Metabolic Clearance Rate Of Glucose Research Articles

LONG-TERM IMPROVEMENT OF GLUCOSE HOMEOSTASIS AND BODY COMPOSITION IN PATIENTS UNDERGOING LAPAROSCOPIC SLEEVE GASTRECTOMY.

Laparoscopic sleeve gastrectomy (SG) has gained popularity as a metabolic procedure, but its long-term effectiveness for Romanian patients remains unclear. To assess the long-term efficacy of SG for Romanian patients and to evaluate the differences between 5 years and 1 year follow-up. A longitudinal, prospective analysis of collected data from 68 patients undergoing SG between 2009 and 2014 was performed. Long-term outcomes at 5 years were analyzed in terms of total weight loss (%TWL), excess weight loss (%EWL), body composition and glucose homeostasis. All patients meeting the standard criteria for SG before inclusion were prospectively enrolled in the study. Of the 68 patients, eight were lost to follow-up, therefore, 60 patients (41.7±12.5 years, baseline body mass index [BMI] 44.6±9.9Kg/m2) were analyzed. The BMI decreased at 12 months with 30.7% from the preoperative BMI (p<0.001) and subsequently stabilized at 5 years.TWL and EWL were 30.6% and 83.1%, respectively at 1 year, with a slightly increase at 5 years.Therapeutic success rate (%EWL≥50) and diabetes remission rate (Buchwald criteria) were 93.3% and respectively 63.6% at 5 years. Insulin sensitivity index and metabolic clearance rate of glucose increased with 92.5% and 60.1% respectively, in the third month from baseline (p<0.001), while estimated second phase of insulin secretion decreased with 7.9% in the first month postoperatively (p=0.04), remaining stable afterwards. SG was effective in terms of %EWL, body composition and glucose homeostasis improvement for Romanian patients, the outcomes stabilizing after 1 year follow-up.

The Effect of a Vegetarian vs Conventional Hypocaloric Diabetic Diet on Thigh Adipose Tissue Distribution in Subjects with Type 2 Diabetes: A Randomized Study

ABSTRACTObjective: The aim of our study was to compare the effects of a vegetarian and a conventional diet on thigh adipose tissue distribution in subjects with type 2 diabetes (T2D).Methods: Seventy-four subjects with T2D were randomly assigned to either follow a vegetarian diet (V, n = 37) or a control group who followed an isocaloric conventional anti-diabetic diet (C, n = 37). Both diets were calorie restricted (−500 kcal/day). To measure insulin sensitivity, the hyperinsulinemic (1 mU.kg−1.min−1) isoglycemic clamp was conducted. β-Cell function was assessed using a mathematical model after a test meal. Magnetic resonance imaging of the thigh was performed. All subjects were examined at 0, 3, and 6 months. Statistical analyses were performed using repeated measures analysis of variance and a multivariate regression model.Results: Greater reduction was observed in total leg area in V (−13.6 cm2 [95% confidence interval [CI], −14.2 to −12.9] in V vs −9.9 cm2 [95% CI, −10.6 to −9.2] in C; Gxt p < 0.001). The reduction in subcutaneous fat was comparable in response to both diets (Gxt, p = 0.64). Subfascial fat was reduced only in response to a vegetarian diet (−0.82 [95% CI, −1.13 to −0.55] cm2 in V vs −0.44 [95% CI, −0.78 to +0.02] cm2 in C; Gxt, p = 0.04). The reduction in intramuscular fat tended to be greater in response to a vegetarian diet (−1.78 [95% CI, −2.26 to −1.27] cm2 in V vs −0.57 [95% CI, −1.06 to −0.09] cm2 in C; Gxt, p = 0.12). Changes in subcutaneous and subfascial fat correlated with changes in glycated hemoglobin (HbA1c), fasting plasma glucose, and β-cell insulin sensitivity. After adjustment for changes in body mass index (BMI), correlations remained significant for changes in fasting plasma glucose and β-cell insulin sensitivity and with changes in triglycerides.Conclusions: Our data indicate the importance of both subcutaneous and subfascial fat in relationship to glucose and lipid metabolism.Abbreviations: BMI , body mass index; C , control group; FPG , fasting plasma glucose; Gxt , interaction between group and time; HbA1c , glycated hemoglobin; MCR , metabolic clearance rate of glucose; OPLS , orthogonal projections to latent structure; T2D , type 2 diabetes; V , vegetarian group

