Forearm Glucose Uptake Research Articles

Tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes

Aims/hypothesisRecent evidence suggests that reduced synthesis of nitric oxide in endothelial cells, i.e. endothelial dysfunction, contributes to the impaired action of insulin in the vasculature of patients with type 2 diabetes. We investigated whether selective inhibition of phosphodiesterase-5 by tadalafil has beneficial effects on peripheral microcirculation and glucose uptake in these patients.MethodsWe enrolled seven postmenopausal women with type 2 diabetes and ten age-matched healthy women as controls in a placebo-controlled study to evaluate the acute metabolic effects of tadalafil. We performed microdialysis and blood flow measurements in muscle, and sampled arterial and deep venous blood before and after a single dose of tadalafil 20 mg or placebo. Circulating glucose and insulin levels, muscle capillary recruitment as reflected by permeability surface area for glucose (PSglu) and forearm glucose uptake were measured.ResultsIn women with type 2 diabetes, but not in the control group, tadalafil induced increases in the incremental AUC for PSglu (tadalafil vs placebo 41 ± 11 vs 4 ± 2 ml [100 g]−1 min−1, p < 0.05) and forearm glucose uptake (46 ± 9 vs 8 ± 4 µmol [100 g]−1 min−1, p < 0.05). The variable that best predicted forearm glucose uptake was PSglu, which explained 70% of its variance. However, fasting glucose and insulin concentrations were similar following treatment with placebo or tadalafil in the two groups.Conclusions/interpretationThis study suggests that tadalafil evokes positive metabolic effects in insulin-resistant women with type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-010-1819-4) contains supplementary material, which is available to authorised users.

Regulation of Glucose Uptake by Endothelin-1 in Human Skeletal Musclein Vivoandin Vitro

Expression of the vasoconstrictor and proinflammatory peptide endothelin (ET)-1 is increased in insulin-resistant (IR) subjects. The aim of this study was to investigate whether ET-1 regulates skeletal muscle glucose uptake in IR subjects in vivo and in cultured human skeletal muscle cells. Eleven subjects participated in three protocols using brachial artery infusion of: A) BQ123 (10 nmol/min) and BQ788 (10 nmol/min) (ET(A) and ET(B) receptor antagonist, respectively), followed by coinfusion with insulin (0.05 mU/kg/min); B) insulin alone; and C) insulin followed by coinfusion with ET-1 (20 pmol/min). Forearm blood flow (FBF) and forearm glucose uptake (FGU) were determined. Glucose uptake and molecular signaling were determined in cultured skeletal muscle cells. ET(A)/ET(B) receptor blockade increased FGU by 63% (P < 0.05). Coadministration of insulin caused a further 2-fold increase in FGU (P < 0.001). ET(A)/ET(B) receptor blockade combined with insulin resulted in greater FGU than insulin infusion alone (P < 0.005). ET(A)/ET(B) receptor blockade increased FBF by 30% (P < 0.05), with a further 16% increase (P < 0.01) during insulin coinfusion. ET-1 decreased basal FBF by 35% without affecting FGU. ET-1 impaired basal and insulin-stimulated glucose uptake in cultured muscle cells (P < 0.01) via an effect that was prevented by ET(A)/ET(B) receptor blockade. ET(A)/ET(B) receptor blockade enhances basal and insulin-stimulated glucose uptake in IR subjects. ET-1 directly impairs glucose uptake in skeletal muscle cells via a receptor-dependent mechanism. These data suggest that ET-1 regulates glucose metabolism via receptor-dependent mechanisms in IR subjects.

