Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography.

Nuutila, Pirjo; Raitakari, Maria; Laine, Hanna; Kirvelä, Olli; Takala, Tuomo; Utriainen, Tapio; Mäkimattila, Sari; Pitkänen, Olli‐Pekka; Ruotsalainen, Ulla; Iida, Hidehiro; Knuuti, Juhani; Yki‐Järvinen, Hannele

doi:10.1172/jci118601

Cited by 152 publications

(136 citation statements)

References 61 publications

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“…The results of the present study are contradictory to previous reports showing that acute intravenous administration of agents with endothelium-dependent vasodilation activity, such as adenosine or bradykinin, failed to improve glucose utilization, despite a significant increment in local blood flow (24,25). The discrepancy between our data and those shown in the previous studies (24,25) may be the result of different experimental approaches, such as those which acutely infused intravenous bradikynin (24) or adenosine (25) for a few hours.…”

Section: Euglycemic-hyperinsulinemic Clampcontrasting

confidence: 99%

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Long-Term Oral l-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

Piatti¹,

Monti²,

Valsecchi³

et al. 2001

Diabetes Care

186

119

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OBJECTIVE -The aim of this study was to evaluate whether long-term administration of L-arginine acting through a normalization of NO/cyclic-guanosine-3Ј,5Ј-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. RESEARCH DESIGN AND METHODS-A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into two groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo (orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemichyperinsulinemic clamp combined with [6, H 2 ]glucose infusion. A total of 10 normal subjects underwent the same test as control subjects.RESULTS -In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34%, whereas it decreased systolic blood pressure and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal.CONCLUSIONS -L-Arginine treatment significantly improves but does not completely normalize peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes Care 24:875-880, 2001C ontradictory results have been found concerning the influence of insulin on nitric oxide (NO), a potent molecule with vasodilatory function. Baron et al. (1,2) showed that insulinmediated vasodilation is largely dependent on the action of insulin on NO release, whereas Petrie et al. (3) have shown that endothelial NO synthesis and insulin sensitivity are positively correlated in healthy individuals. In addition, in obese patients and patients with type 2 diabetes, the insulin-mediated vasodilatory response seems blunted (4). However, Yki-Jarvinen et al. (5) were unable to find any correlation between insulin action and increment in blood flow in normal and obese subjects, although all agree that methacoline-induced vasodilation is impaired in insulin-resistant subjects.L-Arginine is a precursor for NO, and both in vitro and in vivo studies have demonstrated that L-arginine can augment vascular dilation under certain conditions (6). Experimental studies in cholesterol-fed rabbits have shown that dietary supplementation with L-arginine causes attenuation of endothelial dysfunction with increased NO activity, resulting in reduced platelet activation (7), monocyte adhesion (8), and a marked reduction in aortic and coronary atherosclerosis (9). Moreover, in young hypercholesterolemic adults, the administr...

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Section: Euglycemic-hyperinsulinemic Clampcontrasting

confidence: 99%

“…The discrepancy between our data and those shown in the previous studies (24,25) may be the result of different experimental approaches, such as those which acutely infused intravenous bradikynin (24) or adenosine (25) for a few hours. In the present study, Larginine was administered chronically for 30 days.…”

Section: Euglycemic-hyperinsulinemic Clampcontrasting

confidence: 99%

Long-Term Oral l-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

Piatti¹,

Monti²,

Valsecchi³

et al. 2001

Diabetes Care

186

119

View full text Add to dashboard Cite

show abstract

“…However, based on the arguments in the previous paragraph, vasodilators that increase total limb blood flow, such as adenosine [6], bradykinin [7], sodium nitroprusside [8], low doses of IGF-1 [9] and adrenaline [10], would not be expected to increase glucose uptake or overcome insulin resistance. However, not all vasodilators may act in the same way, and MC may be one such example.…”

Section: Discussionmentioning

confidence: 99%

“…A number of vasodilators increase limb blood flow in human subjects in vivo and these include adenosine [6], bradykinin [7], sodium nitroprusside [8], low doses of IGF-1 [9] and adrenaline [10]. Nevertheless, none of these has increased glucose uptake or overcome insulin resistance.…”

