Increase In Endogenous Glucose Production Research Articles

Effect of Halothane Anesthesia on Glucose Utilization and Production in Adolescents

It should be possible to avoid variations in plasma glucose concentration during anesthesia by adjusting glucose infusion rate to whole-body glucose uptake. To study this hypothesis, we measured glucose utilization and production, before and during halothane anesthesia. After an overnight fast, six adolescents between 12 and 17 yr of age were infused with tracer doses of [6,6-2H2]glucose for 2 h before undergoing anesthesia, and the infusion was continued after induction, until the beginning of surgery. Plasma glucose concentration was monitored throughout, and free fatty acids, lactate, insulin, and glucagon concentrations were measured before and during anesthesia. Despite the use of a glucose-free maintenance solution, plasma glucose concentration increased slightly but significantly 5 min after induction (5.3 +/- 0.4 vs. 4.5 +/- 0.4 mmol.l-1, P < 0.05). This early increase corresponded to a significant increase in endogenous glucose production over basal conditions (4.1 +/- 0.4 vs. 3.6 +/- 0.2 mg.kg-1.min-1, P < 0.05), with no concomitant change in peripheral glucose utilization. Fifteen minutes after induction, both glucose utilization and production rates decreased steadily and were 20% less than basal values by 35 min after induction (2.9 +/- 0.3 vs. 3.6 +/- 0.2 mg.kg-1.min-1, P < 0.05). Similarly, glucose metabolic clearance rate decreased by 25% after 35 min. Despite the increase in blood glucose concentration, anesthesia resulted in a significant decrease in plasma insulin concentration. These data suggest that halothane anesthesia per se affects glucose metabolism. The decrease in peripheral glucose utilization and metabolic clearance rates and the blunted insulin release question the relevance of glucose infusion in these clinical settings.

Effect of tumor necrosis factor on substrate and amino acid kinetics in conscious dogs.

Two groups of conscious dogs were studied using isotopic tracer techniques to test the hypothesis that tumor necrosis factor (TNF) affects glucose production, lipolysis, amino acid, and protein kinetics. [1-13C]leucine, [15N2]urea, [6,6-2H2]glucose, and [2H5]glycerol were infused to determine the leucine, urea, glucose, and lipid kinetics, and NaH14CO3 was infused to determine the rate of CO2 production. In one group, after a 2-h basal period (period 1), recombinant human TNF was infused (prime, 2.5 micrograms/kg; constant, 62.5 ng.kg-1.min-1) for 2 h (period 2; group 1, n = 15). Group 2 received saline rather than TNF in period 2 (n = 3). TNF infusion caused a significant increase in endogenous glucose production, a significant increase in glucose clearance rate, and a decrease in glycerol flux. Although TNF infusion did not change leucine flux, leucine oxidation increased by 49% (P < 0.0001), and nonoxidative leucine disappearance decreased during TNF infusion by 13% (P < 0.0001). TNF infusion also caused a significant increase (18%) in endogenous urea production. TNF significantly increased plasma glucagon concentration. We conclude that TNF causes a shift toward carbohydrate metabolism and stimulates the oxidation of amino acids. Whereas whole body protein breakdown is not affected by TNF, protein synthesis is impaired, leading to an increase in net protein breakdown.

Effects of treadmill exercise on fuel metabolism in hepatic cirrhosis

We studied whole body and regional fuel metabolism before, during, and after 90 min of treadmill exercise at 50% of maximal aerobic capacity (VO2max) in four subjects with hepatic cirrhosis and in four normal volunteers. Rates of endogenous glucose production (EGP) were measured using D-[6-3H]glucose infusions and fuel oxidation using indirect calorimetry. In the basal state, cirrhotic subjects had similar rates of EGP compared with controls. Forearm release of alanine and lactate was significantly greater in cirrhotic subjects (P less than 0.05), suggesting increased basal rates of gluconeogenesis. During exercise, EGP increased 2- to 2.5-fold in control subjects (P less than 0.01) but did not increase in cirrhotic subjects. Despite lower glucose concentrations in cirrhotic subjects, progressive hypoglycemia did not occur during exercise, probably because cirrhotic subjects demonstrated increased plasma concentrations of fat-derived substrates and derived a greater percentage of total energy requirement from fat oxidation than did controls (P less than 0.05) and because forearm muscle glucose extraction was significantly lower in cirrhotic subjects compared with controls (0.5 vs. 3.6%, respectively; P less than 0.05). During recovery, control subjects demonstrated significant increases in EGP rates compared with both the basal and exercise periods, but cirrhotic subjects showed no increase. In conclusion, cirrhotic subjects failed to demonstrate the normal increase in EGP during and after exercise. Significant hypoglycemia during exercise did not occur, possibly because of the increased availability of fat-derived fuels, which may spare the requirement for circulating glucose as an oxidative fuel for exercising muscle tissues.

Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects

Raised levels of free fatty acids (FFA) compete with glucose for utilization by insulin-sensitive tissues, and, therefore, they may induce insulin resistance in the normal subject. The influence of experimental elevations in FFA levels on glucose metabolism in native insulin-resistant states is not known. We studied seven women with moderate obesity (63% above their ideal body weight) but normal glucose tolerance with the use of the insulin clamp technique with or without an infusion of Intralipid + heparin. Upon raising plasma insulin levels to ∼60 μU/mL while maintaining euglycemia, whole body glucose utilization ( 3H-3-glucose) rose similarly without (from 66 ± 7 to 113 ± 11 mg/min m 2, P < .02) or with (from 70 ± 7 to 137 ± 19 mg/min m 2, P < .02) concomitant lipid infusion. In contrast, endogenous glucose production was considerably (73%) suppressed (from 66 ± 7 to 15 ± 8 mg/min m 2, P < .001) during the clamp without lipid, but declined only marginally (from 70 ± 7 to 48 ± 7 mg/min m 2, NS) with lipid administration. The difference between the control and the lipid study was highly significant ( P < .02), and amounted to an average of 3.8 g of relative glucose overproduction during the second hour of the clamp. Blood levels of lactate rose by 34 ± 15% (.1 > P > .05) in the control study but only by 17 ± 10% (NS) during lipid infusion. Blood pyruvate concentrations fell in both sets of experiments (by ∼45% at the end of the study) with similar time courses. In contrast, blood alanine levels did not change from baseline during the control clamp (181 ± 18 v 185 ± 14 μmol/L) whereas they fell slightly (11 ± 3%) but consistently (175 ± 15 v 196 ± 14 μmol/L, P < .02) during lipid infusion. Furthermore, a positive correlation was found to exist in the pooled data between the decrease in blood alanine concentrations and the corresponding increase in endogenous glucose production ( r = .59, P < .02). We conclude that in the obese subject an increased supply of fatty fuels fails to inhibit insulin-mediated glucose disposal but induces hepatic insulin resistance. The greater availability of exogenous glucose precursors (glycerol) and the lower circulating levels of endogenous precursors (lactate and alanine) suggest that the observed increase in endogenous glucose production is sustained by hepatic gluconeogenesis.

Epinephrine-stimulated glucose production is not diminished by starvation: evidence for an effect on gluconeogenesis.

We infused physiological doses of epinephrine (1.2 microgram/m2 X min) into six healthy obese subjects in the postabsorptive state and after 3-4 days of starvation. During starvation, a reduction in hepatic glycogen stores was demonstrated by the absence of a rise in plasma glucose and glucose production (using [3-3H]glucose) in response to glucagon infusion. The increases in plasma epinephrine and glucose during the epinephrine infusion were comparable before and after starvation. Most importantly, the increase in endogenous glucose production produced by epinephrine was virtually unaffected, i.e. the initial rise in glucose production (59% vs. 49%), the incremental area under the curve (2.6 vs. 3.1 g/m2), and the spike-decline pattern of the response were no different before and after starvation, respectively. Similarly, epinephrine-induced elevations in gluconeogenic precursors (lactate and alanine) were not altered by starvation. However, starvation accentuated the rise in FFA by 200%. We conclude that starvation does not diminish the rise in endogenous glucose production in response to stress-like elevations of epinephrine. This occurs even though the liver fails to respond to high physiological doses of glucagon, possibly because epinephrine enhances the mobilization of gluconeogenic precursors and FFA. These data suggest that epinephrine is a potent stimulator of gluconeogenesis and may be more effective than glucagon in accelerating glucose production in patients with depleted glycogen stores.

