12 research outputs found
Impact de lâinsuffisance rĂ©nale chronique sur les transporteurs de glucose et les effets subsĂ©quents sur la rĂ©sistance Ă lâinsuline
Parmi lâensemble des dĂ©sordres mĂ©taboliques retrouvĂ©s en insuffisance rĂ©nale chronique (IRC), la rĂ©sistance Ă lâinsuline demeure lâun des plus importantes Ă considĂ©rer en raison des risques de morbiditĂ© et de mortalitĂ© quâelle engendre via les complications cardiovasculaires. Peu dâĂ©tudes ont considĂ©rĂ© la modulation de transporteurs de glucose comme mĂ©canisme sous-jacent Ă lâapparition et Ă la progression de la rĂ©sistance Ă lâinsuline en IRC. Nous avons explorĂ© cette hypothĂšse en Ă©tudiant lâexpression de transporteurs de glucose issus dâorganes impliquĂ©s dans son homĂ©ostasie (muscles, tissus adipeux, foie et reins) via lâutilisation dâun modĂšle animal dâIRC (nĂ©phrectomie 5/6e). La sensibilitĂ© Ă lâinsuline a Ă©tĂ© dĂ©terminĂ©e par un test de tolĂ©rance au glucose (GTT), oĂč les rĂ©sultats reflĂštent une intolĂ©rance au glucose et une hyperinsulinĂ©mie, et par les Ă©tudes de transport au niveau musculaire qui tĂ©moignent dâune diminution du mĂ©tabolisme du glucose en IRC (~31%; p<0,05). La diminution significative du GLUT4 dans les tissus pĂ©riphĂ©riques (~40%; p<0,001) peut ĂȘtre Ă lâorigine de la rĂ©sistance Ă lâinsuline en IRC. De plus, lâaugmentation de lâexpression protĂ©ique de la majoritĂ© des transporteurs de glucose (SGLT1, SGLT2, GLUT1; p<0,05) au niveau rĂ©nal en IRC engendre une plus grande rĂ©absorption de glucose dont lâhyperglycĂ©mie subsĂ©quente favorise une diminution du GLUT4 exacerbant ainsi la rĂ©sistance Ă lâinsuline. LâĂ©lĂ©vation des niveaux protĂ©iques de GLUT1 et GLUT2 au niveau hĂ©patique tĂ©moigne dâun dĂ©faut homĂ©ostatique du glucose en IRC. Les rĂ©sultats jusquâici dĂ©montrent que la modulation de lâexpression des transporteurs de glucose peut ĂȘtre Ă lâorigine de la rĂ©sistance Ă lâinsuline en IRC.
Lâimpact de la parathyroĂŻdectomie (PTX) sur lâexpression du GLUT4 a Ă©tĂ© Ă©tudiĂ© Ă©tant donnĂ© que la PTX pourrait corriger lâintolĂ©rance au glucose en IRC. Nos rĂ©sultats dĂ©montrent une amĂ©lioration de lâintolĂ©rance au glucose pouvant ĂȘtre attribuable Ă la moins grande rĂ©duction de lâexpression protĂ©ique du GLUT4 dans les tissus pĂ©riphĂ©riques et ce malgrĂ© la prĂ©sence dâIRC. LâexcĂšs de PTH, secondaire Ă lâhyperparathyroĂŻdie, pourrait alors ĂȘtre Ă lâorigine de la rĂ©sistance Ă lâinsuline en IRC en affectant lâexpression du GLUT4.
