Methods for assessment of the rate of onset and offset of insulin action during nonsteady state in humans

1993 ◽  
Vol 264 (4) ◽  
pp. E548-E560 ◽  
Author(s):  
P. C. Butler ◽  
A. Caumo ◽  
A. Zerman ◽  
P. C. O'Brien ◽  
C. Cobelli ◽  
...  
Keyword(s):  
Steady State ◽  
Insulin Action ◽  
Specific Activity ◽  
Glucose Turnover ◽  
Complete Suppression ◽  
Glucose Release ◽  
Hepatic Glucose ◽  
Nonsteady State ◽  
Hepatic Glucose Release ◽  
State Error

Measurement of glucose turnover under non-steady-state conditions has proven problematic. When the mass of the glucose pool is not changing (i.e., glucose concentrations are constant) non-steady-state error can be minimized if all glucose entering the circulation has the same specific activity as plasma [radioactive infused glucose (hot-GINF) method]. Alternatively, a second tracer can be used to measure the effective volume of glucose [variable-pV method of Issekutz (T. Issekutz, R. Issekutz, and D. Elahi. (Can. J. Physiol. 52:215-224, 1974)]. To determine whether these techniques provide concordant assessments of insulin action under non-steady-state conditions, glucose turnover was measured in six subjects. After initiation of insulin (0.6 mU.kg-1 x min-1), both methods indicated similar rates of suppression of hepatic glucose release, which was complete by approximately 100-120 min. In contrast, the traditional fixed-pV method of Steele (R. Steele, J. Wall, R. DeBodo, and N. Altszuler. Am. J. Physiol. 187:15-24 1956) underestimated turnover (P < 0.01) resulting in apparent complete suppression of glucose release within approximately 40 min (P < 0.01 vs. other methods). The hot-GINF and variable-pV methods also yielded similar estimates of turnover after discontinuation of insulin. Both indicated that resumption of hepatic glucose release was slower (P < 0.01) and fall of glucose uptake faster (P < 0.01) than suggested by the fixed-pV method. Thus both the hot-GINF and variable-pV methods avoid non-steady-state error introduced by the fixed-pV method and provide concordant assessments of the rate of onset and offset of insulin action.

Hepatic and extrahepatic insulin action in humans: measurement in the absence of non-steady-state error

1993 ◽  
Vol 264 (4) ◽  
pp. E561-E566 ◽  
Author(s):  
H. Katz ◽  
P. Butler ◽  
M. Homan ◽  
A. Zerman ◽  
A. Caumo ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Insulin Action ◽  
Insulin Dose ◽  
Glucose Turnover ◽  
Dilution Technique ◽  
Response Curves ◽  
Glucose Release ◽  
Hepatic Glucose ◽  
Nonsteady State ◽  
Hepatic Glucose Release

The isotope dilution technique has been extensively used to assess insulin action in humans. To determine if nonsteady state (NSS) has led to erroneous estimates of hepatic and extrahepatic insulin sensitivity, we measured glucose turnover in healthy subjects during infusion of insulin at rates of 0.25, 0.6, and 2.0 mU.kg-1.min-1. Turnover was calculated using Steele's traditional NSS equations [fixed-effective volume (pV) method] as well as with methods [radioactive infused glucose (hot-GINF) or variable pV] designed to minimize NSS error. In contrast to the fixed-pV method, both the hot-GINF and variable-pV methods indicated that several hours were required for suppression of hepatic glucose release at all insulin concentrations and that small increases in plasma insulin (approximately 100 pmol/l) had comparable effects on glucose disappearance and hepatic glucose release. Nevertheless, despite these differences, when turnover during the final hour of the insulin infusions was plotted vs. the prevailing insulin concentration, all three methods yielded similar insulin dose-response curves for suppression of hepatic glucose release. Thus despite previous errors in measurement of glucose turnover, the widely accepted belief that the human liver is exquisitely sensitive to small changes in insulin is correct.

