scholarly journals Expression and Regulation of Facilitative Glucose Transporters in Equine Insulin-Sensitive Tissue: From Physiology to Pathology

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Véronique A. Lacombe
Keyword(s):  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporters ◽  
Whole Body ◽  
Glucose Disposal ◽  
Class Iii ◽  
Rate Limiting Step ◽  
Altered Glucose ◽  
Insulin Dependent ◽  
Rate Limiting

Glucose uptake is the rate-limiting step in glucose utilization in mammalians and is tightly regulated by a family of specialized proteins, called the facilitated glucose transporters (GLUTs/SLC2). GLUT4, the major isoform in insulin-responsive tissue, translocates from an intracellular pool to the cell surface and as such determines insulin-stimulated glucose uptake. However, despite intensive research over 50 years, the insulin-dependent and -independent pathways that mediate GLUT4 translocation are not fully elucidated in any species. Insulin resistance (IR) is one of the hallmarks of equine metabolic syndrome and is the most common metabolic predisposition for laminitis in horses. IR is characterized by the impaired ability of insulin to stimulate glucose disposal into insulin-sensitive tissues. Similar to other species, the functional capability of the insulin-responsive GLUTs is impaired in muscle and adipose tissue during IR in horses. However, the molecular mechanisms of altered glucose transport remain elusive in all species, and there is still much to learn about the physiological and pathophysiological functions of the GLUT family members, especially in regard to class III. Since GLUTs are key regulators of whole-body glucose homeostasis, they have received considerable attention as potential therapeutic targets to treat metabolic disorders in human and equine patients.

Neural control of glucose uptake by skeletal muscle after central administration of NMDA

1995 ◽  
Vol 268 (2) ◽  
pp. R492-R497 ◽  
Author(s):  
C. H. Lang ◽  
M. Ajmal ◽  
A. G. Baillie
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Neural Control ◽  
Plasma Insulin ◽  
Regional Blood Flow ◽  
Muscle Blood Flow ◽  
Whole Body ◽  
Glucose Disposal ◽  
Central Administration

Intracerebroventricular injection of N-methyl-D-aspartate (NMDA) produces hyperglycemia and increases whole body glucose uptake. The purpose of the present study was to determine in rats which tissues are responsible for the elevated rate of glucose disposal. NMDA was injected intracerebroventricularly, and the glucose metabolic rate (Rg) was determined for individual tissues 20-60 min later using 2-deoxy-D-[U-14C]glucose. NMDA decreased Rg in skin, ileum, lung, and liver (30-35%) compared with time-matched control animals. In contrast, Rg in skeletal muscle and heart was increased 150-160%. This increased Rg was not due to an elevation in plasma insulin concentrations. In subsequent studies, the sciatic nerve in one leg was cut 4 h before injection of NMDA. NMDA increased Rg in the gastrocnemius (149%) and soleus (220%) in the innervated leg. However, Rg was not increased after NMDA in contralateral muscles from the denervated limb. Data from a third series of experiments indicated that the NMDA-induced increase in Rg by innervated muscle and its abolition in the denervated muscle were not due to changes in muscle blood flow. The results of the present study indicate that 1) central administration of NMDA increases whole body glucose uptake by preferentially stimulating glucose uptake by skeletal muscle, and 2) the enhanced glucose uptake by muscle is neurally mediated and independent of changes in either the plasma insulin concentration or regional blood flow.

Prevention of skeletal muscle insulin resistance by dietary cod protein in high fat-fed rats

2001 ◽  
Vol 281 (1) ◽  
pp. E62-E71 ◽  
Author(s):  
Charles Lavigne ◽  
Frédéric Tremblay ◽  
Geneviève Asselin ◽  
Hélène Jacques ◽  
André Marette
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Amino Acids ◽  
Glucose Uptake ◽  
Soy Protein ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance

