Absorption and disposition of a glucose load in the conscious dog

The quantitative disposition of an intragastrically administered glucose load was studied in eight conscious 18-h fasted dogs using isotopic and arteriovenous (A-V) techniques. During the control period, the gut utilized 25% of the basal net hepatic glucose output (2.8 +/- 0.2 mg.kg-1.min-1). After glucose ingestion, 80% of the load was absorbed as glucose, 11% was converted across the gut to lactate and alanine, and 4% was oxidized to CO2. Two percent of the load remained in the gut 4 h after glucose administration and 3% was unaccounted for. During the absorptive period, net hepatic glucose balance (NHGB) varied considerably (mean range = output of 1.8 to uptake of 9.1 mg.kg-1.min-1), while endogenous hepatic glucose production (Ra hp) showed a consistent 80% suppression. The total net hepatic glucose uptake during the absorptive period (150 +/- 10 min) accounted for the disposal of 24 +/- 10% of the ingested load, and the amount of glucose escaping the splanchnic bed was 40 +/- 3%. Overall NHGB correlated positively with basal arterial glucose and insulin levels and negatively with basal arterial glycerol and FFA and with peak absorptive arterial glucose and insulin levels. These data suggest that the hepatic response to an ingested glucose load depends in part on the degree of metabolic fast of the animal at the time of glucose ingestion; the latter may be a major determinant of the roles played by the tissues in glucose disposal.

Download Full-text

Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00566.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. E958-E964 ◽

Cited By ~ 14

Author(s):

Sylvain Cardin ◽

Konstantin Walmsley ◽

Doss W. Neal ◽

Phillip E. Williams ◽

Alan D. Cherrington

Keyword(s):

Hepatic Glucose Production ◽

Control Period ◽

Glucose Production ◽

Heart Rate Change ◽

Vagus Nerves ◽

Hepatic Glucose Metabolism ◽

Vagal Blockade ◽

Hepatic Glucose ◽

Cooling Coils ◽

Glucose Output

We determined if blocking transmission in the fibers of the vagus nerves would affect basal hepatic glucose metabolism in the 18-h-fasted conscious dog. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon) was employed. A 40-min control period was followed by a 90-min test period. In one group, stainless steel cooling coils (Sham, n = 5) were perfused with a 37°C solution, while in the other (Cool, n = 6), the coils were perfused with −20°C solution. Vagal blockade was verified by heart rate change (80 ± 9 to 84 ± 14 beats/min in Sham; 98 ± 12 to 193 ± 22 beats/min in Cool). The arterial glucose level was kept euglycemic by glucose infusion. No change in tracer-determined glucose production occurred in Sham, whereas in Cool it dropped significantly (2.4 ± 0.4 to 1.9 ± 0.4 mg · kg−1· min−1). Net hepatic glucose output did not change in Sham but decreased from 1.9 ± 0.3 to 1.3 ± 0.3 mg · kg−1· min−1in the Cool group. Hepatic gluconeogenesis did not change in either group. These data suggest that vagal blockade acutely modulates hepatic glucose production by inhibiting glycogenolysis.

Download Full-text

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.4.e806 ◽

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.

Download Full-text

Islet cell responses to glucose in human transplanted pancreas

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1991.261.6.e800 ◽

1991 ◽

Vol 261 (6) ◽

pp. E800-E808 ◽

Cited By ~ 2

Author(s):

D. Elahi ◽

B. A. Clark ◽

M. McAloon-Dyke ◽

G. Wong ◽

R. Brown ◽

...

