics during exercise. ObjectivesThis exploratory study primarily aimed to determine the effect of KE plus carbohydrate supplementation on glucose oxidation during steady-state exercise and physical performance compared with carbohydrate alone. MethodsUsing a randomly assigned, crossover design, 12 men consumed 573 mg KE/kg body mass plus 110 g glucose (KE+CHO) or 110 g glucose (CHO) before and during 90 min of steady-state treadmill exercise [54 ± 3% peak oxygen uptake (V˙O2peak)] wearing a weighted vest (30% body mass; 25 ± 3 kg). Glucose oxidation and turnover were determined using indirect calorimetry and stable isotopes. Participants performed an unweighted time to exhaustion (TTE; 85% V˙O2peak) after steady-state exercise and a weighted (25 ± 3 kg) 6.4 km time trial (TT) the next day after consuming a bolus of KE+CHO or CHO. Data were analyzed by paired t-tests and mixed model ANOVA. ResultsβHB concentrations were higher (P < 0.05) after exercise [2.1 mM (95% CI: 1.6, .6)] and the TT [2.6 mM (2.1, 3.1)] in KE+CHO compared with CHO. TTE was lower [−104 s (−201, −8)], and TT performance was slower [141 s (19,262)] in KE+CHO than in CHO (P < 0.05). Exogenous [−0.01 g/min (−0.07, 0.04)] and plasma [−0.02 g/min (−0.08, 0.04)] glucose oxidation and metabolic clearance rate {MCR [0.38 mg·kg−1·min−1 (−0.79, 1.54)]} were not different, and glucose rate of appearance [−0.51 mg·kg−1·min−1 (−0.97, −0.04)], and disappearance [−0.50 mg·kg−1·min−1 (−0.96, −0.04)] were lower (P < 0.05) in KE+CHO compared with CHO during steady-state exercise. ConclusionsIn the current study, rates of exogenous and plasma glucose oxidation and MCR were not different between treatments during steady-state exercise, suggesting blood glucose utilization is similar between KE+CHO and CHO. KE+CHO supplementation also results in lower physical performance compared with CHO alone.This trial was registered at www.clinicaltrials.gov as NCT04737694.

Differences in Insulin Sensitivity, Secretion, and the Metabolic Clearance Rate of Glucose in Newly Diagnosed Type 2 Diabetes Mellitus Patients: The Influences of Body Mass Index and Fatty Liver.

Background: Obesity and nonalcoholic fatty liver disease are strongly associated with type 2 diabetes mellitus (T2DM), affecting insulin sensitivity and β-cell function. They interact, exacerbating the development of hyperinsulinemia to T2DM. Methods: Through oral glucose tolerance and insulin secretion tests, the relationships between insulin sensitivity and secretion, glucose clearance, body mass index (BMI), and fatty liver were studied in newly diagnosed T2DM patients. The homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-β), insulin sensitivity index (ISI), and metabolic clearance rate (MCR) of glucose were calculated to analyze insulin sensitivity and β-cell function. Results: There were no differences in HOMA-IR, HOMA-β, first-phase insulin secretion (1st PH), second-phase insulin secretion (2nd PH), ISI, or MCR between lean fatty liver and lean nonfatty liver patients. Both overweight/obesity (ow/ob) and patients with fatty liver increased HOMA-IR, and decreased ISI and MCR. In the ow/ob subgroup, patients with fatty liver had severe insulin resistance but greater HOMA-β, 1st PH, and 2nd PH than individuals with nonfatty liver. The difference in MCR between fatty liver and nonfatty liver groups was not significant. Conclusion: BMI and hepatic steatosis are independent determinants of increased insulin resistance and decreased MCR. However, it is steatosis, not BMI, related to the increase in insulin secretion.

