Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs

2002 ◽  
Vol 282 (2) ◽  
pp. E286-E296 ◽  
Author(s):  
Mary Courtney Moore ◽  
Shosuke Satake ◽  
Bryan Baranowski ◽  
Po-Shiuan Hsieh ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Portal Vein ◽  
Glucose Utilization ◽  
Conscious Dogs ◽  
Peripheral Insulin Sensitivity ◽  
Sham Procedure ◽  
Peripheral Insulin Resistance ◽  
Hepatic Nerves ◽  
Arterial Insulin

We tested the hypothesis that the loss of hepatic nerves decreases peripheral insulin sensitivity. Surgical hepatic denervation (DN) was performed in 22 dogs ∼16 days before study; 7 dogs (Sham-Sal) had a sham procedure. A euglycemic hyperinsulinemic (1 mU · kg−1 · min−1; arterial insulin 35 ± 1 μU/ml in all dogs) clamp was performed in conscious dogs. From 0 to 90 min of the clamp, all dogs received the same treatment; then the DN dogs were divided into three groups. From 90 to 180 min, DN-PeA ( n = 7) and DN-PoA ( n = 7) groups received acetylcholine 2.5 μg · kg−1 · min−1 via peripheral or portal vein, respectively, and DN-Sal ( n= 8) received no acetylcholine. During 150–180 min, the Sham-Sal, DN-Sal, DN-PeA, and DN-PoA groups exhibited glucose infusion rates of 12.4 ± 0.8, 9.3 ± 0.8 ( P < 0.05 vs. Sham-Sal), 9.1 ± 0.1 ( P < 0.05 vs. Sham-Sal), and 12.7 ± 1.6 mg · kg−1 · min−1; nonhepatic glucose uptakes of 11.5 ± 0.9, 8.9 ± 0.7 ( P < 0.05 vs. Sham-Sal), 8.6 ± 0.9 ( P < 0.05 vs. Sham-Sal), and 11.9 ± 1.7 mg · kg−1 · min−1; net hindlimb glucose uptakes of 18.4 ± 2.1, 13.7 ± 1.1 ( P< 0.05 vs. Sham-Sal), 17.5 ± 1.9, and 16.7 ± 3.2 mg/min; and glucose utilization rates of 14.4 ± 1.4, 10.4 ± 0.8 ( P < 0.05 vs. Sham-Sal), 9.8 ± 0.9 ( P< 0.05 vs. Sham-Sal), and 13.6 ± 1.8 mg · kg−1 · min−1, respectively. DN caused peripheral insulin resistance, and intraportal but not peripheral acetylcholine restored insulin sensitivity.

scholarly journals Duration of rise in free fatty acids determines salicylate's effect on hepatic insulin sensitivity

2013 ◽  
Vol 217 (1) ◽  
pp. 31-43 ◽  
Author(s):  
Sandra Pereira ◽  
Wen Qin Yu ◽  
María E Frigolet ◽  
Jacqueline L Beaudry ◽  
Yaniv Shpilberg ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Muscle Protein ◽  
Hepatic Insulin Resistance ◽  
Skeletal Muscle Protein ◽  
Protein Levels ◽  
Peripheral Insulin Resistance ◽  
Plasma Ffa ◽  
A Site

We have shown in rats that sodium salicylate (SS), which inhibits IkBa kinase B (IKKB), prevents hepatic and peripheral insulin resistance caused by short-term (7 h) i.v. administration of Intralipid and heparin (IH). We wished to further determine whether this beneficial effect of SS persisted after prolonged (48 h) IH infusion, which better mimics the chronic free fatty acid (FFA) elevation of obesity. Hence, we performed hyperinsulinemic euglycemic clamps with tritiated glucose methodology to determine hepatic and peripheral insulin sensitivity in rats infused with saline, IH, IH and SS, or SS alone. SS prevented peripheral insulin resistance (P<0.05) caused by prolonged plasma FFA elevation; however, it did not prevent hepatic insulin resistance. In skeletal muscle, protein levels of phospho-IkBa were augmented by prolonged IH administration and this was prevented by SS, suggesting that IH activates while SS prevents the activation of IKKB. Markers of IKKB activation, namely protein levels of phospho-IkBa and IkBa, indicated that IKKB is not activated in the liver after prolonged FFA elevation. Phosphorylation of serine 307 at insulin receptor substrate (IRS)-1, which is a marker of proximal insulin resistance, was not altered by IH administration in the liver, suggesting that this is not a site of hepatic insulin resistance in the prolonged lipid infusion model. Our results suggest that the role of IKKB in fat-induced insulin resistance is time and tissue dependent and that hepatic insulin resistance induced by prolonged lipid elevation is not due to an IRS-1 serine 307 kinase.

