Effects of lactate on glucose metabolism in healthy subjects and in severely injured hyperglycemic patients

1995 ◽  
Vol 268 (4) ◽  
pp. E630-E635 ◽  
Author(s):  
L. Tappy ◽  
M. C. Cayeux ◽  
P. Schneiter ◽  
C. Schindler ◽  
E. Temler ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Multiple Trauma ◽  
Hepatic Glucose Production ◽  
Metabolic Stress ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Carbohydrate Oxidation ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
Endogenous Glucose

Hepatic glucose production is autoregulated during infusion of gluconeogenic precursors. In hyperglycemic patients with multiple trauma, hepatic glucose production and gluconeogenesis are increased, suggesting that autoregulation of hepatic glucose production may be defective. To better understand the mechanisms of autoregulation and its possible alterations in metabolic stress, lactate was coinfused with glucose in healthy volunteers and in hyperglycemic patients with multiple trauma or critical illness. In healthy volunteers, infusion of glucose alone nearly abolished endogenous glucose production. Lactate increased gluconeogenesis (as indicated by a decrease in net carbohydrate oxidation with no change in total [13C]carbohydrate oxidation) but did not increase endogenous glucose production. In patients with metabolic stress, endogenous glucose production was not suppressed by exogenous glucose, but lactate did not further increase hepatic glucose production. It is concluded that 1) in healthy humans, autoregulation of hepatic glucose production during infusion of lactate is still present when glycogenolysis is suppressed by exogenous glucose and 2) autoregulation of hepatic glucose production is not abolished in hyperglycemic patients with metabolic stress.

Effects of dexamethasone on hepatic glucose production and fructose metabolism in healthy humans

1997 ◽  
Vol 273 (2) ◽  
pp. E315-E320 ◽  
Author(s):  
P. Tounian ◽  
P. Schneiter ◽  
S. Henry ◽  
J. Delarue ◽  
L. Tappy
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Healthy Men ◽  
Fructose Metabolism ◽  
Healthy Humans ◽  
Hepatic Glucose ◽  
Endogenous Glucose ◽  
Total Glucose ◽  
Administration Rate

This study was designed to determine whether glucocorticoids alter autoregulation of glucose production and fructose metabolism. Two protocols with either dexamethasone (DEX) or placebo (Placebo) were performed in six healthy men during hourly ingestion of[13C]fructose (1.33 mmol.kg-1.h-1) for 3 h. In both protocols, endogenous glucose production (EGP) increased by 8 (Placebo) and 7% (DEX) after fructose, whereas gluconeogenesis from fructose represented 82 (Placebo) and 72% (DEX) of EGP. Fructose oxidation measured from breath 13CO2 was similar in both protocols [9.3 +/- 0.7 (Placebo) and 9.6 +/- 0.5 mumol.kg-1.min-1 (DEX)]. Nonoxidative carbohydrate disposal, calculated as fructose administration rate minus net carbohydrate oxidation rate after fructose ingestion measured by indirect calorimetry, was also similar in both protocols [5.8 +/- 0.8 (Placebo) and 5.9 +/- 2.0 mumol.kg-1.min-1 (DEX)]. We concluded that dexamethasone 1) does not alter the autoregulatory process that prevents a fructose-induced increase in gluconeogenesis from increasing total glucose production and 2) does not affect oxidative and nonoxidative pathways of fructose. This indicates that the insulin-regulated enzymes involved in these pathways are not affected in a major way by dexamethasone.

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 Effects of 11β-hydroxysteroid dehydrogenase-1 inhibition on hepatic glycogenolysis and gluconeogenesis

2013 ◽  
Vol 304 (7) ◽  
pp. E747-E756 ◽  
Author(s):  
J. J. Winnick ◽  
C. J. Ramnanan ◽  
V. Saraswathi ◽  
J. Roop ◽  
M. Scott ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hydroxysteroid Dehydrogenase ◽  
Endogenous Glucose Production ◽  
Exogenous Glucose ◽  
Basal Period ◽  
Therapeutic Value ◽  
Hepatic Glucose ◽  
Metabolic Challenge ◽  
Glucose Output

