Insulin sensitivity of glucose and fat metabolism in severe sepsis

2000 ◽  
Vol 99 (4) ◽  
pp. 321-328 ◽  
Author(s):  
Cécile CHAMBRIER ◽  
Martine LAVILLE ◽  
Khalid RHZIOUAL BERRADA ◽  
Michelle ODEON ◽  
Paul BOULÉTREAU ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Insulin Infusion ◽  
Glucose Utilization ◽  
Fat Metabolism ◽  
Glucose Production ◽  
Normal Subjects ◽  
Endogenous Glucose Production ◽  
Exogenous Insulin ◽  
Control Subjects ◽  
Endogenous Glucose

In order to quantify the changes in insulin sensitivity, particularly of endogenous glucose production and fat metabolism, in patients with severe sepsis, a prospective study was conducted in five normal subjects and in five patients with severe sepsis hospitalized in an intensive care unit. The responses of endogenous glucose production, glucose utilization, plasma fatty acids and ketone body concentrations to progressive increase in plasma insulin levels (exogenous insulin infusion rates of 0, 0.5, 1 and 2 m-unitsċmin-1ċkg-1) were measured using the isoglycaemic clamp technique. Total glucose turnover was determined with D-[6,6-2H2]glucose. In each group, plasma glucose was maintained at basal levels (control subjects, 4.32±0.22 mmolċl-1; patients with sepsis, 7.10±2.29 mmolċl-1; P < 0.05). Plasma insulin concentrations were comparable in the two groups at an insulin infusion rate of 0.4 m-unitċmin-1ċkg-1 for controls and 0.5 m-unitċmin-1ċkg-1 for patients with sepsis, but differed following infusion at 2 m-unitċmin-1ċkg-1 (control subjects, 102±13.4 m-unitsċl-1; patients with sepsis, 124.8±19.7 m-unitsċl-1; P < 0.05). Endogenous glucose production was completely suppressed in control subjects by the first insulin infusion (0.4 m-unitċmin-1ċkg-1), but was only suppressed during infusion at 1 m-unitċmin-1ċkg-1 insulin in patients with sepsis. The glucose utilization rate increased significantly with exogenous insulin infusion in control subjects, but did not increase in patients with sepsis. Plasma non-esterified (free) fatty acid and ketone body levels were significantly decreased in both groups by the infusion of exogenous insulin, but the sensitivity of lipolysis was impaired in patients with sepsis. In conclusion, sepsis impaired to a varying extent the action of insulin on endogenous glucose production, glucose utilization, lipolysis and ketogenesis. Whole-body glucose uptake was the most affected, with a total lack of response to the elevated insulin levels obtained in this study. Suppression of endogenous glucose production and lipolysis could only be achieved with higher doses of insulin than those required in normal subjects.

Insulin regulation of renal glucose metabolism in humans

1999 ◽  
Vol 276 (1) ◽  
pp. E78-E84 ◽  
Author(s):  
Eugenio Cersosimo ◽  
Peter Garlick ◽  
John Ferretti
Keyword(s):  
Glucose Metabolism ◽  
Insulin Infusion ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Saline Infusion ◽  
Saline Control ◽  
Control Group ◽  
Renal Gluconeogenesis ◽  
Endogenous Glucose