scholarly journals Smoothelin-Like Protein 1 Regulates Development and Metabolic Transformation of Skeletal Muscle in Hyperthyroidism

2021 ◽  
Vol 12 ◽  
Author(s):  
Evelin Major ◽  
Ferenc Győry ◽  
Dániel Horváth ◽  
Ilka Keller ◽  
István Tamás ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glycogen Synthesis ◽  
C2c12 Cells ◽  
Great Promise ◽  
Hexokinase Ii ◽  
Peripheral Insulin Resistance ◽  
Expression Of Genes ◽  
Metabolic Transformation

Hyperthyroidism triggers a glycolytic shift in skeletal muscle (SKM) by altering the expression of metabolic proteins, which is often accompanied by peripheral insulin resistance. Our previous results show that smoothelin-like protein 1 (SMTNL1), a transcriptional co-regulator, promotes insulin sensitivity in SKM. Our aim was to elucidate the role of SMTNL1 in SKM under physiological and pathological 3,3′,5-Triiodo-L-thyronine (T3) concentrations. Human hyper- and euthyroid SKM biopsies were used for microarray analysis and proteome profiler arrays. Expression of genes related to energy production, nucleic acid- and lipid metabolism was changed significantly in hyperthyroid samples. The phosphorylation levels and activity of AMPKα2 and JNK were increased by 15% and 23%, respectively, in the hyperthyroid samples compared to control. Moreover, SMTNL1 expression showed a 6-fold decrease in the hyperthyroid samples and in T3-treated C2C12 cells. Physiological and supraphysiological concentrations of T3 were applied on differentiated C2C12 cells upon SMTNL1 overexpression to assess the activity and expression level of the elements of thyroid hormone signaling, insulin signaling and glucose metabolism. Our results demonstrate that SMTNL1 selectively regulated TRα expression. Overexpression of SMTNL1 induced insulin sensitivity through the inhibition of JNK activity by 40% and hampered the non-genomic effects of T3 by decreasing the activity of ERK1/2 through PKCδ. SMTNL1 overexpression reduced IRS1 Ser307 and Ser612 phosphorylation by 52% and 53%, respectively, in hyperthyroid model to restore the normal responsiveness of glucose transport to insulin. SMTNL1 regulated glucose phosphorylation and balances glycolysis and glycogen synthesis via the downregulation of hexokinase II by 1.3-fold. Additionally, mitochondrial respiration and glycolysis were measured by SeaHorse analysis to determine cellular metabolic function/phenotype of our model system in real-time. T3 overload strongly increased the rate of acidification and a shift to glycolysis, while SMTNL1 overexpression antagonizes the T3 effects. These lines of evidence suggest that SMTNL1 potentially prevents hyperthyroidism-induced changes in SKM, and it holds great promise as a novel therapeutic target in insulin resistance.

No changes of peripheral insulin resistance in polycystic ovary syndrome after long-term reduction of endogenous androgens with leuprolide

1995 ◽  
Vol 133 (6) ◽  
pp. 718-722 ◽  
Author(s):  
Antonino Lasco ◽  
Domenico Cucinotta ◽  
Alfonso Gigante ◽  
Giulia Denuzzo ◽  
Marilena Pedulla ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Obese Women ◽  
Ovary Syndrome ◽  
Control Subjects ◽  
Peripheral Insulin Resistance ◽  
Androgen Levels

