Glucose Uptake In Humans Research Articles

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma.

AimsOur aim was to investigate the glucose uptake in cancer patients suffering from different entities, using 18F‐FDG positron emission tomography–computed tomography scans. We further aimed at identifying potential variables altering cardiac and skeletal muscle glucose metabolism.Methods and resultsIn a retrospective cohort study, we analysed cardiac and skeletal muscle 18F‐FDG uptake in onco‐positron emission tomography–computed tomography scans in adult patients suffering from Hodgkin's lymphoma, non‐Hodgkin's lymphoma, and non‐lymphatic cancer including patients suffering from thyroid cancer, bronchial carcinoma, and malignant melanoma. Univariate logistic regression models were created for increased cardiac and skeletal muscle 18F‐FDG uptake using cancer entity, sex, age, previous radiation, previous chemotherapy, diabetes, obesity, serum glucose levels, renal function, and thyroid function as parameters. Multivariate models were created by selecting variables according to Akaike's information criterion in a step‐down approach. Between 2014 and 2018, a total of 337 consecutive patients suffering from Hodgkin's lymphoma (n = 52), non‐Hodgkin's lymphoma (n = 57), and non‐lymphatic cancer (n = 228) were included in the analysis. Univariate logistic regression models showed high serum glucose levels to be associated with lower absorption rates in both cardiac and skeletal muscle (odds ratio [OR] 0.38 [0.23, 0.60, 95% confidence interval—CI], P < 0.0001, and 0.52 [0.33, 0.82, 95% CI], P < 0.005, respectively). Hodgkin's lymphoma was associated with an increase in cardiac uptake (OR 2.4 [1.3, 4.5, 95% CI], P < 0.005). Decreased skeletal muscle 18F‐FDG uptake was noted in elderly and obese patients. In our multivariate analysis, Hodgkin's lymphoma patients showed higher cardiac 18F‐FDG uptake, while non‐Hodgkin's lymphoma patients did not differ significantly from non‐lymphatic cancer patients (OR 1.6 [0.7, 3.3, 95% CI], P = 0.24). High serum glucose levels and prior chemotherapy were both associated with a significantly decreased cardiac 18F‐FDG uptake (OR 0.40 [0.24, 0.65, 95% CI], P < 0.0005, and 0.50 [0.27, 0.90, 95% CI], P < 0.05, respectively). Notably, prior chemotherapy did not influence FDG uptake in skeletal muscle to the same extent. Obesity and older age were both significantly associated with decreased gluteal 18F‐FDG uptake (OR 0.49 [0.27, 0.89, 95% CI], P < 0.05, and 0.47 [0.25, 0.87, 95% CI], P < 0.05).ConclusionsOur data provide evidence for metabolic alterations in patients with Hodgkin's lymphoma related to cardiac glucose uptake in humans. This effect was independent from skeletal muscle metabolism.

Elevated Nonesterified Fatty Acids (NEFA) Are Associated with Blunted Hyperglycemia-Induced Increments in Brain Glucose Levels