Eighteen healthy subjects had arterialized hand and renal veins catheterized after an overnight fast. Systemic and renal glucose and glycerol kinetics were measured with [6,6-2H2]glucose and [2-13C]glycerol before and after 180-min peripheral infusions of insulin at 0.125 (LO) or 0.25 (HI) mU ⋅ kg−1 ⋅ min−1with variable [6,6-2H2]dextrose or saline (control). Renal plasma flow was determined by plasma p-aminohippurate clearance. Arterial insulin increased from 37 ± 8 to 53 ± 5 (LO) and to 102 ± 10 pM (HI, P < 0.01) but not in control (35 ± 8 pM). Arterial glucose did not change and averaged 5.2 ± 0.1 (control), 4.7 ± 0.2 (LO), and 5.1 ± 0.2 (HI) μmol/ml; renal vein glucose decreased from 4.8 ± 0.2 to 4.5 ± 0.2 μmol/ml (LO) and from 5.3 ± 0.2 to 4.9 ± 0.1 μmol/ml (HI) with insulin but not saline infusion (5.3 ± 0.1 μmol/ml). Endogenous glucose production decreased from 9.9 ± 0.7 to 6.9 ± 0.5 (LO) and to 5.7 ± 0.5 (HI) μmol ⋅ kg−1 ⋅ min−1; renal glucose production decreased from 2.5 ± 0.6 to 1.5 ± 0.5 (LO) and to 1.2 ± 0.6 (HI) μmol ⋅ kg−1 ⋅ min−1, whereas renal glucose utilization increased from 1.5 ± 0.6 to 2.6 ± 0.7 (LO) and to 2.9 ± 0.7 (HI) μmol ⋅ kg−1 ⋅ min−1after insulin infusion (all P < 0.05 vs. baseline). Neither endogenous glucose production (10.0 ± 0.4), renal glucose production (1.1 ± 0.4), nor renal glucose utilization (0.8 ± 0.4) changed in the control group. During insulin infusion, systemic gluconeogenesis from glycerol decreased from 0.67 ± 0.05 to 0.18 ± 0.02 (LO) and from 0.60 ± 0.04 to 0.20 ± 0.02 (HI) μmol ⋅ kg−1 ⋅ min−1( P < 0.01), and renal gluconeogenesis from glycerol decreased from 0.10 ± 0.02 to 0.02 ± 0.02 (LO) and from 0.15 ± 0.03 to 0.09 ± 0.03 (HI) μmol ⋅ kg−1 ⋅ min−1( P < 0.05). In contrast, during saline infusion, systemic (0.66 ± 0.03 vs. 0.82 ± 0.05 μmol ⋅ kg−1 ⋅ min−1) and renal gluconeogenesis from glycerol (0.11 ± 0.02 vs. 0.41 ± 0.04 μmol ⋅ kg−1 ⋅ min−1) increased ( P < 0.05 vs. baseline). We conclude that glucose production and utilization by the kidney are important insulin-responsive components of glucose metabolism in humans.

Activation of liver G-6-Pase in response to insulin-induced hypoglycemia or epinephrine infusion in the rat

2002 ◽  
Vol 282 (4) ◽  
pp. E905-E910 ◽  
Author(s):  
Isabelle Bady ◽  
Carine Zitoun ◽  
Ludovic Guignot ◽  
Gilles Mithieux
Keyword(s):  
Insulin Infusion ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Epinephrine Infusion ◽  
Liver Lobe ◽  
Endogenous Glucose ◽  
Tracer Dilution ◽  
Glucose Supply ◽  
Adrenalectomized Rats ◽  
Stimulation Of

This study was conducted to test the hypothesis of the activation of glucose-6-phosphatase (G-6-Pase) in situations where the liver is supposed to sustain high glucose supply, such as during the counterregulatory response to hypoglycemia. Hypoglycemia was induced by insulin infusion in anesthetized rats. Despite hyperinsulinemia, endogenous glucose production (EGP), assessed by [3-3H]glucose tracer dilution, was paradoxically not suppressed in hypoglycemic rats. G-6-Pase activity, assayed in a freeze-clamped liver lobe, was increased by 30% in hypoglycemia ( P < 0.01 vs. saline-infused controls). Infusion of epinephrine (1 μg · kg−1 · min−1) in normal rats induced a dramatic 80% increase in EGP and a 60% increase in G-6-Pase activity. In contrast, infusion of dexamethasone had no effect on these parameters. Similar insulin-induced hypoglycemia experiments performed in adrenalectomized rats did not induce any stimulation of G-6-Pase. Infusion of epinephrine in adrenalectomized rats restored a stimulation of G-6-Pase similar to that triggered by hypoglycemia in normal rats. These results strongly suggest that specific activatory mechanisms of G-6-Pase take place and contribute to EGP in situations where the latter is supposed to be sustained.

scholarly journals Insulin action and glucose metabolism in sheep fed on dried-grass or ground, maize-based diets

1985 ◽  
Vol 54 (2) ◽  
pp. 459-471 ◽  
Author(s):  
A. N. Janes ◽  
T. E. C. Weekes ◽  
D. G. Armstrong
Keyword(s):  
Glucose Metabolism ◽  
Insulin Action ◽  
Plasma Insulin ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Whole Body ◽  
Glucose Disposal ◽  
Metabolic Clearance ◽  
Endogenous Glucose