Ketone Ester Plus Carbohydrate Supplementation Impairs Physical Performance And Decreases Glucose Turnover Versus Carbohydrate Alone

BACKGROUND: Ketone esters combined with carbohydrate have been reported to enhance physical performance compared to carbohydrate alone. Improvements in physical performance are suggested to result from sparing of glucose for fuel use during exercise; however, no studies have examined the effect of ketone supplementation on glucose kinetics. PURPOSE: Determine the effect of ketone ester plus carbohydrate (KE + CHO) supplementation on physical performance and glucose kinetics during steady-state aerobic exercise. METHODS: Twelve men (mean ± SD; 29 ± 5 y, 26 ± 3 kg/m2) completed this randomized, double-blind, crossover study. After controlling exercise and diet for 48 h, participants consumed a KE + CHO (KE: 573 mg KE/kg body mass, CHO: 110 g glucose) or CHO (110 g glucose) drink before and during 90 min of steady-state treadmill exercise (54 ± 3 % VO2peak) with a weighted vest (30% body mass; 25 ± 3 kg). Glucose kinetics during exercise were determined using indirect calorimetry and tracer techniques ([6,6-2H2] glucose and 13C glucose). Participants performed an unweighted time to exhaustion test (TTE; 85 % VO2peak) following steady-state exercise. After 24 h of controlled feeding, participants consumed a bolus of KE + CHO or CHO and completed a weighted 4-mile time trial (TT; 25 ± 3 kg). RESULTS: β-hydroxybutyrate concentrations were higher (P < 0.05) after exercise (2.3 ± 0.8 vs. 0.1 ± 0.1 mM) and the TT (2.7 ± 0.8 vs. 0.1 ± 0.1 mM) in KE + CHO than CHO. TTE was lower (761 ± 429 vs. 865 ± 458 sec) and TT performance was slower (55.0 ± 7.4 vs. 52.9 ± 6.6 min) in KE + CHO than CHO (P < 0.05). Exogenous (0.5 ± 0.1 vs. 0.5 ± 0.1 g/min) and plasma (0.6 ± 0.1 vs. 0.6 ± 0.1 g/min) glucose oxidation rates in the last 40 min of steady-state exercise were the same between KE + CHO and CHO (P > 0.05). Glucose rate of appearance (6.5 ± 1.4 vs. 7.0 ± 1.6 mg/kg/min) and disappearance (6.7 ± 1.3 vs. 7.2 ± 1.6 mg/kg/min) during steady-state exercise was lower (P < 0.05) in KE + CHO than CHO, and metabolic clearance rate (MCR) did not differ between treatments (10.5 ± 3.0 vs. 10.1 ± 3.4 mL/kg/min; P > 0.05). CONCLUSION: KE + CHO impaired TT and TTE performance compared to CHO alone. Though glucose turnover was lower, similar rates of exogenous glucose oxidation and MCR during steady-state exercise in KE + CHO and CHO suggests performance decrements occur independent of glucose kinetics.

Effects of metabolic syndrome on fuel utilization during exercise on middle-aged moderately trained individuals.

People with the metabolic syndrome (MetS) may have blunted exercise stimulation of metabolism explaining their resistance to lower blood glucose and triglycerides with exercise training. Glycerol and glucose rate of appearance (Ra) in plasma and substrate oxidation were determined at rest and during cycle ergometer exercise at three increasing intensities (55, 80 and 95% of maximal heart rate) in 9 middle-aged (61±7 yr) individuals with MetS. Data were compared to 8 healthy-younger (29±10 yr) individuals matched for habitual exercise training and fat free mass (Healthy-young). At rest, fasting plasma triglycerides (TG), blood glucose and insulin were higher in MetS than in Healthy-young (38%, 42% and 85%, respectively; all p<0.05). At rest, and during low intensity exercise (32-43% VO2MAX), plasma glycerol Ra (index of whole-body lipolysis) and glucose Ra and Rd (index of glucose appearance and disposal) were similar in MetS and Healthy-young. Fat oxidation peaked at low intensity exercise similarly in MetS and Healthy-young (0.273±0.082 vs 0.272±0.078 g·min-1, respectively; p = 0.961). Ra glycerol increased with exercise intensity but was lower in MetS at moderate and high exercise intensities (i.e., 60-100% VO2MAX; p<0.05). Metabolic clearance rate of glucose at high intensity (85-100% VO2MAX) was lower in MetS compared to Healthy-young (p = 0.029). The MetS that develops in middle adulthood, reduces exercise lipolysis and plasma glucose clearance at high exercise intensities, but does not blunt fat or carbohydrate metabolism at low exercise intensity.