Recently, we have demonstrated that obesity and T2DM are associated with blunted brain glucose transport capacity during acute hyperglycemia in humans, which was also associated with higher total NEFA levels. Palmitic acid has been shown in vitro to suppress brain glucose uptake by downregulating GLUT1 expression in brain endothelial cells. Thus, this current study was undertaken to determine whether specific NEFA composition is associated with blunted human brain glucose transport capacity. Plasma NEFA composition was assessed using Gas-Chromatography Mass-Spectroscopy in 8 healthy lean (HC) (4F/4M, age 33±11 years, BMI 23±2 kg/m2, HbA1C 5.0±0.2), 10 obese (OB) (6F/4M, age 34±11 years, BMI 39±6 kg/m2, HbA1C 5.3±0.3), and 6 T2DM individuals (5F/1M, age 52±5 years, BMI 33±2 kg/m2, HbA1C 9.5±1.3) at the end of a 2-hour hyperglycemic clamp (220mg/dl) and correlated with previously measured changes in intracerebral glucose levels. Blunted rise in brain glucose levels was observed in OB and T2DM vs. HC individuals (p&amp;lt;0.05). Plasma long-chain non-esterified fatty acids (LCFA) including saturated (myristic acid, palmitic acid, stearic acid), monounsaturated (palmitoleic acid, oleic acid) and polyunsaturated (linoleic acid, an essential fatty acid) were different across all 3 groups (p&amp;lt;0.05). Moreover, these LCFAs negatively correlated with hyperglycemia-induced change in brain glucose levels (myristic r=-0.45; p=0.03, palmitic: r=-0.49, p=0.02; stearic r=-0.44, p=0.04; palmitoleic r=-0.49, p=0.02; oleic r=-0.49, p=0.02; linoleic r=-0.41, p=0.05). Our results demonstrate an inverse relationship between elevated LCFA levels and blunted brain glucose uptake in humans, which appears to be non-specific for NEFA composition. As the ability to transport glucose into the brain is crucial for energy homeostasis, these findings highlight a potential role for NEFAs to modulate brain glucose transport and metabolism and in turn cognitive function. Disclosure W. Lam: None. L. Jiang: None. G. Butrico: None. G. Cline: None. E. Sanchez Rangel: None. M. Hamza: None. L. Parikh: None. R. Belfort-DeAguiar: Research Support; Self; GlaxoSmithKline plc.. D.L. Rothman: None. G.F. Mason: Consultant; Self; UCB, Inc., Sumitomo Dainippon Pharma Co., Ltd. R. Sherwin: Other Relationship; Self; QuintilesIMS, MannKind Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; ICON plc.. J. Hwang: None.

Gerald “Jerry” M Reaven: the “father of insulin resistance”

Gerald “Jerry” M Reaven was a pioneer in insulin research, whose discoveries formed the basis of the concept of metabolic syndrome. He is credited with developing the first quantitative method...

Short-term green tea extract supplementation attenuates the postprandial blood glucose and insulin response following exercise in overweight men.

Green tea extract (GTE) ingestion improves glucose homeostasis in healthy and diabetic humans, but the interactive effect of GTE and exercise is unknown. The present study examined the effect of short-term GTE supplementation on the glycemic response to an oral glucose load at rest and following an acute bout of exercise, as well as substrate oxidation during exercise. Eleven sedentary, overweight men with fasting plasma glucose (FPG) ≥5.6 mmol·L-1 (age, 34 ± 13 years; body mass index = 32 ± 5 kg·m-2; FPG = 6.8 ± 1.0; mean ± SD) ingested GTE (3× per day, 1050 mg·day-1 total) or placebo (PLA) for 7 days in a double-blind, crossover design. The effects of a 75-g glucose drink were assessed on 4 occasions during both GTE and PLA treatments: On days 1 and 5 at rest, and again following an acute bout of exercise on days 3 and 8. The glycemic response was assessed via an indwelling continuous glucose monitor (CGM) and venous blood draws. At rest, 1-h CGM glucose area under the curve was not different (P > 0.05), but the postexercise response was lower after GTE versus PLA (330 ± 53 and 393 ± 65 mmol·L-1·min-1, main effect of treatment, P < 0.05). The 1-h postprandial peaks in venous blood glucose (8.6 ± 1.6 and 9.8 ± 2.2 mmol·L-1) and insulin (96 ± 59 and 124 ± 68 μIU·ml-1) were also lower postexercise with GTE versus PLA (time × treatment interactions, P < 0.05). In conclusion, short-term GTE supplementation did not affect postprandial glucose at rest; however, GTE was associated with an attenuated glycemic response following a postexercise oral glucose load. These data suggest that GTE might alter skeletal muscle glucose uptake in humans.

Dynamic Glucose-Enhanced (DGE) MRI: Translation to Human Scanning and First Results in Glioma Patients.

