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 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.

scholarly journals Angiotensin II Enhances Insulin Sensitivity in Vitro and in Vivo

Endocrinology ◽  
2005 ◽  
Vol 146 (5) ◽  
pp. 2246-2254 ◽  
Author(s):  
Chi-Chang Juan ◽  
Yueh Chien ◽  
Liang-Yi Wu ◽  
Wei-Ming Yang ◽  
Chih-Ling Chang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Angiotensin Ii ◽  
Glucose Uptake ◽  
Intracellular Signaling ◽  
Binding Capacity ◽  
Critical Role ◽  
At1 Antagonist

Abstract The renin-angiotensin system plays a critical role in the pathogenesis of obesity, obesity-associated hypertension, and insulin resistance. However, the biological actions of angiotensin II (AII) on insulin sensitivity remain controversial. Because angiotensinogen and AII receptors are expressed on adipose tissue, we investigated the effect of AII on the insulin sensitivity of isolated rat adipocytes. The results of a receptor binding assay showed the maximal AII binding capacity of adipocytes to be 8.3 ± 0.9 fmol/7 × 106 cells and the dissociation constant to be 2.72 ± 0.11 nm. Substantial expression of both type 1 and 2 AII (AT1 and AT2) receptors was detected by RT-PCR. AII had no effect on basal glucose uptake, but significantly potentiated insulin-stimulated glucose uptake; this effect was abolished by the AT1 antagonist, losartan. In addition, AII did not alter the insulin binding capacity of adipocytes, but increased insulin-stimulated tyrosine phosphorylation of the insulin receptor β-subunit, Akt phosphorylation, and translocation of glucose transporter 4 to the plasma membrane. AII potentiated insulin-stimulated glucose uptake through the AT1 receptor and by alteration of the intracellular signaling of insulin. Intraperitoneal injection of Sprague Dawley rats with AII increased insulin sensitivity in vivo. In conclusion, we have shown that AII enhances insulin sensitivity both in vitro and in vivo, suggesting that dysregula-tion of the insulin-sensitizing effect of AII may be involved in the development of insulin resistance.

scholarly journals PL - 026 Mismatch between skeletal muscle glucose delivery, interstitial concentration and membrane permeability may limit insulin sensitivity after exercise

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Glenn McConell ◽  
Kim Sjøberg ◽  
Frederik Ceutz ◽  
Lasse Gliemann ◽  
Michael Nyberg ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Concentration ◽  
Insulin Signalling ◽  
Work Load ◽  
Leg Blood Flow ◽  
Interstitial Glucose ◽  
Sarcolemmal Permeability