Regulation of Glucose Uptake by Endothelin-1 in Human Skeletal Muscle in Vivo and in Vitro

Context: Expression of the vasoconstrictor and proinflammatory peptide endothelin (ET)-1 is increased in insulin-resistant (IR) subjects. Objective: The aim of this study was to investigate whether ET-1 regulates skeletal muscle glucose uptake in IR subjects in vivo and in cultured human skeletal muscle cells. Design and Participants: Eleven subjects participated in three protocols using brachial artery infusion of: A) BQ123 (10 nmol/min) and BQ788 (10 nmol/min) (ETA and ETB receptor antagonist, respectively), followed by coinfusion with insulin (0.05 mU/kg/min); B) insulin alone; and C) insulin followed by coinfusion with ET-1 (20 pmol/min). Main Outcome Measures: Forearm blood flow (FBF) and forearm glucose uptake (FGU) were determined. Glucose uptake and molecular signaling were determined in cultured skeletal muscle cells. Results: ETA/ETB receptor blockade increased FGU by 63% (P < 0.05). Coadministration of insulin caused a further 2-fold increase in FGU (P < 0.001). ETA/ETB receptor blockade combin...

Intra-arterial AICA-riboside administration induces NO-dependent vasodilation in vivo in human skeletal muscle

In animal models, administration of the adenosine analog AICA-riboside has shown beneficial effects on ischemia-reperfusion injury and glucose homeostasis. The vascular and/or metabolic effects of AICA-riboside administration in humans remain to be established. AICA-riboside was infused intra-arterially in four different dosages up to 8 mg x min(-1) x dl(-1) in 24 healthy subjects. Forearm blood flow (FBF) and glucose uptake and plasma glucose, free fatty acid, and AICA-riboside concentrations were assessed. We also combined AICA-riboside infusion (2 mg x min(-1) x dl(-1)) with the intra-arterial administration of the adenosine receptor antagonist caffeine (90 microg x min(-1) x dl(-1); n = 6) and with the endothelial NO synthase inhibitor l-NMMA (0.4 mg x min(-1) x dl(-1); n = 6). Additional in vitro experiments were performed to explain our in vivo effects of AICA-riboside in humans. AICA-riboside increased FBF dose dependently from 2.0 +/- 0.2 to 13.2 +/- 1.9 ml x min(-1) x dl(-1) maximally (P < 0.05 for all dosages). The latter was not reduced by caffeine administration but was significantly attenuated by l-NMMA infusion. Despite high plasma AICA-riboside concentrations, forearm glucose uptake did not change. In vitro experiments showed rapid uptake of AICA-riboside by the equilibrative nucleoside transporter in erythrocytes and subsequent phosphorylation to AICA-ribotide. We conclude that AICA-riboside induces a potent vasodilator response in humans that is mediated by NO. Despite high local plasma concentrations, AICA-riboside does not increase skeletal muscle glucose uptake.

Ischaemia and insulin, but not ischaemia and contraction, act synergistically in stimulating muscle glucose uptake in vivo in humans

Ischaemia, like muscle contraction, has been reported to induce skeletal muscle glucose uptake in in vitro models. This stimulating effect appears independent of insulin and is probably mediated by activation of AMPK (AMP-activated protein kinase). In the present study, we hypothesized that in vivo in humans ischaemia- and insulin-induced glucose uptake are additive, and that the combined impact of ischaemia and contraction on glucose uptake is of a similar magnitude when each is applied separately. We assessed the effects of ischaemia with and without euglycaemic-hyperinsulinaemia (clamp; protocol 1) and with and without muscle contraction (protocol 2) on muscle FGU (forearm glucose uptake) in healthy subjects. Furthermore, we assessed the impact of ischaemia on FBF (forearm blood flow; plethysmography). In protocol 1, ischaemia increased FGU from 0.6+/-0.1 at baseline to 5.5+/-1.9 micromol x min(-1) x dl(-1), and insulin increased FGU to 1.6+/-0.3 micromol x min(-1) x dl(-1) (P<0.05 for both). The combination of ischaemia+insulin increased FGU to 15.5+/-2.2 micromol x min(-1) x dl(-1) (P<0.05 compared with each stimulus alone). Maximal FBF obtained after ischaemia was similar with and without hyperinsulinaemia. In protocol 2, isometric contraction increased FGU from 0.3+/-0.1 to 2.7+/-0.8 micromol x min(-1) x dl(-1) (P<0.05), but FGU was not significantly different from ischaemia compared with ischaemia+contraction. However, combined ischaemia+contraction resulted in a greater increase in FBF. In summary, ischaemia and insulin independently stimulate skeletal muscle glucose uptake in vivo in humans, whereas ischaemia and contraction do not. The observed differential effects of these stimuli on glucose uptake appear to be unrelated to changes in muscle blood flow.

