scholarly journals Portal glucose infusion-glucose clamp measures hepatic influence on postprandial systemic glucose appearance as well as whole body glucose disposal

2010 ◽  
Vol 298 (2) ◽  
pp. E346-E353 ◽  
Author(s):  
Dan Zheng ◽  
Viorica Ionut ◽  
Vahe Mooradian ◽  
Darko Stefanovski ◽  
Richard N. Bergman
Keyword(s):  
Steady State ◽  
Portal Vein ◽  
Glucose Production ◽  
Glucose Clamp ◽  
Glucose Infusion ◽  
Whole Body ◽  
Glucose Disposal ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
Glucose Supply

The full impact of the liver, through both glucose production and uptake, on systemic glucose appearance cannot be readily studied in a classical glucose clamp because hepatic glucose metabolism is regulated not only by portal insulin and glucose levels but also portal glucose delivery (the portal signal). In the present study, we modified the classical glucose clamp by giving exogenous glucose through portal vein, the “portal glucose infusion (PoG)-glucose clamp”, to determine the net hepatic effect on postprandial systemic glucose supply along with the measurement of whole body glucose disposal. By comparing systemic rate of glucose appearance (Ra) with portal glucose infusion rate (PoGinf), we quantified “net hepatic glucose addition (NHGA)” in the place of endogenous glucose production determined in a regular clamp. When PoG-glucose clamps ( n = 6) were performed in dogs at basal insulinemia and hyperglycemia (∼150 mg/dl, portal and systemic), we measured consistently higher Ra than PoGinf (4.2 ± 0.6 vs. 2.9 ± 0.6 mg·kg−1·min−1 at steady state, P < 0.001) and thus positive NHGA at 1.3 ± 0.1 mg·kg−1·min−1, identifying net hepatic addition of glucose to portal exogenous glucose. In contrast, when PoG-glucose clamps ( n = 6) were performed at hyperinsulinemia (∼250 pmol/l) and systemic euglycemia (portal hyperglycemia due to portal glucose infusion), we measured consistently lower Ra than PoGinf (13.1 ± 2.4 vs. 14.3 ± 2.4 mg·kg−1·min−1, P < 0.001), and therefore negative NHGA at −1.1 ± 0.1 mg·kg−1·min−1, identifying a switch of the liver from net production to net uptake of portal exogenous glucose. Steady-state whole body glucose disposal was 4.1 ± 0.5 and 13.0 ± 2.4 mg·kg−1·min−1, respectively, determined as in a classical glucose clamp. We conclude that the PoG-glucose clamp, simulating postprandial glucose entry and metabolism, enables simultaneous assessment of the net hepatic effect on postprandial systemic glucose supply as well as whole body glucose disposal in various animal models (rodents, dogs, and pigs) with established portal vein catheterization.

Underestimation of hepatic glucose production by radioactive and stable tracers

1987 ◽  
Vol 252 (5) ◽  
pp. E606-E615 ◽  
Author(s):  
G. M. Argoud ◽  
D. S. Schade ◽  
R. P. Eaton
Keyword(s):  
Infusion Rate ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Glucose Infusion Rate ◽  
Glucose Disposal ◽  
Methodological Error ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
The Difference

Although negative hepatic glucose production rates are physiologically impossible, they have been observed when hepatic glucose production is measured with the tracer-dilution technique during the hyperinsulinemic, euglycemic glucose clamp. Because hepatic glucose production is determined from the difference between tracer-derived glucose disposal and the known exogenous glucose infusion rate, the negative values for hepatic glucose production must result from an underestimation of glucose disposal by the tracer technique. In the current investigation, tracer-derived glucose disposal was measured in 25 subjects undergoing hyperinsulinemic, euglycemic clamps. Glucose disposal was measured with both radioactive and stable isotopes that utilize different methodologies, to determine whether discriminant metabolism of the isotopes versus methodological error leads to underestimation of tracer-derived glucose disposal. Both the radioactive and stable methodologies underestimated the exogenous glucose infusion rate during the hyperinsulinemic euglycemic clamp by 27 and 17%, respectively. Mean hepatic glucose production was -2.1 +/- 0.2 and -1.3 +/- 0.2 mg X kg-1 X min-1 as determined by the radioactive and stable isotope methodologies, respectively. Methodological error was an unlikely cause of this underestimation because it occurred with two different methodologies. The most likely explanation for underestimated rates of glucose disposal determined by the two types of isotope methodologies is discrepant metabolism of glucose tracers in comparison with unlabeled glucose.

