5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside renders glucose output by the liver of the dog insensitive to a pharmacological increment in insulin

2005 ◽  
Vol 289 (6) ◽  
pp. E1039-E1043 ◽  
Author(s):  
Raul C. Camacho ◽  
D. Brooks Lacy ◽  
Freyja D. James ◽  
E. Patrick Donahue ◽  
David H. Wasserman
Keyword(s):  
Portal Vein ◽  
Vena Cava ◽  
Glucose Production ◽  
Suppressive Effect ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Output ◽  
Study Protocols ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Arterial Insulin

This study aimed to test whether stimulation of net hepatic glucose output (NHGO) by increased concentrations of the AMP analog, 5-aminoimidazole-4-carboxamide-1-β-d-ribosyl-5-monophosphate, can be suppressed by pharmacological insulin levels. Dogs had sampling (artery, portal vein, hepatic vein) and infusion (vena cava, portal vein) catheters and flow probes (hepatic artery, portal vein) implanted >16 days before study. Protocols consisted of equilibration (−130 to −30 min), basal (−30 to 0 min), and hyperinsulinemic-euglycemic (0–150 min) periods. At time ( t) = 0 min, somatostatin was infused, and basal glucagon was replaced via the portal vein. Insulin was infused in the portal vein at either 2 (INS2) or 5 (INS5) mU·kg−1·min−1. At t = 60 min, 1 mg·kg−1·min−1portal venous 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) infusion was initiated. Arterial insulin rose ∼9- and ∼27-fold in INS2 and INS5, respectively. Glucagon, catecholamines, and cortisol did not change throughout the study. NHGO was completely suppressed before t = 60 min. Intraportal AICAR stimulated NHGO by 1.9 ± 0.5 and 2.0 ± 0.5 mg·kg−1·min−1in INS2 and INS5, respectively. AICAR stimulated tracer-determined endogenous glucose production similarly in both groups. Intraportal AICAR infusion significantly increased hepatic acetyl-CoA carboxylase (ACC, Ser79) phosphorylation in INS2. Hepatic ACC (Ser79) phosphorylation, however, was not increased in INS5. Thus intraportal AICAR infusion renders hepatic glucose output insensitive to pharmacological insulin. The effectiveness of AICAR in countering the suppressive effect of pharmacological insulin on NHGO occurs even though AICAR-stimulated ACC phosphorylation is completely blocked.

scholarly journals Unlike mice, dogs exhibit effective glucoregulation during low-dose portal and peripheral glucose infusion

2004 ◽  
Vol 286 (2) ◽  
pp. E226-E233 ◽  
Author(s):  
Mary Courtney Moore ◽  
Sylvain Cardin ◽  
Dale S. Edgerton ◽  
Ben Farmer ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Low Dose ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Output ◽  
Arterial Blood ◽  
Hepatic Glucose ◽  
Arterial Blood Glucose ◽  
Hepatic Portal ◽  
Glucose Output ◽  
Arteriovenous Difference

Portal infusion of glucose in the mouse at a rate equivalent to basal endogenous glucose production causes hypoglycemia, whereas peripheral infusion at the same rate causes significant hyperglycemia. We used tracer and arteriovenous difference techniques in conscious 42-h-fasted dogs to determine their response to the same treatments. The studies consisted of three periods: equilibration (100 min), basal (40 min), and experimental (180 min), during which glucose was infused at 13.7 μmol· kg–1·min–1 into a peripheral vein (PE, n = 5) or the hepatic portal (PO, n = 5) vein. Arterial blood glucose increased ∼0.8 mmol/l in both groups. Arterial and hepatic sinusoidal insulin concentrations were not significantly different between groups. PE exhibited an increase in nonhepatic glucose uptake (non-HGU; Δ8.6 ± 1.2 μmol·kg–1·min–1) within 30 min, whereas PO showed a slight suppression (Δ–3.7 ± 3.1 μmol·kg–1·min–1). PO shifted from net hepatic glucose output (NHGO) to uptake (NHGU; 2.5 ± 2.8 μmol·kg–1·min–1) within 30 min, but PE still exhibited NHGO (6.0 ± 1.9 μmol·kg–1·min–1) at that time and did not initiate NHGU until after 90 min. Glucose rates of appearance and disappearance did not differ between groups. The response to the two infusion routes was markedly different. Peripheral infusion caused a rapid enhancement of non-HGU, whereas portal delivery quickly activated NHGU. As a result, both groups maintained near-euglycemia. The dog glucoregulates more rigorously than the mouse in response to both portal and peripheral glucose delivery.