In the present study, we tested the hypothesis that fish protein may represent a key constituent of fish with glucoregulatory activity. Three groups of rats were fed a high-fat diet in which the protein source was casein, fish (cod) protein, or soy protein; these groups were compared with a group of chow-fed controls. High-fat feeding led to severe whole body and skeletal muscle insulin resistance in casein- or soy protein-fed rats, as assessed by the euglycemic clamp technique coupled with measurements of 2-deoxy-d-[3H]glucose uptake rates by individual tissues. However, feeding cod protein fully prevented the development of insulin resistance in high fat-fed rats. These animals exhibited higher rates of insulin-mediated muscle glucose disposal that were comparable to those of chow-fed rats. The beneficial effects of cod protein occurred without any reductions in body weight gain, adipose tissue accretion, or expression of tumor necrosis factor-α in fat and muscle. Moreover, L6 myocytes exposed to cod protein-derived amino acids showed greater rates of insulin-stimulated glucose uptake compared with cells incubated with casein- or soy protein-derived amino acids. These data demonstrate that feeding cod protein prevents obesity-induced muscle insulin resistance in high fat-fed obese rats at least in part through a direct action of amino acids on insulin-stimulated glucose uptake in skeletal muscle cells.

scholarly journals MON-647 Mechanisms of Insulin Resistance in Skeletal Muscle in Women with PCOS

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Rhiannon K Patten ◽  
Andrew J McAinch ◽  
Raymond J Rodgers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Reproductive Age ◽  
Whole Body ◽  
Dependent Manner ◽  
Cultured Myotubes ◽  
Tgfβ Superfamily

Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder affecting metabolic, reproductive and mental health of 8-13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 85% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole body insulin-stimulated glucose uptake, however, in PCOS this is reduced about 27% when assessed by hyperinsulinemic euglycemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). Previous work suggested that Transforming Growth Factor Beta (TGFβ) superfamily ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30ng/ml), a novel TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=10) and healthy controls (n=10). AMH negatively affected glucose uptake and insulin signalling increasing p-IRS1 (ser312) in a dose-dependent manner in myotubes from both women with and without PCOS. AMH did not appear to activate the canonical TGFβ/BMP signalling pathway. Conversely, TGFβ1 had an opposite effect in both PCOS and control myotubes cultures, decreasing phosphorylation of IRS1 (ser312) and enhancing glucose uptake via Smad2/3 signalling. In conclusion, these results suggest that AMH may play a role in skeletal muscle IR observed in PCOS, however, further research is required to elucidate its mechanisms of action and broader impact in this syndrome. References: (1) Stepto et al. Hum Reprod 2013 Mar;28(3):777-784. (2) Cassar et al. Hum Reprod 2016 Nov;31(11):2619-2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al. J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372-5381. (5) Raja-Khan et al. Reprod Sci 2014 Jan;21(1):20-31.

scholarly journals Leptin administration improves skeletal muscle insulin responsiveness in diet-induced insulin-resistant rats

2001 ◽  
Vol 280 (1) ◽  
pp. E130-E142 ◽  
Author(s):  
Ben B. Yaspelkis ◽  
James R. Davis ◽  
Maziyar Saberi ◽  
Toby L. Smith ◽  
Reza Jazayeri ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Whole Body ◽  
Glucose Disposal ◽  
High Fat ◽  
Insulin Resistant ◽  
Skeletal Muscle Glucose Uptake ◽  
Uptake And Transport

In addition to suppressing appetite, leptin may also modulate insulin secretion and action. Leptin was administered here to insulin-resistant rats to determine its effects on secretagogue-stimulated insulin release, whole body glucose disposal, and insulin-stimulated skeletal muscle glucose uptake and transport. Male Wistar rats were fed either a normal (Con) or a high-fat (HF) diet for 3 or 6 mo. HF rats were then treated with either vehicle (HF), leptin (HF-Lep, 10 mg · kg−1 · day−1 sc), or food restriction (HF-FR) for 12–15 days. Glucose tolerance and skeletal muscle glucose uptake and transport were significantly impaired in HF compared with Con. Whole body glucose tolerance and rates of insulin-stimulated skeletal muscle glucose uptake and transport in HF-Lep were similar to those of Con and greater than those of HF and HF-FR. The insulin secretory response to either glucose or tolbutamide (a pancreatic β-cell secretagogue) was not significantly diminished in HF-Lep. Total and plasma membrane skeletal muscle GLUT-4 protein concentrations were similar in Con and HF-Lep and greater than those in HF and HF-FR. The findings suggest that chronic leptin administration reversed a high-fat diet-induced insulin-resistant state, without compromising insulin secretion.