Short term elevation in dietary protein intake does not worsen insulin resistance or lipids in older adults with metabolic syndrome: a randomized-controlled trial

BackgroundThere is a great deal of controversy as to whether higher protein intake improves or worsens insulin sensitivity in humans. The purpose of the study was to determine the influence of a short-term elevation in dietary protein on hepatic and peripheral insulin sensitivity in twelve older subjects (51–70 yrs) with metabolic syndrome.MethodsIndividuals were randomly assigned to one of the dietary groups: recommended protein intake (RPI, 10% of daily calorie intake) or elevated protein intake (EPI, 20% of daily calorie intake) for 4 weeks. Prior to and immediately following the dietary intervention, subjects were studied with primed continuous infusion of [6,6-2H2]glucose and [1-13C]glucose dissolved in drink during the dual tracer oral glucose tolerance test (DT OGTT) to determine hepatic and peripheral insulin sensitivity. Plasma lipids were measured pre- and post-dietary intervention.ResultsIn both intervention groups: 1) hepatic insulin sensitivity as assessed by the endogenous glucose rate of appearance (glucose Ra), 2) peripheral insulin sensitivity as assessed by the metabolic clearance rate of glucose normalized to plasma glucose concentration (MCR) and/or the rate of glucose utilization (Rd) or 3) glucose/insulin AUC were unaffected by the diets. Moreover, fasting lipid was not affected by RPI or EPI.ConclusionOur findings suggest that a short-term elevation in EPI with correspondingly higher branched chain amino acid (BCAA) contents has no detrimental impact on hepatic and peripheral insulin sensitivity or plasma lipid parameters in older adults with metabolic syndrome.Trial registrationClinicalTrials.gov Identifier: NCT02885935; This trial was registered retrospectively (Study start date, April 01, 2013, date of registration, August 26, 2016).

Dioscorea esculenta-induced increase in muscle sex steroid hormones is associated with enhanced insulin sensitivity in a type 2 diabetes rat model.

The effects of chronic Dioscorea esculenta administration and exercise training on muscle sex steroid hormone levels and insulin resistance in type 2 diabetes rats was assessed. Twenty-week-old male Otsuka Long Evans Tokushima Fatty (OLETF) rats were assigned randomly to the control, D. esculenta treatment, D. esculenta with 5α-reductase inhibitor treatment, or the exercise training groups (running at 25 m/min for 1 h, 5 d/wk; n = 10 each group). Eight weeks of D. esculenta treatment or exercise training significantly attenuated the increase in plasma insulin and fasting glucose levels. Plasma and muscle concentrations of dehydroepiandrosterone and 5α-dihydrotestosterone (DHT) and the expression of 5α-reductase increased significantly in the D. esculenta-treated and exercise training groups, and both treatments led to the upregulation of glucose transporter-4 translocation with concomitant increases in PKB and PKC-ζ/λ phosphorylation. Furthermore, the glucose metabolic clearance rate, which represents insulin sensitivity, increased significantly in both the D. esculenta-treated and exercise training groups. These effects were suppressed by administration of the DHT synthetic inhibitor. Together, these findings suggest that the D. esculenta-induced increase in muscle sex steroid hormone levels helps decrease insulin resistance in type 2 diabetes.-Sato, K., Fujita, S., Iemitsu, M. Dioscorea esculenta-induced increase in muscle sex steroid hormones is associated with enhanced insulin sensitivity in a type 2 diabetes rat model.

Intramyocellular lipid content in subjects with impaired fasting glucose after telmisartan treatment, a randomised cross-over trial

Ectopic lipid accumulation in skeletal muscle is associated with insulin resistance. Telmisartan improves metabolic parameters in type 2 diabetic patients. The aim of our study was to evaluate the in vivo effect of telmisartan on intramyocellular lipid content (IMCL) in subjects with impaired fasting glucose (IFG) by magnetic resonance spectroscopy (MRS). We enrolled 10 subjects with IFG in a cross-over, placebo-controlled, randomized, double-blind trial, treated with 3 weeks of telmisartan (160 mg daily) or placebo. After completing each treatment, a hyperinsulinaemic euglycaemic clamp (1 mU/kg per min; 5 mmol/l; 120 min) to assess insulin action (metabolic clearance rate of glucose, MCR) and 1H MRS of the m. tibialis anterior using a MR Scanner Siemens Vision operating at 1.5 T to evaluate IMCL content, were performed. Plasma adipokine levels were determined simultaneously. Telmisartan treatment resulted in a lower fasting plasma glucose (FPG) (p < 0.05), but insulin action was comparable to after placebo. Telmisartan did not affect IMCL content. After placebo, IMCL correlated negatively with total cholesterol (p < 0.001), MCR (p < 0.05) and adiponectin (p < 0.05) and positively with FPG (p < 0.05). After telmisartan treatment there was only a positive correlation between IMCL and TNFα (p < 0.05). IMCL content is related to parameters of glucose metabolism and insulin action in sedentary IFG subjects. A short telmisartan treatment did not affect the IMCL content despite its positive effect on FPG. The improvement in FPG was probably mediated through interference with other metabolic pathways.