Effects of infused fructose on endogenous glucose production, gluconeogenesis, and glycogen metabolism

1994 ◽  
Vol 267 (5) ◽  
pp. E710-E717 ◽  
Author(s):  
P. Tounian ◽  
P. Schneiter ◽  
S. Henry ◽  
E. Jequier ◽  
L. Tappy
Keyword(s):  
Control Experiment ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Glycogen Metabolism ◽  
Endogenous Glucose Production ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Endogenous Glucose ◽  
Glycogen Deposition ◽  
Glucose Output

To determine the mechanisms that prevent an increase in gluconeogenesis from increasing hepatic glucose output, six healthy women were infused with [1-13C]fructose (22 mumol.kg-1.min-1), somatostatin, insulin, and glucagon. In control experiment, non-13C-enriched fructose was infused at the same rate without somatostatin, and [U-13C]glucose was infused to measure specifically plasma glucose oxidation. Endogenous glucose production (EGP, [6,6-2H]glucose), net carbohydrate oxidation (CHOox, indirect calorimetry), and fructose oxidation (13CO2) were measured. EGP rate did not increase after fructose infusion with (13.1 +/- 1.2 vs. 12.9 +/- 0.3 mumol.kg-1.min-1) and without (10.3 +/- 0.5 vs. 9.7 +/- 0.5 mumol.kg-1.min-1) somatostatin, despite the fact that gluconeogenesis increased. Nonoxidative fructose disposal, corresponding mainly to glycogen synthesis, was threefold net glycogen deposition, the latter calculated as fructose infusion minus CHOox (14.8 +/- 1.1 and 4.3 +/- 2.0 mumol.kg-1.min-1). It is concluded that 1) the mechanism by which EGP remains constant when gluconeogenesis from fructose increases is independent of changes in insulin and 2) simultaneous breakdown and synthesis of glycogen occurred during fructose infusion.

Effect of a selective rise in hepatic artery insulin on hepatic glucose production in the conscious dog

1999 ◽  
Vol 276 (4) ◽  
pp. E806-E813
Author(s):  
Dana K. Sindelar ◽  
Kayano Igawa ◽  
Chang A. Chu ◽  
Jim H. Balcom ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Portal Vein ◽  
Hepatic Artery ◽  
Insulin Infusion ◽  
Hepatic Glucose Production ◽  
Control Period ◽  
Glucose Production ◽  
Insulin Level ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Selective Increase

