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Keywords: insulin sensitivity
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Soumyalekshmi Nair, Nanthini Jayabalan, Dominic Guanzon, Carlos Palma, Katherin Scholz-Romero, Omar Elfeky, Felipe Zuñiga, Valeska Ormazabal, Emilio Diaz, Gregory E. Rice, Gregory Duncombe, Thomas Jansson, Harold David McIntyre, Martha Lappas, Carlos Salomon
Journal:
Clinical Science
Clin Sci (Lond) (2018) 132 (22): 2451–2467.
Published: 30 November 2018
... exosomes. Here we investigated whether placental exosomes in GDM carry a specific set of miRNAs associated with skeletal muscle insulin sensitivity. Exosomes were isolated from chorionic villous (CV) explants from both women with Normal Glucose Tolerant (NGT) and GDM pregnancies. Using miRNA sequencing, we...
Abstract
There is increasing evidence that miRNAs, which are enriched in nanovesicles called exosomes, are important regulators of gene expression. When compared with normal pregnancies, pregnancies with gestational diabetes mellitus (GDM) are associated with skeletal muscle insulin resistance as well as increased levels of circulating placental exosomes. Here we investigated whether placental exosomes in GDM carry a specific set of miRNAs associated with skeletal muscle insulin sensitivity. Exosomes were isolated from chorionic villous (CV) explants from both women with Normal Glucose Tolerant (NGT) and GDM pregnancies. Using miRNA sequencing, we identified a specific set of miRNAs selectively enriched with exosomes and compared with their cells of origin indicating a specific packaging of miRNAs into exosomes. Gene target and ontology analysis of miRNA differentially expressed in exosomes secreted in GDM compared with NGT are associated with pathways regulating cell migration and carbohydrate metabolism. We determined the expression of a selected set of miRNAs in placenta, plasma, and skeletal muscle biopsies from NGT and GDM. Interestingly, the expression of these miRNAs varied in a consistent pattern in the placenta, in circulating exosomes, and in skeletal muscle in GDM. Placental exosomes from GDM pregnancies decreased insulin-stimulated migration and glucose uptake in primary skeletal muscle cells obtained from patients with normal insulin sensitivity. Interestingly, placental exosomes from NGT increase migration and glucose uptake in response to insulin in skeletal muscle from diabetic subjects. These findings suggest that placental exosomes might have a role in the changes on insulin sensitivity in normal and GDM pregnancies.
Includes: Supplementary data
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2016) 130 (22): 2083–2086.
Published: 11 October 2016
... fermentation of non-digestible foods such as dietary fibres. They can interact with host tissues by modulating the activity of histone deacetylases and activating G-protein-coupled receptors such as GPR43 [ 5 ]. dietary fibres fat oxidation gut microbiota insulin sensitivity PYY © 2016 The...
Abstract
Gut micro-organisms are recognized as crucial regulators of host immunity and the microbiota has been implicated in several inflammatory, immune, inflammatory or even psychiatric disorders. Therefore the analysis of the complex interactions between gut microbiota and the host is currently under intense investigation. Most of our knowledge stems from the study of animal models while translational research and data in humans are necessary to move the field forward and to evolve to diagnostic and therapeutic application. Amongst the microbial by-products, short chain fatty acids such as acetate yielded by fermentation of non-digestible fibers, were pointed as metabolic modulators. Here we highlight a study evaluating the effects of colonic infusion of one of the short chain fatty acids, acetate, in a cohort of overweight and obese normoglycaemic subjects.
Articles
Francis B. Stephens, Buddhike Mendis, Chris E. Shannon, Scott Cooper, Catharine A. Ortori, David A. Barrett, Peter Mansell, Kostas Tsintzas
Journal:
Clinical Science
Clin Sci (Lond) (2014) 127 (5): 315–322.
Published: 07 May 2014
... effect was not due to differences in muscle acylcarnitine content. acylcarnitine insulin sensitivity mitochondrial overload omega-3 polyunsaturated fatty acid pyruvate dehydrogenase skeletal muscle • Recent clinical studies suggest that skeletal muscle insulin resistance may arise...
Abstract
Acylcarnitine accumulation in skeletal muscle and plasma has been observed in numerous models of mitochondrial lipid overload and insulin resistance. Fish oil n3PUFA (omega-3 polyunsaturated fatty acids) are thought to protect against lipid-induced insulin resistance. The present study tested the hypothesis that the addition of n3PUFA to an intravenous lipid emulsion would limit muscle acylcarnitine accumulation and reduce the inhibitory effect of lipid overload on insulin action. On three occasions, six healthy young men underwent a 6-h euglycaemic–hyperinsulinaemic clamp accompanied by intravenous infusion of saline (Control), 10% Intralipid® [n6PUFA (omega-6 polyunsaturated fatty acids)] or 10% Intralipid®+10% Omegaven® (2:1; n3PUFA). The decline in insulin-stimulated whole-body glucose infusion rate, muscle PDCa (pyruvate dehydrogenase complex activation) and glycogen storage associated with n6PUFA compared with Control was prevented with n3PUFA. Muscle acetyl-CoA accumulation was greater following n6PUFA compared with Control and n3PUFA, suggesting that mitochondrial lipid overload was responsible for the lower insulin action observed. Despite these favourable metabolic effects of n3PUFA, accumulation of total muscle acylcarnitine was not attenuated when compared with n6PUFA. These findings demonstrate that n3PUFA exert beneficial effects on insulin-stimulated skeletal muscle glucose storage and oxidation independently of total acylcarnitine accumulation, which does not always reflect mitochondrial lipid overload.
Includes: Supplementary data
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2011) 120 (4): 153–160.