Impaired endothelial function and insulin action in first-degree relatives of patients with type 2 diabetes mellitus

First-degree relatives (FDR) of patients with type 2 diabetes mellitus are at increased risk of developing type 2 diabetes mellitus. We studied if endothelial dysfunction of the resistance vessels is present and may coexist with metabolic insulin resistance in FDR. Male FDR (n = 13; 26 ± 1 years; body mass index, 25 ± 1 kg m 2 [mean ± SEM]) and matched control subjects (CON) (n = 22; 25 ± 1 years; body mass index, 24 ± 1 kg m 2) were studied by hyperinsulinemic (40 mU min −1⋅m −2) isoglycemic clamp combined with brachial arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography upon stimulation with systemic hyperinsulinemia (291 ± 11 pmol/L, pooled data from both groups) and upon intraarterial infusion of adenosine (ADN) and acetylcholine (ACH) ± hyperinsulinemia. Forearm blood flow response to ADN and ACH was less in FDR vs CON ( P < .05); systemic hyperinsulinemia added to the FBF effect of ADN in CON ( P < .05) but not in FDR. In addition, FDR demonstrated impaired FBF to hyperinsulinemia (2.1 ± 0.2 vs 4.0 ± 0.6 mL 100 mL −1 min −1) in FDR and CON, respectively ( P < .05). Both M-value (5.0 ± 0.7 vs 7.0 ± 0.5 mg min −1 kg −1) and forearm glucose clearance (0.6 ± 0.1 vs 1.4 ± 0.4 mL 100 mL −1⋅min −1) were diminished in FDR compared with CON (all P < .05). FDR demonstrated endothelial dysfunction of the resistance vessels in addition to impaired insulin-stimulated increase in bulk flow. Moreover, FDR demonstrated whole-body insulin resistance as well as decreased basal and insulin-stimulated forearm glucose uptake. It remains to be established whether FDR also demonstrate impaired insulin-stimulated microvascular function.

Increased Protein Turnover and Proteolysis Is an Early and Primary Feature of Short-Term Experimental Hyperthyroidism in Healthy Women

Hyperthyroidism increases energy expenditure, glucose turnover, lipolysis, and protein breakdown. Our objective was to test whether increased protein breakdown occurs independently of other catabolic effects in mild experimental hyperthyroidism. We conducted a single-blind, randomized, placebo-controlled, crossover study. Protein dynamics of the whole body and of the forearm muscles were measured by amino acid tracer dilution technique ([(15)N]phenylalanine and [(2)H(4)]tyrosine). All subjects underwent a 3-h study in the basal state followed by a 3-h euglycemic clamp study. The study took place at a university clinical research unit. Eight healthy women (24-46 yr old) participated. Intervention included 6 d thyroid hormone (T(4) 50 microg and T(3) 0.67 microg/kg.d) or placebo administration. Thyroid hormone administration led to mild T(3) hyperthyroidism with more than a doubling of T(3) levels and suppression of TSH. Energy expenditure and body composition was unchanged. Glucose infusion rates, forearm glucose uptake, and levels of lipid intermediates were also alike. Basal whole-body phenylalanine flux and tyrosine flux (reflecting whole-body protein breakdown) were increased (P < 0.05) as were whole-body protein synthesis rate (P = 0.05). Basal forearm rate of appearance and disappearance for phenylalanine (reflecting muscle protein breakdown and synthesis) were similar. Mild short-term experimental hyperthyroidism increases whole-body protein turnover and breakdown before any measurable changes in energy expenditure or glucose and fat metabolism, suggesting that amino acid and protein metabolism is an early and primary target for thyroid hormone action in humans.