Underestimation of glucose turnover corrected with high-performance liquid chromatography purification of [6-3H]glucose

1990 ◽  
Vol 258 (1) ◽  
pp. E228-E233
Author(s):  
W. F. Schwenk ◽  
P. C. Butler ◽  
M. W. Haymond ◽  
R. A. Rizza
Keyword(s):  
High Performance Liquid Chromatography ◽  
Liquid Chromatography ◽  
Infusion Rate ◽  
High Performance ◽  
Glucose Infusion Rate ◽  
Glucose Turnover ◽  
Glucose Release ◽  
Hepatic Glucose ◽  
Mean Glucose ◽  
Hepatic Glucose Release

We have recently reported that during infusion of commercially available [6-3H]glucose, a radioactive nonglucose contaminant may accumulate in plasma causing errors in the measurement of glucose turnover. To determine whether purification of this tracer by HPLC (high-performance liquid chromatography) before infusion would eliminate the contaminant in plasma and remove the underestimation of glucose turnover reported during hyperinsulinemia, four normal subjects each underwent two 5-h euglycemic clamps during infusion of insulin (1 mU.kg-1.min-1). Glucose turnover was measured with either commercially available [6-3H]glucose or with HPLC-purified [6-3H]glucose. HPLC analysis of samples from the clamps done with commercially available [6-3H]glucose showed that 9.7% of the infused tracer and 26% of the "plasma glucose 3H radioactivity" were contaminants. In contrast, no contaminant was observed in the plasma during infusion of HPLC-purified [6-3H]glucose. During the last hour of the clamp, mean glucose turnover using commercially available [6-3H]glucose was less (P less than 0.01) than the mean glucose infusion rate (7.6 +/- 0.3 vs. 10.5 +/- 0.3 mg.kg-1.min-1) yielding apparent "negative" (P less than 0.001) hepatic glucose release. In contrast, when HPLC-purified [6-3H]glucose was employed, glucose turnover equaled the glucose infusion rate (10.4 +/- 0.9 vs. 10.2 +/- 0.9 mg.kg-1.min-1) and hepatic glucose release was no longer negative. We conclude that removal of a tritiated nonglucose contaminant in [6-3H]glucose by HPLC yields correct estimations of glucose turnover at steady state.

Role of glucose in corneal metabolism

1985 ◽  
Vol 249 (5) ◽  
pp. C409-C416 ◽  
Author(s):  
R. S. Thies ◽  
L. J. Mandel
Keyword(s):  
Oxygen Consumption ◽  
Steady State ◽  
Specific Activity ◽  
Krebs Cycle ◽  
Lactate Production ◽  
Minor Component ◽  
Acid Oxidation ◽  
Endogenous Fatty Acid ◽  
Nonsteady State ◽  
A Minor

Glucose catabolism by glycolysis and the Krebs cycle was examined in the isolated rabbit cornea incubated with [6-14C]glucose. The production of [14C]lactate and 14CO2 from this substrate provided minimal values for the fluxes through these pathways since the tissue was in metabolic steady state but not isotopic steady state during the 40-min incubation. The specific activity of lactate under these conditions was one-third of that for [6-14C]glucose, and label dilution by exchange with unlabeled alanine was minimal, suggesting that glycogen degradation was primarily responsible for this dilution of label in the Embden-Meyerhof pathway. In addition, considerable label accumulation was found in glutamate and aspartate. Calculations revealed that these endogenous amino acid pools were not isotopically equilibrated after the incubation period, suggesting that they were responsible for the isotopic nonsteady state by exchange dilution through transaminase reactions with labeled intermediates. An estimate of glucose oxidation by the Krebs cycle, which was corrected for label dilution by exchange, indicated that glucose could account for most of the measured corneal oxygen consumption that was coupled to oxidative phosphorylation. A minor component of this respiration could not be accounted for by glucose or glycogen oxidation. Additional experiments suggested that endogenous fatty acid oxidation was probably also active under these conditions. Finally, reciprocal changes in plasma membrane Na+-K+-ATPase activity induced by ouabain and nystatin were found to concomitantly alter oxygen consumption rates and [14C]lactate production from [6-14C]glucose. These results demonstrated the capacity for regulating glycolysis and the Krebs cycle in response to changing energy demands in the cornea.

scholarly journals Effects of Adenine and Guanine on Hepatic Glucose Release and on the Action of Insulin on the Liver

Nature ◽  
1964 ◽  
Vol 203 (4950) ◽  
pp. 1186-1186 ◽  
Author(s):  
A. KALDOR ◽  
Z. EL BAZ RIHAN ◽  
T. R. NICHOLS ◽  
W. J. H. BUTTERFIELD
Keyword(s):  
Glucose Release ◽  
Hepatic Glucose ◽  
Hepatic Glucose Release