Published: 02 November 2010
... a cohort of young adults (mean age 22 years) and their siblings participating in a longitudinal study of cardiovascular risk ( n =370). Insulin sensitivity was determined by euglycaemic insulin clamp. EDD (endothelium-dependent dilation) was determined by flow-mediated dilation using high-resolution...
Abstract
To examine influence of insulin resistance and other clinical risk factors for the MetS (metabolic syndrome) on vascular structure and function in young adults. This cross-sectional study was conducted in a cohort of young adults (mean age 22 years) and their siblings participating in a longitudinal study of cardiovascular risk ( n =370). Insulin sensitivity was determined by euglycaemic insulin clamp. EDD (endothelium-dependent dilation) was determined by flow-mediated dilation using high-resolution ultrasound imaging of the brachial artery. EID (endothelium-independent dilation) was determined by NTG (nitroglycerine)-mediated dilation. The diameter and cIMT (intima–media thickness) of the carotid artery were also measured. There was no significant difference between males and females for age or body mass index. However, males had significantly higher glucose and triacylglycerol (triglyceride) levels, while the females had significantly higher HDL-C (high-density lipoprotein-cholesterol) and insulin sensitivity (13.00±0.33 compared with 10.71±0.31 mg·kg −1 of lean body mass·min −1 , P <0.0001). Although peak EDD was significantly lower (6.28±0.26 compared with 8.50±0.28%, P <0.0001) in males than females, this difference was largely explained by adjustment for brachial artery diameter ( P =0.15). Peak EID also was significantly lower in males than females (20.26±0.44 compared with 28.64±0.47%, P <0.0001), a difference that remained significantly lower after adjustment for brachial artery diameter. Males had a significantly greater cIMT compared with females (females 0.420±0.004 compared with males 0.444±0.004 mm, P =0.01), but when adjusted for carotid diameter, there was no significant difference ( P =0.163). Although there were gender differences in vascular function and structure in the young adult population examined in this study, many of the differences were eliminated simply by adjusting for artery diameter. However, the lower EID observed in males could not be explained by artery diameter. Future studies need to continue to examine influence of gender on EID and other measures of vascular function.
Articles
Ruth C. R. Meex, Esther Phielix, Vera B. Schrauwen-Hinderling, Esther Moonen-Kornips, Gert Schaart, Patrick Schrauwen, Matthijs K. C. Hesselink
Journal:
Clinical Science
Clin Sci (Lond) (2010) 119 (7): 293–301.
Published: 25 June 2010
... concurrently. Statin intake may blunt mitochondrial function and the adaptive response to exercise training. Thus combining exercise training with statin administration may have adverse effects. We examined whether improvements in cardiometabolic risk factors, insulin sensitivity and mitochondrial function...
Abstract
Exercise training is advocated in insulin resistance and statins are used to treat hyperlipidaemia, two cardiometabolic risk factors often presenting concurrently. Statin intake may blunt mitochondrial function and the adaptive response to exercise training. Thus combining exercise training with statin administration may have adverse effects. We examined whether improvements in cardiometabolic risk factors, insulin sensitivity and mitochondrial function mediated by progressive exercise training are affected by statin use. A group of 14 obese elderly males on statins (ST) and 22 matched control subjects (C) were examined. Results on in vivo mitochondrial function [MRS (magnetic resonance spectroscopy)], mitochondrial density (Western blotting), insulin sensitivity (clamp) and metabolic flexibility (indirect calorimetry) were compared before and after a 12-week combined progressive exercise training programme (3×per week; 45 min per session). Except for LDL (low-density lipoprotein) cholesterol, all pre-training values were comparable between statin users and control subjects. In vivo mitochondrial function and mitochondrial density improved by training in both groups. Interestingly, blood-lipid profile, insulin sensitivity (+72%), non-oxidative and oxidative glucose disposal (+38% and +112%) and insulin-mediated suppression of fat oxidation (−62%) improved only in the ST group. We conclude that statin treatment did not impede exercise performance or tolerance, mitochondrial function or mass. In addition, training-induced improvements in glucose homoeostasis were preserved in the ST group. Strikingly, the insulin-sensitizing effect of training was more prominent in the ST group than in the C group. The combined prescription of statins along with exercise training is safe and should be considered for subjects prone to develop insulin resistance.
Includes: Supplementary data
Articles
Burak Salgin, Alison J. Sleigh, Rachel M. Williams, Sarah J. Jackson, Les J. Bluck, Peter R. Murgatroyd, Sandy M. Humphreys, Sally Harding, T. Adrian Carpenter, David B. Dunger
Journal:
Clinical Science
Clin Sci (Lond) (2009) 117 (3): 111–118.
Published: 02 July 2009
... infusion rates during a hyperinsulinaemic–euglycaemic clamp (M-value). The aim of the present study was to explore how IMCL levels relate to the insulin-mediated suppression of endogenous glucose production [hepatic S I (insulin sensitivity)] and increase in glucose disposal (peripheral S I ). In the...
Abstract
Increased levels of IMCL (intramyocellular lipid) have been shown to be associated with reduced steady-state glucose infusion rates during a hyperinsulinaemic–euglycaemic clamp (M-value). The aim of the present study was to explore how IMCL levels relate to the insulin-mediated suppression of endogenous glucose production [hepatic S I (insulin sensitivity)] and increase in glucose disposal (peripheral S I ). In the present study, 11 healthy young adults (7 male, 4 female; aged 21–31 years) undertook, in random order, an hyperinsulinaemic–euglycaemic clamp combined with stable glucose isotope enrichment to measure peripheral and hepatic S I , a 1 H-MRS (proton-magnetic resonance spectroscopy) scan to determine IMCL levels and a DXA (dual-energy X-ray absorptiometry) scan to assess body composition. IMCL levels (range, 3.2–10.7) were associated with whole-body fat mass ( r =0.787, P =0.004), fat mass corrected for height ( r =0.822, P =0.002) and percentage of central fat mass ( r =0.694, P =0.02), but were not related to whole-body FFM (fat-free mass; r =−0.472, P =0.1). IMCL levels correlated closely with the M-value ( r =−0.727, P =0.01) and FFM-corrected peripheral S I ( r =−0.675, P =0.02), but were not related to hepatic S I adjusted for body weight ( r =0.08, P =0.8). The results of the present study suggest that IMCL accumulation may be a sensitive marker for attenuations in peripheral, but not hepatic, S I in normal populations. Given the close relationship of IMCL levels to whole-body and central abdominal fat mass, relative increases in the flux of lipids from adipose tissue to the intramyocellular compartment may be an integral part of the mechanisms underlying reductions in S I .