Sensitivity of exercise-induced increase in hepatic glucose production to glucose supply and demand

1994 ◽  
Vol 267 (3) ◽  
pp. E411-E421 ◽  
Author(s):  
C. M. Berger ◽  
P. J. Sharis ◽  
D. P. Bracy ◽  
D. B. Lacy ◽  
D. H. Wasserman
Keyword(s):  
Hepatic Glucose Production ◽  
Supply And Demand ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Exogenous Glucose ◽  
Period 2 ◽  
Significant Difference ◽  
Exercise Induced ◽  
Glucose Supply ◽  
Arterial Glucose

It was hypothesized that the exercise-induced changes in glucoregulatory hormones and glucose production (Ra) occur as a result of a small deficit in glucose availability. To test this, 18-h fasted dogs performed 150 min of treadmill exercise with either the liver as the sole source of glucose (controls, n = 5) or with glucose infused from 0 to 50 min (period 1) and from 100 to 150 min (period 3) at rates designed to track the glucose utilization (Rd) response (ExoGlc, n = 5). The liver alone supplied glucose from 50 to 100 min (period 2). Isotopic and arteriovenous methods were used to assess Ra, Rd, and gluconeogenesis (GNG). Variable [3H]glucose infusion and frequent sampling were used to facilitate Ra measurements. Arterial glucose declined by -3.1 +/- 1.4, -4.3 +/- 2.9, and -6.4 +/- 3.7 mg/dl in periods 1-3 in controls (changes are mean values during each of the 50-min periods; P < 0.05). In ExoGlc, arterial glucose did not deviate from basal in periods 1 (+0.1 +/- 1.8 mg/dl) and 3 (+1.5 +/- 4.5 mg/dl) but fell from basal (P < 0.05) by the same amount as controls in period 2 (-5.7 +/- 2.1 mg/dl). Matching the Rd response with exogenous glucose led to increases in arterial and portal vein plasma insulin levels (P < 0.05) but did not affect glucagon, norepinephrine, epinephrine, and cortisol levels. Ra was elevated by 3.1 +/- 0.5, 4.0 +/- 1.1, and 4.7 +/- 1.1 mg.kg-1.min-1 in periods 1-3 in controls (P < 0.05). In ExoGlc, Ra rose by 0.0 +/- 0.4, 4.1 +/- 1.4 (P < 0.05), and 0.4 +/- 0.7 mg.kg-1.min-1, respectively, in periods 1-3. The rise in Ra was reduced in periods 1 and 3 of ExoGlc compared with controls (P < 0.02). GNG rose to approximately 250% basal in controls and did not respond with any significant difference in ExoGlc. In summary, the exercise-induced increases in counterregulatory hormones and GNG are present even when a deficit in glucose supply is eliminated by an exogenous glucose infusion. In contrast, the fall in insulin and the rise in hepatic glycogenolysis are greatly attenuated. The regulatory components affected by exogenous glucose predominate at the liver as deviations in plasma glucose of approximately 4% correspond to approximately 60% changes in Ra.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of acute running exercise on whole body insulin action in obese male SHHF/Mcc-facp rats

1994 ◽  
Vol 77 (2) ◽  
pp. 534-541 ◽  
Author(s):  
J. Gao ◽  
W. M. Sherman ◽  
S. A. McCune ◽  
K. Osei
Keyword(s):  
Heart Failure ◽  
Insulin Sensitivity ◽  
Acute Exercise ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Insulin Responsiveness ◽  
Obese Male

