scholarly journals Assessment of hepatic insulin extraction from in vivo surrogate methods of insulin clearance measurement

2018 ◽  
Vol 315 (4) ◽  
pp. E605-E612 ◽  
Author(s):  
Isaac Asare-Bediako ◽  
Rebecca L. Paszkiewicz ◽  
Stella P. Kim ◽  
Orison O. Woolcott ◽  
Cathryn M. Kolka ◽  
...  
Keyword(s):  
Steady State ◽  
Clearance Rate ◽  
Intravenous Glucose Tolerance Test ◽  
Primary Response ◽  
Metabolic Clearance ◽  
Intravenous Glucose ◽  
Decay Rate Constant ◽  
Steady State Method ◽  
Hepatic Insulin Extraction

Hyperinsulinemia, accompanied by reduced first-pass hepatic insulin extraction (FPE) and increased secretion, is a primary response to insulin resistance. Different in vivo methods are used to estimate the clearance of insulin, which is assumed to reflect FPE. We compared two methodologically different but commonly used indirect estimates with directly measured FPE in healthy dogs ( n = 9). The indirect methods were 1) metabolic clearance rate of insulin (MCR) during the hyperinsulinemic-euglycemic clamp (EGC), a steady-state method, and 2) fractional clearance rate of insulin (FCR) during the frequently sampled intravenous glucose tolerance test (FSIGT), a dynamic method. MCR was calculated as the ratio of insulin infusion rate to steady-state plasma insulin. FCR was calculated as the exponential decay rate constant of the injected insulin. Directly measured FPE is based on the difference in insulin measurements during intraportal vs. peripheral vein insulin infusions. We found a strong correlation between indirect FCR (min−1) and FPE (%). In contrast, we observed a poor association between MCR (ml·min−1·kg−1) and FPE (%). Our findings in canines suggest that FCR measured during FSIGT can be used to estimate FPE. However, MCR calculated during EGC appears to be a poor surrogate for FPE.

Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage

2008 ◽  
Vol 294 (1) ◽  
pp. E15-E26 ◽  
Author(s):  
Ranganath Muniyappa ◽  
Sihoon Lee ◽  
Hui Chen ◽  
Michael J. Quon
Keyword(s):  
Steady State ◽  
Insulin Sensitivity ◽  
Intravenous Glucose Tolerance Test ◽  
Optimal Choice ◽  
Glucose Clamp ◽  
Therapeutic Interventions ◽  
Oral Glucose ◽  
Specific Method ◽  
Intravenous Glucose

Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance.

Validation of a new method for determination of free fatty acid turnover

1987 ◽  
Vol 252 (3) ◽  
pp. E431-E438 ◽  
Author(s):  
J. M. Miles ◽  
M. G. Ellman ◽  
K. L. McClean ◽  
M. D. Jensen
Keyword(s):  
Steady State ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Clearance Rate ◽  
Experimental Period ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
State Equations ◽  
Tracer Methods

The accuracy of tracer methods for estimating free fatty acid (FFA) rate of appearance (Ra), either under steady-state conditions or under non-steady-state conditions, has not been previously investigated. In the present study, endogenous lipolysis (traced with 14C palmitate) was suppressed in six mongrel dogs with a high-carbohydrate meal 10 h before the experiment, together with infusions of glucose, propranolol, and nicotinic acid during the experimental period. Both steady-state and non-steady-state equations were used to determine oleate Ra ([3H]oleate) before, during, and after a stepwise infusion of an oleic acid emulsion. Palmitate Ra did not change during the experiment. Steady-state equations gave the best estimates of oleate inflow approximately 93% of the known oleate infusion rate overall, while errors in tracer estimates of inflow were obtained when non-steady-state equations were used. The metabolic clearance rate of oleate was inversely related to plasma concentration (P less than 0.01). In conclusion, accurate estimates of FFA inflow were obtained when steady-state equations were used, even under conditions of abrupt and recent changes in Ra. Non-steady-state equations, in contrast, may provide erroneous estimates of inflow. The decrease in metabolic clearance rate during exogenous infusion of oleate suggests that FFA transport may follow second-order kinetics.