Insulin resistance in patients with type 1 diabetes assessed by glucose clamp studies: systematic review and meta-analysis.

The aim of this study was to perform a systematic review and meta-analysis on insulin resistance in adult patients with type 1 diabetes mellitus compared to healthy controls, assessed by hyperinsulinemic euglycemic clamp studies. We conducted a systematic search of publications using PubMed, EMBASE, Web of Science and COCHRANE Library. Hyperinsulinemic euglycemic clamp studies comparing adult patients with type 1 diabetes mellitus to healthy controls were eligible. Primary outcome measures were pooled mean differences of insulin sensitivity of endogenous glucose production (EGP), of glucose uptake and of lipolysis. We estimated mean (standardized) differences and 95% CIs using random effects meta-analysis. We included 38 publications in this meta-analysis. The weighed mean differences in EGP during hyperinsulinemia between patients and controls was 0.88 (95% CI: 0.47, 1.29) in the basal state and 0.52 (95% CI: 0.09, 0.95) in insulin stimulated conditions, indicating decreased hepatic insulin sensitivity in patients. Insulin sensitivity of glucose uptake was either reported as M value (M), glucose infusion rate (GIR), glucose disposal rate (GDR) or metabolic clearance rate (MCR). Weighed mean differences were similar for M -3.98 (95% CI: -4.68, -3.29) and GIR -4.61 (95% CI: -5.86, -3.53). Weighed mean difference for GDR was -2.43 (95% CI: -3.03, -1.83) and -3.29 (95% CI: -5.37, -1.22) for MCR, indicating decreased peripheral insulin sensitivity in patients. Insulin mediated inhibition of lipolysis was decreased in patients, reflected by increased non-esterified fatty acid levels. Insulin resistance is a prominent feature of patients with type 1 diabetes mellitus and involves hepatic, peripheral and adipose tissues.

The effect of metformin on glucose homeostasis during moderate exercise.

We investigated the role of metformin on glucose kinetics during moderate exercise. Before, during, and after a 45-min bout of exercise at 60% VO2max, glucose kinetics were determined by isotope tracer technique in patients with type 2 diabetes mellitus with metformin treatment (DM2+Met) or without metformin treatment (DM2) and in healthy control subjects (CON) matched for BMI and age. Glucoregulatory hormones and metabolites were measured throughout the study. Plasma glucose concentration was unchanged during exercise in CON but decreased in DM2. No significant change was found in DM2+Met. Hormones and metabolites showed no differences among the groups except for elevated exercise-induced concentrations of lactate in DM2 (area under the curve [AUC] 31 ± 1% vs. CON) and glucagon in DM2 (AUC 5 ± 1% vs. DM2+Met). Free fatty acid levels were lower in DM2+Met than in DM2 (AUC -14 ± 1%). Absolute values of the baseline glucose rate of appearance (Ra) were elevated in DM2 and DM2+Met, but the increase in glucose Ra relative to baseline was blunted in DM2 (19 ± 1%) and DM2+Met (18 ± 4%) compared with CON (46 ± 4%). Glucose rate of disappearance relative to baseline increased more in CON (31 ± 3%) than in DM2 (6 ± 1%) and DM2+Met (21 ± 2%), showing a small increase caused by metformin. Glucose metabolic clearance rate relative to baseline was similar during exercise in DM2 (33 ± 1%) and CON (35 ± 3%) but was improved in DM2+Met (37 ± 3%) compared with DM2. Metformin has a positive effect on glucose homeostasis during exercise.

Lack of impact of angiotensin-converting enzyme gene polymorphism and salt intake on insulin resistance and limb blood flow.