Hypoglycemic effects of antioxidant-rich plant extracts on postprandial glycemic responses in participants with prediabetes (GLARE study)

Background: Plant extracts may help to improve glycemic control in individuals with poor glycemic control. However, few studies have been investigated in the prediabetes cohort, which is a high-risk condition for T2DM. Thus, this study aimed to investigate the acute effect of grape seed, rooibos tea, and olive leaf extracts on postprandial blood glucose and insulin in participants with prediabetes. Methods: An acute, single-blind, placebo-controlled, non-randomized, crossover study (ACTRN12617000837325) where placebo and extracts of grape seed, rooibos tea and olive leaf standardized for total antioxidant capacity were given separately during an oral glucose tolerance test to participants (n=19, five men and fourteen women, aged 65.0 ± 1.6 years, Body Mass Index (BMI) 27.3 ± 1.1 kg/m2) with prediabetes (Glycated hemoglobin A1c (HbA1c) 42 ± 1 mmol/mol). The primary outcome incremental area under the curve of glucose (iAUCglucose) was examined with other glycemic measures. Data was analyzed using linear mixed model for repeated measures. Secondary analysis was conducted by stratifying participants into either a healthier or less healthy subgroup based on the postprandial time to glucose and insulin peaks, with the less healthy subgroup experiencing delayed glucose and/or insulin peaks.Results: There were no overall significant changes to glucose and insulin measures between all plant extracts and placebo (p&gt;0.05). Upon secondary analysis, all extracts affected glycemic responses in the less healthy subgroup. Compared to placebo, grape seed reduced plasma iAUCglucose(p=0.016, 21.9% reduction), 2 h postprandial glucose (2hPG) (p=0.034, 14.7% reduction) and metabolic clearance rate of glucose (MCRglucose) (p=0.016, 16.7% increase). It also improved insulin indices such as 2 h postprandial insulin (2hPI) (p=0.029, 22.4% reduction) and Stumvoll overall insulin sensitivity index (ISIoverall) (p=0.028, 15.0% increase). Rooibos tea extract significantly improved β-cell function as demonstrated by the increased oral disposition index (DI) (p=0.031, 32.4% increase) compared to placebo. Olive leaf extract significantly increased incremental area under the curve of insulin (iAUCinsulin) (p=0.040, 16.7% increase). Conclusion: Grape seed, rooibos tea and olive leaf extracts demonstrated acute hypoglycemic benefits in adults with prediabetes and having less healthy metabolic profiles. A chronic study on the plant extracts is warranted to determine their longer-term impact on prediabetes.Trial Registration ID: ACTRN12617000837325Keywords: grape seed extract; rooibos tea extract; olive leaf extract; impaired glycemic control; hyperglycemia; hypoglycemic effects; insulin sensitivity; beta-cell function

Metabolomic profiles are reflective of hypoxia-induced insulin resistance during exercise in healthy young adult males.