LâIRC partage de nombreuses similitudes avec le prĂ©diabĂšte quant aux dĂ©faillances du mĂ©tabolisme du glucose tout comme lâhyperinsulinĂ©mie et lâintolĂ©rance au glucose. Aucune Ă©tude nâa tentĂ© dâĂ©valuer si lâIRC pouvait ultimement mener au diabĂšte. Nos rĂ©sultats ont par ailleurs dĂ©montrĂ© que lâinduction dâune IRC sur un modĂšle animal prĂ©disposĂ© (rats Zucker) engendrait une accentuation de leur intolĂ©rance au glucose tel que constatĂ© par les plus hautes glycĂ©mies atteintes lors du GTT. De plus, certains dâentre eux avaient des glycĂ©mies Ă jeun dont les valeurs surpassent les 25 mmol/L. Il est alors possible que lâIRC puisse mener au diabĂšte via lâĂ©volution de la rĂ©sistance Ă lâinsuline par lâaggravation de lâintolĂ©rance au glucose.Of all metabolic disorders found in chronic renal failure (CRF), insulin resistance remains one of the most important to consider because of the risk of morbidity and mortality it causes via cardiovascular complications. Few studies have considered the modulation of glucose transporters as the mechanism underlying the emergence and progression of insulin resistance in CRF. We explored this hypothesis by studying the expression of glucose transporters from organs involved in its homeostasis (muscle , fat , liver and kidneys) through the use of an animal model reflecting CRF (5/6th nephrectomy). The insulin sensitivity was determined by a glucose tolerance test (GTT), where the results reflect glucose intolerance and hyperinsulinemia , and transport studies in muscle show a decrease in glucose uptake in CRF ratss (~31% , p<0.05). The significant decrease in GLUT4 in peripheral tissues (~40%, p<0.001) may be the cause of insulin resistance in CRF. Furthermore, increased protein expression of the majority of glucose transporters (SGLT1, SGLT2, GLUT1, p<0.05) within the kidney in CRF causes greater glucose reabsorption in which consequential hyperglycemia promotes a decrease in GLUT4 thus exacerbating insulin resistance. Elevated protein levels of GLUT1 and GLUT2 in the liver reflects an impaired glucose homeostasis in CRF. The results show that the modulation of the expression of glucose transporters may be responsible for insulin resistance in CRF.
The impact of parathyroidectomy (PTX) on the expression of GLUT4 was studied since PTX is known to correct glucose intolerance in CRF. Our results show an improvement in glucose intolerance which may be due to less reduction of GLUT4 protein expression in peripheral tissues despite the presence of CRF. The excess of PTH, linked to secondary hyperparathyroidism, could be held responsible to the presence of insulin resistance in CRF by affectant GLUT4 expression.
CRF shares many similarities with prediabetes in regards to impaired glucose metabolism such as hyperinsulinemia and glucose intolerance. No studies have attempted to assess whether CRF could lead to diabetes. Our results demonstrated that the induction of CRF in a predisposed animal model (Zucker rats) provoked greater glucose intolerance as evidenced by the highest blood glucose levels reached in the GTT. In addition, some of them had fasting blood glucose levels whose values exceeded 25 mmol/L. It is therefore possible that CRF can lead to diabetes through the evolution of insulin resistance by the worsening of glucose intolerance
Mechanism of insulin resistance in a rat model of kidney disease and the risk of developing type 2 diabetes.
International audienceChronic kidney disease is associated with homeostatic imbalances such as insulin resistance. However, the underlying mechanisms leading to these imbalances and whether they promote the development of type 2 diabetes is unknown. The effect of chronic kidney disease on insulin resistance was studied on two different rat strains. First, in a 5/6th nephrectomised Sprague-Dawley rat model of chronic kidney disease, we observed a correlation between the severity of chronic kidney disease and hyperglycemia as evaluated by serum fructosamine levels (p<0.0001). Further, glucose tolerance tests indicated an increase of 25% in glycemia in chronic kidney disease rats (p<0.0001) as compared to controls whereas insulin levels remained unchanged. We also observed modulation of glucose transporters expression in several tissues such as the liver (decrease of â40%, pâ€0.01) and muscles (decrease of â29%, pâ€0.05). Despite a significant reduction of â37% in insulin-dependent glucose uptake in the muscles of chronic kidney disease rats (p<0.0001), the development of type 2 diabetes was never observed. Second, in a rat model of metabolic syndrome (Zucker Leprfa/fa), chronic kidney disease caused a 50% increased fasting hyperglycemia (p<0.0001) and an exacerbated glycemic response (p<0.0001) during glucose challenge. Similar modulations of glucose transporters expression and glucose uptake were observed in the two models. However, 30% (p<0.05) of chronic kidney disease Zucker rats developed characteristics of type 2 diabetes. Thus, our results suggest that downregulation of GLUT4 in skeletal muscle may be associated with insulin resistance in chronic kidney disease and could lead to type 2 diabetes in predisposed animals
Glucose and insulin responses to an intraperitoneal glucose tolerance test.