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Normal Subjects ◽

Systemic Circulation ◽

Glucose Disposal ◽

Complete Suppression ◽

Transplant Patients ◽

Hyperglycemic Clamp ◽

Hepatic Glucose ◽

Glucose Output

Postsurgery, pancreas transplantation results in alterations of carbohydrate metabolism. Additionally, immunosuppressive therapy impacts on glucose regulation. We evaluated the hormonal and metabolic responses of pancreas allografts, utilizing the hyperglycemic clamp technique coupled with the tritiated glucose methodology, in 11 volunteers who had received simultaneous pancreas-kidney transplantation (P-K) with systemic drainage. Their responses were compared with seven volunteers who had received only a kidney (K) graft and with seven normal control (C) volunteers. Although basal glucose and hepatic glucose output were similar in all three groups, basal insulin, C-peptide, glucagon, and pancreatic polypeptide were highest in the P-K group and lowest in normal subjects. During hyperglycemia, all groups showed a similar characteristic, initial complete suppression of hepatic glucose production, with recovery followed by a later suppression. Peripheral glucose uptake was similar in P-K and C subjects but decreased in K patients. Systemic insulin levels were fourfold higher in the pancreas transplant patients than in healthy subjects. Thus, under basal and hyperglycemic stimulation, 1) hepatic glucose homeostasis is regulated normally, even with pancreatic drainage into the systemic circulation; 2) overall glucose disposal is normal in P-K patients because of marked hyperinsulinemia; and 3) there is loss of tonic inhibition of endocrine pancreatic function secondary to pancreatic denervation.

Download Full-text

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.252.2.e230 ◽

1987 ◽

Vol 252 (2) ◽

pp. E230-E236 ◽

Cited By ~ 1

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.

Download Full-text

NSAID-Induced Enteropathy Affects Regulation of Hepatic Glucose Production by Decreasing GLP-1 Secretion

Nutrients ◽

10.3390/nu14010120 ◽

2021 ◽

Vol 14 (1) ◽

pp. 120

Author(s):

Hussein Herz ◽

Yang Song ◽

Yuanchao Ye ◽

Liping Tian ◽

Benjamin Linden ◽

...

Keyword(s):

Glucose Tolerance ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Treated Group ◽

Endogenous Glucose Production ◽

Glucose Disposal ◽

Control Group ◽

Euglycemic Hyperinsulinemic Clamp ◽

Insulin Levels ◽

Hepatic Glucose

Background/Aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9—a GLP-1 receptor antagonist—worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

Download Full-text

Peripheral effects of insulin dominate suppression of fasting hepatic glucose production

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.6.e1020 ◽

1990 ◽

Vol 258 (6) ◽

pp. E1020-E1032 ◽

Cited By ~ 25

Author(s):

M. Ader ◽

R. N. Bergman

Keyword(s):

Specific Activity ◽

Hepatic Glucose Production ◽

Insulin Dose ◽

Glucose Production ◽

Insulin Levels ◽

Exogenous Glucose ◽

Hepatic Glucose ◽

Glucose Output ◽

Gluconeogenic Substrates ◽

Intraportal Infusion

Insulin may suppress hepatic glucose production directly, or indirectly via suppression of release of gluconeogenic substrates from extrasplanchnic tissues. To compare these mechanisms, we performed insulin dose-response experiments in conscious dogs at euglycemia, during somatostatin infusion, and intraportal glucagon replacement. Insulin was sequentially infused either intraportally (0.05, 0.20, 0.40, 1.0, 1.4, and/or 3.0; protocol I) or systemically at half the intraportal rate (0.025, 0.10, 0.20, 0.50, 0.70, and/or 1.5 mU.min-1.kg-1; protocol II). Exogenous glucose infused during clamps was labeled with 3-[3H]glucose (2 microCi/g) to prevent a fall in plasma specific activity (P greater than 0.2) that may have contributed to previous underestimations of hepatic glucose output (HGO). Portal insulins were up to threefold higher during intraportal infusion, but peripheral insulin levels were not different between the intraportal and systemic protocols [7 +/- 5 vs. 9 +/- 1, 12 +/- 4 vs. 13 +/- 6, 16 +/- 3 vs. 27 +/- 5, 70 +/- 23 vs. 48 +/- 8, 83 +/- 3 vs. 86 +/- 21, and 128 vs. 120 +/- 14 microU/ml for paired insulin doses; P greater than 0.06 by analysis of variance (ANOVA)]. Despite higher portal insulin levels in protocol I, HGO suppression was equivalent in the two protocols when systemic insulin was matched, from 3.3 +/- 0.1 to near-total suppression at 0.3 mg.min-1.kg-1 at the highest insulin infusion rate (3.0 mU.min-1.kg-1; P less than 0.0001) with intraportal insulin, from 2.9 +/- 0.8 to -0.8 +/- 0.2 mg.min-1.kg-1 in protocol II (P less than 0.001). Suppression of HGO was similar at matched systemic insulin, regardless of portal insulin, suggesting the primacy of insulin's action on the periphery in its restraint of hepatic glucose production.