The aim of this study was to determine the effect of prolonged 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11β-HSD1 inhibitor (HSD1-I; n = 6) or placebo (PBO; n = 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3×-basal), epinephrine (5×-basal), and insulin (2×-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I ( P < 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11β-HSD1 inhibition ( P < 0.05) due to a reduction in net hepatic glycogenolysis ( P < 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization ( P < 0.05) and the suppression of lipolysis were increased ( P < 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11β-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.

scholarly journals The impact of obesity, sex, and diet on hepatic glucose production in cats

2009 ◽  
Vol 296 (4) ◽  
pp. R936-R943 ◽  
Author(s):  
Saskia Kley ◽  
Margarethe Hoenig ◽  
John Glushka ◽  
Eunsook S. Jin ◽  
Shawn C. Burgess ◽  
...  
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Citrate Synthase ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Metabolism ◽  
Peripheral Insulin Resistance ◽  
Pyruvate Cycling ◽  
Hepatic Glucose ◽  
The Impact

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using 2H2O, [U-13C3]propionate, and [3,4-13C2]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin ( P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats ( P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP ( P < 0.003). Female obese cats had ∼1.5 times higher fluxes through phosphoenolpyruvate carboxykinase ( P < 0.02) and citrate synthase ( P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold ( P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

Altered fluxes responsible for reduced hepatic glucose production and gluconeogenesis by exogenous glucose in rats

1997 ◽  
Vol 272 (1) ◽  
pp. E163-E172 ◽  
Author(s):  
M. K. Hellerstein ◽  
R. A. Neese ◽  
J. M. Schwarz ◽  
S. Turner ◽  
D. Faix ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Total Production ◽  
Distribution Analysis ◽  
Intravenous Glucose ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
Flow Through ◽  
Glucose Output

The net release of glucose from the liver, or hepatic glucose production (HGP), and apparent gluconeogenesis (GNG) are reduced by exogenous glucose. We investigated the changes in metabolic fluxes responsible. Flux through the hepatic GNG pathway was quantified by mass isotopomer distribution analysis (MIDA) from [2-13C]glycerol. Unidirectional flux across hepatic glucose-6-phosphatase (G-6-Pase), or total hepatic glucose output (THGO), and hepatic glucose cycling (HGC) were also measured by using glucuronate (GlcUA) to correct for glucose 6-phosphate (G-6-P) labeling. Infusion of glucose (15-30 mg.kg-1.min-1 iv) to 24 h-fasted rats caused two important metabolic alterations. First was a significant increase in hepatic glucose uptake and HGC: > 60% of THGO was from HGC. Second, although flux through hepatic G-6-P increased (from 15.7 to 17.7-22.7 mg.kg-1.min-1), the partitioning of G-6-P flux changed markedly [from 30-35% to 55-60% entering UDP-glucose (UDP-Glc), P < 0.01]. Total flux through the GNG pathway remained active during intravenous glucose, but increased partitioning into UDP-Glc lowered GNG flux plasma glucose by 50%. In summary, the suppression of HGP and GNG flux into glucose is not primarily due to reduced carbon flow through hepatic G-6-Pase or the hepatic GNG pathway. THGO persists, but hepatic G-6-P is derived increasingly from plasma glucose, and flow through GNG persists, but the partitioning coefficient of G-6-P into UDP-Glc doubles. These adjustments permit net HGP to fall despite increased total production of hepatic G-6-P during administration of glucose.

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.

Evidence against important catecholamine compensation for absent glucagon counterregulation

1991 ◽  
Vol 260 (2) ◽  
pp. E203-E212 ◽  
Author(s):  
P. De Feo ◽  
G. Perriello ◽  
E. Torlone ◽  
C. Fanelli ◽  
M. M. Ventura ◽  
...  
Keyword(s):  
Plasma Glucose ◽  
Glucose Utilization ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Plasma Glucagon ◽  
Counterregulatory Hormones ◽  
Exogenous Glucose ◽  
Hepatic Glucose ◽  
Clamp Study