Section: Introductionmentioning

confidence: 99%

Vascular and metabolic effects of methacholine in relation to insulin action in muscle

et al. 2006

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Aims/hypothesis: Methacholine (MC) is a nitric oxide vasodilator, but unlike other vasodilators, it potentiates insulin-mediated glucose uptake by muscle. The present study aimed to resolve whether this action was the result of a vascular effect of MC leading to increased muscle perfusion or a direct effect of MC on the myocytes. We hypothesise that vascular-mediated insulin-stimulated glucose uptake responses to MC occur at lower doses than direct myocyte MC-mediated increases in glucose uptake. Methods: The vascular and metabolic effects of this vasodilator were examined in rats in vivo using a novel local infusion technique, and in the pump-perfused rat hindlimb under conditions of constant flow. Results: Local infusion of low-dose MC (0.3 μmol/l) into the epigastric artery of one leg (test) in vivo markedly increased femoral blood flow and decreased vascular resistance, without effects in the contra-lateral leg. Capillary recruitment, but not glucose uptake, was increased in the test leg. All increases caused by MC were confined to the test leg and blocked by local infusion into the test leg of N ω -nitro-L-arginine methyl ester (L-NAME), but not by infusion of N ω -nitro-D-arginine methyl ester (D-NAME). In the constant-flow pumpperfused rat hindlimb, infusion of 0.6 μmol/l MC vasodilated the pre-constriction effected by 70 nmol/l noradrenaline or 300 nmol/l serotonin, and this was blocked by 10 μmol/l L-NAME. 2-Deoxyglucose in muscle was increased by 30 μmol/l MC (p<0.05), but was unaffected by 3 μmol/l MC. All increases in 2-deoxyglucose uptake by 30 μmol/l MC were blocked by 10 μmol/l L-NAME. Conclusions/interpretation: MC has dose-dependent effects both on the vasculature and on muscle metabolism. At low dose (0.3-3 μmol/l), MC is a potent vasodilator in muscle, both in vivo and in vitro, without metabolic effects; at higher doses (≥30 μmol/l) MC has a direct metabolic effect leading to increased glucose uptake. Both the vascular and metabolic effects are sensitive to L-NAME. The lowdose enhancement of insulin action in vivo by MC, which has been reported previously, thus seems to be attributable to vascular effects.

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“…Bradykinin also increases glucose uptake in muscular cells and primary adipocytes by triggering GLUT4 (SLC2A4) translocation through insulin-dependent and -independent pathways (Isami et al 1996, Kishi et al 1998, Beard et al 2006. However, in humans, the effect of kinins on muscle glucose uptake remains controversial , Nuutila et al 1996, Mahajan et al 2004.…”

Section: Introductionmentioning

confidence: 99%

Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man

Potier¹,

Waeckel²,

Fumeron³

et al. 2014

Journal of Endocrinology

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The kallikrein-kinin system has been suggested to participate in the control of glucose metabolism. Its role and the role of angiotensin-I-converting enzyme, a major kinininactivating enzyme, are however the subject of debate. We have evaluated the consequence of deficiency in tissue kallikrein (TK), the main kinin-forming enzyme, on the development of insulin resistance and diabetes in mice and man. Mice with inactivation of the TK gene were fed a high-fat diet (HFD) for 3 months, or crossed with obese, leptindeficient (ob/ob) mice to generate double ob/ob-TK-deficient mutants. In man, a loss-offunction polymorphism of the TK gene (R53H) was studied in a large general population cohort tested for insulin resistance, the DESIR study (4843 participants, 9 year follow-up). Mice deficient in TK gained less weight on the HFD than their WT littermates. Fasting glucose level was increased and responses to glucose (GTT) and insulin (ITT) tolerance tests were altered at 10 and 16 weeks on the HFD compared with standard on the diet, but TK deficiency had no influence on these parameters. Likewise, ob-TK K/K mice had similar GTT and ITT responses to those of ob-TK C/C mice. TK deficiency had no effect on blood pressure in either model. In humans, changes over time in BMI, fasting plasma glucose, insulinemia, and blood pressure were not influenced by the defective 53H-coding TK allele. The incidence of diabetes was not influenced by this allele. These data do not support a role for the TK-kinin system, protective or deleterious, in the development of insulin resistance and diabetes.

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Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography.

Cited by 152 publications

References 61 publications

Long-Term Oral l-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

Long-Term Oral l-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

Vascular and metabolic effects of methacholine in relation to insulin action in muscle

Tissue kallikrein deficiency, insulin resistance, and diabetes in mouse and man

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