1. The effect of an exogenous supply of glucose, provided by the digestion of maize starch in the small intestine, on endogenous glucose metabolism and insulin action was studied in sheep using the euglycaemic insulin clamp procedure.2. Insulin was infused intravenously at rates of 0.2, 0.5, 1.0 and 6.0 mU/min per kg live weight for four consecutive periods in each of four sheep fed on dried-grass and maize-based diets. Glucose was also infused intravenously at a variable rate, sufficient to maintain the plasma glucose concentration at basal levels. Whole-body rates of glucose metabolism were determined using a continuous infusion of [6-3H]glucose.3. From the resultinginsulin dose-response curves, it was observed that, when the sheep were fed on the dried-grass diet, the responsiveness of glucose metabolism to insulin was less than that reported for non-ruminants.4. When fed the maize-based diet, the glucose metabolic clearance rates (MCR) observed during insulin infusions were significantly greater (P < 0.05) than those observed for the dried-grass diet. However, after correcting for the non-insulin-mediated glucose disposal, differences between diets were not significant.5. The sensitivity of glucose utilization to insulin was not affected by diet. The plasma insulin concentrations causing half-maximal insulin-mediated glucose MCR were 103 (SE 21) and 85 (SE 11) mU/l for the dried-grass and maize-based diets respectively.6. The sensitivity of endogenous glucose production to insulin was also unaffected by diet. The plasma insulin concentrations resulting in the suppression of endogenous glucose production to half the basal level were 80 (SE 26) and 89 (SE 29) mU/l for the dried-grass and maize-based diets respectively.7. It is concluded that the observed increase in glucose utilization on the maize-based diet was due partly to a slight change in responsiveness to insulin and also partly to a change in the rate of non-insulin-mediated glucose disposal.

Glucose metabolism in pregnant sheep when placental growth is restricted

1989 ◽  
Vol 257 (2) ◽  
pp. R350-R357 ◽  
Author(s):  
J. A. Owens ◽  
J. Falconer ◽  
J. S. Robinson
Keyword(s):  
Glucose Metabolism ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Gravid Uterus ◽  
Glucose Turnover ◽  
Fetal Sheep ◽  
Arterial Blood ◽  
Pregnant Sheep ◽  
Endogenous Glucose

The effect of restricting placental growth on glucose metabolism in pregnant sheep in late gestation was determined by primed constant infusions of D-[U-14C]- and D-[2-3H]glucose and antipyrine into fetuses of six control sheep and six sheep from which endometrial caruncles had been removed before pregnancy (caruncle sheep). In the latter, placental and fetal weights were reduced, as was the concentration of glucose in fetal arterial blood. Fetal glucose turnover in caruncle sheep was only 52-59% of that in controls, largely because of lower umbilical loss of glucose back to the placenta (38-39% of control) and lower fetal glucose utilization (61-74% of control). However, fetal glucose utilization on a weight-specific basis was similar in control and caruncle sheep. Significant endogenous glucose production occurred in control and caruncle fetal sheep. Maternal glucose production and partition of glucose between the gravid uterus and other maternal tissues were similar in control and caruncle sheep. In conclusion, when placental and fetal growth are restricted, fetal glucose utilization is maintained by reduced loss of glucose back to the placenta and mother and by maintaining endogenous glucose production.

Peripheral and hepatic resistance to insulin and hepatic resistance to glucagon in uraemic subjects

1988 ◽  
Vol 118 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Ole Schmitz
Keyword(s):  
Insulin Resistance ◽  
Insulin Infusion ◽  
Serum Insulin ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Glucose Disposal ◽  
Peripheral Tissues ◽  
Endogenous Glucose

Abstract. To characterize endogenous glucose production in uraemia, nondialyzed uraemic patients and controls were exposed to two major modulating hormones, insulin and glucagon. Nineteen uraemic and 15 healthy subjects underwent either a 2-step (insulin infusion rates: 0.45 and 1.0 mU·kg−1·min−1) or a 3-step (insulin infusion rates: 0.1, 0.2 and 0.3 mU·kg−1·min−1 sequential euglycaemic insulin clamp. Average steady state serum insulin concentrations were almost identical during all five infusion rates in uraemic patients (16,22, 26, 31 and 66 mU/l) and controls (15, 19, 24, 33 and 68 mU/l). At all steps, insulin infusion was accompanied by significantly lower glucose disposal rates ([3−3H]glucose) in uraemic patients compared with controls (P < 0.05 or less). Moreover, the restraining potency of insulin on endogenous glucose production was much more prominent in healthy than in uraemic subjects at the lowest three infusion rates (0.6 ± 1.0 versus 1.4 ± 0.3 (mean ± 1 sd), −0.3 ± 0.7 versus 0.7 ± 0.3, and −1.1 ± 0.7 versus 0.2 ± 0.6 mg·kg−1·min−1; P < 0.05, P < 0.01 and P < 0.01, respectively), implying a shift to the right of the dose-response curve in uraemia. In contrast, basal values were comparable (2.4 ± 0.3 versus 2.2 ± 0.6 mg·kg−1·min−1) as the difference vanished at higher infusion rates, i.e. peripheral insulinaemia above ≈30 mU/l. Another 7 uraemic patients and 7 controls were infused with glucagon at constant rates of 4 or 6 ng·kg−1·min−1, respectively, for 210 min concomitant with somatostatin (125 μg/h) and tritiated glucose. The ability of glucagon to elevate plasma glucose was markedly attenuated in uraemic patients compared with controls during the initial 60 min of glucagon exposure. This difference was entirely due to diminished hepatic glucose production (3.5 ± 0.8 versus 4.8 ± 1.0 mg·kg−1·min−1; P < 0.05). In conclusion, in addition to insulin resistance in peripheral tissues, uraemia is also associated with hepatic insulin resistance. Furthermore, glucagon challenge implies impaired early endogenous glucose release in uraemia suggesting a superimposed hepatic resistance to glucagon.