To assess the counterregulatory role of glucagon and to test the hypothesis that catecholamines can largely compensate for an impaired glucagon response, four studies were performed in seven normal volunteers. In all studies, insulin was infused subcutaneously (15 mU.m-2.min-1) and increased circulating insulin approximately twofold to levels (26 +/- 1 microU/ml) observed with intensive insulin therapy. In study 1, plasma glucose fluxes (D-[3-3H]glucose) and plasma substrate and counterregulatory hormone concentrations were simply monitored; plasma glucose decreased from 87 +/- 2 mg/dl and plateaued at 51 +/- 2 mg/dl for 3 h. In study 2 [pituitary-adrenal-pancreatic (PAP) clamp], secretion of insulin and counterregulatory hormones (except for catecholamines) was prevented by somatostatin (0.5 mg/h i.v.) and metyrapone (0.5 g/4 h per os), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of glucagon response), the PAP clamp was performed with maintenance of plasma glucagon at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. The PAP clamp (study 2) reproduced glucose concentrations and fluxes observed in study 1. In studies 3 and 4, isolated lack of glucagon response did not affect glucose utilization but caused an early and persistent decrease in hepatic glucose production (approximately 60%) that caused plasma glucose to decrease to 38 +/- 2 mg/dl (P less than 0.01 vs. control 62 +/- 2 mg/dl), despite compensatory increases in plasma epinephrine. We conclude that, in a model of clinical hypoglycemia, glucagon's effect on hepatic glucose production is a dominant counterregulatory factor in humans and that its absence cannot be compensated for by increased epinephrine secretion.

Alterations in carbohydrate metabolism in response to short-term dietary carbohydrate restriction

2005 ◽  
Vol 289 (2) ◽  
pp. E306-E312 ◽  
Author(s):  
Matthew P. Harber ◽  
Simon Schenk ◽  
Ariel L. Barkan ◽  
Jeffrey F. Horowitz
Keyword(s):  
Glucose Uptake ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Carbohydrate Oxidation ◽  
Metabolic Effects ◽  
Glucose Disposal ◽  
Carbohydrate Restriction ◽  
Dietary Carbohydrate ◽  
Endogenous Glucose ◽  
Glucose Availability

Dietary carbohydrate restriction (CR) presents a challenge to glucose homeostasis. Despite the popularity of CR diets, little is known regarding the metabolic effects of CR. The purpose of this study was to examine changes in whole body carbohydrate oxidation, glucose availability, endogenous glucose production, and peripheral glucose uptake after dietary CR, without the confounding influence of a negative energy balance. Postabsorptive rates of glucose appearance in plasma (Ra; i.e., endogenous glucose production) and disappearance from plasma (Rd; i.e., glucose uptake) were measured using isotope dilution methods after a conventional diet [60% carbohydrate (CHO), 30% fat, and 10% protein; kcals = 1.3 × resting energy expenditure (REE)] and after 2 days and 7 days of CR (5% CHO, 60% fat, and 35% protein; kcals = 1.3 × REE) in eight subjects (means ± SE; 29 ± 4 yr; BMI 24 ± 1 kg/m2) during a 9-day hospital visit. Postabsorptive plasma glucose concentration was reduced ( P = 0.01) after 2 days but returned to prediet levels the next day and remained at euglycemic levels throughout the diet (5.1 ± 0.2, 4.3 ± 0.3, and 4.8 ± 0.4 mmol/l for prediet, 2 days and 7 days, respectively). Glucose Ra and glucose Rd were reduced to below prediet levels (9.8 ± 0.6 μmol·kg−1·min−1) after 2 days of CR (7.9 ± 0.3 μmol·kg−1·min−1) and remained suppressed after 7 days (8.3 ± 0.4 μmol·kg−1·min−1; both P < 0.001). A greater suppression in carbohydrate oxidation, compared with the reduction in glucose Rd, led to an increased (all P ≤ 0.05) rate of nonoxidative glucose disposal at 7 days (5.2 ± 0.5 μmol·kg−1·min−1), compared with 2 days (2.7 ± 0.5 μmol·kg−1·min−1) and prediet (1.6 ± 0.8 μmol·kg−1·min−1). In response to eucaloric CR, a marked increase in nonoxidative glucose disposal may help maintain systemic glucose availability.

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