Effects of Intrabrachial Metacholine Infusion on Muscle Capillary Recruitment and Forearm Glucose Uptake during Physiological Hyperinsulinemia in Obese, Insulin-Resistant Individuals

Impairment of insulin-mediated capillary recruitment in skeletal muscle contributes to a hampered glucose uptake in obesity. The objective of this study was to evaluate whether metacholine (MCh), a nitric oxide vasodilator, potentiates muscle capillary recruitment and forearm glucose uptake (FGU) during physiological hyperinsulinemia. The double-forearm technique [i.e. infused vs. control (Ctrl) forearm] was combined with im microdialysis during an oral glucose tolerance test in 15 nondiabetic, obese subjects divided into a group of insulin-resistant (IR) (n = 7) and insulin-sensitive (n = 8) individuals. After the oral glucose tolerance test, forearm blood flow in the Ctrl forearm was unchanged, whereas it increased about 3-fold (P < 0.0001 vs. baseline) in response to MCh. Capillary permeability surface area product for glucose (PS(glu)) (capillary recruitment), FGU, and interstitial insulin concentrations increased significantly over time (P < 0.001) in both forearms. Compared with insulin-sensitive, the IR subjects exhibited lower PS(glu) (P < 0.001) and FGU (P < 0.01) in the Ctrl arm, whereas this difference was insignificant in the MCh arm despite the blunted forearm blood flow increase. Moreover, in IR individuals MCh significantly (P < 0.05) ameliorated the delayed onset of insulin action, i.e. the FGU response to hyperinsulinemia. Finally, we found PS(glu) to be a strong and independent predictor of FGU response (adjusted R(2) 0.72; P < 0.0001). MCh-induced vasodilation may improve the microvascular and metabolic responses to physiological hyperinsulinemia in obese, IR individuals. Further studies are required to unravel whether stimulation of nitric oxide production in skeletal muscle may represent an attractive therapeutic approach to bypassing cellular resistance to glucose disposal.

Last Word on Point:Counterpoint: There is/is not capillary recruitment in active skeletal muscle during exercise

TO THE EDITOR: The vigorous commentary on this debate underscores the importance of understanding muscle microvascular perfusion and its control.

Dose-Response Effects of Free Fatty Acids on Glucose and Lipid Metabolism during Somatostatin Blockade of Growth Hormone and Insulin in Humans

GH and other stress hormones stimulate lipolysis, which may result in free fatty acid (FFA)-mediated insulin resistance. However, there are also indications that FFAs in the very low physiological range have the same effect. The objective of the study was to address systematically the dose-response relations between FFAs and insulin sensitivity. We therefore examined eight healthy men for 8 h (6 h basal and 2 h glucose clamp) on four occasions. Intralipid was infused at varying rates (0, 3, 6, 12 microl.kg(-1).min(-1)); lipolysis was blocked by acipimox; and endogenous GH, insulin, and glucagon secretion was blocked by somatostatin and subsequently replaced at fixed rates. This resulted in four different FFA levels between 50 and 2000 micromol/liter, with comparable levels of insulin and counterregulatory hormones. Both in the basal state and during insulin stimulation, we saw progressively decreased glucose disposal, nonoxidative glucose disposal, and forearm muscle glucose uptake at FFA levels above 500 micromol/liter. Apart from forearm glucose uptake, the very same parameters were decreased at low FFA levels (approximately 50 micromol/liter). FFA rate of disposal was linearly related to the level of FFAs, whereas lipid oxidation reached a maximum at FFA levels approximately 1000 micromol/liter. In the presence of comparable levels of all major metabolic hormones, insulin sensitivity peaks at physiological levels of FFAs with a gradual decrease at elevated as well as suppressed FFA concentrations. These data constitute comprehensive dose-response curves for FFAs in the full physiological range from close to zero to above 2000 micromol/liter.