Inhibition by insulin of hepatic glucose production in the normal dog

1965 ◽  
Vol 208 (2) ◽  
pp. 301-306 ◽  
Author(s):  
R. Steele ◽  
J. S. Bishop ◽  
A. Dunn ◽  
N. Altszuler ◽  
I. Rathgeb ◽  
...  
Keyword(s):  
Production Rate ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Release ◽  
Endogenous Insulin ◽  
Intravenous Insulin ◽  
Hepatic Glucose ◽  
Endogenous Glucose

Glucose-C14 was given intravenously in trace amount as an initial dose followed by continuous infusion to tag the circulating glucose of normal unanesthetized dogs in the post-absorptive state. The rate of dilution of this circulating tagged glucose by new (C12) glucose produced endogenously was measured. The release to the blood of such new glucose, presumably almost entirely from liver, was reduced by half during the 1st hr of intravenous insulin infusion at 0.1 U/kg per hr or more, provided that enough glucose was also infused to limit hypoglycemia. During the 2nd hr new glucose release was reduced by three-quarters or more. Insulin infusion at lower rates (02–.04 U/kg per hr), along with glucose, produced smaller effects. Glucose alone, infused intravenously in amounts sufficient to raise plasma glucose concentration, and hence presumed to enhance endogenous insulin secretion, reduced new glucose release by half during the 1st hr of infusion at one-half to one and one-half times the resting endogenous glucose production rate In the 2nd or 3rd hr, with glucose infusion increased to two to five times the resting endogenous glucose production rate, new glucose release was reduced by three-fourths or more.

scholarly journals Higher Endogenous Glucose Production During OGTT vs Isoglycemic Intravenous Glucose Infusion

2016 ◽  
Vol 101 (11) ◽  
pp. 4377-4384 ◽  
Author(s):  
Asger Lund ◽  
Jonatan I. Bagger ◽  
Mikkel Christensen ◽  
Magnus Grøndahl ◽  
Gerrit van Hall ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Hemoglobin A1c ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Oral Glucose ◽  
Control Subjects ◽  
Nondiabetic Control ◽  
Endogenous Glucose

Context: Oral glucose ingestion elicits a larger insulin response and delayed suppression of glucagon compared to isoglycemic IV glucose infusion (IIGI). Objective: We studied whether these differences translate into effects on endogenous glucose production (EGP) and glucose disposal in patients with type 2 diabetes and nondiabetic control subjects. Design: This was a single-blinded, randomized, crossover study. Setting: The study was conducted at a specialized research unit. Participants: Ten patients with type 2 diabetes (age, [mean ± SD] 57.1 ± 6.7 years; body mass index, 29.0 ± 4.3 kg/m2; hemoglobin A1c, 53.8 ± 11.0 mmol/mol; duration of diabetes, 9.2 ± 5.0 years) and 10 matched nondiabetic control subjects (age, 56.0±10.7 years; body mass index, 29.8 ± 2.9 kg/m2; hemoglobin A1c, 33.8 ± 5.5 mmol/mol) participated. Interventions: Three experimental days: 75 g-oral glucose tolerance test (OGTT), IIGI, and IIGI+glucagon (IIGI with a concomitant IV glucagon infusion [0.8 ng/kg/min from 0 to 25 minutes] designed to mimic portal glucagon concentrations during OGTT in the type 2 diabetic group) were undertaken. Main Outcome Measures: Glucose kinetics were assessed by tracer methodology. Results: Glucose rate of disappearance was higher during the OGTT vs IIGI in the control group, but similar on all days in the diabetic group. Surprisingly, in both groups, EGP was more suppressed during IIGI than during OGTT, and exogenous glucagon infusion during IIGI did not restore EGP to the levels observed during OGTT. Conclusion: EGP was less suppressed during OGTT than during IIGI in both patients with type 2 diabetes and in nondiabetic control subjects. Based on the present experimental design, it was not possible to attribute this difference to the delayed glucagon suppression observed in the initial phase of the OGTT.