Abstract 610: Ineffective Suppression of Adipocyte Lipolysis in Metabolic Syndrome: An in vivo Test for Adipocyte Insulin Resistance

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Jennifer L Ford ◽  
Raymond C Boston ◽  
Rachel E Walker ◽  
Gregory C Shearer
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Lipid Droplet ◽  
Minimal Model ◽  
Initial Rate ◽  
Intravenous Glucose Tolerance Test ◽  
Intravenous Glucose ◽  
In Vivo Test

Background: Insulin resistance is a major contributor to metabolic syndrome, disrupting both glucose and non-esterified fatty acid (NEFA) dynamics through ineffective glucose clearance and decreased suppression of lipid droplet lipolysis. The minimal model of glucose dynamics is used for glycemic insulin sensitivity however it does not measure adipocyte insulin sensitivity, the primary determinant of plasma NEFA. An in-vivo approach to measuring adipocyte insulin sensitivity using NEFA is employed, comparing healthy and metabolic syndrome subjects. Both the models are employed to estimate insulin sensitivity and validate the NEFA approach. Objective: To test the use of NEFA kinetics to measure adipocyte insulin sensitivity compared to the glucose minimal model. Approach and results: Metabolic syndrome (n=56) and optimally healthy (n=14) subjects underwent a frequently sampled intravenous glucose tolerance test, and plasma analyzed for insulin, glucose, and NEFA. Insulin sensitivity ( S I ) and glucose effectiveness ( S G ) were calculated from the glucose minimal model. S I was 1.7 (mU/L) -1 min -1 and 0.40 (mU/L) -1 /min -1 and S G was 0.027 min -1 and 0.017 min -1 for the healthy and metabolic syndrome groups, respectively, indicating substantial glycemic insulin resistance in the latter. A model using glucose as the driver for NEFA kinetics was then applied. We found the initial rate of NEFA utilization by tissues (NU) was less, but the threshold glucose (tG) and glucose concentration required for a unit change in lipolysis inhibition ( G i ) were greater in metabolic syndrome verses healthy (NU: 0.050[0.045, 0.057] vs. 0.068[0.054, 0.086] p=0.03; tG: 6.7[6.2, 7.2] vs. 5.0[4.3, 5.9] p=0.001; G i : 0.30[0.25, 0.35] vs. 0.17[0.07, 0.27] p=0.02). No differences were found in initial rate of NEFA production or glucose utilization. Conclusion: Our results indicate that suppression of lipid-droplet lipolysis requires greater stimulus in metabolic syndrome compared to insulin sensitive adipocytes. Further, the rate of NEFA removal is less in metabolic syndrome. These results reveal components of insulin sensitivity not demonstrated by the glucose model. The NEFA model provides a measurement of adipocyte insulin sensitivity not captured by glycemic indices.

Increased thyroxine turnover after 3,3′,4,4′,5,5′-hexabromobiphenyl injection and lack of effect on peripheral triiodothyronine production

1990 ◽  
Vol 68 (8) ◽  
pp. 1079-1084 ◽  
Author(s):  
P. A. Spear ◽  
P. Higueret ◽  
H. Garcin
Keyword(s):  
Clearance Rate ◽  
Liver Microsomes ◽  
Type I ◽  
Metabolic Clearance ◽  
Fractional Clearance ◽  
Male Wistar Rats ◽  
Fold Induction ◽  
Dose Dependent ◽  
Peripheral Metabolism

Juvenile male Wistar rats were injected i.p. with 0, 20, or 40 mg/kg 3,3′,4,4′,5,5′-hexabromobiphenyl and blood samples collected periodically up to 28 days. A dose-dependent depression of the serum thyroxine level was detected, while the circulating triiodothyronine concentration was not affected by the biphenyl congener. Thyroxine turnover in vivo 7 days after injection of the 20 mg/kg dose revealed significant increases of various clearance parameters relative to controls. The fractional clearance rate (day−1) increased by 84%, the daily metabolic clearance rate (mL∙kg−1∙day−1) increased by 128%, and the daily thyroxine disposal rate (ng∙kg−1∙day−1) increased by 41%. Also, the thyroxine distribution space (mL/kg) increased by 21%. These results indicated greater thyroxine binding in major organs as well as a marked increase in the peripheral metabolism of thyroxine. The increased thyroxine metabolism is explained by a 4.8-fold induction of uridine 5′-diphosphoglucuronyltransferase activity in liver microsomes. The type I 5′-deiodinase activity in liver homogenates and endogenous concentrations of the cofactor for this reaction, glutathione, were not affected by the biphenyl. This result means that homeostatic mechanisms involving thyroxine conversion to triiodothyronine do not explain the maintenance of serum T3 under these conditions.Key words: thyroxine, triiodothyronine, thyroxine turnover, deiodinase, 3,3′,4,4′,5,5′-hexabromobiphenyl, uridine 5′-diphosphoglucuronyltransferase, glutathione.