Increased insulin‐stimulated endothelin‐1 release is a distinct vascular phenotype distinguishing Cushing's disease from metabolic syndrome

Although much is known about the anti-inflammatory effects of an acute corticosteroid therapy, little is known about the effects on chronic hypercortisolism on endothelial dysfunction and proinflammatory alterations in patients with Cushing's disease (CD). We studied 9 patients with CD, 10 patients with metabolic syndrome and 27 normal controls. The tests consisted of an intravenous bolus of 0.1 U/kg insulin combined with a euglycaemic clamp technique with an arterialized forearm and assessment of the training parameters deep-venous balance of forearm glucose uptake (as an index of insulin sensitivity); NO(x) (nitric oxide end-products), c-GMP (second messenger of nitric oxide) and endothelin-1 release, as indices of endothelial function and proinflammatory systemic markers. Forearm glucose uptake incremental area was significantly lower in Cushing's disease and in the metabolic syndrome than in controls, suggesting a state of severe insulin resistance. Compared to controls and to the metabolic syndrome, basal and insulin-stimulated NO(x) release incremental areas were significantly reduced in Cushing's disease, while forearm c-GMP release was similarly decreased in CD and metabolic syndrome. By contrast, endothelin-1 incremental areas after insulin bolus were significantly higher in CD than in controls and the metabolic syndrome, in the presence of increased TNF-alpha, IL-6 and CRP levels. Forearm glucose uptake incremental area significantly correlated with NO(x) incremental area, forearm c-GMP release incremental area, TNF-alpha levels and ET-1 incremental area. In patients with CD, supraphysiological insulin levels are not able to overcome the insulin resistance due to chronic hypercortisolism. Furthermore, an increased proatherogenic risk profile is characterized by decreased nitric oxide synthesis and activity, enhanced endothelin-1 levels and increased proinflammatory markers.

Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals

Our objectives were to quantitate insulin-stimulated inward glucose transport and glucose phosphorylation in forearm muscle in lean and obese nondiabetic subjects, in lean and obese type 2 diabetic (T2DM) subjects, and in normal glucose-tolerant, insulin-resistant offspring of two T2DM parents. Subjects received a euglycemic insulin (40 mU.m(-2).min(-1)) clamp with brachial artery/deep forearm vein catheterization. After 120 min of hyperinsulinemia, a bolus of d-mannitol/3-O-methyl-d-[(14)C]glucose/d-[3-(3)H]glucose (triple-tracer technique) was given into brachial artery and deep vein samples obtained every 12-30 s for 15 min. Insulin-stimulated forearm glucose uptake (FGU) and whole body glucose metabolism (M) were reduced by 40-50% in obese nondiabetic, lean T2DM, and obese T2DM subjects (all P < 0.01); in offspring, the reduction in FGU and M was approximately 30% (P < 0.05). Inward glucose transport and glucose phosphorylation were decreased by approximately 40-50% (P < 0.01) in obese nondiabetic and T2DM groups and closely paralleled the decrease in FGU. The intracellular glucose concentration in the space accessible to glucose was significantly greater in obese nondiabetic, lean T2DM, obese T2DM, and offspring compared with lean controls. We conclude that 1) obese nondiabetic, lean T2DM, and offspring manifest moderate-to-severe muscle insulin resistance (FGU and M) and decreased insulin-stimulated glucose transport and glucose phosphorylation in forearm muscle; these defects in insulin action are not further reduced by the combination of obesity plus T2DM; and 2) the increase in intracelullar glucose concentration under hyperinsulinemic euglycemic conditions in obese and T2DM groups suggests that the defect in glucose phosphorylation exceeds the defect in glucose transport.

Biguanides Enhance Glucose Utilization and Insulin Action in Peripheral Tissues: An Old Finding from the Sixties of the Last Century

In their interesting studies, Magalhães et al. found an increase of blood flow and forearm glucose uptake by metformin [1]. The authors state that “this new effect probably contributes or could be the consequence of the improvement in vascular function” and conclude that this biguanide “acts in insulin resistance by increasing glucose peripheral uptake”.