Objective The relationship between skeletal muscle perfusion, interstitial glucose concentration and sarcolemmal permeability to glucose in exercise-induced increases in muscle insulin sensitivity is not well established. A single bout of exercise increases skeletal muscle insulin sensitivity through coordinated increases in insulin-stimulated microvascular perfusion and insulin signalling  Reducing leg and muscle microvascular blood flow with local nitric oxide synthase (NOS) inhibition during a hyperinsulinaemic euglycaemic clamp reduces leg glucose uptake in a previously exercised, but not in a contralateral non-exercised leg, without affecting insulin signalling in either leg  (Sjoberg et al. 2017). Therefore, it is possible that the reduction in muscle perfusion decreases muscle interstitial glucose concentration to a point that limits skeletal muscle insulin-stimulated glucose uptake following exercise. We examined this using microdialysis of vastus lateralis muscle. Methods Ten healthy males (Age: 27±1 yr., Weight: 77.7±2.3 kg, BMI 23.9±0.5, VO2 peak: 50.7±1.5 ml·kg-1·min-1) performed 60 min of 1-legged knee extensor exercise at 80% of 1-legged peak work load with three 5 min intervals at 100% 1-legged peak work load. Participants then rested for 4 hours and catheters were inserted into the femoral artery and vein of both legs for subsequent measurement of leg glucose uptake and for femoral artery infusion of the NOS inhibitor NG-monomethyl L-arginine acetate (L-NMMA) and the vasodilator ATP. Catheters were also placed in antecubital veins for infusion of insulin and glucose. Three microdialysis catheters, with a semi-permeable membrane the length of 30 mm and a molecular cut-off at 20,000 dalton, were inserted into the vastus lateral muscle of both legs. Glucose and D-[6-3H(N)]glucose were added to the perfusate. Four hours after discontinuing the exercise a 225 minute euglycaemic hyperinsulinaemic clamp was initiated (insulin infusion 1.4 mU-1kg-1min). Ninety min into the clamp L-NMMA was infused at a constant rate (0.4 mg·kg-1 leg mass·min-1) into both femoral arteries for 45 min. The insulin infusion was maintained for another 90 min and during the last 45 min ATP (0.3 μmol∙ml-1) was infused locally into both femoral arteries at a rate of 200-350 μl∙min-1 to obtain a leg blood flow that was double the blood flow during insulin only infusion. A second control protocol was undertaken that was identical in regards to exercise and recovery but no insulin, L-NMMA or ATP was infused. Results During the clamp leg glucose uptake and leg blood flow were higher (P<0.05) in the previously exercised than the control leg whereas the interstitial glucose concentration decreased to lower (P<0.05) values in the exercised (~3.1mM) than the control (~4.8mM) leg. Estimated sarcolemmal glucose permeability was twice as high (P<0.05) in the exercised compared with the rested leg. The NOS inhibitor L-NMMA decreased LBF in both legs and interstitial glucose concentration dropped to ~2.3 mM in the exercised but only to ~3.7 mM in non-exercised muscle. This abrogated the augmented effect of insulin on LGU in the exercised leg while apparent sarcolemmal permeability to glucose remained unchanged with L-NMMA in both legs. Doubling leg blood flow by local infusion of ATP increased leg glucose uptake in both legs without any major change in interstitial glucose concentration or sarcolemmal permeability to glucose. Conclusions These findings suggest that during flow restriction due to L-NMMA, the interstitial glucose concentration becomes limiting for leg glucose uptake in exercised but not in non-exercised muscle. Therefore, the vasodilatory effect of insulin is an important component of the increased insulin sensitivity to stimulate glucose uptake following exercise by limiting the drop in the interstitial glucose concentration that occurs due to the increased sarcolemmal permeability to glucose. Reference Sjoberg, K. A., C. Frosig, R. Kjobsted, L. Sylow, M. Kleinert, A. C. Betik, C. S. Shaw, B. Kiens, J. F. P. Wojtaszewski, S. Rattigan, E. A. Richter, and G. K. McConell. Exercise Increases Human Skeletal Muscle Insulin Sensitivity via Coordinated Increases in Microvascular Perfusion and Molecular Signaling.  Diabetes  66: 1501-10, 2017.

scholarly journals Peripheral insulin resistance in ILK-depleted mice by reduction of GLUT4 expression

2017 ◽  
Vol 234 (2) ◽  
pp. 115-128 ◽  
Author(s):  
Marco Hatem-Vaquero ◽  
Mercedes Griera ◽  
Andrea García-Jerez ◽  
Alicia Luengo ◽  
Julia Álvarez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Chow Diet ◽  
Peripheral Tissues ◽  
Akt Phosphorylation ◽  
Glut4 Expression

The development of insulin resistance is characterized by the impairment of glucose uptake mediated by glucose transporter 4 (GLUT4). Extracellular matrix changes are induced when the metabolic dysregulation is sustained. The present work was devoted to analyze the possible link between the extracellular-to-intracellular mediator integrin-linked kinase (ILK) and the peripheral tissue modification that leads to glucose homeostasis impairment. Mice with general depletion of ILK in adulthood (cKD-ILK) maintained in a chow diet exhibited increased glycemia and insulinemia concurrently with a reduction of the expression and membrane presence of GLUT4 in the insulin-sensitive peripheral tissues compared with their wild-type littermates (WT). Tolerance tests and insulin sensitivity indexes confirmed the insulin resistance in cKD-ILK, suggesting a similar stage to prediabetes in humans. Under randomly fed conditions, no differences between cKD-ILK and WT were observed in the expression of insulin receptor (IR-B) and its substrate IRS-1 expressions. The IR-B isoform phosphorylated at tyrosines 1150/1151 was increased, but the AKT phosphorylation in serine 473 was reduced in cKD-ILK tissues. Similarly, ILK-blocked myotubes reduced their GLUT4 promoter activity and GLUT4 expression levels. On the other hand, the glucose uptake capacity in response to exogenous insulin was impaired when ILK was blocked in vivo and in vitro, although IR/IRS/AKT phosphorylation states were increased but not different between groups. We conclude that ILK depletion modifies the transcription of GLUT4, which results in reduced peripheral insulin sensitivity and glucose uptake, suggesting ILK as a molecular target and a prognostic biomarker of insulin resistance.