We postulated the mechanism for the association between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and insulin sensitivity might relate to changes in blood flow regulation. We studied the association of this polymorphism with insulin action, and insulin-mediated changes in limb blood flow (LBF), under conditions of high and low salt intake. We also studied effects of genotype and salt loading on renin-angiotensin-aldosterone system (RAAS) activity. Twenty people with (10 I/I; 10 D/D) and 23 without (10 I/I; 13 D/D), type 2 diabetes were studied during 6 days of 40 mmol/day and 220 mmol/day sodium diet in a randomized, double-blind cross-over fashion. On the sixth day of each condition, we measured 24-h blood pressure, plasma volume, LBF and insulin sensitivity during hyperinsulinaemic clamp at low (40 mU/m(2) /min) and high (600 mU/m(2) /min) dose insulin infusion. Salt intake variation produced greater effects on the renin-angiotensin-aldosterone system than ACE genotype. Diabetes status and insulin infusion were associated with differences in the metabolic clearance rate of glucose, (P < 0·001 for each) and insulin infusion increased LBF (P < 0·001). However, ACE genotype and salt intake had no consistent impacts on either variable in nondiabetic and diabetic subgroups, or in the combined group. Reported differences in insulin sensitivity between ACE genotypes were not found in this study under strict regulation of sodium intake. Insulin sensitivity was also unaffected in either group by sodium loading. ACE genotype and salt status do not impact on insulin sensitivity through changes in limb blood flow during hyperinsulinaemia.

The Acute Effects of Interval- Vs Continuous-Walking Exercise on Glycemic Control in Subjects With Type 2 Diabetes: A Crossover, Controlled Study

Glycemic control improves with physical activity, but the optimal exercise mode is unknown. The objective of the study was to determine whether interval-based exercise improves postprandial glucose tolerance and free-living glycemia more than oxygen consumption- and time duration-matched continuous exercise. This was a crossover, controlled study with trials performed in randomized order. The study was conducted in hospitalized and ambulatory care. PATIENTS diagnosed with type 2 diabetes mellitus (n=10, no withdrawals) participated in the study. Subjects performed three 1-hour interventions: 1) interval walking (IW; repeated cycles of 3 min of slow and fast walking); 2) continuous walking (CW); and 3) control (CON). Oxygen consumption (VO2) was measured continuously to match mean VO2 between exercise sessions (∼75% VO2peak). A mixed-meal tolerance test (MMTT; 450 kcal, 55% carbohydrate) with stable glucose isotopic tracers was provided after each intervention, and glucose kinetics were measured during the following 4 hours. Free-living glycemic control was assessed for approximately 32 hours after the MMTT using continuous glucose monitoring. VO2 was well matched between the exercise interventions. IW decreased the mean and maximal incremental plasma glucose during the MMTT when compared with the CON (mean 1.2 ± 0.4 vs 2.0 ± 0.5 mmol/L, P < .001; maximal 3.7 ± 0.6 vs 4.6 ± 0.7 mmol/L, P = .005) and mean when compared with CW (1.7 ± 0.4 mmol/L, P = .02). No differences in the mean or maximal incremental plasma glucose values were seen between the CW and CON. The metabolic clearance rate of glucose during the MMTT was increased in the IW compared with CW (P = .049) and CON (P < .001). Continuous glucose monitoring mean glucose was reduced in IW compared with CW for the rest of the intervention day (8.2 ± 0.4 vs 9.3 ± 0.7 mmol/L, P = .03), whereas no differences were found between IW and CW the following day. One interval-based exercise session improves glycemic control in type 2 diabetes mellitus subjects when compared with an oxygen consumption- and time duration-matched continuous exercise session.

Vegetarian diet-induced increase in linoleic acid in serum phospholipids is associated with improved insulin sensitivity in subjects with type 2 diabetes