Articles
Matthew D. Hordern, Louise M. Cooney, Elaine M. Beller, Johannes B. Prins, Thomas H. Marwick, Jeff S. Coombes
Journal:
Clinical Science
Clin Sci (Lond) (2008) 115 (9): 273–281.
Published: 01 October 2008
...Matthew D. Hordern; Louise M. Cooney; Elaine M. Beller; Johannes B. Prins; Thomas H. Marwick; Jeff S. Coombes The aim of the present study was to determine the effects of a 4-week exercise training intervention on blood glucose, insulin sensitivity, BMI (body mass index) and cardiorespiratory...
Abstract
The aim of the present study was to determine the effects of a 4-week exercise training intervention on blood glucose, insulin sensitivity, BMI (body mass index) and cardiorespiratory fitness in patients with Type 2 diabetes, and to identify and establish criteria for patients who are more likely to improve their blood glucose from short-term exercise training. A randomized, controlled trial of exercise training, comprising two supervised and one non-supervised sessions of individualized cardiorespiratory and resistance exercise per week, was performed in 132 healthy patients with Type 2 diabetes (exercise training group, n =68), with the aim of accumulating a minimum of 150 min of moderate-intensity exercise for 4 weeks. BMI, waist circumference, blood pressure, blood lipid profile, blood glucose, insulin, insulin sensitivity [calculated by HOMA IR (homoeostasis model assessment of insulin resistance) and QUICKI (quantitative insulin check index)], β-cell function (calculated by HOMA β-Cell ), HbA 1c (glycated haemoglobin) and V ̇ O 2max (maximal oxygen consumption) were measured at baseline and at 4 weeks. The exercise training group had significant improvements in V ̇ O 2max , BMI and triacylglycerols (triglycerides). There were no significant changes in blood glucose, HOMA IR , QUICKI or HOMA β-Cell . Decreases in blood glucose were significantly predicted by baseline blood glucose and HbA 1c , with these variables accounting for 15.9% of the change in blood glucose ( P <0.001). ROC (receiver operator characteristic) curve analysis revealed that patients with a blood glucose >8.85 mmol/l (sensitivity=73%, specificity=78%) and HbA 1c >7.15% (sensitivity=79%, specificity=60%) were more likely to achieve a clinically significant decrease in blood glucose. In conclusion, in apparently healthy patients with Type 2 diabetes, a 4-week exercise intervention improved cardiorespiratory fitness, BMI and triacylglycerols. Elevated blood glucose and HbA 1c predicted improvements in blood glucose.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2008) 114 (1): 59–64.
Published: 30 November 2007
...Faidon Magkos; Yannis Tsekouras; Stavros A. Kavouras; Bettina Mittendorfer; Labros S. Sidossis A single bout of moderate-intensity exercise increases whole-body insulin sensitivity for 12–48 h post-exercise; however, the relationship between exercise energy expenditure and the improvement in...
Abstract
A single bout of moderate-intensity exercise increases whole-body insulin sensitivity for 12–48 h post-exercise; however, the relationship between exercise energy expenditure and the improvement in insulin sensitivity is not known. We hypothesized that the exercise-induced increase in whole-body insulin sensitivity, assessed with HOMA IR (homoeostasis model assessment of insulin resistance), is directly related to the energy expended during exercise. We studied 30 recreationally active non-obese men (age, 27±5 years; body mass index, 24±2 kg/m 2 ) in the post-absorptive state on two separate occasions: once after exercising at 60% of V ̇ O 22peak (peak oxygen consumption) for 30–120 min on the preceding afternoon (expending a total of 1.28–5.76 MJ) and once after an equivalent period of rest. Blood samples were obtained the following morning. Exercise-induced changes in HOMA IR were curvilinearly related to exercise energy expenditure ( r =−0.666, P =0.001) with a threshold of approx. 3.77 MJ (900 kcal) for improvements in HOMA IR to be manifested. In particular, HOMA IR was reduced by 32±24% ( P =0.003) in subjects who expended more than 3.77 MJ during exercise, but did not change for those who expended fewer than 3.77 MJ (−2±21%; P =0.301). Furthermore, the magnitude of change in HOMA IR after exercise was directly associated with baseline (i.e. resting) HOMA IR ( r =−0.508, P =0.004); this relationship persisted in multivariate analysis. We conclude that improved whole-body insulin resistance after a single bout of exercise is curvilinearly related to exercise energy expenditure, and requires unfeasible amounts of exercise for most sedentary individuals.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2008) 114 (1): 65–71.
Published: 30 November 2007
...Robert Hägerkvist; Leif Jansson; Nils Welsh The aim of the present study was to investigate whether imatinib affects insulin sensitivity and glucose disposal in HF (high-fat)-fed rats. Sprague–Dawley rats were fed either a standard pelleted rat food (low-fat diet) or an HF diet (60% fat) for 8...