This study utilized the obese male spontaneously hypertensive heart failure rat (SHHF/Mcc-facp), which has metabolic features very similar to human non-insulin-dependent diabetes mellitus. The purpose of this study was to assess the insulin sensitivity and responsiveness of whole body glucose disposal and insulin suppressability of hepatic glucose production with use of the euglycemic-hyperinsulinemic clamp procedure in 12- to 15-wk-old SHHF/Mcc-facp rats at rest (OS) and 2.5 h after a single session of acute exercise (OE). Lean male SHHF/Mcc-facp rats were sedentary (LS) control animals. At least three clamps producing different insulin-stimulated responses were performed on each animal in a randomized order. At this age the obese animals are normotensive and have not developed congestive heart failure. Compared with LS, OS were significantly hyperglycemic and hyperinsulinemic and insulin sensitivity and responsiveness of whole body glucose uptake and insulin suppressability of hepatic glucose production were significantly decreased. Compared with LS and OS, acute exercise significantly decreased resting plasma glucose but did not alter plasma insulin. Compared with OS, acute exercise significantly increased the insulin responsiveness of whole body glucose disposal but did not affect the sensitivity of whole body glucose disposal or insulin suppressability of hepatic glucose production. Compared with LS, however, acute exercise did not “normalize” the insulin responsiveness of whole body glucose disposal. Thus a single acute exercise session improves but does not normalize whole body insulin resistance in the SHHF/Mcc-facp rat.

Effects of physiological hyperinsulinemia on the intracellular metabolic partition of plasma glucose

1993 ◽  
Vol 265 (6) ◽  
pp. E943-E953 ◽  
Author(s):  
R. C. Bonadonna ◽  
S. del Prato ◽  
E. Bonora ◽  
G. Gulli ◽  
A. Solini ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Healthy Subjects ◽  
Glucose Oxidation ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glucose Infusion ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Glucose Recycling

Methodology for assessing the glycolytic and oxidative fluxes from plasma glucose, by measuring 3H2O and 14CO2 rates of production during [3-3H]- and [U-14C]glucose infusion, was tested in healthy subjects. In study 1, during staircase 3H2O infusion in six subjects, calculated rates of 3H2O appearance agreed closely with 3H2O infusion rates. In study 2, when [2-3H]glucose and NaH14CO3 were infused in four subjects in the basal state and during a 4-h euglycemic insulin (approximately 70 microU/ml) clamp, accurate estimates of the rates of [2-3H]glucose detritiation were obtained (94-97% of the expected values), and the recovery factor of NaH14CO3 did not change during hyperinsulinemia. In study 3, 11 subjects underwent a 4-h euglycemic insulin (approximately 70 microU/ml) clamp with [3-3H]- and [U-14C]glucose infusion and measurement of gaseous exchanges by indirect calorimetry to estimate the rates of total glycolysis, glycogen synthesis, glucose oxidation, nonoxidative glycolysis, hepatic glucose production, glucose recycling, and glucose conversion to fat. Hyperinsulinemia stimulated glycogen synthesis above baseline more than glycolysis [increment of 4.78 +/- 0.37 vs. 2.0 +/- 0.17 mg.min-1 x kg-1 of lean body mass (LBM), respectively, P < 0.01] and incompletely suppressed (approximately 87%) hepatic glucose production. The major component of nonoxidative glycolysis shifted from glucose recycling in the postabsorptive state (approximately 57% of nonoxidative glycolysis) to glucose conversion to fat during hyperinsulinemia (approximately 59% of nonoxidative glycolysis). Lipid oxidation during the insulin clamp was negatively correlated with both isotopic glucose oxidation (r = -0.822, P < 0.002) and glycolysis (r = -0.582, P < 0.07). In conclusion, in healthy subjects, glycogen synthesis plays a greater role than glycolysis and glucose oxidation in determining insulin-mediated glucose disposal. Part of insulin-mediated increase in glycolysis/oxidation might be secondary to the relief of the competition between fat and glucose for oxidation.