BACKGROUND AND AIMS:Fatty acids are important cellular constituents that may affect many metabolic processes relevant for the development of diabetes and its complications. We showed previously that vegetarian diet leads to greater increase in metabolic clearance rate of glucose (MCR) than conventional hypocaloric diet. The aim of this secondary analysis was to explore the role of changes in fatty acid composition of serum phospholipids in diet- and exercise-induced changes in MCR in subjects with type 2 diabetes (T2D).METHODS:Subjects with T2D (n=74) were randomly assigned into a vegetarian group (VG, n=37) following vegetarian diet or a control group (CG, n=37) following a conventional diet. Both diets were calorie restricted (−500 kcal day–1). Participants were examined at baseline, 12 weeks of diet intervention and 24 weeks (subsequent 12 weeks of diet were combined with aerobic exercise). The fatty acid composition of serum phospholipids was measured by gas liquid chromatography. MCR was measured by hyperinsulinemic isoglycemic clamp. Visceral fat (VF) was measured by magnetic resonance imaging.RESULTS:Linoleic acid (LA; 18:2n6) increased in VG (P=0.04), whereas it decreased in CG (P=0.04) in response to dietary interventions. It did not change significantly after the addition of exercise in either group (group × time P<0.001). In VG, changes in 18:2n6 correlated positively with changes in MCR (r=+0.22; P=0.04) and negatively with changes in VF (r=−0.43; P=0.01). After adjustment for changes in body mass index, the association between 18:2n6 and MCR was no longer significant. The addition of exercise resulted in greater changes of phospholipid fatty acids composition in VG than in CG.CONCLUSION:We demonstrated that the insulin-sensitizing effect of a vegetarian diet might be related to the increased proportion of LA in serum phospholipids.

Insulin action in primary hyperaldosteronism before and after surgical or pharmacological treatment.

The relationship between arterial hypertension and insulin resistance has long been established. We used primary hyperaldosteronism as a model of the relationship between secondary hypertension and insulin sensitivity. Our group consisted of 9 patients with arterial hypertension caused by primary hyperaldosteronism. Five of these patients with aldosterone producing adenoma were operated on and four patients with idiopathic hyperaldosteronism were treated with spironolactone. Hyperinsulinaemic euglycaemic clamp technique was performed before and at least 6 months following the treatment to evaluate the insulin action. Significantly lower glucose disposal rate (M), insulin sensitivity index (M/I) and decreased metabolic clearance rate of glucose (MCR(G)) were found in patients before treatment as compared to healthy controls. In both treated groups the blood pressure and plasma potassium concentrations returned to normal values, whereas plasma aldosterone levels were normalised only after surgical removal of the adenoma. Significantly improved insulin action (M/I: 30.2 +/- 5.9 vs. 51.4 +/-12.2 micromol.kg(-1).min(-1) per mU.l(-1) x 100, p = 0.017) was observed in patients after operation of aldosterone producing adenoma. In contrast, spironolactone treatment of patients with idiopathic hyperaldosteronism did not significantly influence insulin action (M/I: 24.5 +/- 7.3 vs. 18.7 +/- 7.6 micromol.kg(-1).min(-1) per mU.l(-1) x 100, p = 0.198). Since plasma aldosterone concentrations have been normalised only in patients after removal of the adenoma whereas they remained increased in spironolactone treated group, we suppose that aldosterone itself could play a role in the development of impaired insulin action.

Central Dopaminergic Activity Influences Metabolic Parameters in Healthy Men

Background/Aims: Central dopaminergic activity is probably linked to regulation of glucose and lipid metabolism and weight maintenance. The aim of our study was to evaluate the relationship between central dopaminergic activity measured using the apomorphine challenge test and metabolic parameters in healthy men. Methods: Forty-two healthy men (average age 43.5 ± 7.4 years, body mass index, BMI, 27.4 ± 5.7) were examined anthropometrically and biochemically (glycemia, lipids, glycated hemoglobin). Central dopaminergic activity was assessed as the area under the curve (AUC) of prolactin (PRL) and growth hormone (GH) responses to the apomorphine challenge test after sublingual administration of apomorphine in a dose of 0.033 mg/kg. Insulin resistance was quantified by calculation of glucose disposal and metabolic clearance rate during a euglycemic hyperinsulinemic clamp on two insulin levels (1 and 10 mIU/kg/min). Linear regression was used for statistical analysis. Results: Hormonal responses correlated negatively with age (for AUC/GH r = -0.33; p = 0.031) and BMI (AUC/GH r = -0.41; p = 0.007). After adjustment for age and BMI, a statistically significant negative correlations between AUC/PRL and total cholesterol (r = -0.41; p = 0.007), AUC/GH and HbA1c (r = -0.37; p = 0.016) and AUC/GH and HOMA (homeostasis model assessment; r = -0.345; p = 0.025) were observed. Conclusion: Central dopaminergic activity declines with age and BMI. Higher total cholesterol, glycated hemoglobin and insulin resistance parameters are connected with lower central dopamine tone.