Intraportal administration of neuropeptide Y and hepatic glucose metabolism

2008 ◽  
Vol 294 (4) ◽  
pp. R1197-R1204 ◽  
Author(s):  
Makoto Nishizawa ◽  
Masakazu Shiota ◽  
Mary Courtney Moore ◽  
Stephanie M. Gustavson ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Neuropeptide Y ◽  
Glucose Uptake ◽  
Infusion Rate ◽  
Whole Body ◽  
Glucose Disposal ◽  
Control Group ◽  
Intravenous Glucose ◽  
Hepatic Glucose ◽  
Hepatic Glucose Uptake

We examined whether intraportal delivery of neuropeptide Y (NPY) affects glucose metabolism in 42-h-fasted conscious dogs using arteriovenous difference methodology. The experimental period was divided into three subperiods (P1, P2, and P3). During all subperiods, the dogs received infusions of somatostatin, intraportal insulin (threefold basal), intraportal glucagon (basal), and peripheral intravenous glucose to increase the hepatic glucose load twofold basal. Following P1, in the NPY group ( n = 7), NPY was infused intraportally at 0.2 and 5.1 pmol·kg−1·min−1 during P2 and P3, respectively. The control group ( n = 7) received intraportal saline infusion without NPY. There were no significant changes in hepatic blood flow in NPY vs. control. The lower infusion rate of NPY (P2) did not enhance net hepatic glucose uptake. During P3, the increment in net hepatic glucose uptake (compared with P1) was 4 ± 1 and 10 ± 2 μmol·kg−1·min−1 in control and NPY, respectively ( P < 0.05). The increment in net hepatic fractional glucose extraction during P3 was 0.015 ± 0.005 and 0.039 ± 0.008 in control and NPY, respectively ( P < 0.05). Net hepatic carbon retention was enhanced in NPY vs. control (22 ± 2 vs. 14 ± 2 μmol·kg−1·min−1, P < 0.05). There were no significant differences between groups in the total glucose infusion rate. Thus, intraportal NPY stimulates net hepatic glucose uptake without significantly altering whole body glucose disposal in dogs.

Effect of glycemia and nonesterified fatty acids on forearm glucose uptake in normal humans

1991 ◽  
Vol 261 (3) ◽  
pp. E304-E311 ◽  
Author(s):  
M. Walker ◽  
G. R. Fulcher ◽  
C. F. Sum ◽  
H. Orskov ◽  
K. G. Alberti
Keyword(s):  
Fatty Acid ◽  
Blood Glucose ◽  
Glucose Uptake ◽  
Whole Body ◽  
Glucose Disposal ◽  
Nonesterified Fatty Acid ◽  
Nonesterified Fatty Acids ◽  
Glucose Levels ◽  
And Control ◽  
Blood Glucose Concentrations

The purpose of this study was to examine the effect of physiological plasma nonesterified fatty acid (NEFA) levels on insulin-stimulated forearm and whole body glucose uptake and substrate oxidation during euglycemia and hyperglycemia. Seven healthy men received Intralipid and heparin for 210 min in two studies, with saline as control in two further studies. Insulin (0.05 U.kg-1.h-1) was infused from 60 min, and euglycemia was maintained during lipid (EL) and control (EC) studies, and hyperglycemia was maintained in the other studies (HL and HC). Forearm NEFA uptake was comparable in the lipid studies (+61 +/- 10 and +52 +/- 8 nmol.100 ml forearm-1.min-1, EL and HL) and was suppressed in the controls. With Intralipid, forearm glucose uptake decreased during euglycemia but not during hyperglycemia (+3.85 +/- 0.34 vs. +3.34 +/- 0.25 mumol.100 ml forearm-1.min-1, EC vs. EL, P less than 0.02), with comparable changes in whole body glucose uptake. Glucose oxidation and forearm alanine release decreased with Intralipid at both blood glucose levels, with no significant change in the rates of nonoxidative glucose disposal. These observations support the operation of the glucose-fatty acid cycle at physiological plasma NEFA levels at both blood glucose concentrations, but this was associated with a decrease in peripheral insulin sensitivity only during euglycemia.