Lasco A, Cucinotta D, Gigante A, Denuzzo G, Pedulla M, Trifiletti A, Frisina N. No changes of peripheral insulin resistance in polycystic ovary syndrome after long-term reduction of endogenous androgens with leuprolide. Eur J Endocrinol 1995;133:718–22. ISSN 0804–4643 The aim of this study was to investigate the relationship between plasma insulin levels, peripheral insulin sensitivity and androgen secretion in ten patients with polycystic ovary syndrome and in six obese women as compared with six normal-weight control subjects. During a euglycemic–hyperinsulinemic clamp no significant change of testosterone, androstenedione or dehydroepiandrosterone sulfate plasma levels was observed in the two groups of patients or in the control subjects; insulin sensitivity was clearly reduced and was similar in polycystic ovary patients and in obese women, in spite of the different plasma androgen levels. A long-term (5 months) androgen suppression with the gonadotropin-releasing hormone agonist leuprolide was not able to improve significantly the insulin sensitivity. These results demonstrate that the short-term hyperinsulinemia achieved with the clamp technique does not affect androgen secretion and that insulin resistance, measured with the same technique, is not influenced by long-term suppression of plasma androgen levels in polycystic ovary syndrome. A Lasco, Via Faustina e Tertullo 19, 98100 Messina, Italy

scholarly journals Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation

2015 ◽  
Vol 225 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Sandra Pereira ◽  
Anu Shah ◽  
I George Fantus ◽  
Jamie W Joseph ◽  
Adria Giacca
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Muscle Protein ◽  
Protein Carbonyl ◽  
Hepatic Insulin Resistance ◽  
Skeletal Muscle Protein ◽  
Protein Carbonyl Content ◽  
Peripheral Insulin Resistance ◽  
Plasma Ffa

Circulating free fatty acids (FFAs) are elevated in obesity and cause insulin resistance. The objective of the current study was to determine whether the antioxidantN-acetyl-l-cysteine (NAC) prevented hepatic and peripheral insulin resistance caused by prolonged elevation of plasma FFAs. Chronically cannulated Wistar rats received saline (SAL), Intralipid plus heparin (IH), IH plus NAC, or NAC i.v. infusion for 48 h. Insulin sensitivity was determined using the hyperinsulinemic–euglycemic clamp with tritiated glucose tracer. IH induced hepatic and peripheral insulin resistance (P<0.05). NAC co-infusion did not prevent insulin resistance in the liver, although it was able to prevent peripheral insulin resistance. Prolonged IH infusion did not appear to induce oxidative stress in the liver because hepatic content of protein carbonyl, malondialdehyde, and reduced to oxidized glutathione ratio did not differ across treatment groups. In alignment with our insulin sensitivity results, IH augmented skeletal muscle protein carbonyl content and this was prevented by NAC co-infusion. Taken together, our results indicate that oxidative stress mediates peripheral, but not hepatic, insulin resistance resulting from prolonged plasma FFA elevation. Thus, in states of chronic plasma FFA elevation, such as obesity, antioxidants may protect against peripheral but not hepatic insulin resistance.

scholarly journals Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity

2007 ◽  
Vol 194 (1) ◽  
pp. 131-141 ◽  
Author(s):  
Fernando Escrivá ◽  
M Lucía Gavete ◽  
Yasmín Fermín ◽  
Coralia Pérez ◽  
Nilda Gallardo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Calorie Restriction ◽  
Food Restriction ◽  
Glucose Utilization ◽  
Oral Glucose ◽  
Old Rats ◽  
Total Fat ◽  
Total Body