Bile Acid Sequestration Reduces Plasma Glucose Levels in db/db Mice by Increasing Its Metabolic Clearance Rate

Aims/HypothesisBile acid sequestrants (BAS) reduce plasma glucose levels in type II diabetics and in murine models of diabetes but the mechanism herein is unknown. We hypothesized that sequestrant-induced changes in hepatic glucose metabolism would underlie reduced plasma glucose levels. Therefore, in vivo glucose metabolism was assessed in db/db mice on and off BAS using tracer methodology.MethodsLean and diabetic db/db mice were treated with 2% (wt/wt in diet) Colesevelam HCl (BAS) for 2 weeks. Parameters of in vivo glucose metabolism were assessed by infusing [U-13C]-glucose, [2-13C]-glycerol, [1-2H]-galactose and paracetamol for 6 hours, followed by mass isotopologue distribution analysis, and related to metabolic parameters as well as gene expression patterns.ResultsCompared to lean mice, db/db mice displayed an almost 3-fold lower metabolic clearance rate of glucose (p = 0.0001), a ∼300% increased glucokinase flux (p = 0.001) and a ∼200% increased total hepatic glucose production rate (p = 0.0002). BAS treatment increased glucose metabolic clearance rate by ∼37% but had no effects on glucokinase flux nor total hepatic or endogenous glucose production. Strikingly, BAS-treated db/db mice displayed reduced long-chain acylcarnitine content in skeletal muscle (p = 0.0317) but not in liver (p = 0.189). Unexpectedly, BAS treatment increased hepatic FGF21 mRNA expression 2-fold in lean mice (p = 0.030) and 3-fold in db/db mice (p = 0.002).Conclusions/InterpretationBAS induced plasma glucose lowering in db/db mice by increasing metabolic clearance rate of glucose in peripheral tissues, which coincided with decreased skeletal muscle long-chain acylcarnitine content.

Goshajinkigan (Chinese herbal medicine niu-che-sen-qi-wan) improves insulin resistance in diabetic rats via the nitric oxide pathway.

Goshajinkigan (GJG), an aqueous extract of a combination of 10 herbal medicines, is widely used for the treatment of diabetic neuropathy in Japan. In this study, the effect of GJG on insulin-induced glucose disposal in normal and streptozotocin (STZ) diabetic rats was analyzed using the euglycemic clamp technique. Male Wistar rats, aged 9 weeks, were randomly assigned to six groups: group NS, normal rats receiving saline; group NG, normal rats receiving GJG (800 mg x kg(-1) x day(-1), p.o.); group NGL, normal rats receiving GJG + N(G)-monomethyl-L-arginine (L-NMMA, 1 mg x kg(-1) x min(-1), i.v.); group DS, diabetic rats receiving saline; group DG, diabetic rats receiving GJG; group DGL, diabetic rats receiving GJG + L-NMMA. After daily oral administrations of saline or GJG for one week, euglycemic clamp experiments were performed. The metabolic clearance rates of glucose (MCR) in the DS, DG, and DGL groups (8.7 +/- 2.9, 18.2 +/- 2.5, and 8.1 +/- 1.8 ml x kg(-1) x min(-1), respectively) were significantly lower than those in the NS, NG, and NGL groups (24.1 +/- 4.5, 24.5 +/- 3.1, and 22.2 +/- 2.1 ml x kg(-1) x min(-1), respectively). In addition, the MCR in the DG group was significantly higher than that in the DS and DGL groups, while no significant difference was detected among the NS, NG, and NGL groups. Furthermore, the amelioration of insulin resistance by GJG in diabetic rats was hampered by L-NMMA infusion. These results suggest that daily GJG administrations ameliorate insulin resistance in STZ-diabetic rats, and that the nitric oxide pathway may mediate the effect of GJG.

Training in hypoxia fails to further enhance endurance performance and lactate clearance in well‐trained men and impairs glucose metabolism during prolonged exercise

The aim of this study was to investigate the synergistic effects of endurance training and hypoxia on endurance performance in normoxic and hypoxic conditions (approximately 3000 m above sea level) as well as on lactate and glucose metabolism during prolonged exercise. For this purpose, 14 well-trained cyclists performed 12 training sessions in conditions of normobaric hypoxia (HYP group, n = 7) or normoxia (NOR group, n = 7) over 4 weeks. Before and after training, lactate and glucose turnover rates were measured by infusion of exogenous lactate and stable isotope tracers. Endurance performance was assessed during incremental tests performed in normoxia and hypoxia and a 40 km time trial performed in normoxia. After training, performance was similarly and significantly improved in the NOR and HYP groups (training, P < 0.001) in normoxic conditions. No further effect of hypoxic training was found on markers of endurance performance in hypoxia (training x hypoxia interaction, n.s.). In addition, training and hypoxia had no significant effect on lactate turnover rate. In contrast, there was a significant interaction of training and hypoxia (P < 0.05) on glucose metabolism, as follows: plasma insulin and glucose concentrations were significantly increased; glucose metabolic clearance rate was decreased; and the insulin to glucagon ratio was increased after training in the HYP group. In conclusion, our results show that, compared with training in normoxia, training in hypoxia has no further effect on endurance performance in both normoxic and hypoxic conditions or on lactate metabolic clearance rate. Additionally, these findings suggest that training in hypoxia impairs blood glucose regulation in endurance-trained subjects during exercise.