Abstract
The aim of the present study was to investigate whether imatinib affects insulin sensitivity and glucose disposal in HF (high-fat)-fed rats. Sprague–Dawley rats were fed either a standard pelleted rat food (low-fat diet) or an HF diet (60% fat) for 8 weeks. During the last 10 days of the HF diet regime, rats received saline alone or imatinib (50 or 100 mg/kg of body weight) daily by gavage. The higher dose of imatinib resulted in a decreased psoas fat pad weight in the HF-treated rats. Under euglycaemic hyperinsulinaemic clamp conditions, HF-fed rats exhibited increased insulin concentrations and decreased glucose disposal. The lower (50 mg/kg of body weight), but not the higher (100 mg/kg of body weight), dose of imatinib normalized insulin sensitivity and glucose disposal without affecting glucose metabolism in low-fat-fed rats. Hepatic glucose production at both fasting and hyperinsulinaemic conditions was only weakly affected by imatinib. We conclude that a moderate dose of imatinib efficiently counteracts HF-induced peripheral insulin resistance, and that further studies on the mechanisms by which imatinib increases insulin action in muscle and fat tissues might generate novel strategies for the treatment of Type 2 diabetes.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2007) 113 (3): 141–148.
Published: 02 July 2007
...Raymond R. Townsend; Shiv Kapoor; Christopher B. McFadden The literature on salt intake and insulin sensitivity presents a mixed picture, as some studies have shown an increase, whereas others have shown a decrease, in insulin action as sodium intake is enhanced. In some cases, this may relate to...
Abstract
The literature on salt intake and insulin sensitivity presents a mixed picture, as some studies have shown an increase, whereas others have shown a decrease, in insulin action as sodium intake is enhanced. In some cases, this may relate to the study of salt intake in patients with co-morbidities such as hypertension or diabetes. In the present study, we selected healthy normotensive lean volunteers who underwent a euglycaemic clamp following 6 days of a low-salt diet (20 mmol sodium daily) and, subsequently, 6 days of a high-salt diet (200 mmol sodium daily). Our results show an increase in insulin-mediated glucose disposal during euglycaemic clamp conditions that was significantly higher following the high-salt diet compared with the low-salt diet (7.41±0.41 compared with 6.11±0.40 mg·kg −1 of body weight·min −1 respectively; P =0.03). We measured calf blood flow before and during insulin infusion (no significant change after the two dietary salt interventions was detected) and plasma non-esterified fatty acids (also no significant differences were detected). We observed the expected increases in renin concentration and aldosterone activity in subjects on the low-salt diet, and also observed a significantly less increase in plasma noradrenaline concentration during euglycaemic insulin infusion following the high-salt compared with the low-salt diet. We propose that the 4–5-fold increase in serum aldosterone and the greater increase in plasma noradrenaline concentration following the low-salt intervention compared with the high-salt period may have contributed to the differences in insulin sensitivity following the adjustment in dietary sodium intake.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2007) 112 (4): 257–263.
Published: 17 January 2007
...Umberto Morbiducci; Giacomo Di Benedetto; Alexandra Kautzky-Willer; Giovanni Pacini; Andrea Tura Minimal model analysis of glucose and insulin data from an IVGTT (intravenous glucose tolerance test) is widely used to estimate insulin sensitivity; however, the use of the model often requires...
Abstract
Minimal model analysis of glucose and insulin data from an IVGTT (intravenous glucose tolerance test) is widely used to estimate insulin sensitivity; however, the use of the model often requires intervention by a trained operator and some problems can occur in the estimation of model parameters. In the present study, a new method for minimal model analysis, termed GAMMOD, was developed based on genetic algorithms for the estimation of model parameters. Such an algorithm does not require the fixing of initial values for the parameters (that may lead to unreliable estimates). Our method also implements an automated weighting scheme not requiring manual intervention of the operator, thus improving the usability of the model. We studied a group of 170 women with a history of previous gestational diabetes. Results obtained by GAMMOD were compared with those obtained by MINMOD (a traditional gradient-based algorithm for minimal model analysis). Insulin sensitivity by GAMMOD was (3.86±0.19) compared with (4.33±0.20)×10 −4 μ-units·ml −1 ·min −1 by MINMOD; glucose effectiveness was 0.0236±0.0005 compared with 0.0229±0.0005 min −1 respectively. The difference in the estimation by the two methods was within the precision expected for such metabolic parameters and is probably of no clinical relevance. Moreover, both the coefficient of variation of the estimated parameters and the error of fit were generally lower in GAMMOD, despite the fact that it does not require manual intervention. In conclusion, the GAMMOD approach for parameter estimation in the minimal model provides a reliable estimation of the model parameters and improves the usability of the model, thus facilitating its further use and application in a clinical context.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2005) 109 (6): 513–521.
Published: 23 November 2005
... diabetes glucose effectiveness insulin sensitivity intravenous glucose tolerance test (IVGTT) minimal model stable isotope Interpretation of the IVGTT (intravenous glucose tolerance test) by the minimal model of glucose kinetics is widely used in the determination of S I (insulin...
Abstract
In the present study, we have investigated the use of 1-[ 13 C]glucose and GC/combustion/isotope-ratio MS as an alternative to 6,6-[ 2 H 2 ]glucose and GC/MS in the determination of parameters of glucose metabolism using the IVGTT (intravenous glucose tolerance test) interpreted by labelled (hot) minimal models. The study has been done in four populations, normoglycaemics (subdivided into lean and obese individuals), subjects with impaired glucose tolerance and those with diabetes mellitus. Although the use of carbon label may in some circumstances be compromised by substrate recycling, our hypothesis was that this would not be an issue under the condition of suppression of hepatic glucose production during the short timescale of an IVGTT. In all four groups, we found that the methodology employing the carbon label gave equivalent results to those obtained using the conventional deuterated material, but the sensitivity of the measurement technique in the new approach was sufficient to allow an approx. 15-fold reduction in the quantity of isotope administered. In addition to the clear cost advantages, this represents a significant scientific advance in that true tracer status is more nearly attained in these measurements with near-physiological tracee loads.