scholarly journals Sex-specific programming of adult insulin resistance in guinea pigs by variable perinatal growth induced by spontaneous variation in litter size

2019 ◽  
Vol 316 (4) ◽  
pp. R352-R361
Author(s):  
Dane M. Horton ◽  
David A. Saint ◽  
Kathryn L. Gatford ◽  
Karen L. Kind ◽  
Julie A. Owens
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Metabolism ◽  
Guinea Pigs ◽  
Glucose Utilization ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Whole Body ◽  
Catch Up ◽  
Endogenous Glucose

Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in programming of insulin resistance later in life. Spontaneous IUGR in the guinea pig, due to natural variation in litter size, produces offspring with asymmetric IUGR and neonatal catch-up growth. We hypothesized that spontaneous IUGR and/or accelerated neonatal growth would impair insulin sensitivity in adult guinea pigs. Insulin sensitivity of glucose metabolism was determined by hyperinsulinemic-euglycemic clamp (HEC) in 38 (21 male, 17 female) young adult guinea pigs from litters of two-to-four pups. A subset (10 male, 8 female) were infused with d-[3-3H]glucose before and during the HEC to determine rates of basal and insulin-stimulated glucose utilization, storage, glycolysis, and endogenous glucose production. n males, the insulin sensitivity of whole body glucose uptake ( r = 0.657, P = 0.002) and glucose utilization ( r = 0.884, P = 0.004) correlated positively and independently with birth weight, but not with neonatal fractional growth rate (FGR10–28). In females, the insulin sensitivity of whole body and partitioned glucose metabolism was not related to birth weight, but that of endogenous glucose production correlated negatively and independently with FGR10–28 ( r = −0.815, P = 0.025). Thus, perinatal growth programs insulin sensitivity of glucose metabolism in the young adult guinea pig and in a sex-specific manner; impaired insulin sensitivity, including glucose utilization, occurs after IUGR in males and impaired hepatic insulin sensitivity after rapid neonatal growth in females.

FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis

2002 ◽  
Vol 283 (1) ◽  
pp. E12-E19 ◽  
Author(s):  
Guenther Boden ◽  
Peter Cheung ◽  
T. Peter Stein ◽  
Karen Kresge ◽  
Maria Mozzoli
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Insulin Infusion ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Elevated Plasma ◽  
Heparin Infusion ◽  
Plasma Ffa ◽  
Endogenous Glucose

Free fatty acids (FFA) have been shown to inhibit insulin suppression of endogenous glucose production (EGP). To determine whether this is the result of stimulation by FFA of gluconeogenesis (GNG) or glycogenolysis (GL) or a combination of both, we have determined rates of GNG and GL (with2H2O) and EGP in 16 healthy nondiabetic volunteers (11 males, 5 females) during euglycemic-hyperinsulinemic (∼450 pM) clamping performed either with or without simultaneous intravenous infusion of lipid plus heparin. During insulin infusion, FFA decreased from 571 to 30 μmol/l ( P < 0.001), EGP from 15.7 to 2.0 μmol · kg−1 · min−1( P < 0.01), GNG from 8.2 to 3.7 μmol · kg−1 · min−1( P < 0.05), and GL from 7.4 to −1.7 μmol · kg−1 · min−1( P < 0.02). During insulin plus lipid/heparin infusion, FFA increased from 499 to 1,247 μmol/l ( P< 0.001). EGP decreased 64% less than during insulin alone (−5.1 ± 0.7 vs. −13.7 ± 3.4 μmol · kg−1 · min−1). The decrease in GNG was not significantly different from the decrease of GNG during insulin alone (−2.6 vs. −4.5 μmol · kg−1 · min−1, not significant). In contrast, GL decreased 66% less than during insulin alone (−3.1 vs. −9.2 μmol · kg−1 · min−1, P < 0.05). We conclude that insulin suppressed EGP by inhibiting GL more than GNG and that elevated plasma FFA levels attenuated the suppression of EGP by interfering with insulin suppression of GL.

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