scholarly journals Acute Hypoxia Suppresses Exogenous Glucose Rate Of Appearance And Metabolic Clearance Rate During Steady-state Aerobic Exercise

2020 ◽  
Vol 52 (7S) ◽  
pp. 597-597
Author(s):  
Lee M. Margolis ◽  
Marques A. Wilson ◽  
Claire C. Whitney ◽  
Christopher T. Carrigan ◽  
Nancy E. Murphy ◽  
...  
Keyword(s):  
Steady State ◽  
Aerobic Exercise ◽  
Clearance Rate ◽  
Acute Hypoxia ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Exogenous Glucose

Effect of human pregnancy on metabolic clearance rate of oxytocin

1990 ◽  
Vol 259 (1) ◽  
pp. R21-R24
Author(s):  
S. Thornton ◽  
J. M. Davison ◽  
P. H. Baylis
Keyword(s):  
Clearance Rate ◽  
Late Pregnancy ◽  
High Plasma ◽  
Constant Infusion ◽  
Aminopeptidase Activity ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Human Pregnancy ◽  
In Pregnancy

The metabolic clearance rate (MCR) of oxytocin (OT) was determined by use of constant infusion techniques to achieve low and high plasma OT concentrations in 10 women in late pregnancy and again 8-10 wk postpartum (mean plasma oxytocinase activity was 2.1 IU/ml plasma at term and less than 0.1 IU/ml plasma 8-10 wk postpartum). At the lower plasma OT concentrations (5.0 and 5.2 pg/ml, pregnant and postpartum, respectively) produced by infusion of 17.9 ng/min in pregnancy and 4.3 ng/min postpartum, mean MCR of OT was increased fourfold during pregnancy (5.7 +/- 0.6 and 1.3 +/- 0.1 l/min, pregnant and postpartum, respectively; P less than 0.001). At the higher plasma OT concentrations (8.0 and 8.0 pg/ml, pregnant and postpartum, respectively) produced by infusion of 35.7 ng/min in pregnancy and 8.5 ng/min postpartum, mean MCR of OT was likewise markedly increased during pregnancy compared with postpartum values (7.1 +/- 1.9 and 1.4 +/- 0.1 l/min, respectively; P less than 0.01). The MCR of OT was independent of plasma concentration (between 5 and 8 pg/ml) during pregnancy and in the postpartum period. It is concluded that the MCR of OT is increased markedly during human pregnancy. This may be due to concomitant increases in in vivo cystine aminopeptidase activity or other less specific pregnancy-associated metabolic changes.

Effects of season, protein and nutritional state on glucose tolerance during an annual cycle of growth in young red deer stags

1997 ◽  
Vol 154 (2) ◽  
pp. 275-283 ◽  
Author(s):  
C D McMahon ◽  
I D Corson ◽  
R P Littlejohn ◽  
S K Stuart ◽  
B A Veenvliet ◽  
...  
Keyword(s):  
Steady State ◽  
Glucose Tolerance ◽  
Dietary Protein ◽  
Clearance Rate ◽  
Red Deer ◽  
Growth Cycle ◽  
Intravenous Glucose ◽  
Fed State ◽  
Insulin Resistant ◽  
Glucose Clearance

Abstract Two hypotheses were tested in gonad-intact, young (aged 6–18 months), growing red deer stags during an annual growth cycle. First, that glucose clearance rate is faster during summer than during winter. Secondly, that increased dietary protein availability will enhance winter growth. Stags were randomly assigned into one of two groups: group 1 (n=5) had 16% while group 2 (n=6) had 48% of dietary protein naturally protected against fermentative degradation in the rumen. Total crude protein and energy remained similar for each diet (12 and 14% respectively for protein and 11 MJ metabolisable energy/kg dry matter). Stags were kept indoors in individual pens for 12 months and given monthly intravenous glucose tolerance tests (IVGTT), at a dose of 200 mg/kg, in the fed and fasted (48 h) states to determine both growth and steady-state tissue requirements. Protein level had no effect on food intake, weight gain, insulin kinetics, or glucose clearance rate. In the fed state, insulin peak (highest level after IVGTT) increased (P<0·01) from October (139 pmol/l) to December (247 pmol/l (s.e.d.=42) and remained elevated during the summer, before declining (P<0·01) from February (223 pmol/l) to April (130 pmol/l) (s.e.d.=25). Glucose clearance rate was faster (P<0·05) in December (1·69 litres/min) than June (0·61 litres/min) in the fed state (s.e.d.=0·30), and decreased (P<0·05) from February (1·75 litres/min) to April (0·92 litres/min) (s.e.d.=0·39). During fasting, the pattern of glucose clearance was similar to that observed in the fed state, but the amplitude was lower, while the pattern for insulin peak was similar to that of the fed state. We concluded first, that additional protected protein does not benefit growth during winter. Secondly, we concluded from the fasted, steady-state data that stags are insulin resistant during summer. Thirdly, despite insulin resistance, data on the fed state demonstrated that stags have higher tissue energy requirements during summer growth. Journal of Endocrinology (1997) 154, 275–283

