Attenuation of glucose metabolic changes resulting from TNF-alpha administration by adrenergic blockade

1992 ◽  
Vol 262 (4) ◽  
pp. R628-R635 ◽  
Author(s):  
G. J. Bagby ◽  
C. H. Lang ◽  
N. Skrepnik ◽  
J. J. Spitzer
Keyword(s):  
Glucose Uptake ◽  
Glucose Production ◽  
Whole Body ◽  
Tnf Alpha ◽  
Adrenergic System ◽  
Adrenergic Blockade ◽  
Hepatic Glucose ◽  
Glucose Output

Administration of tumor necrosis factor (TNF-alpha) increases whole body glucose kinetics and stimulates in vivo glucose uptake by several tissues. Because circulating catecholamines are also increased after TNF-alpha administration, the present study was conducted to examine the potential role of the adrenergic system in eliciting these changes. Rats given 150 micrograms TNF-alpha/kg by intravenous infusion over a 30-min period exhibited an increased rate of glucose appearance (glucose Ra). Combined alpha- and beta-adrenergic blockade (phentolamine and propranolol infusion) prevented the TNF-alpha-induced increase in glucose Ra without influencing plasma glucagon or corticosterone levels. TNF-alpha infusion also increased in vivo glucose utilization (Rg), measured with 2-deoxy-[14C]glucose, in spleen (86%), liver (80%), skin (47%), ileum (71%), lung (53%), and heart (112%). Adrenergic blockade prevented the tissue Rg increase in the spleen, liver, and skin; partially reduced it in the ileum; but did not abrogate it in the lung or heart. The effect of blockade was primarily due to inhibition of the TNF-alpha-induced increase in hepatic glucose output. Whereas the adrenergic system plays a major role on the effect of TNF-alpha on whole body glucose production, its importance in directly mediating TNF-alpha's effect on tissue glucose uptake is minimal.

scholarly journals Role of hepatic α- and β-adrenergic receptor stimulation on hepatic glucose production during heavy exercise

1997 ◽  
Vol 273 (5) ◽  
pp. E831-E838 ◽  
Author(s):  
Robert H. Coker ◽  
Mahesh G. Krishna ◽  
D. Brooks Lacy ◽  
Deanna P. Bracy ◽  
David H. Wasserman
Keyword(s):  
Portal Vein ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Test Period ◽  
Saline Control ◽  
Adrenergic Blockade ◽  
Heavy Exercise ◽  
Hepatic Glucose ◽  
Glucose Output

The role of catecholamines in the control of hepatic glucose production was studied during heavy exercise in dogs, using a technique to selectively block hepatic α- and β-adrenergic receptors. Surgery was done >16 days before the study, at which time catheters were implanted in the carotid artery, portal vein, and hepatic vein for sampling and the portal vein and vena cava for infusions. In addition, flow probes were implanted on the portal vein and hepatic artery. Each study consisted of a 100-min equilibration, a 30-min basal, a 20-min heavy exercise (∼85% of maximum heart rate), a 30-min recovery, and a 30-min adrenergic blockade test period. Either saline (control; n= 7) or α (phentolamine)- and β (propranolol)-adrenergic blockers (Blk; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the portal vein during the blockade test period to create supraphysiological levels at the liver. Isotope ([3-3H]glucose) dilution and arteriovenous differences were used to assess hepatic function. Arterial Epi, NE, glucagon, and insulin levels were similar during exercise in both groups. Endogenous glucose production (Ra) rose similarly during exercise to 7.9 ± 1.2 and 7.5 ± 2.0 mg ⋅ kg−1⋅ min−1in control and Blk groups at time = 20 min. Net hepatic glucose output also rose to a similar rate in control and Blk groups with exercise. During the blockade test period, arterial plasma glucose and Rarose to 164 ± 5 mg/dl and 12.0 ± 1.4 mg ⋅ kg−1⋅ min−1, respectively, but were essentially unchanged in Blk. The attenuated response to catecholamine infusion in Blk substantiates the effectiveness of the hepatic adrenergic blockade. In conclusion, these results show that direct hepatic adrenergic stimulation does not participate in the increase in Ra, even during the exaggerated sympathetic response to heavy exercise.