Insulin resistance develops with ageing in humans and rodents. Here, we have studied the evolution of insulin sensitivity with ageing trying to discriminate the role of adiposity from that of ageing in this process. We performed oral glucose tolerance tests and determined overall and tissue-specific glucose utilization under euglycemic-hyper-insulinemic conditions in 3-, 8-, and 24-month-old rats fed ad libitum, and in 8- and 24-month-old rats after 3 months of calorie restriction. Body composition and adipocyte-derived cytokines such as leptin, resistin, and adiponectin were analyzed. Overall insulin sensitivity decreases with ageing. Calorie restriction improves global insulin sensitivity in 8- but not in 24-month-old rats. Insulin-stimulated glucose utilization in adipose tissues decreases in 8 months, while in oxidative muscles it reaches significance only in older rats. Calorie restriction restores adipose tissue insulin sensitivity only in 8-month-old rats and no changes are observed in muscles of 24-month-old rats. Resistin and leptin increase with ageing. Food restriction lowers resistin and increases adiponectin in 8-month-old rats and decreases leptin in both ages. Visceral and total fat increase with ageing and decrease after calorie restriction. We conclude that accretion of visceral fat plays a key role in the development of insulin resistance after sexual maturity, which is reversible by calorie restriction. With aging, accumulation of retroperitoneal and total body fat leads to impaired muscle glucose uptake and to a state of insulin resistance that is difficult to reverse.

scholarly journals Resveratrol prevents insulin resistance caused by short-term elevation of free fatty acids in vivo

2015 ◽  
Vol 40 (11) ◽  
pp. 1129-1136 ◽  
Author(s):  
Sandra Pereira ◽  
Edward Park ◽  
Jessy Moore ◽  
Brandon Faubert ◽  
Danna M. Breen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Free Fatty Acids ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Serine Phosphorylation ◽  
Peripheral Insulin Resistance ◽  
Induce Insulin Resistance

Elevated levels of plasma free fatty acids (FFA), which are commonly found in obesity, induce insulin resistance. FFA activate protein kinases including the proinflammatory IκBα kinase β (IKKβ), leading to serine phosphorylation of insulin receptor substrate 1 (IRS-1) and impaired insulin signaling. To test whether resveratrol, a polyphenol found in red wine, prevents FFA-induced insulin resistance, we used a hyperinsulinemic-euglycemic clamp with a tracer to assess hepatic and peripheral insulin sensitivity in overnight-fasted Wistar rats infused for 7 h with saline, Intralipid plus 20 U·mL−1 heparin (IH; triglyceride emulsion that elevates FFA levels in vivo; 5.5 μL·min−1) with or without resveratrol (3 mg·kg−1·h−1), or resveratrol alone. Infusion of IH significantly decreased glucose infusion rate (GIR; P < 0.05) and peripheral glucose utilization (P < 0.05) and increased endogenous glucose production (EGP; P < 0.05) during the clamp compared with saline infusion. Resveratrol co-infusion, however, completely prevented the effects induced by IH infusion: it prevented the decreases in GIR (P < 0.05 vs. IH), peripheral glucose utilization (P < 0.05 vs. IH), and insulin-induced suppression of EGP (P < 0.05 vs. IH). Resveratrol alone had no effect. Furthermore, IH infusion increased serine (307) phosphorylation of IRS-1 in soleus muscle (∼30-fold, P < 0.001), decreased total IRS-1 levels, and decreased IκBα content, consistent with activation of IKKβ. Importantly, all of these effects were abolished by resveratrol (P < 0.05 vs. IH). These results suggest that resveratrol prevents FFA-induced hepatic and peripheral insulin resistance and, therefore, may help mitigate the health consequences of obesity.

scholarly journals Sex-specific programming of adult insulin resistance in guinea pigs by variable perinatal growth induced by spontaneous variation in litter size

2019 ◽  
Vol 316 (4) ◽  
pp. R352-R361
Author(s):  
Dane M. Horton ◽  
David A. Saint ◽  
Kathryn L. Gatford ◽  
Karen L. Kind ◽  
Julie A. Owens
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Guinea Pigs ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Whole Body ◽  
Catch Up ◽  
Endogenous Glucose

Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in programming of insulin resistance later in life. Spontaneous IUGR in the guinea pig, due to natural variation in litter size, produces offspring with asymmetric IUGR and neonatal catch-up growth. We hypothesized that spontaneous IUGR and/or accelerated neonatal growth would impair insulin sensitivity in adult guinea pigs. Insulin sensitivity of glucose metabolism was determined by hyperinsulinemic-euglycemic clamp (HEC) in 38 (21 male, 17 female) young adult guinea pigs from litters of two-to-four pups. A subset (10 male, 8 female) were infused with d-[3-3H]glucose before and during the HEC to determine rates of basal and insulin-stimulated glucose utilization, storage, glycolysis, and endogenous glucose production. n males, the insulin sensitivity of whole body glucose uptake ( r = 0.657, P = 0.002) and glucose utilization ( r = 0.884, P = 0.004) correlated positively and independently with birth weight, but not with neonatal fractional growth rate (FGR10–28). In females, the insulin sensitivity of whole body and partitioned glucose metabolism was not related to birth weight, but that of endogenous glucose production correlated negatively and independently with FGR10–28 ( r = −0.815, P = 0.025). Thus, perinatal growth programs insulin sensitivity of glucose metabolism in the young adult guinea pig and in a sex-specific manner; impaired insulin sensitivity, including glucose utilization, occurs after IUGR in males and impaired hepatic insulin sensitivity after rapid neonatal growth in females.

scholarly journals Peripheral Insulin Resistance and Impaired Insulin Signaling Contribute to Abnormal Glucose Metabolism in Preterm Baboons

Endocrinology ◽  
2015 ◽  
Vol 156 (3) ◽  
pp. 813-823 ◽  
Author(s):  
Cynthia L. Blanco ◽  
Lisa L. McGill-Vargas ◽  
Amalia Gastaldelli ◽  
Steven R. Seidner ◽  
Donald C. McCurnin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Protein Content ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Glucose Disposal ◽  
Glucose Transporter 1 ◽  
Peripheral Insulin Resistance ◽  
Impaired Insulin

Abstract Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

Combining Various Methods to Assess Insulin Sensitivity in Nonobese Rat after Sleeve Gastrectomy

2018 ◽  
Vol 127 (07) ◽  
pp. 477-484
Author(s):  
Dong Sun ◽  
Yanmin Wang ◽  
Meng Wei ◽  
Zongli Zhang ◽  
Sanyuan Hu
Keyword(s):  
Insulin Resistance ◽  
Sleeve Gastrectomy ◽  
Steady State ◽  
Insulin Sensitivity ◽  
Challenge Test ◽  
Resistance Index ◽  
Control Groups ◽  
Hepatic Insulin Sensitivity ◽  
Peripheral Insulin Sensitivity ◽  
And Control

Abstract Background Sleeve gastrectomy (SG) procedure has been proved to improve insulin sensitivity and sustain anti-diabetic effects. Our aim is to co-use several methods to measure insulin sensitivity and investigate the effect of SG on hepatic and peripheral insulin sensitivity at early and long-term stages of postoperation. Methods Thirty 11-week-old male Goto-Kakizaki rats were divided into SG, sham-operated SG (SOSG), and control groups. They were observed before operation and for 36 weeks of postoperation. Insulin tolerance test (ITT) and homeostasis model of assessment for insulin resistance index(HOMA-IR)were used to measure insulin resistance before operations and at 2 and 36 weeks of postoperation; Pyruvate challenge test (PCT) was administrated to assess the gluconeogenesis capability in order to reflect hepatic insulin sensitivity before operation and at 2 and 36 weeks of postoperation; Hyperinsulinemic euglycemic clamps (HIEC) was conducted before operation and at 2 and 36 weeks of postoperation to calculate the endogenous hepatic glucose production (HGP) at the basal and steady-state for evaluation of hepatic insulin sensitivity, and calculate the exogenous glucose infusion rate (GIR) at the steady-state for evaluation of peripheral insulin sensitivity. Results The data showed that compared with rats in the sham and control groups, rats in SG group had 1) significantly lower AUCITT, HOMA-IR and AUC PCT values at 2 and 36 weeks of postoperation, 2) lower basal state HGP, but not steady-state GIR at 2 weeks of postoperation, and 3) significantly different basal and steady-state HGP and steady-state GIR at 36 weeks of postoperation. In addition, the basal and steady-state HGP and the steady-state GIR were significantly different between rats in SG group at 2 and 36 weeks of postoperation. Conclusions This study explored insulin sensitivity of rats after SG by jointly using a variety of techniques. The results showed that SG time-dependently improved the hepatic and peripheral insulin sensitivity.

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