Insulin action in patients with insulinoma influenced by pharmacological and surgical therapy.

Organic hyperinsulinism due to insulinoma is accompanied by changes of insulin action on receptor and postreceptor levels. The influence of conservative and surgical treatment on insulin sensitivity was examined by euglycaemic hyperinsulinaemic clamps in ten patients with insulinoma. The "responders" (n = 5) and "non-responders" (n = 5) to diazoxide treatment were distinguished by using fasting plasma glucose and insulin concentrations. The index of insulin sensitivity was significantly decreased in pretreated "responders" as compared to healthy persons (19 +/- 3 vs 39 +/- 6 and 20 +/- 3 vs 37 +/- 5 mumol.kg-1.min-1 per mU.l-1 x 100, p < 0.01) and it was improved during diazoxide administration (27 +/- 4 vs 19 +/- 3 and 35 +/- 12 vs 20 +/- 3 mumol.kg-1.min-1 per mU.l-1 x 100, p < 0.05). Significantly decreased insulin sensitivity in pretreated "non-responders" (25 +/- 5 vs 39 +/- 6 and 28 +/- 6 vs 37 +/- 5 mumol.kg-1.min-1 per mU.l-1 x 100, p < 0.05) was not improved by diazoxide administration. Metabolic clearance rate of glucose was significantly higher in "non-responders" as compared to "responders" and healthy persons (12.7 +/- 3.4 vs 7.9 +/- 2.7 and 7.4 +/- 2.4 ml.min-1.kg-1, p < 0.05) already in pretreated state. An inverse relationship was found between metabolic clearance rate of glucose and of insulin (r = 0.72, p < 0.001). Plasma glucose, insulin concentration, index of insulin sensitivity, and metabolic clearance rate of glucose and of insulin were normalized after surgical removal of an insulinoma in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid.

Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore, pharmacological intervention should aim to improve insulin sensitivity. Thioctic acid (TA), a naturally occurring compound, was shown to enhance glucose utilization in various experimental models after acute and chronic administration. It also increased insulin-stimulated glucose disposal in patients with NIDDM after acute administration. This pilot study was initiated to see whether this compound also augments glucose disposal in humans after repeated treatment. Twenty patients with NIDDM received TA (500 mg/ 500 ml NaCl, 0.9%) as daily infusions over a period of ten days. A hyperinsulinaemic, isoglycaemic glucose-clamp was done on day 0 and day 11. Parenteral administration of TA resulted in a significant increase of insulin-stimulated glucose-disposal by about 30% (metabolic clearance rate for glucose, 2.5 +/- 0.3 vs. 3.2 +/- 0.4 ml/kg/min and insulin-sensitivity-index: 3.5 +/- 0.5 vs. 4.7 +/- 0.4 mg/kg/microU/ml; p < 0.05, Wilcoxon-Rank-Sum-Test). There were no changes in fasting plasma levels for glucose or insulin; this can be explained, however, by the short period of treatment and observation. This is the first clinical study to show that a ten day administration of TA is able to improve resistance of insulin-stimulated glucose disposal in NIDDM. Experimental data suggest several mechanisms in the mode of action. As the present investigation was an uncontrolled pilot trial, the encouraging results call for controlled studies to further elucidate the clinical relevance of the findings and the mode of action of this compound.

Amino acid polymorphism Gly 972 Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with type 2 diabetes.