scholarly journals Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations

2019 ◽  
Vol 105 (3) ◽  
pp. e158-e171 ◽  
Author(s):  
Yevgeniya S Kushchayeva ◽  
Megan Startzell ◽  
Elaine Cochran ◽  
Sungyoung Auh ◽  
Hilal Sekizkardes ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Thyroid Hormone ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Receptor Gene ◽  
Whole Body ◽  
Glucose Disposal ◽  
Isotopic Tracers ◽  
Insulin Receptor Gene ◽  
Brown Adipose

Abstract Context Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. Objective To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. Design Single-arm, open-label study of liothyronine. Setting National Institutes of Health. Participants Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. Intervention Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months’ treatment in those with hemoglobin A1c (HbA1c) &gt; 7% (n = 4). Outcomes Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. Results There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P &lt; 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P &lt; 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. Conclusion Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone–related systemic toxicity. Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.

scholarly journals Is the canine corpus luteum an insulin-sensitive tissue?

2016 ◽  
Vol 231 (3) ◽  
pp. 223-233 ◽  
Author(s):  
Liza Margareth Medeiros de Carvalho Sousa ◽  
Renata dos Santos Silva ◽  
Vanessa Uemura da Fonseca ◽  
Rafael Magdanelo Leandro ◽  
Thiago Senna Di Vincenzo ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Corpus Luteum ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Hypoxia Inducible Factor ◽  
Glucose Disposal ◽  
Luteal Cell ◽  
Luteal Function ◽  
Luteal Cells ◽  
Glut4 Expression

This study aimed to determine in the canine corpus luteum throughout the dioestrus (1) the influence of insulin on glucose uptake; (2) the regulation of genes potentially involved; and (3) the influence of hypoxia on glucose transporter expression and steroidogenesis, after treatment with cobalt chloride (CoCl2). Glucose uptake by luteal cells increased 2.7 folds (P < 0.05) in response to insulin; a phenomenon related to increased expression of glucose transporter (GLUT) 4 and phosphorylation of protein kinase B (AKT). The gene expression of insulin receptor and SLC2A4 (codifier of GLUT4) genes after insulin stimulation increased on day 20 post ovulation (p.o.) and declined on day 40 p.o. (P < 0.05). Regarding potentially involved molecular mechanisms, the nuclear factor kappa B gene RELA was upregulated on days 30/40 p.o., when SLC2A4 mRNA was low, and the interleukin 6 (IL6) gene was upregulated in the first half of dioestrus, when SLC2A4 mRNA was high. CoCl2 in luteal cell cultures increased the hypoxia-inducible factor HIF1A/HIF1A and the SLC2A4/GLUT4 expression, and decreased progesterone (P4) production and hydroxyl-delta-5-steroid dehydrogenase 3 beta (HSD3B) mRNA expression (P < 0.05). This study shows that the canine luteal cells are responsive to insulin, which stimulates glucose uptake in AKT/GLUT4-mediated pathway; that may be related to local activity of RELA and IL6. Besides, the study reveals that luteal cells under hypoxia activate HIF1A-modulating luteal function and insulin-stimulated glucose uptake. These data indicate that insulin regulates luteal cells’ glucose disposal, participating in the maintenance and functionality of the corpus luteum.

Non-insulin-mediated glucose uptake in fed and fasted sheep

2000 ◽  
Vol 71 (3) ◽  
pp. 453-463 ◽  
Author(s):  
T. E. C. Weekes ◽  
Y. Obara ◽  
M. T. Rose
Keyword(s):  
Glucose Uptake ◽  
Glucose Utilization ◽  
Whole Body ◽  
Glucose Disposal ◽  
Metabolic Clearance ◽  
Normal Glucose ◽  
Total Glucose ◽  
A Minor ◽  
Turn Over ◽  
The Brain