In the present study we compared the hepatic effects of a selective increase in hepatic sinusoidal insulin brought about by insulin infusion into the hepatic artery with those resulting from insulin infusion into the portal vein. A pancreatic clamp was used to control the endocrine pancreas in conscious overnight-fasted dogs. In the control period, insulin was infused via peripheral vein and the portal vein. After the 40-min basal period, there was a 180-min test period during which the peripheral insulin infusion was stopped and an additional 1.2 pmol ⋅ kg−1⋅ min−1of insulin was infused into the hepatic artery (HART, n = 5) or the portal vein (PORT, n = 5, data published previously). In the HART group, the calculated hepatic sinusoidal insulin level increased from 99 ± 20 (basal) to 165 ± 21 pmol/l (last 30 min). The calculated hepatic artery insulin concentration rose from 50 ± 8 (basal) to 289 ± 19 pmol/l (last 30 min). However, the overall arterial (50 ± 8 pmol/l) and portal vein insulin levels (118 ± 24 pmol/l) did not change over the course of the experiment. In the PORT group, the calculated hepatic sinusoidal insulin level increased from 94 ± 30 (basal) to 156 ± 33 pmol/l (last 30 min). The portal insulin rose from 108 ± 42 (basal) to 192 ± 42 pmol/l (last 30 min), whereas the overall arterial insulin (54 ± 6 pmol/l) was unaltered during the study. In both groups hepatic sinusoidal glucagon levels remained unchanged, and euglycemia was maintained by peripheral glucose infusion. In the HART group, net hepatic glucose output (NHGO) was suppressed from 9.6 ± 2.1 μmol ⋅ kg−1⋅ min−1(basal) to 4.6 ± 1.0 μmol ⋅ kg−1⋅ min−1(15 min) and eventually fell to 3.5 ± 0.8 μmol ⋅ kg−1⋅ min−1(last 30 min, P < 0.05). In the PORT group, NHGO dropped quickly ( P < 0.05) from 10.0 ± 0.9 (basal) to 7.8 ± 1.6 (15 min) and eventually reached 3.1 ± 1.1 μmol ⋅ kg−1⋅ min−1(last 30 min). Thus NHGO decreases in response to a selective increase in hepatic sinusoidal insulin, regardless of whether it comes about because of hyperinsulinemia in the hepatic artery or portal vein.

Effect of infusion of insulin into portal vein on hepatic extraction of insulin in anesthetized dogs

1975 ◽  
Vol 228 (5) ◽  
pp. 1580-1588 ◽  
Author(s):  
PE Harding ◽  
G Bloom ◽  
JB Field
Keyword(s):  
Portal Vein ◽  
Insulin Infusion ◽  
Significant Proportion ◽  
Fold Increase ◽  
Constant Infusion ◽  
Hepatic Extraction ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Anesthetized Dogs ◽  
Glucose Output

Hepatic extraction of insulin was examined in anesthetized dogs before and after constant infusion of insulin (20 and 50 mU/min) with use of samples from the portal vein, mesenteric vein, left common hepatic vein, and the femoral artery. In 19 dogs, measurement of portal vein insulin concentration indicated an overall recovery of 110% of the insulin infused. The range varied from 9 to 303%, indicating the potential for serious error in sampling the portal vein. Equilibrium arterial insulin concentrations were achieved 20 min after starting the infusion. Prior to insulin infusion, hepatic extraction of insulin averaged 4.56 plus or minus 0.43 mUmin, representing an extraction coefficient of 0.42 of the insulin presented to the liver. The proportion of insulin extracted by the liver did not change significantly during insulin infusion despite a 10-fold increase in portal vein insulin concentrations. During the infusion of insulin, a significant proportion of the extraheptic clearance of insulin occurred in the mesenteric circulation. Infusion of insulin was associated with a significant increase in insulin extraction by tissues other than the liver and splanchnic beds. Initially, hepatic glucose output average 36 plus or minus 3 mg/min; by 20 min after insulin infusion, it was 16 plus or minus 5 mg/min. Despite continuation of insulin infusion, hepatic glucose output returned to control values even though arterial glucose concentration continued to fall. Hepatic glucose output increased with termination of insulin infusion.

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.

