Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans

In vivo glucose uptake can occur via two mechanisms, namely, insulin-mediated glucose uptake (IMGU) and non-insulin-mediated glucose uptake (NIMGU). Although the principal tissue sites for IMGU are skeletal muscle, the tissue sites for NIMGU at a given serum glucose concentration are not known. To examine this issue, rates of whole body glucose uptake (Rd) were measured at basal and during glucose clamp studies performed at euglycemia (approximately 90 mg/dl) and hyperglycemia (approximately 220 mg/dl) in six lean healthy men. Studies were performed during hyperinsulinemia (approximately 70 microU/ml) and during somatostatin-induced insulinopenia to measure IMGU and NIMGU, respectively. During each study, leg glucose balance (arteriovenous catheter technique) was also measured. With this approach, rates of whole body skeletal muscle IMGU and NIMGU can be estimated, and the difference between overall Rd and skeletal muscle glucose uptake represents non-skeletal muscle Rd. The results indicate that approximately 20% of basal Rd is into skeletal muscle. During insulinopenia approximately 86% of body NIMGU occurs in non-skeletal muscle tissues at euglycemia. When hyperglycemia was created, whole body NIMGU increased from 128 +/- 6 to 213 +/- 18 mg/min (P less than 0.01); NIMGU into non-skeletal muscle tissues was 134 +/- 11 and 111 +/- 6 mg/min at hyperglycemia and euglycemia, respectively, P = NS. Therefore, virtually all the hyperglycemia induced increment in NIMGU occurred in skeletal muscle. During hyperinsulinemia, IMGU in skeletal muscle represented 75 and 95% of body Rd, at euglycemia and hyperglycemia, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.1.e130 ◽

2001 ◽

Vol 280 (1) ◽

pp. E130-E142 ◽

Cited By ~ 44

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.

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IL-6 is not essential for exercise-induced increases in glucose uptake

Journal of Applied Physiology ◽

10.1152/japplphysiol.00946.2012 ◽

2013 ◽

Vol 114 (9) ◽

pp. 1151-1157 ◽

Cited By ~ 12

Author(s):

Hayley M. O'Neill ◽

Rengasamy Palanivel ◽

David C. Wright ◽

Tara MacDonald ◽

James S. Lally ◽

...

Keyword(s):

Skeletal Muscle ◽

Steady State ◽

Glucose Uptake ◽

Substrate Utilization ◽

Treadmill Running ◽

Glucose Clearance ◽

Skeletal Muscle Glucose Uptake ◽

Exercise Induced ◽

Similar Body

Interleukin-6 (IL-6) increases glucose uptake in resting skeletal muscle. IL-6 is released from skeletal muscle during exercise; however; it is not known whether this IL-6 response is important for exercise-induced increases in skeletal muscle glucose uptake. We report that IL-6 knockout (KO) mice, 4 mo of age, have similar body weight to wild-type (WT), and, under resting conditions, oxygen consumption, food intake, substrate utilization, glucose tolerance, and insulin sensitivity are not different. Maximal exercise capacity is also similar to WT. We investigated substrate utilization and glucose clearance in vivo during steady-state treadmill running at 70% of maximal running speed and found that WT and IL-6 KO mice had similar rates of substrate utilization, muscle glucose clearance, and phosphorylation of AMP-activated protein kinase T172. These data provide evidence that IL-6 does not play a major role in regulating substrate utilization or skeletal muscle glucose uptake during steady-state endurance exercise.

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The Role of TGFβ Ligands and Signalling on Insulin Resistance in Skeletal Muscle in Women With PCOS

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.906 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A443-A444