Recent animal studies have shown that d-glucose is a potential biodegradable magnetic resonance imaging (MRI) contrast agent for imaging glucose uptake in tumors. We show herein the first translation of that use of d-glucose to human studies. Chemical exchange saturation transfer (CEST) MRI at a single frequency offset optimized for detecting hydroxyl protons in d-glucose was used to image dynamic signal changes in the human brain at 7 T during and after d-glucose infusion. Dynamic glucose enhanced (DGE) image data from 4 normal volunteers and 3 glioma patients showed a strong signal enhancement in blood vessels, while a spatially varying enhancement was found in tumors. Areas of enhancement differed spatially between DGE and conventional gadolinium-enhanced imaging, suggesting complementary image information content for these 2 types of agents. In addition, different tumor areas enhanced with d-glucose at different times after infusion, suggesting a sensitivity to perfusion-related properties such as substrate delivery and blood-brain barrier (BBB) permeability. These preliminary results suggest that DGE MRI is feasible for studying glucose uptake in humans, providing a time-dependent set of data that contains information regarding arterial input function, tissue perfusion, glucose transport across the BBB and cell membrane, and glucose metabolism.

Gerald M. Reaven, MD: Demonstration of the central role of insulin resistance in type 2 diabetes and cardiovascular disease.

Gerald M. Reaven, MD, could easily be epitomized as the “Father of Insulin Resistance.” (For those who do not know Dr. Reaven, he would humbly raise objection to being called Dr. Reaven rather than Jerry.) That said, Jerry is credited with developing the insulin suppression test, the first quantitative method to measure insulin-mediated glucose uptake in humans (1). Using this technique, he established the importance of insulin resistance in human disease, and importantly, in type 2 diabetes (2,3). In nondiabetic individuals, he demonstrated the role of insulin resistance/compensatory hyperinsulinemia in the development of 1 ) hypertriglyceridemia (4) and low HDL concentrations (5), 2 ) decreased urinary uric acid clearance and hyperuricemia (6), 3 ) decreased LDL particle diameter (7), 4 ) enhanced postprandial lipemia and remnant lipoprotein accumulation (8), 5 ) increased levels of plasminogen activator inhibitor-1 (9), 6 ) salt sensitivity (10), 7 ) essential hypertension (11), and 8 ) increased sympathetic nervous system activity (12). In addition to emphasizing the role of insulin resistance/compensatory hyperinsulinemia in increasing the likelihood of an individual developing one or more of the consequences listed above, he first pointed out the clustering of these abnormalities. It is clear now that this group of clinical abnormalities, initially designated Syndrome X, is an important factor leading to cardiovascular disease. Syndrome X was introduced to the medical community in his now famous Banting Lecture in 1988 (13) and only later became known as metabolic syndrome. Jerry was born in Gary, IN, on 28 July 1928, but spent most of his precollege years living in Cleveland, OH, thus accounting for his lifelong allegiance to the Cleveland Indians baseball team and a great deal of frustration on his part during their many less-than-stellar seasons. Jerry matriculated at the University of Chicago and graduated in 1949, also the year of his marriage to his …

Insulin stimulation regulates AS160 and TBC1D1 phosphorylation sites in human skeletal muscle

INTRODUCTION:Individuals with obesity and type 2 diabetes (T2D) are typically insulin resistant, exhibiting impaired skeletal muscle glucose uptake. Animal and cell culture experiments have shown that site-specific phosphorylation of the Rab-GTPase-activating proteins AS160 and TBC1D1 is critical for GLUT4 translocation facilitating glucose uptake, but their regulation in human skeletal muscle is not well understood.METHODS:Here, lean, obese and T2D subjects underwent a euglycemic-hyperinsulinemic clamp, and vastus lateralis muscle biopsies were obtained before, and at 30 and 180 min post insulin infusion.RESULTS:Obese and T2D subjects had higher body mass indexes and fasting insulin concentrations, and T2D subjects showed insulin resistance. Consistent with the clamp findings, T2D subjects had impaired insulin-stimulated phosphorylation of AS160 Thr642, a site previously shown to be important in glucose uptake in rodents. Interestingly, insulin-stimulated phosphorylation of TBC1D1 Thr590, a site shown to be regulated by insulin in rodents, was only increased in T2D subjects, although the functional significance of this difference is unknown.CONCLUSION:These data show that insulin differentially regulates AS160 and TBC1D1 phosphorylation in human skeletal muscle. Impaired insulin-stimulated glucose uptake in T2D subjects is accompanied by dysregulation of AS160 and TBC1D1 phosphorylation in skeletal muscle, suggesting that these proteins may regulate glucose uptake in humans.