The Gly 972 Arg variant in the insulin receptor substrate-1 (IRS-1) gene may interact with the pathogenesis of common insulin-resistance disorders raising the hypothesis that the mutation may predispose to type 2 diabetes. We examined the codon 972 variant in 144 non-diabetic first degree relatives of patients with type 2 diabetes (FDR), who underwent extensive phenotyping: Glucose tolerance was determined by an oral glucose load, insulin sensitivity by euglycaemic-hyperinsulinaemic glucose clamp (glucose metabolic clearance rate, MCR) and body composition by bioelectrical impedance. 20 (14%) of the FDR showed the Gly 972 Arg variant in heterozygous form, 2 (1.3%) probands were homozygous. Carriers of the polymorphism did not differ in MCR independent of body weight and total body fat. The polymorphism does not seem to determine clamp-derived insulin sensitivity. Despite identical fasting plasma glucose, carriers of the polymorphism showed a slightly lower fasting serum insulin and lower insulin response to an oral glucose load but higher glucose concentrations. In an obese subgroup (BMI > 25) the polymorphism did not show a higher frequency and was not associated with lower insulin sensitivity. In the investigated group of young, healthy relatives of type 2 diabetes patients, the frequency of the mutation corresponded to that of a diabetic population. In summary our data show that the polymorphism is not suitable to predict insulin resistance.

COX‐2‐mediated Inflammation in Fat Is Crucial for Obesity‐linked Insulin Resistance and Fatty Liver

The aim was to examine the role of cyclooxygenase (COX)-2-mediated inflammation in the development of obese linked insulin resistance and fatty liver. The rats were fed separately regular diet (CONT), high-fat diet (HFD) ad libitum, or energy restrictedly for 12 weeks. Rats fed HFD ad libitum were further divided into three subgroups co-treated with vehicle (HFa), or a selective COX-2 inhibitor celecoxib (HFa-Cel) or mesulid (HFa-Mes). Euglycemic hyperinsulinemic clamp (EHC) experiment was performed at the end of study. Another set of rats with similar grouping was further divided into those with a 4, 8, or 12-week intervention period for hepatic sampling. Body weight was increased significantly and similarly in HFa, HFa-Cel, and HFa-Mes. Time-dependent increases in plasma insulin, glucose, 8-isoprostanes, leptin levels, homeostasis model assessment of insulin resistance (HOMA-IR) and hepatic triglyceride contents shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. During EHC period, the reduction in stimulation of whole body glucose uptake, suppression of hepatic glucose production and metabolic clearance rate of insulin shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The enhanced COX-2 and tumor necrosis factor-alpha (TNF-alpha) but attenuated PPAR-gamma and C/EBP-alpha mRNA expressions in epididymal fat shown in HFa were significantly reversed in HFa-Cel and HFa-Mes. The increases in average cell size of adipocytes and CD68 positive cells shown in HFa were also significantly reversed in HFa-Cel and HFa-Mes. Our findings suggest that COX-2 activation in fat inflammation is important in the development of insulin resistance and fatty liver in high fat induced obese rats.

Net protein anabolic response is not altered during hyperaminoacidemic (hyperAA) clamp in men with Type 2 Diabetes (T2D)

Reduced 24h net protein balance in hyperglycemic T2D was explained by less protein accretion during hyperinsulinemic euglycemic, isoaminoacidemic (isoAA) clamps. We tested whether protein anabolism would worsen with glycemia at 8.0 mM and AA at iso (fasting) or hyper (postprandial). Eight T2D men (57±2 y; BMI: 34±2; FPG: 8.4±0.6mM) underwent hyperinsulinemic (600 pM), hyperglycemic clamps with glucose and leucine kinetics measured at 2 steady‐states: isoAA and hyperAA. Results are compared to 10 T2D and 10 lean nondiabetic men studied euglycemic, isoAA and 9 studied hyperglycemic, hyperAA.In T2D 1) Leucine flux was higher (4.3±0.1 vs. 3.1±0.2 micromol/FFM.min) but net protein balance not different (0±.03 micromol/FFM.min) with isoAA when glycemia was at 8.0 vs. 5.5; net balance was less than in lean (0.25±0.02); however response to hyperAA was as in lean (0.9±.09) 2) endogenous glucose production was less suppressed (1.7±0.4 vs. 0.7±0.2mg/FFM.min) and glucose uptake higher (4.8±.6 vs. 3.6±0.3 mg/FFM.min) with glycemia at 8 vs. 5.5 and with hyperAA. 3) hyperAA did not lower glucose metabolic clearance rate (3.3±0.3 vs. 3.6±0.4 ml/FFM.min), as in lean (9.3±0.7 vs. 5.7±0.4). Thus, protein anabolic response to postprandial AA in T2D is not altered despite indication of insulin resistance of protein. (CIHR)