Articles
L. W. E. SABELIS, P. J. SENDEN, B. C. M. TE BOEKHORST, H. J. HULZEBOS, A. VAN DE WIEL, T. W. VAN HAEFTEN, M. L. ZONDERLAND, W. L. MOSTERD
Journal:
Clinical Science
Clin Sci (Lond) (2004) 106 (5): 459–466.
Published: 01 May 2004
...L. W. E. SABELIS; P. J. SENDEN; B. C. M. TE BOEKHORST; H. J. HULZEBOS; A. VAN DE WIEL; T. W. VAN HAEFTEN; M. L. ZONDERLAND; W. L. MOSTERD To determine the effect of training on insulin sensitivity (IS) and how this relates to peak V O 2 (peak oxygen uptake) in CHF (chronic heart failure), 77 CHF...
Abstract
To determine the effect of training on insulin sensitivity (IS) and how this relates to peak V O 2 (peak oxygen uptake) in CHF (chronic heart failure), 77 CHF patients (New York Heart Association class, II/III; men/women, 59/18; age, 60±9 years; body mass index, 26.7±3.9 kg/m 2 ; left ventricular ejection fraction, 26.9±8.1%; expressed as means±S.D.) participated in the study. Patients were randomly assigned to a training or control group (TrG or CG respectively). Sixty-one patients completed the study. Patients participated in training (combined strength and endurance exercises) four times per week, two times supervised and two times at home. Before and after intervention, anthropometry, IS (euglycaemic hyperinsulinaemic clamp) and peak V O 2 (incremental cycle ergometry) were assessed. Intervention did not affect IS significantly, even though IS increased by 20% in TrG and 11% in CG (not significant). Peak V O 2 increased as a result of training (6% increase in TrG; 2% decrease in CG; P <0.05). In both groups (TrG and CG), the change in IS correlated positively with the change in peak V O 2 ( r =0.30, P <0.05). Training resulted in an increase in peak V O 2 , but not in IS. Whether physical training actually increases IS in CHF patients remains unclear.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2003) 105 (5): 531–532.
Published: 01 November 2003
...Ian F. GODSLAND After more than 20 years, minimal model analysis of intravenous glucose tolerance test glucose and insulin concentrations continues to be widely employed in studies of insulin sensitivity and insulin resistance. Moreover, problems encountered in solving the minimal model equations...
Abstract
After more than 20 years, minimal model analysis of intravenous glucose tolerance test glucose and insulin concentrations continues to be widely employed in studies of insulin sensitivity and insulin resistance. Moreover, problems encountered in solving the minimal model equations continue to find new solutions. Bayesian techniques enable prior knowledge to be incorporated into parameter estimation routines. They offer particular advantages in the measurement of insulin sensitivity with the minimal model, and provide an elegant means of improving model identification success rates and parameter precision. This comment describes the study by Agbaje and colleagues in this issue of Clinical Science that exemplifies a new phase in the evolution of minimal model practice.
Articles
Olorunsola F. AGBAJE, Stephen D. LUZIO, Ahmed I. S. ALBARRAK, David J. LUNN, David R. OWENS, Roman HOVORKA
Journal:
Clinical Science
Clin Sci (Lond) (2003) 105 (5): 551–560.
Published: 01 November 2003
...Olorunsola F. AGBAJE; Stephen D. LUZIO; Ahmed I. S. ALBARRAK; David J. LUNN; David R. OWENS; Roman HOVORKA We adopted Bayesian analysis in combination with hierarchical (population) modelling to estimate simultaneously population and individual insulin sensitivity ( S I ) and glucose effectiveness...
Abstract
We adopted Bayesian analysis in combination with hierarchical (population) modelling to estimate simultaneously population and individual insulin sensitivity ( S I ) and glucose effectiveness ( S G ) with the minimal model of glucose kinetics using data collected during insulin-modified intravenous glucose tolerance test (IVGTT) and made comparison with the standard non-linear regression analysis. After fasting overnight, subjects with newly presenting Type II diabetes according to World Health Organization criteria ( n =65; 53 males, 12 females; age, 54±9 years; body mass index, 30.4±5.2 kg/m 2 ; means±S.D.) underwent IVGTT consisting of a 0.3 g of glucose bolus/kg of body weight given at time zero for 2 min, followed by 0.05 unit of insulin/kg of body weight at 20 min. Bayesian inference was carried out using vague prior distributions and log-normal distributions to guarantee non-negativity and, thus, physiological plausibility of model parameters and associated credible intervals. Bayesian analysis gave estimates of S I in all subjects. Non-linear regression analysis failed in four cases, where Bayesian analysis-derived S I was located in the lower quartile and was estimated with lower precision. The population means of S I and S G provided by Bayesian analysis and non-linear regression were identical, but the interquartile range given by Bayesian analysis was tighter by approx. 20% for S I and by approx. 15% for S G . Individual insulin sensitivities estimated by the two methods were highly correlated ( r S =0.98; P <0.001). However, the correlation in the lower 20% centile of the insulin-sensitivity range was significantly lower than the correlation in the upper 80% centile ( r S =0.71 compared with r S =0.99; P <0.001). We conclude that the Bayesian hierarchical analysis is an appealing method to estimate S I and S G , as it avoids parameter estimation failures, and should be considered when investigating insulin-resistant subjects.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2002) 102 (2): 223–231.