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 ◽

Insulin Signalling ◽

Signalling Pathway ◽

Whole Body ◽

Insulin Signalling Pathway ◽

Cultured Myotubes ◽

Tgfβ Superfamily

Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting metabolic and reproductive health of 8–13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 38–95% 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 by about 27% when assessed by a euglycaemic-hyperinsulinaemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that in vivo environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). A potential environmental mechanism contributing to the development of peripheral IR may be the extracellular matrix remodelling and aberrant transforming growth factor beta (TGFβ) signalling. Previous work demonstrated that TGFβ superfamily ligands are involved in the increased collagen deposition and fibrotic tissue in the ovaries, and suggested that these ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5 ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30 ng/ml), a TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=5) and healthy controls (n=5). TGFβ1 did not have a significant effect on insulin signalling but induced expression of some ECM related genes and proteins, and increased glucose uptake via Smad2/3 signalling in myotubes from both groups. Conversely, AMH did not appear to activate the TGFβ/Smad signalling pathway and had no significant impact on insulin signalling or glucose uptake in any of the groups. In conclusion, these findings suggest that TGFβ1, but not AMH, may play a role in skeletal muscle ECM remodelling/fibrosis and glucose metabolism in PCOS but does not have a direct effect on insulin signalling pathway. Further research is required to elucidate its contribution to the development of in vivo skeletal muscle IR 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.

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Insulin action on heart and skeletal muscle glucose uptake in weight lifters and endurance athletes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.4.e706 ◽

1999 ◽

Vol 276 (4) ◽

pp. E706-E711 ◽

Cited By ~ 10

Author(s):

Teemu O. Takala ◽

Pirjo Nuutila ◽

Juhani Knuuti ◽

Matti Luotolahti ◽

Hannele Yki-Järvinen

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Left Ventricular Mass ◽

Left Ventricular ◽

Endurance Athletes ◽

Whole Body ◽

Euglycemic Hyperinsulinemic Clamp ◽

Ventricular Mass ◽

Weight Lifters ◽

Skeletal Muscle Glucose Uptake

There are no studies comparing myocardial metabolism between endurance- and resistance-trained athletes. We used 2-deoxy-2-[18F]fluoro-d-glucose and positron emission tomography combined with the euglycemic hyperinsulinemic clamp technique to compare the ability of insulin to stimulate myocardial, skeletal muscle, and whole body glucose uptake between weight lifters ( n = 8), endurance athletes ( n = 8), and sedentary men ( n = 9). Maximal aerobic power (ml ⋅ kg− 1⋅ min− 1) was higher in the endurance athletes (71 ± 2, P < 0.001) than the weight lifters (42 ± 2) and the sedentary men (42 ± 2). Skeletal muscle glucose uptake (μmol ⋅ kg muscle− 1⋅ min− 1) was enhanced in the endurance athletes (125 ± 16, P < 0.01) but was similar in weight lifters (59 ± 12) and sedentary (63 ± 7) men. The rate of glucose uptake per unit mass of myocardium (μmol ⋅ kg− 1⋅ min− 1) was similarly decreased in endurance athletes (544 ± 50) and weight lifters (651 ± 45) compared with sedentary men (1,041 ± 78, P < 0.001 vs. endurance athletes and weight lifters). Both groups of athletes had increased left ventricular mass. Consequently, total left ventricular glucose uptake was comparable in all groups. These data demonstrate that aerobic but not resistance training is associated with enhanced insulin sensitivity in skeletal muscle. Despite this, cardiac changes are remarkably similar in weight lifters and endurance athletes and are characterized by an increase in left ventricular mass and diminished insulin-stimulated glucose uptake per heart mass.

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Microvascular Recruitment Is an Early Insulin Effect That Regulates Skeletal Muscle Glucose Uptake In Vivo

Diabetes ◽

10.2337/diabetes.53.6.1418 ◽

2004 ◽

Vol 53 (6) ◽

pp. 1418-1423 ◽

Cited By ~ 268

Author(s):

M. A. Vincent ◽

L. H. Clerk ◽

J. R. Lindner ◽

A. L. Klibanov ◽

M. G. Clark ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Insulin Effect ◽

Skeletal Muscle Glucose Uptake ◽

Microvascular Recruitment

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Constitutively Active CaMKK Stimulates Skeletal Muscle Glucose Uptake in Insulin-Resistant Mice In Vivo

Diabetes ◽

10.2337/db13-0452 ◽

2013 ◽

Vol 63 (1) ◽

pp. 142-151 ◽

Cited By ~ 12

Author(s):

J. M. Hinkley ◽

J. L. Ferey ◽

J. J. Brault ◽

C. A. S. Smith ◽

L. A. A. Gilliam ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Insulin Resistant ◽

Skeletal Muscle Glucose Uptake ◽

Constitutively Active

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Skeletal muscle mass: evaluation of neutron activation and dual-energy X-ray absorptiometry methods

Journal of Applied Physiology ◽

10.1152/jappl.1996.80.3.824 ◽

1996 ◽

Vol 80 (3) ◽

pp. 824-831 ◽

Cited By ~ 174

Author(s):

Z. M. Wang ◽

M. Visser ◽

R. Ma ◽

R. N. Baumgartner ◽

D. Kotler ◽

...

