scholarly journals Adipose tissue and skeletal muscle insulin-mediated glucose uptake in insulin resistance: role of blood flow and diabetes

2018 ◽  
Vol 108 (4) ◽  
pp. 749-758 ◽  
Author(s):  
Ele Ferrannini ◽  
Patricia Iozzo ◽  
Kirsi A Virtanen ◽  
Miikka-Juhani Honka ◽  
Marco Bucci ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Blood Supply ◽  
Insulin Resistant ◽  
Femoral Muscle

Abstract Background Adipose tissue glucose uptake is impaired in insulin-resistant states, but ex vivo studies of human adipose tissue have yielded heterogeneous results. This discrepancy may be due to different regulation of blood supply. Objective The aim of this study was to test the flow dependency of in vivo insulin-mediated glucose uptake in fat tissues, and to contrast it with that of skeletal muscle. Design We reanalyzed data from 159 individuals in which adipose tissue depots—subcutaneous abdominal and femoral, and intraperitoneal—and femoral skeletal muscle were identified by MRI, and insulin-stimulated glucose uptake ([18F]-fluoro-2-deoxyglucose) and blood flow ([15O]-H2O) were measured simultaneously by positron emission tomography scanning. Results Individuals in the bottom tertile of whole-body glucose uptake [median (IQR) 36 (17) µmol. kg fat-free mass (kgFFM)−1 . min−1 .nM−1] displayed all features of insulin resistance compared with the rest of the group [median (IQR) 97 (71) µmol . kgFFM−1 .min−1 . nM−1]. Rates of glucose uptake were directly related to the degree of insulin resistance in all fat depots as well as in skeletal muscle. However, blood flow was inversely related to insulin sensitivity in each fat depot (all P ≤ 0.03), whereas femoral muscle blood flow was not significantly different between insulin-resistant and insulin-sensitive subjects, and was not related to insulin sensitivity. Furthermore, in subjects performing one-leg exercise, blood flow increased 5- to 6-fold in femoral muscle but not in the overlying adipose tissue. The presence of diabetes was associated with a modest increase in fat and muscle glucose uptake independent of insulin resistance. Conclusions Reduced blood supply is an important factor for the impairment of in vivo insulin-mediated glucose uptake in both subcutaneous and visceral fat. In contrast, the insulin resistance of glucose uptake in resting skeletal muscle is predominantly a cellular defect. Diabetes provides a modest compensatory increase in fat and muscle glucose uptake that is independent of insulin resistance.

Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites

2006 ◽  
Vol 100 (5) ◽  
pp. 1467-1474 ◽  
Author(s):  
Jong Sam Lee ◽  
Srijan K. Pinnamaneni ◽  
Su Ju Eo ◽  
In Ho Cho ◽  
Jae Hwan Pyo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Polyunsaturated Fatty Acids ◽  
Glucose Uptake ◽  
High Fat ◽  
Insulin Resistant ◽  
L6 Myotubes ◽  
Lipid Metabolites

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

Effect of exercise training on in vivo insulin-stimulated glucose uptake in intra-abdominal adipose tissue in rats

2000 ◽  
Vol 278 (1) ◽  
pp. E25-E34 ◽  
Author(s):  
L. H. Enevoldsen ◽  
B. Stallknecht ◽  
J. D. Fluckey ◽  
H. Galbo
Keyword(s):  
Insulin Resistance ◽  
Blood Flow ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Insulin Resistance Syndrome ◽  
Fat Depots ◽  
Lower Glucose ◽  
Interstitial Glucose ◽  
And Training

Intra-abdominal obesity may be crucial in the pathogenesis of the insulin-resistance syndrome, and training may alleviate this condition. We compared insulin-mediated glucose uptake in vivo in three intra-abdominal adipose tissues (ATs; retroperitoneal, parametrial, and mesenteric) and in subcutaneous AT and also studied the effect of training. Rats were either swim trained (15 wk, n = 9) or sedentary ( n = 16). While the rats were under anesthesia, a hyperinsulinemic (∼900 pM), euglycemic clamp was carried out and local glucose uptake was measured by both the 2-deoxy-d-[3H]glucose and microdialysis techniques. Blood flow was measured by microspheres. Upon insulin stimulation, blood flow generally decreased in AT. Flow was higher in mesenteric tissue than in other ATs, whereas insulin-mediated glucose uptake did not differ between ATs. Training doubled the glucose infusion rate during hyperinsulinemia, in part, reflecting an effect in muscle. During hyperinsulinemia, interstitial glucose concentrations were lower, glucose uptake per 100 g of tissue was higher in AT in trained compared with sedentary rats, and training influenced glucose uptake identically in all ATs. In conclusion, differences between ATs in insulin sensitivity with respect to glucose uptake do not explain that insulin resistance is associated with intra-abdominal rather than subcutaneous obesity. Furthermore, training may be beneficial by enhancing insulin sensitivity in intra-abdominal fat depots.