Published: 14 January 2002
...Jason M.R. GILL; Sara L. HERD; Natassa V. TSETSONIS; Adrianne E. HARDMAN Moderate exercise improves insulin sensitivity and reduces triacylglycerol (triglyceride; TG) concentrations. We hypothesized that changes in insulin sensitivity are an important determinant of exercise-induced changes in...
Abstract
Moderate exercise improves insulin sensitivity and reduces triacylglycerol (triglyceride; TG) concentrations. We hypothesized that changes in insulin sensitivity are an important determinant of exercise-induced changes in postprandial TG concentrations. Altogether, 38 men and 43 women, all of whom were normotriglyceridaemic and normoglycaemic, each underwent two oral fat tolerance tests with different pre-conditions: control (no exercise) and prior exercise (90min of exercise at 60% of maximal O 2 uptake the day before). Venous blood samples were obtained in the fasting state and for 6h after a high-fat mixed meal. In the control trial there were significant correlations between log fasting TG concentration and log fasting insulin concentration ( r = 0.42, P < 0.0005) and between log postprandial TG response (area under the curve) and log postprandial insulin response ( r = 0.48, P < 0.0005). Prior exercise reduced the fasting TG concentration by 18.2±2.2% (mean±S.E.M.) ( P < 0.0005), the postprandial TG response by 21.5±1.9% ( P < 0.0005), the fasting insulin concentration by 3.8±3.1% ( P < 0.01) and the postprandial insulin response by 11.9±2.5% ( P < 0.0005). However, there was no relationship between the exercise-induced changes in log fasting TG and log fasting insulin ( r = 0.08, P = 0.50), nor between the exercise-induced changes in log postprandial TG response and log postprandial insulin response ( r = 0.04, P = 0.70). These data suggest that the reductions in fasting and postprandial TG levels elicited by a session of moderate-intensity exercise are not mediated by an increase in insulin sensitivity.
Articles
Effect of salt-loading on blood pressure, insulin sensitivity and limb blood flow in normal subjects
Journal:
Clinical Science
Clin Sci (Lond) (1998) 95 (2): 157–164.
Published: 01 August 1998
...M. FOO; A. E. DENVER; S. W. COPPACK; J. S. YUDKIN 1. The aim of this study was to determine the effects of high (220 ;mmol/day) and low (40 ;mmol/day) salt intake for 6 days on blood pressure, leg blood flow and insulin sensitivity in 18 ;healthy normotensive subjects. 2. Twenty-four-hour...
Abstract
1. The aim of this study was to determine the effects of high (220 ;mmol/day) and low (40 ;mmol/day) salt intake for 6 days on blood pressure, leg blood flow and insulin sensitivity in 18 ;healthy normotensive subjects. 2. Twenty-four-hour ambulatory blood pressure was measured at baseline, during salt-loading and salt-depletion. Insulin sensitivity was determined by a two-step euglycaemic–hyperinsulinaemic clamp (low and high insulin infusion rates: 40 and 600 ;m-unit·min -1 ·m -2 respectively) and leg blood flow by plethysmography. 3. Salt-loading resulted in changes in weight [change between salt-loading and salt-restriction: δ =+0.45 (S.D.±0.69) ;kg, P = 0.015], plasma renin [δ =-11.5 (S.D.±12.9) ; μ -units/l, P = 0.001] and urinary noradrenaline [δ =-8.6 (S.D.±18.7) ;nmol/mmol creatinine, P = 0.05]. There were borderline significant increases in 24-h systolic blood pressure [δ =+5.8 (S.D.±14.2) mmHg, P = 0.06] and plasma volume [δ =+0.29 (S.D.±0.67) litres, P = 0.08]. 4. Insulin sensitivity was similar in both salt states. Geometric mean metabolic clearance rate of low-dose insulin: low salt, 5.13 (S.D.×/÷1.35) dl/min; high salt, 4.94 (S.D.×/÷1.37) dl/min, P = 1.0. Geometric mean metabolic clearance rate of high-dose insulin: low salt, 9.68 ;dl/min (S.D.×/÷1.30); high salt, 9.68 (S.D.×/÷1.27) dl/min, P = 0.69. 5. Leg blood flow response to high-dose insulin on high salt increased significantly compared with low salt. Percentage change of blood flow on low salt, δ =+36.6 (S.D.±22.9)% versus high salt, δ =+66.8 (S.D.±52.2)%, P = 0.03. 6. There were no significant relationships between salt-related changes in limb blood flow and changes in insulin sensitivity at either insulin infusion rate. 7. We conclude that salt-loading, despite changing body weight, the renin–angiotensin–aldosterone system, urinary noradrenaline and the leg blood flow response to insulin, has no significant effect on insulin sensitivity. Salt-loading causes dissociated effects on insulin-induced vasodilatation and glucose disposal.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1998) 94 (2): 175–180.
Published: 01 February 1998
...R. Butler; A.D. Morris; A. D. Struthers 1. Recent evidence shows that skeletal muscle blood flow is an important determinant of insulin sensitivity and that insulin-mediated vasodilatation is nitric oxide dependent. These results have given rise to the hypothesis that endothelial nitric oxide...