Evidence for an intrahepatic contribution to the waning effect of glucagon on glucose production in the conscious dog.

We previously showed that infusion of glucagon at four times the basal rate into conscious dogs given somatostatin and basal replacement amounts of insulin caused hyperglycemia (217 15 mg/dl) for at least 3 h and an initial increment in hepatic glucose production of 5.5 0.8 mg/kg . min. After 3 h, however, the effect of hyperglucagonemia on glucose production had declined by 85%. The aim of the present study was to determine the importance of hyperglycemia in the "downregulation" of the action of glucagon. Six overnight-fasted conscious dogs were given somatostatin (0.8 microgram/kg . min) plus basal intraportal replacement amounts of insulin (263 microunits/kg . min) and glucagon (0.65 ng/kg . min). Hyperglycemia (276 12 md/dl) was established after 2 h by the infusion of exogenous glucose. The glucagon infusion rate was then increased fourfold 1 h later, so that the plasma glucagon level rose from 95 16 to 227 35 pg/ml. The glucose concentration was maintained at a fixed value despite the increase in glucagon by decreasing the glucose infusion rate by an amount equal to the increase in endogenous glucose production induced by the hormone. Glucose production was measured using a primed infusion of 3H-glucose. With the insulin (11 2 microunits/ml) and glucose levels fixed, the elevation in glucagon caused an initial increment of 5.1 0.7 mg/kg . min in glucose production which was followed by a fall of only 2.5 0.4 mg/kg . min (50%) over the next 3 hr. Thus, when the plasma glucagon level is raised fourfold under conditions in which insulin mobilization cannot occur, the effect of hyperglucagonemia on glucose production will be partially offset by the resulting hyperglycemia and partly inhibited by an hepatic factor(s).

Lack of an increase in endogenous glucose production during insulin-induced hypoglycemia in the rat.

Journal Article Lack of an Increase in Endogenous Glucose Production During Insulin-Induced Hypoglycemia in the Rat Get access J. COLE, J. COLE *Department of Physiology, University of Ottawa Ottawa, Ontario, Canada Search for other works by this author on: Oxford Academic Google Scholar C. J. ACHOU, C. J. ACHOU *Department of Physiology, University of Ottawa Ottawa, Ontario, Canada Search for other works by this author on: Oxford Academic Google Scholar G. HETENYI, JR. G. HETENYI, JR. *Department of Physiology, University of Ottawa Ottawa, Ontario, Canada Search for other works by this author on: Oxford Academic Google Scholar Endocrinology, Volume 93, Issue 6, 1 December 1973, Pages 1438–1441, https://doi.org/10.1210/endo-93-6-1438 Published: 01 December 1973 Article history Received: 18 April 1972 Published: 01 December 1973

Stimulation of glucose production by hypoxia in newborn dogs.

The aim of the experiments was to examine the role of hypoxia as a possible regulator of hepatic glucose production in newborn dogs. In pups 1–30 days of age the rate of endogenous (hepatic) glucose production increased when the animals were ventilated with a gas mixture containing 10% or 5% O2. During a single 45 min exposure to hypoxia the increase in glucose production was significantly correlated with the O2 saturation in arterial blood. A second exposure to the more severe hypoxia (5% O2) following the first (10% O2) led to a second increase in the concentration of glucose in plasma and in glucose production. In pups less than 10 days of age, the increases during the second hypoxic period were only transient. During a 60 min rest following exposure to the more severe hypoxia (5% O2) basal glucose production rates and plasma concentrations were not reestablished. The metabolic clearance rate of glucose was not changed by hypoxia. There was a significant drop in plasma free fatty acid level. The increase in endogenous glucose production to hypoxia in pups indicates that the liver in the newborn animal is capable of increasing the rate of glucose production and that the known lack of a response to hypoglycemia is due to the absence of the feedback between glucose production and extracellular glucose concentration.