Metabolic and thermogenic effects of lactate infusion in humans

1993 ◽  
Vol 265 (3) ◽  
pp. E504-E512 ◽  
Author(s):  
E. Ferrannini ◽  
A. Natali ◽  
L. S. Brandi ◽  
R. Bonadonna ◽  
S. V. De Kreutzemberg ◽  
...  
Keyword(s):  
Glucose Utilization ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Major Change ◽  
Sodium Lactate ◽  
Whole Body ◽  
Glucose Disposal ◽  
Experimental Conditions ◽  
Hepatic Glucose ◽  
Lactate Infusion

Lactate has been suggested to interfere with intermediary metabolism by restricting both lipolysis and glucose utilization. To test this hypothesis, in paired studies in healthy volunteers, sodium lactate (25 mumol.min-1 x kg-1) or saline was infused for 1 h in the fasting state and during 2 h of euglycemic (4.75 mM) hyperinsulinemia (approximately 400 pmol/l). Hyperlactatemia (approximately 2 mM) had no inhibitory effect on fasting free fatty acid or glycerol levels nor did it alter the suppressive action of insulin on these substrates. Likewise, sodium lactate infusion did not influence hepatic glucose production ([3-3H]glucose technique) or its suppression by insulin. During the clamp, hyperlactatemia was associated with a small increase in whole body glucose disposal (34.9 +/- 4.1 vs. 30.3 +/- 3.7 mumol.min-1 x kg-1, P < 0.05) with no major change in the pattern of substrate (carbohydrate vs. lipid) oxidation. By simultaneously measuring arteriovenous gradients across the deep tissues of the forearm (forearm technique), it was found that hyperlactatemia did not impede insulin-mediated glucose uptake; furthermore, it could be estimated that muscle tissues were responsible for the disposal of roughly one-fifth of the lactate load. Whole body energy expenditure was stimulated above the level achieved with hyperinsulinemia when lactate was also infused. Thus, under the present experimental conditions, physiological hyperlactatemia did not interfere with lipolysis, hepatic glucose production, or whole body or forearm muscle glucose utilization, or with insulin action on these processes, and was accompanied by a strong thermogenic effect.

Role of a negative arterial-portal venous glucose gradient in the postexercise state

1999 ◽  
Vol 277 (6) ◽  
pp. E1038-E1045 ◽  
Author(s):  
Pietro Galassetti ◽  
Yoshiharu Koyama ◽  
Robert H. Coker ◽  
Drury B. Lacy ◽  
Alan D. Cherrington ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Vena Cava ◽  
Experimental Period ◽  
Glucose Infusion ◽  
Whole Body ◽  
Glucose Disposal ◽  
Prior Exercise ◽  
Basal Period ◽  
Hepatic Glucose ◽  
Venous Glucose

Prior exercise stimulates muscle and liver glucose uptake. A negative arterial-portal venous glucose gradient (a-pv grad) stimulates resting net hepatic glucose uptake (NHGU) but reduces muscle glucose uptake. This study investigates the effects of a negative a-pv grad during glucose administration after exercise in dogs. Experimental protocol: exercise (−180 to −30 min), transition (−30 to −20 min), basal period (−20 to 0 min), and experimental period (0 to 100 min). In the experimental period, 130 mg/dl arterial hyperglycemia was induced via vena cava (Pe, n = 6) or portal vein (Po, n = 6) glucose infusions. Insulin and glucagon were replaced at fourfold basal and basal rates. During the experimental period, the a-pv grad (mg/dl) was 3 ± 1 in Pe and −10 ± 2 in Po. Arterial insulin and glucagon were similar in the two groups. In Pe, net hepatic glucose balance (mg ⋅ kg−1⋅ min−1, negative = uptake) was 4.2 ± 0.3 (basal period) and −1.2 ± 0.3 (glucose infusion); in Po it was 4.1 ± 0.5 and −3.2 ± 0.4, respectively ( P < 0.005 vs. Pe). Total glucose infusion (mg ⋅ kg−1⋅ min−1) was 11 ± 1 in Po and 8 ± 1 in Pe ( P < 0.05). Net hindlimb and whole body nonhepatic glucose uptakes were similar. Conclusions: the portal signal independently stimulates NHGU after exercise. Conversely, prior exercise eliminates the inhibitory effect of the portal signal on glucose uptake by nonhepatic tissues. The portal signal therefore increases whole body glucose disposal after exercise by an amount equal to the increase in NHGU.