Abstract
1. Recent evidence shows that skeletal muscle blood flow is an important determinant of insulin sensitivity and that insulin-mediated vasodilatation is nitric oxide dependent. These results have given rise to the hypothesis that endothelial nitric oxide inhibition may decrease insulin sensitivity in humans. 2. We examined this hypothesis directly by evaluating the effects of systemic nitric oxide synthase inhibition with N G -monomethyl l-arginine (3 mg h −1 kg −1 ) on whole-body glucose uptake (euglycaemic hyperinsulinaemic clamp) and calf blood flow (bilateral calf venous occlusion plethysmography) in 16 healthy male subjects in a randomized, double-blind, placebo-controlled, crossover study. 3. N G -Monomethyl l-arginine infusion was associated with a pressor effect (119/61 ± 2/2 compared with 114/58 ± 2/2 mmHg for placebo; P < 0.001), and a negative chronotropic response (57 ± 2 compared with 62 ± 2 beats/min for placebo; P < 0.001). The glucose infusion rate was significantly increased after infusion of N G -monomethyl l-arginine (8.9 ± 0.9 compared with 7.9 ± 0.8 mg min −1 kg −1 for placebo; P = 0.002). Whole-body glucose uptake increased during the clamp, with values of 9.4 ± 0.7 and 10.9 ± 0.8 mg min −1 kg −1 for placebo and N G -monomethyl l-arginine respectively ( P = 0.036; 95% confidence interval 0.2,2.8). N G -Monomethyl l-arginine was associated with increased calf blood flow by comparison with placebo ( P < 0.05, area under curve). 4. These data show for the first time that systemic inhibition of nitric oxide synthesis increases rather than decreases whole-body glucose uptake. We suggest that the higher skeletal muscle blood flow seen after N G -monomethyl l-arginine may explain the observed increase in whole-body glucose uptake.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1995) 88 (4): 427–432.
Published: 01 April 1995
... results suggest that intraperitoneal insulin, while resulting in better glycaemic control and improved insulin sensitivity than subcutaneous insulin, increases serum triacylglycerol and total cholesterol and reduces high-density lipoprotein-cholesterol, possibly via a direct effect on the liver. 21...
Abstract
1. The metabolic effects of intraperitoneal and subcutaneous insulin delivery were compared in a crossover manner in six C-peptide-negative diabetic patients with end-stage renal disease on continuous ambulatory peritoneal dialysis. Each treatment period lasted at least 3 months. Hyperinsulinaemic euglycaemic clamp was performed and glucose turnover assessed using [3- 3 H]glucose as a tracer. 2. During intraperitoneal delivery the daily insulin dose was 2.4 times higher than during subcutaneous administration and glycaemic control was significantly better (HbA 1c 7.63% ± 0.46% and 9.52% ± 0.51% during intraperitoneal and subcutaneous insulin respectively, P < 0.01). The number of hypoglycaemic episodes was lower during intraperitoneal insulin than during subcutaneous therapy. 3. Intraperitoneal insulin resulted in an enhanced glucose disposal rate ( P < 0.01) and reduced fasting hepatic glucose production ( P < 0.01). High-density lipoprotein-cholesterol decreased and the ratio of low-density lipoprotein/high-density lipoprotein-cholesterol increased significantly ( P < 0.05) during intraperitoneal insulin delivery. 4. The results suggest that intraperitoneal insulin, while resulting in better glycaemic control and improved insulin sensitivity than subcutaneous insulin, increases serum triacylglycerol and total cholesterol and reduces high-density lipoprotein-cholesterol, possibly via a direct effect on the liver.
Articles
C. A. Abbott, M. I. MacKness, S. Kumar, A. O. Olukoga, C. Gordon, S. Arrol, D. Bhatnagar, A. J. M. Boulton, P. N. Durrington
Journal:
Clinical Science
Clin Sci (Lond) (1993) 85 (1): 77–81.
Published: 01 July 1993
... 2 diabetes, serum butyrylcholinesterase activity was correlated with log serum fasting triacylglycerol concentration ( r = 0.41 and r = 0.43, respectively, P <0.001). In the type 2 population serum butyrylcholinesterase activity was also correlated with insulin sensitivity ( r = −0.51, P <...
Abstract
1. The activity of serum butyrylcholinesterase (‘pseudocholinesterase’, EC3.1.1.8) was investigated in 56 patients with type 1 diabetes mellitus, 51 patients with type 2 diabetes mellitus and 101 healthy control subjects. 2. Butyrylcholinesterase activity was significantly elevated in both type 1 (8.10 ± 3.35 units/ml) and type 2 (7.22 ± 1.95 units/ml) diabetes compared with the control subjects (4.23 ± 1.89 units/ml) ( P <0.001). 3. In the patients with type 1 and type 2 diabetes, serum butyrylcholinesterase activity was correlated with log serum fasting triacylglycerol concentration ( r = 0.41 and r = 0.43, respectively, P <0.001). In the type 2 population serum butyrylcholinesterase activity was also correlated with insulin sensitivity ( r = −0.51, P <0.001). 4. Serum butyrylcholinesterase activity was unrelated to age, gender, serum γ-glutamyltranspeptidase activity, body mass index, or treatment for diabetes in both the diabetic populations. 5. In 37 non-diabetic patients with butyrylcholinesterase deficiency serum triacylglycerol levels were in the normal range. 6. These results are consistent with the view that butyrylcholinesterase may have a role in the altered lipoprotein metabolism in hypertriglyceridaemia associated with insulin insensitivity or insulin deficiency in diabetes mellitus.
Articles
R. Heyligenberg, J. A. Romijn, M. J. T. Hommes, E. Endert, J. K. M. Eeftinck Schattenkerk, H. P. Sauerwein
Journal:
Clinical Science
Clin Sci (Lond) (1993) 84 (2): 209–216.
Published: 01 February 1993
... insulin sensitivity. However, these results may also be related to the confounding effect of increased non-insulin-mediated glucose uptake in acquired immunodeficiency syndrome, which will result in an erroneously presumed increased insulin sensitivity. To study the contribution of non-insulin-mediated...