Metformin Increases Blood Flow and Forearm Glucose Uptake in a Group of Non-obese Type 2 Diabetes Patients

The present study was designed to determine the effects of metformin on the forearm glucose uptake and blood flow after an oral glucose challenge. Eleven normal subjects, and ten non-obese type 2 diabetes patients without medication of anti-hyperglycemic drug and with medication of metformin for four weeks, were studied after an overnight fast (12-14 h) and 3 hours after ingestion of 75 g of glucose. Peripheral glucose metabolism was analyzed by the forearm technique combined with indirect calorimetry. The forearm glucose uptake increased in diabetes patients taking metformin (63.5+/-9.1 VS. 39.1+/-5.3 mg/100 ml FA. 3 h). The increase of forearm glucose uptake was due to increase of blood flow. The glucose oxidation was greater in the group treated with metformin, compared to the same group without anti-hyperglycemic drug (19.3+/-2.6 VS. 7.7+/-2.6 mg/100 ml FA. 3 hrs). The free fatty acids were higher in diabetes patients, which normalized after taking metformin. In conclusion, it was found that in these participants metformin acts in insulin resistance; it increases glucose muscle uptake and blood flow. The enhancement of blood flow and lower free fatty acids, not described yet, could be direct effects of the drug or due to reduced glucose toxicity. These positive effects must be responsible for the improvement in vascular function.

Metabolic Aspects of Insulin Resistance in Individuals Born Small for Gestational Age

Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19–23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-ζ, the two subunits of phosphoinositol 3-kinase (i.e., p85α and p110β) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association.

Antecedent hypoglycemia does not alter increased epinephrine-induced lipolysis in type 1 diabetes mellitus

Type 1 diabetic subjects have decreased epinephrine responses to hypoglycemia that may be counterbalanced by increased β-adrenergic sensitivity. The goal of this study was to determine whether type 1 diabetic subjects have increased metabolic response to epinephrine and to determine the effect of antecedent hypoglycemia on these responses. Muscular glucose uptake across the forearm (forearm glucose uptake, Fick principle) and lipolysis (free fatty acid and glycerol levels) were studied before and during a 4-hour euglycemic, hyperinsulinemic (40 mU · m −2 · min −1) clamp with epinephrine infusion (0.015 μg · kg −1 · min −1) over 3 hours. Subjects were studied twice, once with antecedent hypoglycemia (2.8 mmol/L for two 2-hour sessions) and once with antecedent euglycemia (5 mmol/L) the day prior. Free fatty acid and glycerol concentrations were higher, and total body glucose utilization and forearm glucose uptake during epinephrine were lower in diabetic than in control subjects ( P < .05). Antecedent hypoglycemia had no effect. These results demonstrate that type 1 diabetic subjects have increased lipolysis and decreased glucose utilization in response to epinephrine. These effects are not altered by antecedent hypoglycemia.

Quinapril Treatment Increases Insulin-Stimulated Endothelial Function and Adiponectin Gene Expression in Patients with Type 2 Diabetes

Angiotensin-converting enzyme inhibitors reduce cardiovascular mortality and improve endothelial function in type 2 diabetic patients. We hypothesized that 2 months of quinapril treatment would improve insulin-stimulated endothelial function and glucose uptake in type 2 diabetic subjects and simultaneously increase the expression of genes that are pertinent for endothelial function and metabolism. Twenty-four type 2 diabetic subjects were randomized to receive 2 months of quinapril 20 mg daily or no treatment in an open parallel study. Endothelium-dependent and -independent vasodilation was studied during serotonin or sodium nitroprusside infusion in the diabetic patients and in 15 healthy subjects. Endothelial function, insulin-stimulated endothelial function, and insulin-stimulated glucose uptake were measured before and after quinapril treatment. Blood flow was measured by venous occlusion plethysmography. Gene expression was measured by real-time PCR. Quinapril treatment increased insulin-stimulated endothelial function in the type 2 diabetic subjects (P = 0.005), whereas forearm glucose uptake was unchanged. Endothelial function was also increased by quinapril (P = 0.001). Systolic and diastolic blood pressures were reduced by quinapril (P < 0.001). Quinapril increased adiponectin gene expression in vascular tissue obtained from sc adipose biopsies. Quinapril treatment increases insulin-stimulated endothelial function in patients with type 2 diabetes. Increased vascular adiponectin gene expression may contribute to this beneficial effect.