Pharmacokinetics and organ-specific metabolism of calcitonin gene-related peptide in sheep

1988 ◽  
Vol 118 (1) ◽  
pp. 25-31 ◽  
Author(s):  
K. G. Braslis ◽  
A. Shulkes ◽  
D. R. Fletcher ◽  
K. J. Hardy
Keyword(s):  
Steady State ◽  
Clearance Rate ◽  
Half Life ◽  
Calcitonin Gene Related Peptide ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Related Peptide ◽  
Modes Of Action ◽  
Calcitonin Gene ◽  
Organ Specific

ABSTRACT Calcitonin gene-related peptide (CGRP) is a product of the calcitonin gene with a widespread distribution in neural tissue of the brain, gut and perivascular nerves. Infusion of CGRP produces multiple biological effects, but the physiological significance of these findings will be influenced by the sites and rates of CGRP metabolism. The metabolic clearance rate and half-life of disappearance of human CGRP were estimated in conscious sheep after infusing CGRP at 1 or 5 pmol/kg per min to steady-state conditions. The particular organs involved in the clearance of CGRP were assessed by measuring the inflow and outflow concentrations across the liver, gut, kidney, lung and brain. The metabolic clearance rate at steady state was 22·6 ± 2·1 (s.e.m.) and 15·0±1·7 ml/kg per min for the 1 and 5 pmol/kg per min doses respectively. The half-life of disappearance was bi-exponential: 3·6±0·3 min for the first phase and 13·6±1·0 min for the second phase. High-pressure liquid chromatography of plasma at equilibrium revealed only a single peak coeluting with CGRP(1–37): no immunoreactive metabolites were detected. These pharmacokinetic values are intermediate between that of a neurotransmitter and a hormone and are therefore consistent for a peptide with both circulatory and neurotransmitter modes of action. The kidney, with an arterial–renal vein gradient of 14%, and the liver, with a portal– hepatic vein gradient of 25%, were the major organs involved in the clearance of CGRP. The specific organ clearance, however, accounted for only one-third of the whole body metabolic clearance rate of CGRP, suggesting that other more generalized degradative systems are involved, such as endothelial-bound enzymes of blood vessels. This information on clearance and organ-specific metabolism should form a basis for evaluating the physiological roles and modes of action of CGRP. J. Endocr. (1988) 118,25–31

Metabolic clearance rate of adrenocorticotropin in the rat

1977 ◽  
Vol 55 (5) ◽  
pp. 1079-1083 ◽  
Author(s):  
Josée Lalonde ◽  
Maurice Normand
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Clearance Rate ◽  
Intravenous Infusion ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Plasma Acth ◽  
Adrenal Cells ◽  
Acth Concentration ◽  
Acth Release

The metabolic clearance rate (MCR) of adrenocorticotropin (ACTH) was estimated after the intravenous infusion of graded rates of the hormone (40–2560 μU/min per 100 g body weight) in rats pretreated with chlorpromazine, morphine, and Nembutal, a preparation which proved effective in blocking endogenous ACTH release. The hormone was infused over a period of 45 min, at which time the plasma ACTH concentration had reached a steady state. A specific and sensitive bioassay, based on the corticosterone production of dispersed adrenal cells, was used to measure the plasma ACTH concentration. With increasing infusion rates of ACTH, a threefold decrease in the MCR of ACTH was observed. Previous studies of our group have shown that the MCR of corticosterone increases as a function of the infusion rate of the steroid. It appears, therefore, that the metabolism of these two hormonal links of the hypothalarno–pituitary–adrenocortical axis vary in opposite fashions as a function of the secretion rate of the hormone.

Sign in / Sign up

Export Citation Format

Share Document