Abstract
1. One of the metabolic features of acquired immunodeficiency syndrome is increased tissue glucose uptake documented by euglycaemic-hyperinsulinaemic clamp studies, suggesting increased insulin sensitivity. However, these results may also be related to the confounding effect of increased non-insulin-mediated glucose uptake in acquired immunodeficiency syndrome, which will result in an erroneously presumed increased insulin sensitivity. To study the contribution of non-insulin-mediated glucose uptake to total tissue glucose uptake in acquired immunodeficiency syndrome, we conducted a hypoinsulinaemic clamp study in clinically stable human immunodeficiency virus-infected (Centers for Disease Control class IV) men ( n = 7) and healthy subjects ( n = 5). Glucose uptake was measured by a primed, continuous infusion of [3- 3 H]glucose in the postabsorptive state and during somatostatin-induced insulinopenia at euglycaemic (≈5.3 mmol/l) and hyperglycaemic (≈11 mmol/l) glucose concentrations. 2. Basal glucose concentration (patients, 5.2 ± 0.1 mmol/l; control subjects, 5.3 ± 0.1 mmol/l) and basal glucose tissue uptake (patients, 15.9 ± 0.5 μmol min −1 kg −1 fat-free mass; control subjects, 15.2 ± 0.4 μmol min −1 kg −1 fat-free mass) were not different between the two groups. 3. Euglycaemic glucose uptake during somatostatin infusion, reflecting non-insulin-mediated glucose uptake, decreased to 82 ± 3% in patients and 78 ± 2% in control subjects (not significant). Under hyperglycaemic (≈11 mmol/l) conditions with sustained insulinopenia, no differences in glucose uptake existed between the two groups (patients, 16.8 ± 0.6 μmol min −1 kg −1 fat-free mass; control subjects, 16.1 ± 0.3 μmol min −1 kg −1 fat-free mass). 4. Our results indicate that non-insulin-mediated glucose uptake is not increased in acquired immunodeficiency syndrome. Therefore the previously described increase in insulin sensitivity in acquired immunodeficiency syndrome during hyperinsulinaemia is explained by a real increase in insulin sensitivity and not by augmented non-insulin-mediated glucose uptake.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1990) 79 (2): 167–174.
Published: 01 August 1990
... substrate oxidation and forearm alanine exchange provide support for the operation of the glucose—fatty acid cycle. forearm metabolism glucose-fatty acid cycle insulin sensitivity non-insulin-dependent diabetes mellitus plasma non-esterified fatty acids substrate oxidation © 1990 The...
Abstract
1. The purpose of the present study was to maintain physiological plasma non-esterified fatty acid levels and to (i) examine their effect on skeletal muscle insulin-stimulated glucose uptake and metabolite exchange using the forearm technique, and (ii) evaluate their effect on whole-body glucose uptake and fuel oxidation. 2. Intralipid (10%) and heparin (Lipid) or saline (Control) was administered to eight healthy male subjects on separate occasions for 210 min. Insulin, glucagon and somatostatin were administered from 60 to 210 min in each study and euglycaemia was maintained. 3. Plasma non-esterified fatty acid levels plateaued at 420 ±50 μmol/l with the Lipid infusion but were completely suppressed during the Control clamp. Forearm non-esterified fatty acid uptake increased with the Lipid infusion (+ 50±10 nmol min −1 100 ml −1 of forearm) and was accompanied by a significant decrease in forearm glucose uptake (+ 3.23 ± 0.25 versus + 3.65 ± 0.35 μmol min −1 100 ml −1 of forearm, Lipid and Control, respectively; P < 0.05) and alanine release (–84±12 versus −113 ± 15 nmol min −1 100 ml −1 of forearm, Lipid and Control, respectively; P < 0.05). 4. Whole-body glucose uptake showed a comparable decrease with the Lipid infusion (6.36 ±0.81 versus 6.85±0.66 mg min −1 kg −1 ; P < 0.05) and was accompanied by an increase in lipid oxidation (0.33 ±0.08 versus 0.16 ±0.05 mg min −1 kg −1 ; P < 0.02) and a decrease in glucose oxidation (2.93 ±0.23 versus 3.30±0.20 mg min −1 kg −1 ; P < 0.05). 5. We conclude that the maintenance of physiological plasma non-esterified fatty acid levels is associated with a decrease in forearm and whole-body insulin-stimulated glucose uptake. The changes in substrate oxidation and forearm alanine exchange provide support for the operation of the glucose—fatty acid cycle.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (1983) 64 (5): 511–516.
Published: 01 May 1983
... = −0.64, P < 0.01) and to basal triglyceride concentration ( r = −0.69, P < 0.005), but directly to insulin sensitivity ( r = +0.48, P < 0.05), and was unrelated to plasma free fatty acid concentration. 3. Since insulin sensitivity was also related to body mass index and basal triglyceride level...
Abstract
1. We have investigated the possibility that the effect of insulin on triglyceride metabolism is related to the individual's responsiveness to insulin-mediated glucose utilization. Changes in plasma triglyceride levels were determined during 2 h infusions of insulin with glucose that maintained euglycaemia in 17 subjects, some of whom were overweight and/or hypertrigly-ceridaemic. 2. Plasma triglyceride concentrations fell in most subjects (mean ± sd : 19.9 ± 13.0%). The percentage fall in plasma triglyceride was inversely related to body mass index ( r = −0.64, P < 0.01) and to basal triglyceride concentration ( r = −0.69, P < 0.005), but directly to insulin sensitivity ( r = +0.48, P < 0.05), and was unrelated to plasma free fatty acid concentration. 3. Since insulin sensitivity was also related to body mass index and basal triglyceride level stepwise regression analysis was carried out to determine the influence of these three variables on insulin-mediated lowering of plasma triglyceride. The percentage fall in plasma triglyceride remained independently related to insulin sensitivity ( P < 0.05) and to body mass index ( P < 0.05), and these two variables accounted for 44% of the fall in triglyceride. 4. Resistance to insulin (in terms of glucose utilization) may therefore be one significant, independent factor determining the plasma triglyceride concentration.