Intravenous AICAR During Hyperinsulinemia Induces Systemic Hemodynamic Changes but Has No Local Metabolic Effect

AMPK activation may stimulate glucose uptake in skeletal muscle, but the results in humans have so far been inconclusive. The authors investigated whether infusion of the AMPK activator, 5-aminoimidazole-4-carboxamide-riboside (AICAR), increased whole-body glucose infusion rate (GIR) and forearm skeletal muscle glucose uptake (FGU) during hyperin-sulinemia in vivo in healthy humans. Ten participants (paired data: n = 8) underwent 2 euglycemic hyperinsulinemic clamps (60 mU·m(-2)·min(-1), 120 minutes) with concomitant AICAR (67 mg·kg(-1)) or placebo (saline) administration over the last 60 minutes. The authors also measured forearm blood flow (FBF; plethysmography), heart rate, blood pressure, and AICAR and AICA-ribotide (ZMP) concentrations in plasma and erythrocytes. FGU and GIR (T = 95-120 min) did not differ between insulin + AICAR and insulin + placebo. Compared with insulin + placebo, insulin + AICAR raised heart rate more profoundly (T = 60-120 minutes: from 58 ± 3 to 70 ± 3 vs 60 ± 4 to 63 ± 4 bpm for placebo; P < .05 between treatments) and lowered blood pressure significantly. AICAR plasma concentrations increased significantly during AICAR infusion; AICAR was rapidly taken up by erythrocytes and phosphorylated to ZMP. In conclusion, AICAR does not seem to have a direct effect on systemic or local glucose uptake in humans. AICAR increases heart rate and decreases blood pressure, most likely by systemic vasodilation.

Endogenous Nitric Oxide Contributes to Bradykinin-Stimulated Glucose Uptake but Attenuates Vascular Tissue-Type Plasminogen Activator Release

Bradykinin causes vasodilation, stimulates tissue-type plasminogen activator (t-PA) release and, in rodents, increases muscle glucose uptake. Although bradykinin causes vasodilation partly by activating nitric-oxide synthase (NOS), the role of nitric oxide in regulating bradykinin-stimulated t-PA release is uncertain. This study examined the effect of high-dose NOS inhibition on bradykinin-stimulated t-PA release and glucose uptake in humans. We studied 24 healthy (12 women and 12 men), overweight and obese (body mass index >25 kg/m(2)), normotensive, nondiabetic subjects with normal cholesterol. We measured the effect of intra-arterial N(omega)-monomethyl-L-arginine (L-NMMA, 12 micromol/min) on forearm blood flow (FBF), net t-PA release, and glucose uptake at baseline and in response to intra-arterial bradykinin (50-200 ng/min) in subjects pretreated with the cyclooxygenase inhibitor aspirin. Measurements were repeated after isosorbide dinitrate (ISDN; 5 mg) or sildenafil (50 mg). L-NMMA decreased baseline FBF (P < 0.001), increased baseline forearm vascular resistance (P < 0.001), and increased the t-PA arterial-venous gradient (P = 0.04) without affecting baseline net t-PA release or glucose uptake. During L-NMMA, ISDN tended to decrease baseline net t-PA release (P = 0.06). L-NMMA blunted bradykinin-stimulated vasodilation (P < 0.001 for FBF and FVR). Bradykinin increased net glucose extraction (from -80 +/- 23 to -320 +/- 97 microg/min/100 ml at 200 ng/min bradykinin, P = 0.02), and L-NMMA (-143 +/- 50 microg/min/100 ml at 200 ng/min, P = 0.045) attenuated this effect. In contrast, L-NMMA enhanced bradykinin-stimulated t-PA release (39.9 +/- 7.0 ng/min/100 ml versus 30.0 +/- 4.2 ng/min/100 ml at 200 ng/min, P = 0.04 for L-NMMA). In gender-stratified analyses, L-NMMA significantly increased bradykinin-stimulated t-PA release in women (F = 6.7, P = 0.02) but not in men. Endogenous NO contributes to bradykinin-stimulated vasodilation and glucose uptake but attenuates the fibrinolytic response to exogenous bradykinin.