Impact of glutamine supplementation on glucose homeostasis during and after exercise

2005 ◽  
Vol 99 (5) ◽  
pp. 1858-1865 ◽  
Author(s):  
Soh Iwashita ◽  
Phillip Williams ◽  
Kareem Jabbour ◽  
Takeo Ueda ◽  
Hisamine Kobayashi ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Glucose Homeostasis ◽  
Glucose Production ◽  
Hepatic Uptake ◽  
Whole Body ◽  
Glutamine Supplementation ◽  
Hepatic Glucose ◽  
Postexercise Recovery ◽  
Glucose Output ◽  
Treatment Order

The interaction of glutamine availability and glucose homeostasis during and after exercise was investigated, measuring whole body glucose kinetics with [3-3H]glucose and net organ balances of glucose and amino acids (AA) during basal, exercise, and postexercise hyperinsulinemic-euglycemic clamp periods in six multicatheterized dogs. Dogs were studied twice in random treatment order: once with glutamine (12 μmol·kg−1·min−1; Gln) and once with saline (Con) infused intravenously during and after exercise. Plasma glucose fell by 7 mg/dl with exercise in Con ( P < 0.05), but it did not fall with Gln. Gln further stimulated whole body glucose production and utilization an additional 24% above a normal exercise response ( P < 0.05). Net hepatic uptake of glutamine and alanine was greater with Gln than Con during exercise ( P < 0.05). Net hepatic glucose output was increased sevenfold during exercise with Gln ( P < 0.05) but not with Con. Net hindlimb glucose uptake was increased similarly during exercise in both groups ( P < 0.05). During the postexercise hyperinsulinemic-euglycemic period, glucose production decreased to near zero with Con, but it did not decrease below basal levels with Gln. Gln increased glucose utilization by 16% compared with Con after exercise ( P < 0.05). Furthermore, net hindlimb glucose uptake in the postexercise period was increased approximately twofold vs. basal with Gln ( P < 0.05) but not with Con. Net hepatic uptake of glutamine during the postexercise period was threefold greater for Gln than Con ( P < 0.05). In conclusion, glutamine availability modulates glucose homeostasis during and after exercise, which may have implications for postexercise recovery.

scholarly journals Importance of the route of insulin delivery to its control of glucose metabolism

2021 ◽  
Author(s):  
Dale S. Edgerton ◽  
Mary Courtney Moore ◽  
Justin M. Gregory ◽  
Guillaume Kraft ◽  
Alan D. Cherrington
Keyword(s):  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
The Body ◽  
Whole Body ◽  
Direct Effects ◽  
Pancreatic Insulin ◽  
Hepatic Glucose

Pancreatic insulin secretion produces an insulin gradient at the liver compared to the rest of the body (approximately 3:1). This physiologic distribution is lost when insulin is injected subcutaneously, causing impaired regulation of hepatic glucose production and whole body glucose uptake, as well as arterial hyperinsulinemia. Thus, the hepatoportal insulin gradient is essential to the normal control of glucose metabolism during both fasting and feeding. Insulin can regulate hepatic glucose production and uptake through multiple mechanisms, but its direct effects on the liver are dominant under physiologic conditions. Given the complications associated with iatrogenic hyperinsulinemia in patients treated with insulin, insulin designed to preferentially target the liver may have therapeutic advantages.

scholarly journals Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver

2020 ◽  
Vol 117 (12) ◽  
pp. 6733-6740 ◽  
Author(s):  
Thiago M. Batista ◽  
Sezin Dagdeviren ◽  
Shannon H. Carroll ◽  
Weikang Cai ◽  
Veronika Y. Melnik ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Insulin Action ◽  
Hepatic Glucose Production ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Glycogen Accumulation ◽  
Hepatic Glucose ◽  
Glucose Output

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show thatArrdc3is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction inArrdc3messenger RNA, while, conversely, mice with liver-specific KO ofArrdc3(L-Arrdc3KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus,Arrdc3is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

The direct effects of catecholamines on hepatic glucose production occur via α1- and β2-receptors in the dog

2000 ◽  
Vol 279 (2) ◽  
pp. E463-E473 ◽  
Author(s):  
Chang An Chu ◽  
Dana K. Sindelar ◽  
Kayano Igawa ◽  
Stephanie Sherck ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Test Period ◽  
Receptor Subtypes ◽  
Adrenergic Blockade ◽  
Direct Effects ◽  
Period 2 ◽  
Hepatic Glucose ◽  
Group 2 ◽  
Glucose Output