Differential regulation of insulin resistance and hypertension by sex hormones in fructose-fed male rats

2005 ◽  
Vol 289 (4) ◽  
pp. H1335-H1342 ◽  
Author(s):  
Harish Vasudevan ◽  
Hong Xiang ◽  
John H. McNeill
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Sex Hormones ◽  
Threshold Value ◽  
Relative Increase ◽  
Estrogen Treatment ◽  
Male Rats ◽  
Normal Chow

Differences in gender are in part responsible for the development of insulin resistance (IR) and associated hypertension. Currently, it is unclear whether these differences are dictated by gender itself or by the relative changes in plasma estrogen and/or testosterone. We investigated the interrelationships between testosterone and estrogen in the progression of IR and hypertension in vivo in intact and gonadectomized fructose-fed male rats. Treatment with estrogen significantly reduced the testosterone levels in both normal chow-fed and fructose-fed rats. Interestingly, fructose feeding induced a relative increase in estradiol levels, which did not affect IR in both intact and gonadectomized fructose-fed rats. However, increasing the estrogen levels improved insulin sensitivity in both intact and gonadectomized fructose-fed rats. In intact males, fructose feeding increased the blood pressure (140 ± 2 mmHg), which was prevented by estrogen treatment. However, the blood pressure in the fructose-fed estrogen rats (125 ± 1 mmHg) was significantly higher than that of normal chow-fed (113 ± 1 mmHg) and fructose-fed gonadectomized rats. Estrogen treatment did not affect the blood pressure in gonadectomized fructose-fed rats (105 ± 2 mmHg). These data suggest the existence of a threshold value for estrogen below which insulin sensitivity is unaffected. The development of hypertension in this model is dictated solely by the presence or absence of testosterone. In summary, the development of IR and hypertension is governed not by gender per se but by the interactions of specific sex hormones such as estrogen and testosterone.

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.

Abstract 1361: Leukocyte Antigen-Related Phosphatase Regulates Insulin Sensitivity by Interaction with Snapin

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Aleksandr E Vendrov ◽  
Igor Tchivilev ◽  
Xi-Lin Niu ◽  
Juxiang Li ◽  
Marschall S Runge ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Glycogen Synthase ◽  
Serine Phosphorylation ◽  
Snare Complex ◽  
Vascular Pathology ◽  
Wild Type ◽  
Membrane Translocation ◽  
Leukocyte Antigen

Several protein tyrosine phosphatases including leukocyte antigen-related (LAR) phosphatase have been implicated in insulin resistance, which is a risk factor for atherosclerosis. We showed previously that LAR negatively regulates insulin-like growth factor-1 (IGF1) signaling in vascular smooth muscle cells (VSMC) leading to increased proliferation and migration. Absence of LAR also enhanced neointima formation in response to arterial injury in mice. However, the role of LAR-modulated signaling in the development of insulin resistance has not been elucidated. Here, we investigated the function of LAR in regulating glucose uptake and insulin sensitivity. We identified snapin, a SNARE-associated protein involved in glucose transporter Glut4 vesicle fusion with plasma membrane, as a LAR-interacting protein using a yeast two-hybrid screen. IGF1-induced serine phosphorylation of snapin, its translocation to membrane and association with SNARE complex were enhanced in VSMC lacking LAR. Similarly, PI3K-PDK1-PKCζ signaling pathway was more active in LAR-/- cells after IGF1 treatment. This resulted in enhanced Glut4 activation, its membrane translocation and association with snapin. Glut4 membrane translocation and association with snapin after IGF1 treatment were impaired in snapin+/− VSMC. IGF1 treatment also increased serine phosphorylation of GSK3 β in LAR−/− VSMC leading to increased activation of glycogen synthase. Consistent with this, enhanced glucose uptake was observed in LAR−/− VSMC compared to wild-type cells after IGF1 treatment. Basal and IGF1-induced glucose uptake were significantly lower in snapin+/− VSMC than in wild-type cells. Snapin+/− mice had higher levels of blood glucose, lower quantitative insulin sensitivity check index (QUICKI) and impaired response to insulin in insulin tolerance test (ITT) compared to wild-type mice. Decrease of QUICKI and impairment of IIT were more pronounced in snapin+/− mice fed a high-fat diet. In addition, Doppler ultrasonography indicated increased arterial stiffness in snapin+/− mice. Together, these data indicate that LAR negatively regulates snapin phosphorylation which in turn affects glucose uptake leading to the development of insulin resistance and vascular pathology.