scholarly journals Simple modeling allows prediction of steady-state glucose disposal rate from early data in hyperinsulinemic glucose clamps

2010 ◽  
Vol 298 (2) ◽  
pp. E229-E236 ◽  
Author(s):  
Pooja Singal ◽  
Ranganath Muniyappa ◽  
Robin Chisholm ◽  
Gail Hall ◽  
Hui Chen ◽  
...  
Keyword(s):  
Steady State ◽  
Glucose Clamp ◽  
Glucose Infusion ◽  
Glucose Disposal ◽  
Calibration Model ◽  
Data Sets ◽  
Full Data ◽  
Validation Data ◽  
Data Set ◽  
Nonlinear Fitting

After a constant insulin infusion is initiated, determination of steady-state conditions for glucose infusion rates (GIR) typically requires ≥3 h. The glucose infusion follows a simple time-dependent rise, reaching a plateau at steady state. We hypothesized that nonlinear fitting of abbreviated data sets consisting of only the early portion of the clamp study can provide accurate estimates of steady-state GIR. Data sets from two independent laboratories were used to develop and validate this approach. Accuracy of the predicted steady-state GDR was assessed using regression analysis and Altman-Bland plots, and precision was compared by applying a calibration model. In the development data set ( n = 88 glucose clamp studies), fitting the full data set with a simple monoexponential model predicted reference GDR values with good accuracy (difference between the 2 methods −0.37 mg·kg−1·min−1) and precision [root mean square error (RMSE) = 1.11], validating the modeling procedure. Fitting data from the first 180 or 120 min predicted final GDRs with comparable accuracy but with progressively reduced precision [fitGDR-180 RMSE = 1.27 ( P = NS vs. fitGDR-full); fitGDR-120 RMSE = 1.56 ( P < 0.001)]. Similar results were obtained with the validation data set ( n = 183 glucose clamp studies), confirming the generalizability of this approach. The modeling approach also derives kinetic parameters that are not available from standard approaches to clamp data analysis. We conclude that fitting a monoexponential curve to abbreviated clamp data produces steady-state GDR values that accurately predict the GDR values obtained from the full data sets, albeit with reduced precision. This approach may help reduce the resources required for undertaking clamp studies.

scholarly journals Chronic estradiol and progesterone treatment in conscious dogs: effects on insulin sensitivity and response to hypoglycemia

2005 ◽  
Vol 289 (4) ◽  
pp. R1064-R1073 ◽  
Author(s):  
Marcia R. Batista ◽  
Marta S. Smith ◽  
Wanda L. Snead ◽  
Cynthia C. Connolly ◽  
D. Brooks Lacy ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Serum Levels ◽  
Glucose Infusion ◽  
Whole Body ◽  
Glucose Disposal ◽  
Skeletal Muscle Insulin Resistance ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Hepatic Glucose Uptake ◽  
Arteriovenous Difference