scholarly journals Quantification of adipose tissue insulin sensitivity

2016 ◽  
Vol 64 (5) ◽  
pp. 989-991 ◽  
Author(s):  
Esben Søndergaard ◽  
Michael D Jensen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Insulin Resistant ◽  
Healthy Humans ◽  
Metabolic Defects ◽  
Tissue Resistance

In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses.

scholarly journals Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity

2016 ◽  
Vol 310 (3) ◽  
pp. E190-E199 ◽  
Author(s):  
Young-Min Park ◽  
R. Scott Rector ◽  
John P. Thyfault ◽  
Terese M. Zidon ◽  
Jaume Padilla ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
High Capacity ◽  
Tissue Specific ◽  
Subcutaneous White Adipose Tissue ◽  
Brown Adipose ◽  
Glucose Clearance

High-capacity running (HCR) rats are protected against the early (i.e., ∼11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats ( n = 40; aged ∼22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-3H]glucose was used to determine glucose clearance, whereas 2-[14C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR ( P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼40% greater gastrocnemius glucose uptake compared with LCR ( P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR ( P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance.

Lactate release from adipose tissue and skeletal muscle in vivo: defective insulin regulation in insulin-resistant obese women

2007 ◽  
Vol 292 (3) ◽  
pp. E709-E714 ◽  
Author(s):  
Veronica Qvisth ◽  
Eva Hagström-Toft ◽  
Erik Moberg ◽  
Stefan Sjöberg ◽  
Jan Bolinder
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Adipose Tissue ◽  
Lactate Production ◽  
Obese Women ◽  
Local Blood Flow ◽  
Lactate Release ◽  
Insulin Resistant ◽  
Insulin Regulation

To study the local tissue lactate production in the normal state and its possible disturbances in insulin resistance, rates of lactate release from adipose tissue (AT) and skeletal muscle (SM) were compared postabsorptively and during a hyperinsulinemic euglycemic clamp in 11 healthy nonobese and 11 insulin-resistant obese women. A combination of microdialysis, to measure interstitial lactate, and the 133Xe clearance technique, to determine local blood flow, were used. In the controls, local blood flow increased by 40% in SM ( P < 0.05) and remained unchanged in AT, whereas the interstitial-plasma difference in lactate doubled in AT ( P < 0.005) and was unaffected in SM during hyperinsulinemia. In the obese, blood flow and interstitial-plasma difference in lactate remained unchanged in both tissues during hyperinsulinemia. The lactate release (μmol100 g−1min−1) was 1.17 ± 0.22 in SM and 0.43 ± 0.11 in AT among the controls ( P < 0.01) and 0.86 ± 0.23 in SM and 0.83 ± 0.25 in AT among the obese women in the postabsorptive state. During insulin infusion, lactate release in the controls increased to 1.92 ± 0.26 in SM ( P < 0.005) and to 1.14 ± 0.22 in AT ( P < 0.005) but remained unchanged in the obese women. It is concluded that AT and SM are both significant sources of lactate release postabsorptively, and AT is at least as responsive to insulin as SM. The ability to increase lactate release in response to insulin is impaired in AT and SM in insulin-resistant obese women, involving defective insulin regulation of both tissue lactate metabolism and local blood flow.

Carbohydrate Metabolism in Insulin Resistance: Glucose Uptake and Lactate Production by Adipose and Forearm Tissues in Vivo before and after a Mixed Meal

1996 ◽  
Vol 90 (5) ◽  
pp. 409-415 ◽  
Author(s):  
Simon W. Coppack ◽  
Rachel M. Fisher ◽  
Sandy M. Humphreys ◽  
Mo L. Clark ◽  
Jennifer J. Pointon ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Lactate Production ◽  
Insulin Stimulation ◽  
Mixed Meal ◽  
Insulin Resistant ◽  
Obese Subjects ◽  
Stimulation Of

1. To examine whether insulin resistance in vivo is manifest equally in both muscle and adipose tissues, we measured arteriovenous glucose and lactate fluxes across forearm (muscle) and abdominal subcutaneous (adipose) tissue in nine obese, glucose-intolerant subjects and 13 non-obese subjects of similar age and sex. 2. Compared with non-obese subjects, the forearm of the obese subjects was resistant to insulin stimulation of glucose uptake after a mixed meal. In contrast, adipose tissue showed little evidence of insulin stimulation of glucose uptake, and adipose tissue in subjects in both normal and obese groups behaved very similarly (assessed per 100 g of tissue). 3. For lactate flux, adipose tissue behaved very similarly (per 100 g of tissue) in obese and non-obese subjects, and was a consistent lactate exporter. 4. We conclude that insulin resistance of glucose uptake observed in the forearm of obese subjects is not evident in adipose tissue. Adipose tissue glucose uptake in obese, insulin-resistant subjects is similar to that in lean control subjects, although it occurs at elevated circulating insulin and glucose concentrations.

scholarly journals Prep1 Deficiency Induces Protection from Diabetes and Increased Insulin Sensitivity through a p160-Mediated Mechanism

2008 ◽  
Vol 28 (18) ◽  
pp. 5634-5645 ◽  
Author(s):  
Francesco Oriente ◽  
Luis Cesar Fernandez Diaz ◽  
Claudia Miele ◽  
Salvatore Iovino ◽  
Silvia Mori ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Normal Glucose Tolerance ◽  
Glucose Disposal ◽  
Protein Levels ◽  
Normal Glucose ◽  
Enhanced Expression ◽  
The Stability

ABSTRACT We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1 i / i ) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1 i / i muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1α, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1 i / i mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.