The effect of the nitric oxide donor sodium nitroprusside on glucose uptake in human primary skeletal muscle cells

Nitric oxide (NO) has been implicated as an important signaling molecule in the insulin-independent, contraction-mediated glucose uptake pathway and may represent a novel strategy for blood glucose control in patients with type 2 diabetes (T2DM). The current study sought to determine whether the NO donor, sodium nitroprusside (SNP) increases glucose uptake in primary human skeletal muscle cells (HSkMC) derived from both healthy individuals and patients with T2DM. Vastus lateralis muscle cell cultures were derived from seven males with T2DM (aged 54±2years, BMI 31.7±1.2kg/m2, fasting plasma glucose 9.52±0.80mmol/L) and eight healthy individuals (aged 46±2years, BMI 27.1±1.5kg/m2, fasting plasma glucose 4.69±0.12mmol/L). Cultures were treated with both therapeutic (0.2 and 2μM) and supratherapeutic (3, 10 and 30mM) concentrations of SNP. An additional NO donor S-nitroso-N-acetyl-d,l-penicillamine (SNAP) was also examined at a concentration of 50μM. Glucose uptake was significantly increased following both 30 and 60min incubations with the supratherapeutic SNP treatments (P=0.03) but not the therapeutic SNP doses (P=0.60) or SNAP (P=0.54). There was no difference in the response between the healthy and T2DM cell lines with any treatment or dose. The current study demonstrates that glucose uptake is elevated by supratherapeutic, but not therapeutic doses of SNP in human primary skeletal muscle cells derived from both healthy volunteers and patients with T2D. These data confirm that nitric oxide donors have potential therapeutic utility to increase glucose uptake in humans, but that SNP only achieves this in supratherapeutic doses. Further study to delineate mechanisms and the therapeutic window is warranted.

Evaluation of individual skeletal muscle activity by glucose uptake during pedaling exercise at different workloads using positron emission tomography

Skeletal muscle glucose uptake closely reflects muscle activity at exercise intensity levels <55% of maximal oxygen consumption (VO2max). Our purpose was to evaluate individual skeletal muscle activity from glucose uptake in humans during pedaling exercise at different workloads by using [18F]fluorodeoxyglucose (FDG) and positron emission tomography (PET). Twenty healthy male subjects were divided into two groups (7 exercise subjects and 13 control subjects). Exercise subjects were studied during 35 min of pedaling exercise at 40 and 55% VO2max exercise intensities. FDG was injected 10 min after the start of exercise or after 20 min of rest. PET scanning of the whole body was conducted after completion of the exercise or rest period. In exercise subjects, mean FDG uptake [standardized uptake ratio (SUR)] of the iliacus muscle and muscles of the anterior part of the thigh was significantly greater than uptake in muscles of control subjects. At 55% VO2max exercise, SURs of the iliacus muscle and thigh muscles, except for the rectus femoris, increased significantly compared with SURs at 40% VO2max exercise. Our results are the first to clarify that the iliacus muscle, as well as the muscles of the anterior thigh, is the prime muscle used during pedaling exercise. In addition, the iliacus muscle and all muscles in the thigh, except for the rectus femoris, contribute when the workload of the pedaling exercise increases from 40 to 55% VO2max.