The role of α- and β-adrenergic receptor subtypes in mediating the actions of catecholamines on hepatic glucose production (HGP) was determined in sixteen 18-h-fasted conscious dogs maintained on a pancreatic clamp with basal insulin and glucagon. The experiment consisted of a 100-min equilibration, a 40-min basal, and two 90-min test periods in groups 1 and 2, plus a 60-min third test period in groups 3 and 4. In group 1 [α-blockade with norepinephrine (α-blo+NE)], phentolamine (2 μg · kg−1 · min−1) was infused portally during both test periods, and NE (50 ng · kg−1 · min−1) was infused portally at the start of test period 2. In group 2, β-blockade with epinephrine (β-blo+EPI), propranolol (1 μg · kg−1 · min−1) was infused portally during both test periods, and EPI (8 ng · kg−1 · min−1) was infused portally during test period 2. In group 3 (α1-blo+NE), prazosin (4 μg · kg−1 · min−1) was infused portally during all test periods, and NE (50 and 100 ng · kg−1 · min−1) was infused portally during test periods 2 and 3, respectively. In group 4(β2-blo+EPI), butoxamine (40 μg · kg−1 · min−1) was infused portally during all test periods, and EPI (8 and 40 ng · kg−1 · min−1) was infused portally during test periods 2 and 3, respectively. In the presence of α- or α1-adrenergic blockade, a selective rise in hepatic sinusoidal NE failed to increase net hepatic glucose output (NHGO). In a previous study, the same rate of portal NE infusion had increased NHGO by 1.6 ± 0.3 mg · kg−1 · min−1. In the presence of β- or β2-adrenergic blockade, the selective rise in hepatic sinusoidal EPI caused by EPI infusion at 8 ng · kg−1 · min−1 also failed to increase NHGO. In a previous study, the same rate of EPI infusion had increased NHGO by 1.6 ± 0.4 mg · kg−1 · min−1. In conclusion, in the conscious dog, the direct effects of NE and EPI on HGP are predominantly mediated through α1- and β2-adrenergic receptors, respectively.

scholarly journals Autoregulation of hepatic glucose production

1998 ◽  
pp. 240-248 ◽  
Author(s):  
MC Moore ◽  
CC Connolly ◽  
AD Cherrington
Keyword(s):  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Glycogen ◽  
Neural Pathways ◽  
Hepatic Glucose Output ◽  
Counterregulatory Hormones ◽  
Hepatic Glucose ◽  
Glucose Output

In vitro evidence indicates that the liver responds directly to changes in circulating glucose concentrations with reciprocal changes in glucose production and that this autoregulation plays a role in maintenance of normoglycemia. Under in vivo conditions it is difficult to separate the effects of glucose on neural regulation mediated by the central nervous system from its direct effect on the liver. Nevertheless, it is clear that nonhormonal mechanisms can cause significant changes in net hepatic glucose balance. In response to hyperglycemia, net hepatic glucose output can be decreased by as much as 60-90% by nonhormonal mechanisms. Under conditions in which hepatic glycogen stores are high (i.e. the overnight-fasted state), a decrease in the glycogenolytic rate and an increase in the rate of glucose cycling within the liver appear to be the explanation for the decrease in hepatic glucose output seen in response to hyperglycemia. During more prolonged fasting, when glycogen levels are reduced, a decrease in gluconeogenesis may occur as a part of the nonhormonal response to hyperglycemia. A substantial role for hepatic autoregulation in the response to insulin-induced hypoglycemia is most clearly evident in severe hypoglycemia (< or = 2.8 mmol/l). The nonhormonal response to hypoglycemia apparently involves enhancement of both gluconeogenesis and glycogenolysis and is capable of supplying enough glucose to meet at least half of the requirement of the brain. The nonhormonal response can include neural signaling, as well as autoregulation. However, even in the absence of the ability to secrete counterregulatory hormones (glucocorticoids, catecholamines, and glucagon), dogs with denervated livers (to interrupt neural pathways between the liver and brain) were able to respond to hypoglycemia with increases in net hepatic glucose output. Thus, even though the endocrine system provides the primary response to changes in glycemia, autoregulation plays an important adjunctive role.

Pressor doses of angiotensin II increase insulin-mediated glucose uptake in normotensive men

1993 ◽  
Vol 265 (3) ◽  
pp. E362-E366 ◽  
Author(s):  
R. R. Townsend ◽  
D. J. DiPette
Keyword(s):  
Angiotensin Ii ◽  
Glucose Uptake ◽  
Whole Body ◽  
Glucose Disposal ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Cast Doubt ◽  
Normotensive Subjects ◽  
Glucose Output ◽  
Biochemical Action