Download Full-text

Effect of a mixed meal on hepatic lactate and gluconeogenic precursor metabolism in dogs

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1984.247.3.e362 ◽

1984 ◽

Vol 247 (3) ◽

pp. E362-E369 ◽

Cited By ~ 5

Author(s):

M. A. Davis ◽

P. E. Williams ◽

A. D. Cherrington

Keyword(s):

Hepatic Glucose Production ◽

Lactate Production ◽

Glucose Production ◽

Hepatic Uptake ◽

Mixed Meal ◽

Arterial Lactate ◽

Hepatic Glucose ◽

Hepatic Glucose Uptake ◽

Arterial Glucose ◽

Arterial Lactate Level

The present experiments were undertaken to assess lactate and gluconeogenic precursor metabolism in the 30 h following consumption of a mixed meal by the overnight-fasted, conscious dog. The arterial glucose level rose by a maximum of 13 mg/dl 4 h after the meal and had returned to control levels by 12 h. Hepatic glucose production was suppressed for 12 h after feeding, but net hepatic glucose uptake did not occur. The arterial lactate level rose from 0.55 +/- 0.10 to 1.28 +/- 0.14 mM within 1 h of feeding and remained elevated for 12 h. Net hepatic lactate production, measured with an A-V difference technique, rose from 3.5 +/- 2.8 to 19.4 +/- 3.1 mumol X kg-1 X min-1 h after the meal and declined slowly over the next 22 h. The liver then began to consume lactate so that at 30 h net hepatic uptake was 5.7 +/- 0.5 mumol X kg-1 X min-1. The total hepatic uptake of the gluconeogenic amino acids (alanine, glycine, serine, threonine) increased from 5.3 +/- 0.8 to 11.5 +/- 2.5 mumol X kg-1 X min-1 at 1 h and remained elevated for 4 h. The arterial alanine level rose from 0.36 +/- 0.03 to 0.51 +/- 0.04 mM at 2 h and remained elevated for 18 h. Insulin increased from 11 +/- 2 microU/ml to a maximum of 44 +/- 5 4 h after the meal, and the glucagon level rose from 59 +/- 8 pg/ml to a maximum of 150 +/- 22 1 h after feeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00396.2014 ◽

2015 ◽

Vol 308 (4) ◽

pp. E306-E314 ◽

Cited By ~ 13

Author(s):

Satya S. Houin ◽

Paul J. Rozance ◽

Laura D. Brown ◽

William W. Hay ◽

Randall B. Wilkening ◽

...

Keyword(s):

Fetal Liver ◽

Hepatic Glucose Production ◽

Plasma Concentrations ◽

Glucose Production ◽

Late Gestation ◽

Fetal Sheep ◽

Fetal Plasma ◽

Hepatic Glucose ◽

Molar Percent ◽

Glucose Output

Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 ( P < 0.05). The liver transitioned from net glucose uptake (basal, 5.1 ± 1.5 μmol/min) to output by d4 (2.8 ± 1.4 μmol/min; P < 0.05 vs. basal). The [U-13C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 ± 0.01, vs. d4: 0.89 ± 0.01, P < 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 ( P < 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia ( P < 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Download Full-text

Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.1.e1 ◽

1993 ◽

Vol 264 (1) ◽

pp. E1-E10 ◽

Cited By ~ 2

Author(s):

L. Rossetti ◽

S. Farrace ◽

S. B. Choi ◽

A. Giaccari ◽

L. Sloan ◽

...

Keyword(s):

Skeletal Muscle ◽

Glycogen Synthase ◽

Hepatic Glucose Production ◽

Glycogen Synthesis ◽

Plasma Concentrations ◽

Glucose Production ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Intracellular Glucose

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

Download Full-text