5-Aminoimidazole-4-Carboxamide 1-β-d-Ribofuranoside Acutely Stimulates Skeletal Muscle 2-Deoxyglucose Uptake in Healthy Men

Activation of AMP-activated protein kinase (AMPK) in rodent muscle by exercise, metformin, 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR), and adiponectin increases glucose uptake. The aim of this study was to determine whether AICAR stimulates muscle glucose uptake in humans. We studied 29 healthy men (aged 26 +/- 8 years, BMI 25 +/- 4 kg/m(2) [mean +/- SD]). Rates of muscle 2-deoxyglucose (2DG) uptake were determined by measuring accumulation of total muscle 2DG (2DG and 2DG-6-phosphate) during a primed, continuous 2DG infusion. The effects of AICAR and exercise on muscle AMPK activity/phosphorylation and 2DG uptake were determined. Whole-body glucose disposal was compared before and during AICAR with the euglycemic-hyperinsulinemic clamp. Muscle 2DG uptake was linear over 9 h (R(2) = 0.88 +/- 0.09). After 3 h, 2DG uptake increased 2.1 +/- 0.8- and 4.7 +/- 1.7-fold in response to AICAR or bicycle exercise, respectively. AMPK alpha(1) and alpha(2) activity or AMPK phosphorylation was unchanged after 20 min or 3 h of AICAR, but AMPK phosphorylation significantly increased immediately and 3 h after bicycle exercise. AICAR significantly increased phosphorylation of extracellular signal-regulated kinase 1/2, but phosphorylation of beta-acetyl-CoA carboxylase, glycogen synthase, and protein kinase B or insulin receptor substrate-1 level was unchanged. Mean whole-body glucose disposal increased by 7% with AICAR from 9.3 +/- 0.6 to 10 +/- 0.6 mg x kg(-1) x min(-1) (P < 0.05). In healthy people, AICAR acutely stimulates muscle 2DG uptake with a minor effect on whole-body glucose disposal.

High intensity exercise decreases global brain glucose uptake in humans.

Physiological activation increases glucose uptake locally in the brain. However, it is not known how high intensity exercise affects regional and global brain glucose uptake. The effect of exercise intensity and exercise capacity on brain glucose uptake was directly measured using positron emission tomography (PET) and [18F]fluoro-deoxy-glucose ([18F]FDG). Fourteen healthy, right-handed men were studied after 35 min of bicycle exercise at exercise intensities corresponding to 30, 55 and 75% of on three separate days. [18F]FDG was injected 10 min after the start of the exercise. Thereafter exercise was continued for another 25 min. PET scanning of the brain was conducted after completion of the exercise. Regional glucose metabolic rate (rGMR) decreased in all measured cortical regions as exercise intensity increased. The mean decrease between the highest and lowest exercise intensity was 32% globally in the brain (38.6+/-4.6 versus 26.1+/-5.0 micromol (100 g)-1 min-1, P<0.001). Lactate availability during exercise tended to correlate negatively with the observed brain glucose uptake. In addition, the decrease in glucose uptake in the dorsal part of the anterior cingulate cortex (37% versus 20%, P<0.05 between 30% and 75% of VO2max) was significantly more pronounced in subjects with higher exercise capacity. These results demonstrate that brain glucose uptake decreases with increase in exercise intensity. Therefore substrates other than glucose, most likely lactate, are utilized by the brain in order to compensate the increased energy needed to maintain neuronal activity during high intensity exercise. Moreover, it seems that exercise training could be related to adaptive metabolic changes locally in the frontal cortical regions.

Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation

Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-alpha (TNF-alpha) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-alpha infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-alpha directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-alpha infusion increases phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-alpha negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome.

The effect of dynamic knee-extension exercise on patellar tendon and quadriceps femoris muscle glucose uptake in humans studied by positron emission tomography