Hypoxia-induced insulin resistance appears to suppress exogenous glucose oxidation during metabolically matched aerobic exercise during acute (<8 h) high-altitude (HA) exposure. However, a better understanding of this metabolic dysregulation is needed to identify interventions to mitigate these effects. The objective of this study was to determine if differences in metabolomic profiles during exercise at sea level (SL) and HA are reflective of hypoxia-induced insulin resistance. Native lowlanders (n = 8 males) consumed 145 g (1.8 g/min) of glucose while performing 80-min of metabolically matched treadmill exercise at SL (757 mmHg) and HA (460 mmHg) after 5-h exposure. Exogenous glucose oxidation and glucose turnover were determined using indirect calorimetry and dual tracer technique ([13C]glucose and [6,6-2H2]glucose). Metabolite profiles were analyzed in serum as change (Δ), calculated by subtracting postprandial/exercised state SL (ΔSL) and HA (ΔHA) from fasted, rested conditions at SL. Compared with SL, exogenous glucose oxidation, glucose rate of disappearance, and glucose metabolic clearance rate (MCR) were lower (P < 0.05) during exercise at HA. One hundred and eighteen metabolites differed between ΔSL and ΔHA (P < 0.05, Q < 0.10). Differences in metabolites indicated increased glycolysis, tricarboxylic acid cycle, amino acid catabolism, oxidative stress, and fatty acid storage, and decreased fatty acid mobilization for ΔHA. Branched-chain amino acids and oxidative stress metabolites, Δ3-methyl-2-oxobutyrate (r = −0.738) and Δγ-glutamylalanine (r = −0.810), were inversely associated (P < 0.05) with Δexogenous glucose oxidation. Δ3-Hydroxyisobutyrate (r = −0.762) and Δ2-hydroxybutyrate/2-hydroxyisobutyrate (r = −0.738) were inversely associated (P < 0.05) with glucose MCR. Coupling global metabolomics and glucose kinetic data suggest that the underlying cause for diminished exogenous glucose oxidative capacity during aerobic exercise is acute hypoxia-mediated peripheral insulin resistance.

FAT DEPOSITION IN THE NUCHAL REGION IS ASSOCIATED WITH INSULIN RESISTANCE AND LOW METABOLIC CLEARANCE RATE OF GLUCOSE IN ADULT MALES

Background: The role of classical proxies for obesity such as the body mass index (BMI) and waist circumference (WC) in the development of insulin resistance (IR) is well reported. However, there is the dearth of information on the association between subcutaneous fat deposition in the nuchal region and the development of IR.Objective: This study determined the interplay between thickness of cervical fat fold (CFF) and development of IR.Methods: Fifty adult males with CFF and 50 males without CFF were enrolled into this study. Standard Oral Glucose Tolerance Testing (OGTT) was performed and fasting plasma glucose (FPG), 2 hours post prandial glucose (2hrPPG), lipids, fasting insulin (FI), 2 hours postprandial insulin (2hrPPI) levels were determined. Thereafter, indices of IR and estimated metabolic clearance rate of glucose (eMCR) were calculated using standard formula.Results: Levels of FI, 2hrPPI and the median values of indices of IR were significantly higher while median values of indices of insulin sensitivity and eMCR were significantly lower in CFF compared with the controls. Predicting the diagnostic property of CFF for insulin sensitivity with reference to Quantitative Insulin Sensitivity Check Index (QUICKI) cut-off values, the Area Under the Receiver Operating Characteristic Curve (AUROC) was 0.695 (P-value = 0.043) and a CFF cut-off value of 12.5 cm had 75% sensitivity and 55.3% specificity.Conclusion: Adult males with CFF have IR and low eMCR and are thus, prone to developing cardiovascular and metabolic diseases. Also, CFF thickness appears to be a good anthropometric index of insulin resistance.

Acute Hypoxia Suppresses Exogenous Glucose Rate Of Appearance And Metabolic Clearance Rate During Steady-state Aerobic Exercise