ALY688 elicits adiponectin-mimetic signaling and improves insulin action in skeletal muscle cells

2021 ◽  
Author(s):  
Hye Kyoung Sung ◽  
Patricia L. Mitchell ◽  
Sean Gross ◽  
Andre Marette ◽  
Gary Sweeney
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Muscle Cells ◽  
Temporal Analysis ◽  
Skeletal Muscle Cells ◽  
Adiponectin Receptor ◽  
Metabolic Effects

Adiponectin is well established to mediate many beneficial metabolic effects, and this has stimulated great interest in development and validation of adiponectin receptor agonists as pharmaceutical tools. This study investigated the effects of ALY688, a peptide-based adiponectin receptor agonist, in rat L6 skeletal muscle cells. ALY688 significantly increased phosphorylation of several adiponectin downstream effectors, including AMPK, ACC and p38MAPK, assessed by immunoblotting and immunofluorescence microscopy. Temporal analysis using cells expressing an Akt biosensor demonstrated that ALY688 enhanced insulin sensitivity. This effect was associated with increased insulin-stimulated Akt and IRS-1 phosphorylation. The functional metabolic significance of these signaling effects was examined by measuring glucose uptake in myoblasts stably overexpressing the glucose transporter GLUT4. ALY688 treatment both increased glucose uptake itself and enhanced insulin-stimulated glucose uptake. In the model of high glucose/high insulin (HGHI)-induced insulin resistant cells, both temporal studies using the Akt biosensor as well as immunoblotting assessing Akt and IRS-1 phosphorylation indicated that ALY688 significantly reduced insulin resistance. Importantly, we observed that ALY688 administration to high-fat high sucrose fed mice also improve glucose handling, validating its efficacy in vivo. In summary, these data indicate that ALY688 activates adiponectin signaling pathways in skeletal muscle, leading to improved insulin sensitivity and beneficial metabolic effects.

scholarly journals Acute, local infusion of angiotensin II impairs microvascular and metabolic insulin sensitivity in skeletal muscle

2018 ◽  
Vol 115 (3) ◽  
pp. 590-601 ◽  
Author(s):  
Dino Premilovac ◽  
Emily Attrill ◽  
Stephen Rattigan ◽  
Stephen M Richards ◽  
Jeonga Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Skeletal Muscle ◽  
Heart Rate ◽  
Blood Flow ◽  
Glucose Uptake ◽  
Microvascular Blood Flow ◽  
Euglycaemic Clamp ◽  
Hyperinsulinaemic Euglycaemic Clamp ◽  
Skeletal Muscle Glucose Uptake

Abstract Aims Angiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin’s microvascular and metabolic actions in skeletal muscle. Methods and results Adult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic clamp), or insulin (hyperinsulinaemic euglycaemic clamp) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic clamp) infusion. In all animals’ systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic clamp inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin’s effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake. Conclusions Acute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin’s microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects.

Hemodynamic actions of insulin

1994 ◽  
Vol 267 (2) ◽  
pp. E187-E202 ◽  
Author(s):  
A. D. Baron
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Pressor Response ◽  
Physiological Role ◽  
Oxide System ◽  
Maximal Response ◽  
Insulin Resistant ◽  
The Right

There is accumulating evidence that insulin has a physiological role to vasodilate skeletal muscle vasculature in humans. This effect occurs in a dose-dependent fashion within a half-maximal response of approximately 40 microU/ml. This vasodilating action is impaired in states of insulin resistance such as obesity, non-insulin-dependent diabetes, and elevated blood pressure. The precise physiological role of insulin-mediated vasodilation is not known. Data indicate that the degree of skeletal muscle perfusion can be an important determinant of insulin-mediated glucose uptake. Therefore, it is possible that insulin-mediated vasodilation is an integral aspect of insulin's overall action to stimulate glucose uptake; thus defective vasodilation could potentially contribute to insulin resistance. In addition, insulin-mediated vasodilation may play a role in the regulation of vascular tone. Data are provided to indicate that the pressor response to systemic norepinephrine infusions is increased in obese insulin-resistant subjects. Moreover, the normal effect of insulin to shift the norepinephrine pressor dose-response curve to the right is impaired in these patients. Therefore, impaired insulin-mediated vasodilation could further contribute to the increased prevalence of hypertension observed in states of insulin resistance. Finally, data are presented to indicate that, via a yet unknown interaction with the endothelium, insulin is able to increase nitric oxide synthesis and release and through this mechanism vasodilate. It is interesting to speculate that states of insulin resistance might also be associated with a defect in insulin's action to modulate the nitric oxide system.(ABSTRACT TRUNCATED AT 250 WORDS)

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