Both tendon and peritendinous tissue show evidence of metabolic activity, but the effect of acute exercise on substrate turnover is unknown. We therefore examined the influence of acute exercise on glucose uptake in the patellar and quadriceps tendons during dynamic exercise in humans. Glucose uptake was measured in five healthy men in the patellar and quadriceps tendons and the quadriceps femoris muscle at rest and during dynamic knee-extension exercise (25 W) using positron emission tomography and [18F]-2-fluoro-2-deoxy-D-glucose ([18F]FDG). Glucose uptake index was calculated by dividing the tissue activity with blood activity of [18F]FDG. Exercise increased glucose uptake index by 77% in the patellar tendon (from 0.30 +/- 0.09 to 0.51 +/- 0.16, P = 0.03), by 106% in the quadriceps tendon (from 0.37 +/- 0.15 to 0.75 +/- 0.36, P = 0.02), and by 15-fold in the quadriceps femoris muscle (from 0.31 +/- 0.11 to 4.5 +/- 1.7, P = 0.005). The exercise-induced increase in the glucose uptake in neither tendon correlated with the increase in glucose uptake in the quadriceps muscle (r = -0.10, P = 0.87 for the patellar tendon and r = -0.30, P = 0.62 for the quadriceps tendon). These results show that tendon glucose uptake is increased during exercise. However, the increase in tendon glucose uptake is less pronounced than in muscle and the increases are uncorrelated. Thus tendon glucose uptake is likely to be regulated by mechanisms independently of those regulating skeletal muscle glucose uptake.

Exogenous nitric oxide increases basal leg glucose uptake in humans

This study addressed the role of blood flow and nitric oxide in leg glucose uptake. Seven subjects (5 men, 2 women) were studied during conditions of resting blood flow and increased blood flow, achieved by infusion of the nitric oxide (NO) donor sodium nitroprusside (SNP) into the femoral artery. Femoral arterial and venous blood samples were obtained and blood flow was determined by infusion of indocyanine green dye. SNP infusion significantly increased leg blood flow (769 ± 103 v 450 ± 65 mL · min−1 · leg−1, P < .001), but did not affect arterial (4.68 ± 0.13 mmol/L control, 4.63 ± 0.09 mmol/L SNP) or venous (4.60 ± 0.14 mmol/L control, 4.54 ± 0.10 mmol/L SNP) glucose concentrations. Glucose uptake was significantly (P < .01) higher during SNP infusion (65 ± 6 μmol · min−1 · leg−1) than during the basal period (34 ± 6 μmol · min−1 · leg−1), whereas lactate release was unaffected (rest, 45 ± 11 μmol · min−1 · leg−1; SNP, 42 ± 14 μmol · min−1 · leg−1). We conclude that blood flow and/or NO increase basal leg glucose uptake.

The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study.

The effect of basal insulin on global and regional brain glucose uptake and metabolism in humans was studied using 18-fluorodeoxyglucose and positron emission tomography (FDG-PET). Eight healthy male volunteers aged 49.3 +/- 5.1 years were studied twice in random order. On each occasion, they received an infusion of 0.1 mg. kg(-1). min(-1) somatostatin to suppress endogenous insulin production. In one study 0.3 mU. kg(-1). min(-1) insulin was infused to replace basal circulating insulin levels, and in the other study a saline infusion was used as control. We sought stimulatory effects of basal insulin on brain glucose metabolism particularly in regions with deficiencies in the blood-brain barrier and high density of insulin receptors. Insulin levels were 27.07 +/- 1.3 mU/l with insulin replacement and 3.51 +/- 0.4 mU/l without (P = 0.001). Mean global rate of brain glucose utilization was 0.215 +/- 0.030 mmol. kg(-1). min(-1) without insulin and 0.245 +/- 0.021 mmol. kg(-1). min(-1) with insulin (P = 0.008, an average difference of 15.3 +/- 12.5%). Regional analysis using statistical parametric mapping showed that the effect of basal insulin was significantly less in the cerebellum (Z = 5.53, corrected P = 0.031). We conclude that basal insulin has a role in regulating global brain glucose uptake in humans, mostly marked in cortical areas.