We evaluated the effect of chronic (3 wk) subcutaneous treatment with progesterone and estradiol (PE; producing serum levels observed in the 3rd trimester of pregnancy) or placebo (C) on hepatic and whole body insulin sensitivity and response to hypoglycemia in conscious, overnight-fasted nonpregnant female dogs, using tracer and arteriovenous difference techniques. Insulin was infused peripherally for 3 h at 1.8 mU·kg−1·min−1. Glucose was allowed to fall to 3 mM (Hypo) or maintained at 6 mM (Eugly) by peripheral glucose infusion. Insulin concentrations were significantly higher in Eugly-PE ( n = 7) and Hypo-PE ( n = 7) than in Eugly-C ( n = 6) and Hypo-C groups ( n = 7), but there were no significant differences in hepatic insulin extraction. Concentrations of glucagon, cortisol, epinephrine, and norepinephrine did not differ significantly between Eugly groups or between Hypo groups. Whole body glucose disposal, adjusted for the differences in insulin between groups, was 35% higher in Eugly-C vs. Eugly-PE groups ( P < 0.05). Eugly-C and Eugly-PE groups exhibited similar rates of net hepatic glucose uptake, but the rate of glucose appearance was greater in Eugly-PE in the last hour ( P < 0.05). Net hepatic glucose output was greater ( P < 0.05) in Hypo-PE than in Hypo-C groups, and the glucose infusion rate required to maintain equivalent hypoglycemia was less ( P < 0.05). The rate of gluconeogenic flux did not differ between Hypo groups. Chronic progesterone and estradiol exposure caused whole body (primarily skeletal muscle) insulin resistance and enhanced the liver's response to hypoglycemia without altering counterregulatory hormone concentrations.

Effect of a selective rise in hepatic artery insulin on hepatic glucose production in the conscious dog

1999 ◽  
Vol 276 (4) ◽  
pp. E806-E813
Author(s):  
Dana K. Sindelar ◽  
Kayano Igawa ◽  
Chang A. Chu ◽  
Jim H. Balcom ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Portal Vein ◽  
Hepatic Artery ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Control Period ◽  
Glucose Production ◽  
Insulin Level ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Selective Increase

In the present study we compared the hepatic effects of a selective increase in hepatic sinusoidal insulin brought about by insulin infusion into the hepatic artery with those resulting from insulin infusion into the portal vein. A pancreatic clamp was used to control the endocrine pancreas in conscious overnight-fasted dogs. In the control period, insulin was infused via peripheral vein and the portal vein. After the 40-min basal period, there was a 180-min test period during which the peripheral insulin infusion was stopped and an additional 1.2 pmol ⋅ kg−1⋅ min−1of insulin was infused into the hepatic artery (HART, n = 5) or the portal vein (PORT, n = 5, data published previously). In the HART group, the calculated hepatic sinusoidal insulin level increased from 99 ± 20 (basal) to 165 ± 21 pmol/l (last 30 min). The calculated hepatic artery insulin concentration rose from 50 ± 8 (basal) to 289 ± 19 pmol/l (last 30 min). However, the overall arterial (50 ± 8 pmol/l) and portal vein insulin levels (118 ± 24 pmol/l) did not change over the course of the experiment. In the PORT group, the calculated hepatic sinusoidal insulin level increased from 94 ± 30 (basal) to 156 ± 33 pmol/l (last 30 min). The portal insulin rose from 108 ± 42 (basal) to 192 ± 42 pmol/l (last 30 min), whereas the overall arterial insulin (54 ± 6 pmol/l) was unaltered during the study. In both groups hepatic sinusoidal glucagon levels remained unchanged, and euglycemia was maintained by peripheral glucose infusion. In the HART group, net hepatic glucose output (NHGO) was suppressed from 9.6 ± 2.1 μmol ⋅ kg−1⋅ min−1(basal) to 4.6 ± 1.0 μmol ⋅ kg−1⋅ min−1(15 min) and eventually fell to 3.5 ± 0.8 μmol ⋅ kg−1⋅ min−1(last 30 min, P < 0.05). In the PORT group, NHGO dropped quickly ( P < 0.05) from 10.0 ± 0.9 (basal) to 7.8 ± 1.6 (15 min) and eventually reached 3.1 ± 1.1 μmol ⋅ kg−1⋅ min−1(last 30 min). Thus NHGO decreases in response to a selective increase in hepatic sinusoidal insulin, regardless of whether it comes about because of hyperinsulinemia in the hepatic artery or portal vein.

Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase

1993 ◽  
Vol 264 (1) ◽  
pp. E1-E10 ◽  
Author(s):  
L. Rossetti ◽  
S. Farrace ◽  
S. B. Choi ◽  
A. Giaccari ◽  
L. Sloan ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glycogen Synthase ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Plasma Concentrations ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Hepatic Glucose ◽  
Intracellular Glucose

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

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