The effect of pressor doses of angiotensin II infused intravenously on insulin-mediated glucose uptake was determined in normotensive men. A 3-h hyperinsulinemic euglycemic clamp was employed in 14 normotensive subjects to determine insulin-mediated glucose uptake with or without an infusion of angiotensin II (approximately 15 ng.kg-1.min-1), which increased blood pressure by 20/15 mmHg (systolic/diastolic). Addition of angiotensin II increased whole body glucose uptake by 15% (9.2 +/- 0.5 vs. 10.8 +/- 0.8 mg.kg-1 x min-1; P = 0.011), and glucose oxidation (determined by indirect calorimetry) by 25% (4.0 +/- 0.3 vs. 4.9 +/- 0.4 mg.kg-1 x min-1; P < 0.05) over insulin alone. There was no significant increase in hepatic glucose output during angiotensin II infusion (2.2 +/- 0.1 vs. 2.4 +/- 0.1 mg.kg-1 x min-1; P = NS). We conclude that angiotensin II in pressor doses increases insulin-mediated glucose disposal and oxidation. The mechanism for this may involve a redirection of blood flow into skeletal muscle during angiotensin II infusion or a direct biochemical action of angiotensin II. Although performed in lean normotensive subjects, these results cast doubt on a significant role for angiotensin II in the insulin resistance associated with essential hypertension.

Acute effects of insulin-like growth factor I and insulin on glucose metabolism in vivo

1990 ◽  
Vol 259 (4) ◽  
pp. E561-E567 ◽  
Author(s):  
R. T. Moxley ◽  
P. Arner ◽  
A. Moss ◽  
A. Skottner ◽  
M. Fox ◽  
...  
Keyword(s):  
Growth Factor ◽  
Glucose Metabolism ◽  
Metabolic Rate ◽  
Glucose Uptake ◽  
Whole Body ◽  
Hepatic Glucose ◽  
Igf I ◽  
Glucose Metabolic Rate ◽  
Stimulation Of

We have compared the actions of insulin-like growth factor (IGF-I) and insulin on glucose metabolism in vivo, using the glucose clamp technique in rats. Both hormones caused dose-dependent inhibition of hepatic glucose production, stimulation of whole body glucose disposal, and an increase in the glucose metabolic rate of specific muscles. Infusion of IGF-I also decreased the plasma concentration of insulin. An an infusion rate of 0.57 nmol.kg-1.min-1, IGF-I led to stimulation of whole body glucose uptake that was similar to the glucose uptake produced by infusion of 0.01 nmol.kg-1.min-1 insulin. The glucose metabolic rate, as measured by 2-deoxy-D-glucose uptake, was comparable in quadriceps femoris, soleus, and diaphragm muscles during the infusion of 0.57 nmol.kg-1.min-1 IGF-I and 0.01 nmol.kg-1.min-1 insulin. However, at these rates of infusion, IGF-I caused only a 38 +/- 6% inhibition of hepatic glucose output compared with 66 +/- 12% inhibition by insulin (P less than 0.05). Thus, under these conditions, muscle is more responsive than liver to IGF-I, which agrees with the complement of IGF-I receptors in the two tissues.

Role of gluconeogenesis in epinephrine-stimulated hepatic glucose production in humans

1983 ◽  
Vol 245 (3) ◽  
pp. E294-E302 ◽  
Author(s):  
L. Sacca ◽  
C. Vigorito ◽  
M. Cicala ◽  
G. Corso ◽  
R. S. Sherwin
Keyword(s):  
Plasma Insulin ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Base Line ◽  
Epinephrine Infusion ◽  
Hepatic Glucose ◽  
Normal Humans ◽  
Glucose Output ◽  
Sustained Increase

To evaluate the contribution of gluconeogenesis to epinephrine-stimulated glucose production, we infused epinephrine (0.06 micrograms X kg-1 X min-1) for 90 min into normal humans during combined hepatic vein catheterization and [U-14C]alanine infusion. Epinephrine infusion produced a rise in blood glucose (50-60%) and plasma insulin (30-40%), whereas glucagon levels increased only at 30 min (19%, P less than 0.05). Net splanchnic glucose output transiently increased by 150% and then returned to base line by 60 min. In contrast, the conversion of labeled alanine and lactate into glucose increased fourfold and remained elevated throughout the epinephrine infusion. Similarly, epinephrine produced a sustained increase in the net splanchnic uptake of cold lactate (four- to fivefold) and alanine (50-80%) although the fractional extraction of both substrates by splanchnic tissues was unchanged. We conclude that a) epinephrine is a potent stimulator of gluconeogenesis in humans, and b) this effect is primarily mediated by mobilization of lactate and alanine from extrasplanchnic tissues. Our data suggest that the initial epinephrine-induced rise in glucose production is largely due to activation of glycogenolysis. Thereafter, the effect of epinephrine on glycogenolysis (but not gluconeogenesis) wanes, and epinephrine-stimulated gluconeogenesis becomes the major factor maintaining hepatic glucose production.

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