BLOOD FLOW EFFECTS ON GLUCOSE UPTAKE FOLLOWING RESISTANCE EXERCISE

Although the effects of blood flow on insulin-stimulated glucose uptake have been extensively investigated, the relative importance of blood flow per se on glucose uptake remains unclear. The purpose of this study was to determine if elevated muscle blood flow following exercise affects muscle glucose uptake. Six subjects (three males, three females) were studied before and after a strenuous bout of lower-body resistance exercise. Following exercise, blood flow was selectively reduced in one leg to approximately the resting rate by inflation of an arterial balloon catheter. Femoral artery blood flow was determined using doppler ultrasound and femoral arterial and venous blood glucose concentrations were measured with a glucose analyzer. Post-exercise femoral artery blood flow was significantly reduced by balloon inflation (855 ± 93 ml/min in the control leg, 440 ± 106 ml/min in the decreased flow leg). Reduction of post-exercise blood flow resulted in a significant (p < 0.05) reduction in glucose uptake (0.196 ± 0.043 mmolòmin-1òleg-1 vs. 0.109 ± 0.038 mmolòmin-1òleg-1) when only femoral flow was considered. When collateral flow was considered, a trend toward a reduction in glucose uptake persisted (0.154 ± 0.045 mmolòmin-1òleg-1; P = 0.10). We conclude that the rate of blood flow is a determinant of muscle glucose uptake in humans following resistance exercise.

Effect of glucagon-like peptide-1(7-36)-amide on initial splanchnic glucose uptake and insulin action in humans with type 1 diabetes.

In vitro studies indicate that glucagon-like peptide-1(7-36)-amide (GLP-1) can enhance hepatic glucose uptake. To determine whether GLP-1 increases splanchnic glucose uptake in humans, we studied seven subjects with type 1 diabetes on two occasions. On both occasions, glucose was maintained at approximately 5.5 mmo/l during the night using a variable insulin infusion. On the morning of the study, a somatostatin, glucagon, and growth hormone infusion was started to maintain basal hormone levels. Glucose (containing [3H]glucose) was infused via an intraduodenal tube at a rate of 20 micromol.kg(-1).min(-1). Insulin concentrations were increased to approximately 500 pmol/l while glucose was clamped at approximately 8.8 mmol/l for the next 4 h by means of a variable intravenous glucose infusion labeled with [6,6-2H2]glucose. Surprisingly, the systemic appearance of intraduodenally infused glucose was higher (P = 0.01) during GLP-1 infusion than saline infusion, indicating a lower (P < 0.05) rate of initial splanchnic glucose uptake (1.4 +/- 1.5 vs. 4.8 +/- 0.8 micromol.kg(-1).min(-1)). On the other hand, flux through the hepatic uridine-diphosphate- glucose pool did not differ between study days (14.2 +/- 5.5 vs. 13.0 +/- 4.2 micromol.kg(-1).min(-1)), implying equivalent rates of glycogen synthesis. GLP-1 also impaired (P < 0.05) insulin-induced suppression of endogenous glucose production (6.9 +/- 2.9 vs. 1.3 +/- 1.4 micromol.kg(-1).min(-1)), but caused a time-dependent increase (P < 0.01) in glucose disappearance (93.7 +/- 10.0 vs. 69.3 +/- 6.3 micromol.kg(-1).min(-1); P < 0.01) that was evident only during the final hour of study. We conclude that in the presence of hyperglycemia, hyperinsulinemia, and enterally delivered glucose, GLP-1 increases total body but not splanchnic glucose uptake in humans with type 1 diabetes.

Dose-Dependent Effects of Glyburide on Insulin Secretion and Glucose Uptake in Humans

To examine the relationship between plasma glyburide concentrations (0, 50, 100, 200, 400, and 800 nM) and the insulin response and glucose metabolism during euglycemic (4.6 +/- 0.1 mM) and hyperglycemic (11.6 +/- 0.2 mM) conditions. Nine healthy subjects participated in the study. Steady-state plasma glyburide concentrations were achieved by primed continuous intravenous infusion of glyburide. During both euglycemia and hyperglycemia, glyburide enhanced insulin secretion and glucose disposal only to drug levels of 100-200 nM corresponding to an oral dose less than or equal to 10 mg. The data suggest that glyburide (and probably other sulfonylureas), operates within a narrow range of plasma concentrations (50-200 nM), which can be achieved with very low doses of the drug. It remains to be shown whether the threshold of maximal effect also in clinical practice is achieved with lower sulfonylurea doses than that currently used.