BACKGROUND: Previously, we observed that exogenous carbohydrate oxidation is reduced when lowlanders perform steady-state aerobic exercise after 5 h exposure to high altitude (HA). However, the underlying glucose kinetics that may contribute to the reduction in exogenous carbohydrate oxidation during steady-state aerobic exercise performed at HA have not been explored. PURPOSE: Determine glucose turnover responses to exogenous carbohydrate ingestion during metabolically-matched, steady-state aerobic exercise at HA and sea level (SL). METHODS: Using a randomized, crossover design, lowlanders (n = 8 males, mean ± SD, age: 23 ± 2 yr, body mass: 87 ± 10 kg, and VO2peak: SL 4.3 ± 0.2 L/min and HA 2.9 ± 0.2 L/min) consumed 145 g (1.8 g/min) of glucose while performing 80 min of metabolically-matched (SL: 1.66 ± 0.14 L/min V̇O2, 329 ± 28 kcal; HA: 1.59 ± 0.10 L/min V̇O2, 320 ± 19 kcal) treadmill exercise at SL (757 mmHg) and after 5 h of simulated HA (hypobaric hypoxia, 460 mmHg) exposure. Glucose rate of appearance (Ra), disappearance (Rd), and metabolic clearance rate (MCR), were determined during the last 40 min of exercise using primed, constant [6,6-2H2] glucose infusions and 13C glucose-labeled drinks. RESULTS: Exogenous glucose oxidation rate was lower (P < 0.05) at HA (0.35 ± 0.07 g/min) compared to SL (0.44 ± 0.05 g/min). Total glucose Ra was lower (P < 0.05) at HA (12.3 ± 1.5 mg/kg/min) compared to SL (13.8 ± 2.0 mg/kg/min). Exogenous glucose Ra was lower (P < 0.05) at HA (8.9 ± 1.3 mg/kg/min) compared to SL (10.9 ± 2.2 mg/kg/d), but there was no difference between endogenous glucose Ra at HA compared to SL. Glucose Rd and MCR were lower (P < 0.05) at HA (12.7 ± 1.7 mg/kg/min and 9.0 ± 1.8 mg/kg/min) compared to SL (14.3 ± 2.0 mg/kg/min and 12.1 ± 2.3 mg/kg/min). CONCLUSION: Ingesting carbohydrate during steady-state aerobic exercise performed 5 h after arriving at HA is associated with lower exogenous glucose Ra, glucose Rd, and MCR compared to SL. These data suggest that altered glucose kinetics, indicative of either a reduction in exogenous glucose absorption or release from the gut, may contribute to lower exogenous carbohydrate oxidation during exercise upon initial exposure to HA.

Glucose and protein metabolic responses to an energy- but not protein- restricted diet in type 2 diabetes.

To test the effect of energy restriction with maintained protein intake on body composition and on insulin sensitivity of glucose and protein metabolism in adults with type 2 diabetes (T2D). After 3 days of an isoenergetic diet with 1.2 g/kg/d protein, obese adults with T2D (three women, two men) followed a 5-week diet providing 60% of energy requirements with 45% carbohydrate, and with protein maintained at pre-intervention level. Isotopic tracers were used to quantify whole-body glucose (3-3 H-glucose) and protein (13 C-leucine) metabolism pre- (day 4) and post-intervention (day 39), in the postabsorptive state and during a hyperinsulinaemic, isoglycaemic, isoaminoacidaemic clamp. Body composition was measured using dual-energy x-ray absorptiometry. After energy restriction, 6% weight loss occurred via total body (11%) and visceral fat losses (25%), but lean mass was preserved. Fasting glucose level, serum insulin level, homeostatic model assessment of insulin resistance index and C-peptide level decreased significantly (29%, 38%, 54% and 38%, respectively) as did other cardiometabolic risk factors. Between clamp studies, postabsorptive protein turnover and oxidation rates decreased (12% and 32%), resulting in less negative net balance, consistent with protein conservation. The rates of glucose turnover decreased, and glucose metabolic clearance rate improved (24%). During the clamp, protein flux was lower (9%) and breakdown suppressed (12%), and net balance became less negative but not different. Although glucose turnover did not differ, metabolic clearance improved by 47%. In obese adults with T2D, an energy-restricted diet with maintained protein intake of ~1.2 g/kg/d improved the kinetics of protein metabolism (particularly in the postabsorptive state), and preserved lean body mass and increased glucose metabolic clearance rate.

Acute effects of an isocaloric macronutrient-matched breakfast meal containing almonds on glycemic, hormonal, and appetite responses in men with type 2 diabetes: a randomized crossover study.