<p><b>(A)</b> Glucose and <b>(B)</b> Insulin responses to an intraperitoneal glucose tolerance test (2g/kg) performed on SD rats at Day 28 following a 16 hours fast. <b>(C)</b> Glucose and <b>(D)</b> Insulin responses to an intraperitoneal glucose tolerance test (1.5g/kg) performed on Zucker Lepr<sup>fa/fa</sup> rats at Day 28 following a 16 hour fast. Values are mean ± S.D. n = 10 for each group. *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001 as compared to CTL rats. Area under the curve is presented as percentage of controls, on the right corner of each graph.</p
Glucose transporters protein expression in selected organs of CKD rats.
<p>Protein levels are expressed in densitometry units. The densitometry units measured for glucose transporters were normalized to their respective loading control (ÎČ-actin: liver; GAPDH: muscles and adipose tissues; villin-1: kidneys) values. The normalized densitometry units of control rats were arbitrarily defined as 100%. The graph shows the mean expression in CKD rats expressed as percentage of CTL ± S.D of at least 5 rats in each group. *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001 as compared to CTL rats. Protein levels of glucose transporters in the <b>(A)</b> Kidneys and liver of SD rats, <b>(B)</b> Skeletal muscle and white adipose tissue of SD rats. <b>(C)</b>. Skeletal muscle and white adipose tissue in Zucker Lepr<sup>fa/fa</sup> rats. <b>(D)</b>. Representative Western blots for each glucose transporter. Each blot contains examples of three CKD (left) and three CTL (right) SD rats. Measurements at Day 42.</p
Biochemical parameters and body weight of CTL and CKD SD rats at Day 21.
<p>Biochemical parameters and body weight of CTL and CKD SD rats at Day 21.</p
Time of glycosuria apparition in Zucker Lepr<sup>fa/fa</sup> rats.
<p>The graph shows the proportion of rats with glycosuria as confirmed by a positive Diastix<sup>âą</sup> (Bayer) test on two consecutive days for 15 Zucker Lepr<sup>fa/fa</sup> rats per group.</p
Glucose transporters mRNA expression in selected organs of CKD rats.
<p>mRNA encoding glucose transporters in CTL and CKD rats in the indicated tissues were measured by quantitative Real-Time PCR. mRNA levels are expressed in relative quantities and calculated using the ÎÎCT method [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176650#pone.0176650.ref033" target="_blank">33</a>] with their respective housekeeping gene (Villin-1 for kidneys, ÎČ-actin for liver and GAPDH for muscles and adipose tissues). Data was normalized to the mean relative quantity of each gene in CTL rats. The graph shows the mean expression in CKD rats expressed as a percentage of controls ± S.D. of at least 10 rats in each group. *, p<0.05; **, p<0.01; ***, p<0.001; ****, p<0.0001 as compared to CTL rats. <b>(A)</b> Glucose transporters mRNA expression in the kidney and liver of SD rats. <b>(B)</b> GLUT1 and GLUT4 mRNA expression in skeletal muscle and white adipose tissue of SD rats. <b>(C)</b> GLUT1 and GLUT4 mRNA expression in skeletal muscle and white adipose tissue of Zucker Lepr<sup>fa/fa</sup> rats. Measurements at Day 42.</p
<i>Ex vivo</i> accumulation of radio-labeled 2-deoxyglucose in muscles.
<p>Uptake of radio-labeled 2-deoxyglucose in CTL and CKD rat muscles expressed as insulin response vs. basal condition. Basal condition of each muscle was arbitrarily defined as 1,0. Data are expressed as fold increase (mean) ± S.D for at least 5 rats per group. ***, p<0.001; ****, p<0.0001 as compared to CTL rats. <b>(A)</b> Sprague-Dawley rats and <b>(B)</b> Zucker Lepr<sup>fa/fa</sup> rats. Measurements at Day 42.</p
Correlation between serum fructosamine and creatinine in CTL and CKD rats.
<p>Fructosamine concentration expressed as a ratio of fructosamine reported on total protein content in serum, versus creatininemia of <b>(A)</b> n = 26 SD rats and <b>(B)</b> n = 37 Zucker Lepr<sup>fa/fa</sup> rats. Measurements at Day 21.</p