Metabolic and Vascular Effects of Tumor Necrosis Factor-α Blockade with Etanercept in Obese Patients with Type 2 Diabetes

Objective: The pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-α blockade with etanercept could reverse vascular and metabolic insulin resistance. Method and Results: Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions of serotonin, sodium nitroprusside and insulin co-infused with serotonin. β-Cell function was assessed with oral and intra-venous glucose tolerance tests and whole-body insulin sensitivity by hyperinsulinemic euglycemic clamps. Plasma levels of C-reactive protein and interleukin-6 decreased significantly with etanercept (C-reactive protein from 9.9 ± 3.1 to 4.8 ± 1.4 mg l^–1, p = 0.04; interleukin-6 from 3.1 ± 0.4 to 1.9 ± 0.2 ng l^–1, p = 0.03). Vasodilatory responses to serotonin and sodium nitroprusside infusions remained unchanged. Insulin effect on vasodilatation and on whole-body and forearm glucose uptake remained unchanged as well. β-Cell function tended to improve. Conclusion: Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed.

Metabolic and endothelial effects of trimetazidine on forearm skeletal muscle in patients with type 2 diabetes and ischemic cardiomyopathy

The aim of the present study was to evaluate the effect of prolonged inhibition of beta-oxidation on glucose and lipid muscle forearm metabolism and cGMP and endothelin-1 forearm release in patients with type 2 diabetes mellitus and ischemic cardiomyopathy. Fifteen patients were randomly allocated in a double-blind cross-over parallel study with trimetazidine (20 mg tid) or placebo lasting 15 days. At the end of each period, all patients underwent euglycemic hyperinsulinemic clamps with forearm indirect calorimetry and endothelial balance of vasodilator and vasoconstricor factors. Compared with placebo, trimetazidine induced 1) an increase in insulin-induced forearm glucose uptake and glucose oxidation accompanied by a reduction in forearm lipid oxidation and citrate release and 2) a decrease of endothelin-1 release paralleled by a significant increase in forearm cGMP release. Forearm glucose oxidation significantly correlated with cGMP release (r=0.37, P<0.04), whereas forearm lipid oxidation positively correlated with endothelin-1 release (r=0.40, P<0.03). In conclusion, for the first time, we demonstrated that insulin-induced forearm glucose oxidation and forearm cGMP release were increased whereas forearm endothelin-1 release was decreased during trimetazidine treatment. Muscle's metabolic and vascular effects of trimetazidine add new interest in the use of trimetazidine in type 2 diabetic patients with cardiovascular disease.

Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans.

Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin-stimulated endothelial function in humans. Healthy, lean male volunteers were studied. On each study day, 3 acetylcholine (ACh) or sodium nitroprusside (SNP) dose-response studies were performed by infusion into the brachial artery. Before and during the last 2 dose-response studies, insulin and/or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow. Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (P<0.001), and this inhibition was larger during insulin infusion (P=0.01) but not further increased by NG-monomethyl-L-arginine acetate (P=0.2). Insulin potentiated the SNP response less than the ACh response and the effect of TNF-alpha was smaller (P<0.001); TNF-alpha had no effect on the SNP response without insulin infusion. Thus, TNF-alpha inhibition of the combined response to insulin and ACh was likely mediated through inhibition of NO production. These results support the concept that TNF-alpha could play a role in the development of insulin resistance in humans, both in muscle and in vascular tissue.