This randomized crossover study assessed the acute effects of almonds on postprandial glycemic, hormonal, and appetite responses in a sample of 7 men with type 2 diabetes (T2D). Participants completed 2 experimental visits during which a control (white bread, butter, cheese) and a test (white bread, almonds) meal were ingested. Energy, available carbohydrate, total lipid, and protein content were the same in both meals. Blood samples were collected in fasting state as well as 15, 30, 60, 90, 120, and 240 min postprandially for quantifying blood glucose, as well as insulin and glucagon-like peptide-1 (GLP-1) serum concentrations. Subjective appetite sensations were assessed using visual analog scales at the same time-points. Within this sample of participants, the test meal was found to be associated with lower postprandial glycemia and insulinemia, higher GLP-1 serum concentrations, decreased hunger and desire to eat, and increased fullness. The test meal was also associated with an increased estimated glucose metabolic clearance rate, indicating higher postprandial insulin sensitivity. Overall, results suggest that almonds' macronutrient subtype profile could have a beneficial impact on postprandial glycemic, hormonal, and appetite responses in men with T2D. Studies with larger sample sizes are warranted to confirm these findings. Novelty A meal containing almonds (vs. isocaloric macronutrient-matched control) induced lower glycemic and insulinemic responses. A meal containing almonds (vs. isocaloric macronutrient-matched control) induced a greater elevation in postprandial GLP-1 serum concentrations. A meal containing almonds (vs. isocaloric macronutrient-matched control) induced more favourable postprandial appetite responses.

Obesity Status Affects the Relationship Between Protein Intake and Insulin Sensitivity in Late Pregnancy

The purpose of this study was to determine the associations between amount and type of dietary protein intake and insulin sensitivity in late pregnancy, in normal weight and overweight women (29.8 ± 0.2 weeks gestation, n = 173). A 100-g oral glucose tolerance test (OGTT) was administered following an overnight fast to estimate the metabolic clearance rate of glucose (MCR, mg·kg−1·min−1) using four different equations accounting for the availability of blood samples. Total (TP), animal (AP), and plant (PP) protein intakes were assessed using a 3-day food record. Two linear models with MCR as the response variable were fitted to the data to estimate the relationship of protein intake to insulin sensitivity either unadjusted or adjusted for early pregnancy body mass index (BMI) because of the potential of BMI to influence this relationship. There was a positive association between TP (β = 1.37, p = 0.002) and PP (β = 4.44, p < 0.001) intake in the last trimester of pregnancy and insulin sensitivity that weakened when accounting for early pregnancy BMI. However, there was no relationship between AP intake and insulin sensitivity (β = 0.95, p = 0.08). Therefore, early pregnancy BMI may be a better predictor of insulin sensitivity than dietary protein intake in late pregnancy.

1155-P: Effect of Endoscopic Duodenal-Jejunal Bypass Liner on Parameters of Insulin Sensitivity and Secretion in Subjects with Type 2 Diabetes Mellitus and Obesity

Duodenal-jejunal by-pass liner (DJBL) is an endoscopically implantable device designed to non-invasively mimic the effects of surgical gastric by-pass. However, the exact mechanisms responsible for improved glucose control associated with DJBL are still unclear. The aim of our study was to assess the effect of DJBL on insulin sensitivity and secretion in subjects with type 2 diabetes mellitus (T2DM) and obesity. Twenty-one obese subjects with T2DM (15 males, age 52.3 ± 11.2 years) underwent the implantation of the EndoBarrier DJBL (GI Dynamics, U.S.). Anthropometric, biochemical and hormonal parameters were measured before and 10 months after the implantation of DJBL. Insulin sensitivity was assessed using euglycemic-hyperinsulinemic clamp. Standard parameters including glucose disposal rate (M) and metabolic clearance rate of glucose (MCG) were calculated based on clamp results. Over 10 months the implantation of DJBL decreased body weight (body mass index 41.6 ± 6.1 vs. 37.5 ± 4.2 kg/m2, p&amp;lt;0.001) and improved glucose control (fasting blood glucose 10.5 ± 2.5 vs. 8.4 ± 2.4 mmol/l, p&amp;lt;0.001; HbA1C 74.7 ± 17.8 vs. 55.6 ± 12.4 mmol/mol, p&amp;lt;0.001). These improvements were accompanied by a marked increase in insulin sensitivity as shown by the results of the euglycemic-hyperinsulinemic clamp (M 1.5 ± 0.8 vs. 2.6 ± 1.0 mg.kg-1.min-1, p&amp;lt;0.001; MCG 1.4 ± 0.7 vs. 2.6 ± 0.2 mg.kg-1.min-1, p&amp;lt;0.001). In contrast, insulin secretion was not affected by DJBL (fasting insulin 21.8 ± 13.0 vs. 18.5 ± 9.5 mIU/l, p=0.312; C-peptide 2.7 ± 1.1 vs. 2.4 ± 1.1 nmol/l, p=0.172). To conclude the improvement in glucose control associated with the implantation of Endobarrier DJBL is primarily caused by increased insulin sensitivity rather than augmented insulin secretion. Disclosure M. Kudlackova: None. M. Mraz: None. M. Haluzik: None. T. Pelikanova: None. M. Benes: None. D. Lapesova: None. D. Kobrova: None. Z. Vlasakova: None. O. Brizova: None. Z. Lacinova: None. Funding Institute for Clinical and Experimental Medicine (IN00023001)