Effects of fructose on hepatic glucose metabolism in humans

2000 ◽  
Vol 279 (4) ◽  
pp. E907-E911 ◽  
Author(s):  
Mirjam Dirlewanger ◽  
Philippe Schneiter ◽  
Eric Jéquier ◽  
Luc Tappy
Keyword(s):  
Glycogen Synthesis ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Hepatic Glycogen ◽  
Healthy Humans ◽  
Hepatic Glucose Metabolism ◽  
Insulin Requirements ◽  
Hepatic Glucose ◽  
Total Glucose ◽  
Glucose Output

Hepatic and extrahepatic insulin sensitivity was assessed in six healthy humans from the insulin infusion required to maintain an 8 mmol/l glucose concentration during hyperglycemic pancreatic clamp with or without infusion of 16.7 μmol · kg−1 · min−1fructose. Glucose rate of disappearance (GRd), net endogenous glucose production (NEGP), total glucose output (TGO), and glucose cycling (GC) were measured with [6,6-2H2]- and [2-2H1]glucose. Hepatic glycogen synthesis was estimated from uridine diphosphoglucose (UDPG) kinetics as assessed with [1-13C]galactose and acetaminophen. Fructose infusion increased insulin requirements 2.3-fold to maintain blood glucose. Fructose infusion doubled UDPG turnover, but there was no effect on TGO, GC, NEGP, or GRd under hyperglycemic pancreatic clamp protocol conditions. When insulin concentrations were matched during a second hyperglycemic pancreatic clamp protocol, fructose administration was associated with an 11.1 μmol · kg−1 · min−1increase in TGO, a 7.8 μmol · kg−1 · min−1increase in NEGP, a 2.2 μmol · kg−1 · min−1increase in GC, and a 7.2 μmol · kg−1 · min−1decrease in GRd ( P < 0.05). These results indicate that fructose infusion induces hepatic and extrahepatic insulin resistance in humans.

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.

Influence of somatostatin on glucagon- and epinephrine-stimulated hepatic glucose output in the dog.

1979 ◽  
Vol 236 (2) ◽  
pp. E113
Author(s):  
L Saccà ◽  
R Sherwin ◽  
P Felig
Keyword(s):  
Plasma Glucose ◽  
Glucose Production ◽  
Conscious Dogs ◽  
Insulin Deficiency ◽  
Hepatic Glucose Output ◽  
Glucose Kinetics ◽  
Insulin Levels ◽  
Hepatic Glucose ◽  
Glucose Output ◽  
Insulin Replacement

Glucose kinetics were measured using [3-3H]glucose in conscious dogs during the infusion of: 1) glucagon alone; 2) glucagon plus somatostatin with insulin replacement; 3) epinephrine alone; and 4) epinephrine plus somatostatin with insulin and glucagon replacement. Infusion of glucagon alone resulted in a 10-15 mg/dl rise in plasma glucose and a transient 45% rise in glucose production. When somatostatin and insulin were added, a four- to fivefold greater rise in plasma glucose and glucose production was observed. Glucagon levels were comparable to those achieved with infusion of glucagon alone, whereas peripheral insulin levels increased three- to fourfold above baseline, suggesting adequate replacement of preinfusion portal insulin levels. Infusion of epinephrine alone produced a 40% rise in plasma glucose and a 100% rise in glucose production. When somatostatin, insulin, and glucagon were added to epinephrine, the rise in glucose production was reduced in 65% despite replacement of glucagon levels and presumably mild portal insulin deficiency. These findings suggest that somatostatin: 1) potentiates the stimulatory effect of physiologic hyperglucagonemia on glucose production independent of insulin availability and 2) blunts the stimulatory effect of physiologic increments of epinephrine independent of glucagon availability.

Increased net hepatic glucose output from gluconeogenic precursors after high-sucrose diet feeding in male rats

1997 ◽  
Vol 272 (2) ◽  
pp. R526-R531 ◽  
Author(s):  
M. J. Pagliassotti ◽  
P. A. Prach
Keyword(s):  
Insulin Resistance ◽  
Glucose Production ◽  
Male Rats ◽  
Hepatic Insulin Resistance ◽  
Hepatic Glucose Output ◽  
Hepatic Glucose ◽  
Sucrose Diet ◽  
High Sucrose Diet ◽  
Glucose Output ◽  
High Sucrose