Effect of exercise training on in vivo lipolysis in intra-abdominal adipose tissue in rats

2000 ◽  
Vol 279 (3) ◽  
pp. E585-E592 ◽  
Author(s):  
L. H. Enevoldsen ◽  
B. Stallknecht ◽  
J. D. Fluckey ◽  
H. Galbo
Keyword(s):  
Blood Flow ◽  
Abdominal Obesity ◽  
Physical Training ◽  
Insulin Dependent Diabetes Mellitus ◽  
Female Rats ◽  
Dependent Diabetes Mellitus ◽  
Glycerol Concentration ◽  
Epinephrine Infusion ◽  
Fat Depots

Intra-abdominal obesity is associated with cardiovascular disease and non-insulin-dependent diabetes mellitus, and physical training has been suggested to alleviate these conditions. We compared epinephrine-stimulated lipolysis in vivo in three intra-abdominal adipose tissues (ATs: retroperitoneal, parametrial, and mesenteric) and in subcutaneous AT, and we also studied the effect of physical training. Moreover, we studied the effect of physical training on epinephrine-stimulated lipolysis in muscle in vivo. Female rats were either swim trained (15 wk, n = 8) or sedentary ( n = 7). Under anesthesia, a two-stage intravenous epinephrine infusion (60 min of 80 and 200 ng · kg−1 · min−1, respectively) was carried out, and local interstitial glycerol concentration was measured by the microdialysis technique. Blood flow was measured by microspheres. Training increased blood flow in all ATs [on average: 73 ± 12 (trained) vs. 14 ± 4 (sedentary) ml · 100 g−1 · min−1, P < 0.05]; nevertheless, epinephrine-stimulated interstitial glycerol concentrations were increased or unchanged. Interstitial glycerol concentration was higher in intra-abdominal than in subcutaneous AT in both trained and sedentary rats. In skeletal muscle, interstitial glycerol concentration and blood flow did not differ between trained and sedentary rats. In conclusion, in vivo lipolysis is higher both in the basal state and during epinephrine-stimulation in intra-abdominal than in subcutaneous AT, and training may be beneficial in alleviating intra-abdominal obesity by enhancing lipolysis in intra-abdominal fat depots.

Angiotensin II induces insulin resistance independent of changes in interstitial insulin

1999 ◽  
Vol 277 (5) ◽  
pp. E920-E926 ◽  
Author(s):  
Joyce M. Richey ◽  
Marilyn Ader ◽  
Donna Moore ◽  
Richard N. Bergman
Keyword(s):  
Insulin Resistance ◽  
Heart Rate ◽  
Blood Flow ◽  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Glucose Uptake ◽  
Peripheral Resistance ◽  
Glucose Turnover ◽  
Ang Ii

We set out to examine whether angiotensin-driven hypertension can alter insulin action and whether these changes are reflected as changes in interstitial insulin (the signal to which insulin-sensitive cells respond to increase glucose uptake). To this end, we measured hemodynamic parameters, glucose turnover, and insulin dynamics in both plasma and interstitial fluid (lymph) during hyperinsulinemic euglycemic clamps in anesthetized dogs, with or without simultaneous infusions of angiotensin II (ANG II). Hyperinsulinemia per se failed to alter mean arterial pressure, heart rate, or femoral blood flow. ANG II infusion resulted in increased mean arterial pressure (68 ± 16 to 94 ± 14 mmHg, P < 0.001) with a compensatory decrease in heart rate (110 ± 7 vs. 86 ± 4 mmHg, P < 0.05). Peripheral resistance was significantly increased by ANG II from 0.434 to 0.507 mmHg ⋅ ml−1⋅ min ( P < 0.05). ANG II infusion increased femoral artery blood flow (176 ± 4 to 187 ± 5 ml/min, P < 0.05) and resulted in additional increases in both plasma and lymph insulin (93 ± 20 to 122 ± 13 μU/ml and 30 ± 4 to 45 ± 8 μU/ml, P < 0.05). However, glucose uptake was not significantly altered and actually had a tendency to be lower (5.9 ± 1.2 vs. 5.4 ± 0.7 mg ⋅ kg−1⋅ min−1, P > 0.10). Mimicking of the ANG II-induced hyperinsulinemia resulted in an additional increase in glucose uptake. These data imply that ANG II induces insulin resistance by an effect independent of a reduction in interstitial insulin.

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