406-P: Effect of Metformin on Dicarbonyl Stress in Patients with Type 2 Diabetes and Chronic Heart Failure

Background and Aims: Treatment with metformin (MET) in diabetic patients with chronic heart failure (HF) is associated with better cardiovascular outcomes. The endothelial dysfunction, atherosclerosis and macrovascular diabetic complications are associated with excessive generation of reactive dicarbonyls like methylglyoxal (MG). MET has been proposed as a scavenger of methylglyoxal. The aim of the study was to evaluate the effects of MET on substrate metabolism and dicarbonyl stress in patients with DM and HF. Materials and Methods: A randomized, double-blind, placebo-controlled, crossover study in a total time of six months testing the effect of 3- month usage of MET (2 g/day) vs. placebo. A group of 40 treatment naive patients with type 2 DM and HF were included. At the beginning and at the end of each intervention period various metabolic tests were done including hyperinsulinemic-isoglycemic clamp, parameters of dicarbonyl stress like MG, Glutathione (GSH), glutathione disulfide (GSSG), and the activity of Glyoxalase1 (GLO-1). Results: MET significantly reduced HbA1c compared to placebo (p˂0.01). Insulin sensitivity, measured as a metabolic clearance rate of glucose (MCR) during the clamp, improved significantly with MET (p˂0.001) but also, although less significantly, with placebo (p˂0.05), difference between MET and placebo was not significant. Compared to placebo, GHS levels increased after the intervention (baseline vs. MET vs. PL: 866 ± 231 vs. 994 ± 342 vs. 878 ± 266µmol/l, p&amp;lt;0.05). GSH/GSSG ratio was not affected. The levels of MG decreased after MET (p&amp;lt;0.05), decrease after placebo was not significant. The activity of GLO-1 was not affected. Conclusions: Our results on a unique group of patients with heart failure and diabetes support the evidence that one of the cardioprotective pathways of metformin is through reducing dicarbonyl stress. As there was no change in the GLO-1 activity, it might be due to binding and deactivation of reactive dicarbonyls by MET. Disclosure J. Kopecky: None. E. Hošková: None. J. Veleba: None. H. Malinska: None. K. Velebova: None. V. Melenovsky: None. T. Pelikanova: None. Funding Agentura pro zdravotnický výzkum Ceské Republiky (AZV16-27496A)

Prepregnancy Fat Free Mass and Associations to Glucose Metabolism Before and During Pregnancy.