Mechanism of growth hormone-induced postprandial carbohydrate intolerance in humans

1991 ◽  
Vol 260 (4) ◽  
pp. E513-E520 ◽  
Author(s):  
P. Butler ◽  
E. Kryshak ◽  
R. Rizza
Keyword(s):  
Carbon Dioxide ◽  
Growth Hormone ◽  
Glucose Uptake ◽  
Ketone Bodies ◽  
Plasma Concentrations ◽  
Substrate Uptake ◽  
Glucose Release ◽  
Hepatic Glucose ◽  
Hepatic Glucose Release ◽  
Carbohydrate Intolerance

Growth hormone excess can cause postprandial carbohydrate intolerance. To determine the contribution of splanchnic and extrasplanchnic tissues to this process, subjects were fed an isotopically labeled mixed meal after either a 12-h infusion of saline or growth hormone (4 micrograms.kg-1.h-1 [corrected]). Growth hormone infusion resulted in higher glucose and insulin concentrations both before and after meal ingestion. Despite growth hormone-induced hyperglycemia and hyperinsulinemia, postprandial hepatic glucose release and carbon dioxide incorporation into glucose (a qualitative estimate of gluconeogenesis) were similar to those present during saline, suggesting altered hepatic regulation. This was confirmed when glucose was infused in the absence of growth hormone to achieve glucose (and insulin) concentrations comparable to those present during growth hormone infusion. Although growth hormone excess did not alter splanchnic uptake of ingested glucose, it resulted in a fivefold increase in postprandial hepatic glucose release (578 +/- 31 vs. 117 +/- 10 mg.kg-16 h-1, P less than 0.01), less suppression of carbon dioxide incorporation into glucose (-13 +/- 9 vs. -53 +/- 12 mg.kg-1. 6-h-1, P less than 0.01), and lower glucose uptake (1,130 +/- 59 vs. 1,850 +/- 150 mg.kg-1.6 h-1, P less than 0.01). The decrease in postprandial glucose uptake did not appear to be mediated by a change in substrate uptake since postprandial plasma concentrations and forearm balance of lactate, free fatty acids, and ketone bodies did not differ in the presence and absence of growth hormone excess.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative importance of liver, kidney, and substrates in epinephrine-induced increased gluconeogenesis in humans

2003 ◽  
Vol 285 (4) ◽  
pp. E819-E826 ◽  
Author(s):  
Christian Meyer ◽  
Michael Stumvoll ◽  
Stephen Welle ◽  
Hans J. Woerle ◽  
Morey Haymond ◽  
...  
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Relative Importance ◽  
Substrate Availability ◽  
Glucose Release ◽  
Renal Uptake ◽  
Hepatic Glucose ◽  
Liver And Kidney ◽  
The Difference ◽  
Hepatic Glucose Release

Splanchnic and renal net balance measurements indicate that lactate and glycerol may be important precursors for epinephrine-stimulated gluconeogenesis (GNG) in liver and kidney, but the effects of epinephrine on their renal and hepatic conversion to glucose in humans have not yet been reported. We therefore used a combination of renal balance and isotopic techniques in nine postabsorptive volunteers to measure systemic and renal GNG from these precursors before and during a 3-h infusion of epinephrine (270 pmol · kg–1 · min–1) and calculated hepatic GNG as the difference between systemic and renal rates. During infusion of epinephrine, renal and hepatic GNG from lactate increased 4- to 6-fold and accounted for ∼85 and 70% of renal and hepatic glucose release, respectively, at the end of study; renal and hepatic GNG from glycerol increased ∼1.5- to 2-fold and accounted for ∼7–9% of renal and hepatic glucose release at the end of study. The increased renal GNG from lactate and glycerol was due not only to their increased renal uptake (∼3.3- and 1.4-fold, respectively) but also increased renal gluconeogenic efficiency (∼1.8- and 1.5-fold). The increased renal uptake of lactate and glycerol was wholly due to their increased arterial concentrations, since their renal fractional extraction remained unchanged and renal blood flow decreased. We conclude that 1) lactate is the predominant precursor for epinephrine-stimulated GNG in both liver and kidney, 2) hepatic and renal GNG from lactate and glycerol are similarly sensitive to stimulation by epinephrine, and 3) epinephrine increases renal GNG from lactate and glycerol by increasing substrate availability and the gluconeogenic efficiency of the kidney.

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