AbstractIn ruminants and humans, the majority of whole body glucose utilization is not mediated by insulin. However, while in man most non-insulin-mediated glucose utilization (NIMGU) occurs in the brain, in ruminants the locations of NIMGU remain less well defined. As fasting would be expected to limit NIMGU to what would be regarded as an essential minimum, two studies were performed to establish the contribution of NIMGU to total glucose metabolism in fed and fasted sheep. Each study used four adult castrated male sheep. In study 1, a primed continuous infusion of U- [13C] glucose was begun at time 0 and continued for 7 h. After 3 h of isotope infusion (basal period) somatostatin (0•417 µg/kg per min; SS) was administered for 4 h, either alone (SS-only) or together with insulin (1•0 mU/kg per min; SS + insulin) with normal glucose to maintain euglycaemia for 2 h. Normal glucose was then infused for both the SS-only and SS + insulin treatments to induce and maintain hyperglycaemia over the final 2 h of the experiment. In study 2, fed or 72-h fasted sheep were infused with 6-[3H] glucose from time 0 for 8 h, with SS infusion starting at 3 h and continuing for 5 h. After 3 h of SS infusion, glucose was infused to induce and maintain hyperglycaemia. In both studies SS infusion inhibited insulin secretion, however in study 2, SS in fed sheep caused hyperglycaemia; this effect was not significant in the fasted animals. The rate of glucose utilization was reduced by SS-only as it eliminated insulin mediated glucose uptake (IMGU); under such conditions whole body glucose disposal should be NIMGU. In fed sheep, average NIMGU levels represented between proportionately 0•61 and 0•67 of the basal glucose metabolic clearance rate. During the infusion of SS + insulin in fed sheep, NIMGU fell to 0•34 during euglycaemia and 0•33 during hyperglycaemia, as the infused insulin caused IMGU to predominate. In fasted sheep the absolute rates of both IMGU and NIMGU were reduced, though NIMGU as a proportion of total turn-over (IMGU + NIMGU) increased to 0•88 of glucose metabolic clearance. Calculations suggest that, in contrast to man, only a minor proportion of NIMGU is utilized by the brain and central nervous system in fed or fasted sheep. It is suggested that skeletal muscle and the gastro-intestinal tract may make a major contribution to NIMGU, even in fasted sheep.

Acute elevation of plasma lipids does not affect ATP synthesis in human skeletal muscle

2010 ◽  
Vol 299 (1) ◽  
pp. E33-E38 ◽  
Author(s):  
A. Brehm ◽  
M. Krššák ◽  
A. I. Schmid ◽  
P. Nowotny ◽  
W. Waldhäusl ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Plasma Lipids ◽  
Atp Synthesis ◽  
Whole Body ◽  
Glucose Disposal ◽  
Resonance Spectroscopy ◽  
Lipid Infusion ◽  
Acute Elevation ◽  
Plasma Ffa ◽  
Early Effects

Prolonged elevation of plasma triglycerides and free fatty acids (FFA) reduces insulin-stimulated glucose disposal and myocellular flux through ATP synthase (fATPase). However, the early effects of lipids per se on fATPase are as yet unclear. Thus, this study examined glucose disposal and fATPase during 3 h of FFA elevation in the presence of low plasma insulinemia. Euglycemic pancreatic clamps with low-dose insulin supplementation (6 mU·m body surface area−2·min−1) were performed in eight healthy men with (LIP) or without (CON) lipid infusion to measure whole body glucose disposal. 31P/1H magnetic resonance spectroscopy of calf muscle was applied to quantify fATPase and concentrations of glucose 6-phosphate (G6P), inorganic phosphate (Pi), phosphocreatine (PCr), ADP, pH, and IMCL before and during the clamps. Lipid infusion increased plasma FFA approximately twofold and decreased glucose disposal by ∼50% (110–180 min: LIP 0.87 ± 0.45 vs. CON 1.75 ± 0.42 mg·kg−1·min−1, P = 0.002; means ± SD). Intramyocellular G6P tended to rise only under control conditions, whereas PCr, ADP, pH, and IMCL remained unchanged from fasting in LIP and CON. Although Pi concentrations increased by ∼18%, fATPase remained unchanged from fasting during the clamps (LIP 10.2 ± 2.2 vs. CON 10.5 ± 2.6 μmol·g muscle−1·min−1, P = not significant). We conclude that 3 h of lipid elevation fail to affect ATP synthesis despite marked reduction of whole body glucose uptake. This suggests that lipid-induced insulin resistance results primarily from mechanisms decreasing glucose uptake rather than from direct interference of fatty acid metabolites with mitochondrial function.

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