Our aim was to quantify the individual contribution of prepregnancy (PP) fat-free mass (FFM), expressed as [PP-FFM index (PP-FFMI) = FFM (kg)/height (m2)], on markers of glucose homeostasis before and during pregnancy. Body composition was assessed in 43 women before pregnancy using air-displacement plethysmography. Blood was drawn at PP and gestational weeks ∼8 and 30. Relationships between body composition (independent) variables and glucose homeostasis (dependent) variables were assessed using adjusted correlations and simple and multiple linear regression analyses. PP-FFMI was the strongest predictor of plasma insulin concentration [squared partial correlation (Pr2) = 17, P = 0.007] and homeostasis model assessment of insulin resistance (HOMA2-IR) (Pr2 = 16, P = 0.010). At gestation week 30, PP-FFMI and gestational weight gain (GWG) were the strongest predictors of insulin concentration (PP-FFMI: Pr2 = 20, P = 0.010; GWG: Pr2 = 12, P = 0.052) and HOMA2-IR (PP-FFMI: Pr2 = 19, P = 0.012; GWG: Pr2 = 13, P = 0.045). After accounting for PP fat mass index (PP-FMI), PP-FFMI and GWG were independently associated with first-phase insulin response (PP-FFMI: Pr2 = 20, P = 0.009; GWG: Pr2 = 15, P = 0.025) and second-phase insulin response (PP-FFMI: Pr2 = 19, P = 0.011; GWG: Pr2 = 17, P = 0.016). PP-FMI was the strongest predictor of an oral glucose tolerance test‒derived estimated metabolic clearance rate of glucose (PP-FMI: Pr2 = 14, P = 0.037) and estimated insulin sensitivity index (PP-FMI: Pr2 = 13, P = 0.047). PP-FFMI was a predictor of markers of glucose homeostasis before and during pregnancy. Studies assessing the effect of skeletal muscle quality on metabolic regulation during pregnancy are warranted.

Beta-cell Function and Metabolic Clearance Rate of Glucose in Patients with Major Mental Health Disorders on Antipsychotic Drug Treatment

BackgroundInsulin resistance and metabolic alteration continue to be essential features of major mental health disorders (MMHD) with poorly understood and multifaceted mechanisms. This study was carried out to provide information on insulin resistance, beta-cell function, metabolic clearance rate of glucose and their possible interplay with duration of antipsychotic use in patients with major mental health disorders. MethodologyPlasma levels of glucose and insulin were determined in 124 patients with MMHD after an overnight fast and at 30 and 120 min of standard Oral Glucose Tolerance Test. Thereafter, indices of insulin resistance, beta-cell function and estimated metabolic clearance rate of glucose (eMCR) were calculated appropriately. Statistical analysis was done using ANOVA, Kruskal Wallis, independent Student's t-test and Mann-Whitney U. P-values less than 0.05 were considered as statistically significant. ResultsMetabolic factors (fasting and postprandial glucose and insulin), indices of insulin sensitivity and β-cell function were not significantly different when patients with schizophrenia, bipolar and depression were compared with one another. Postprandial insulin level at 30 min (30 min PPI), estimated First and Second Phases of Insulin Release (eFPIR, eSPIR) were significantly lower in patients on atypical antipsychotic drugs [18.15 (3.57-40.35) μIU/ml), 617.63 (320.06-911.31) pmol/l, 180.30 (114.82–249.39) pmol/l] compared with patients on typical antipsychotic drugs [27.48 (13.33–47.68) μIU/ml, 767.69 (530.58-1198.35) pmol/l, 209.89 (154.01-310.97) pmol/l]. Furthermore, the mean waist circumference and body mass index were significantly higher in patients who have been on anti-psychotic drug for more than 10 years compared with patients with less than 5 years history of anti-psychotic use. eMCR of glucose progressively declined with increasing duration of antipsychotic use and it was significantly lower in patients who have been on antipsychotic drugs for more than 10 years [8.09 (5.90-9.44) ml.kg−1.min−1] compared with patients who have been on the drugs for less than 5 years [9.03 (7.47-10.04) ml.kg−1.min−1]. ConclusionPatients on atypical antipsychotics seem to have insulin secretion phases consistent with β-cell dysfunction. Also, chronicity of antipsychotic treatment predisposes patients with major mental health disorders to central adiposity and low metabolic clearance rate of glucose, a forerunner of glucose intolerance.