Keyword(s):

Skeletal Muscle ◽

Neutron Activation ◽

Dual Energy ◽

Whole Body ◽

Axial Tomography ◽

Healthy Men ◽

X Ray ◽

Study Results ◽

Immunodeficiency Syndrome

Although skeletal muscle (SM) is a major body component, whole body measurement methods remain limited and inadequately investigated. The aim of the present study was to evaluate the Burkinshaw in vivo neutron activation analysis (IVNA)-whole body 40K-counting and dual-energy X-ray absorptiometry (DXA) methods of estimating SM by comparison to adipose tissue-free SM measured using multiscan computerized axial tomography (CT). In the Burkinshaw method the potassium-to-nitrogen ratios of SM and non-SM lean tissue are assumed constant; in the DXA method the ratio of appendicular SM to total SM is assumed constant at 0.75. Seventeen healthy men [77.5 +/- 13.8 (SD) kg body wt] and eight men with acquired immunodeficiency syndrome (AIDS; 65.5 +/- 7.6 kg) completed CT, IVNA, and DXA studies. SM measured by CT was 34.4 +/- 6.2 kg for the healthy subjects and 27.2 +/- 4.0 kg for the AIDS patients. Compared with CT, the Burkinshaw method underestimated SM by an average of 6.9 kg (20.1%, P = 0.0001) and 6.3 kg (23.2%, P = 0.01) in the healthy men and the men with AIDS, respectively. The DXA method minimally overestimated SM in both groups (2.0 kg and 5.8% in healthy men, P = 0.001; 1.4 kg and 5.1% in men with AIDS, P = 0.16). This overestimate could be explained by a higher actual than assumed ratio of DXA-measured appendicular SM to total body SM (actual = 0.79 +/- 0.05, assumed = 0.75). The current study results reveal that large errors are present in the Burkinshaw SM method and that substantial refinements in the models that form the basis of this IVNA approach are needed. The model on which the DXA-SM method is based also needs further minor refinements, but this is a promising in vivo approach because of less radiation exposure and lower cost than the IVNA and CT methods.

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Tracing Fasting Glucose Fluxes with Unstressed Catheter Approach in Streptozotocin Induced Diabetic Rats

Journal of Diabetes Research ◽

10.1155/2014/743798 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7

Author(s):

Shichun Du ◽

Hui Wu ◽

Xiao Xu ◽

Ying Meng ◽

Fangzhen Xia ◽

...

Keyword(s):

Skeletal Muscle ◽

Glucose Uptake ◽

Glucose Production ◽

Diabetic Rats ◽

Endogenous Glucose Production ◽

Tracer Injection ◽

Skeletal Muscle Glucose Uptake ◽

Endogenous Glucose

Objective. Blood glucose concentrations of type 1 diabetic rats are vulnerable, especially to stress and trauma. The present study aimed to investigate the fasting endogenous glucose production and skeletal muscle glucose uptake of Streptozotocin induced type 1 diabetic rats using an unstressed vein and artery implantation of catheters at the tails of the rats as a platform.Research Design and Methods. Streptozotocin (65 mg·kg−1) was administered to induce type 1 diabetic state. The unstressed approach of catheters of vein and artery at the tails of the rats was established before the isotope tracer injection. Dynamic measurement of fasting endogenous glucose production was assessed by continuously infusing stable isotope [6, 6-2H2] glucose, while skeletal muscle glucose uptake by bolus injecting radioactively labeled [1-14C]-2-deoxy-glucose.Results. Streptozotocin induced type 1 diabetic rats displayed polydipsia, polyphagia, and polyuria along with overt hyperglycemia and hypoinsulinemia. They also had enhanced fasting endogenous glucose production and reduced glucose uptake in skeletal muscle compared to nondiabetic rats.Conclusions. The dual catheters implantation at the tails of the rats together with isotope tracers injection is a save time, unstressed, and feasible approach to explore the glucose metabolism in animal models in vivo.

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