A high-sucrose diet reduces the ability of insulin to suppress hepatic glucose production (hepatic insulin resistance) in rats. The purpose of the present study was to investigate the contribution of hepatic gluconeogenesis to sucrose-induced hepatic insulin resistance. Single-pass liver perfusions were performed on 24-h food-deprived male Wistar rats after 8 wk on either a high-corn starch (ST; 68% of energy) or high-sucrose (SU; 68% of energy) diet. Hepatic glucose output (HGO, micromol of glucose x min(-1) x g(-1)) in the presence of lactate, alanine, or dihydroxyacetone (DHA) was used as an estimate of gluconeogenic capacity, because liver glycogen levels after the 24-h fast were negligible (<1.2 mg/g). HGO was significantly (P < 0.05) greater in SU vs. ST at all concentrations of lactate, alanine, and DHA. Maximal rates of HGO were 1.9 +/- 0.4 and 2.8 +/- 0.3 at 10 mM lactate, 0.6 +/- 0.2 and 1.4 +/- 0.3 at 10 mM alanine, and 1.7 +/- 0.3 and 2.6 +/- 0.2 at 20 mM DHA in ST and SU, respectively. When HGO was matched between SU and ST with the use of different precursor concentrations, there was a significant (P < 0.05) reduction in the ability of insulin (175 microU/ml) to suppress HGO in SU vs. ST. These data suggest that sucrose feeding increases gluconeogenesis from lactate, alanine, and DHA and that this route of glucose production is resistant to insulin suppression.

Selective suppression of hepatic glucose output by human proinsulin in the dog

1987 ◽  
Vol 252 (2) ◽  
pp. E230-E236 ◽  
Author(s):  
M. Lavelle-Jones ◽  
M. H. Scott ◽  
O. Kolterman ◽  
A. H. Rubenstein ◽  
J. M. Olefsky ◽  
...  
Keyword(s):  
Hepatic Glucose Production ◽  
Hormone Secretion ◽  
Glucose Production ◽  
Glucose Disposal ◽  
Glucose Turnover ◽  
Hepatic Glucose Output ◽  
Glucose Clamp Technique ◽  
Hepatic Glucose ◽  
The Mean ◽  
Glucose Output

By using the euglycemic glucose-clamp technique we have observed the effects of comparable low dose proinsulin and insulin infusions on isotopically determined glucose turnover in 20 anesthetized dogs. In each animal somatostatin (SRIF) infusion was used to suppress endogenous pancreatic hormone secretion and basal glucagon was replaced. Peripheral proinsulin (0.083 micrograms X kg-1 X min-1) and insulin (350 microU X kg-1 X min-1) levels 15- to 20-fold higher than insulin on a molar basis, based on previous observations that proinsulin has only 5-10% the biologic potency of insulin. Three groups of infusion studies were performed: SRIF and glucagon (n = 5); SRIF, glucagon, and proinsulin (n = 10); and SRIF, glucagon, and insulin (n = 5). The mean serum proinsulin level of 2.43 +/- 0.36 pmol/ml achieved represented a 17-fold excess compared with the mean serum insulin level of 0.14 +/- 0.03 pmol (20 +/- 4 microU/ml). At these concentrations, both hormones reduced hepatic glucose production rates by approximately 50% to 2.0 +/- 0.2 mg X kg-1 X min-1 and 1.8 +/- 0.5 mg X kg-1 X min-1, respectively. In contrast, proinsulin failed to stimulate peripheral glucose utilization, whereas insulin led to a 2.0 +/- 0.3 mg X kg-1 X min-1 increment (approximately 50% increase) in glucose uptake (P less than 0.05). Thus at low infusion rates proinsulin exerts its effect predominantly by suppressing hepatic glucose production without measurable stimulation of peripheral glucose disposal. In contrast, for a comparable degree of hepatic glucose output suppression, insulin also significantly stimulates glucose disposal.

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