A comparison of the effects of selective increases in peripheral or portal insulin on hepatic glucose production in the conscious dog
Abstract
We investigated the mechanisms by which peripheral or portal insulin can independently alter liver glucose production. Isotopic ([3-3H]glucose) and arteriovenous difference methods were used in conscious overnight-fasted dogs. A pancreatic clamp (somatostatin plus basal insulin and basal glucagon infusions) was used to control the endocrine pancreas. After a 40-min basal period, a 180-min experimental period followed in which selective increases in peripheral (PERI group, n = 5) or portal-vein (PORT group, n = 5) insulin were induced. In control dogs (CONT group, n = 10), insulin was not increased. Glucagon levels were fixed in all studies, and basal euglycemia was maintained by peripheral glucose infusion in the two experimental groups. In the PERI group, arterial insulin rose from 36 +/- 12 to 120 +/- 12 pmol/l, while portal insulin was unaltered. In the PORT group, portal insulin rose from 108 +/- 42 to 192 +/- 42 pmol/l, while arterial insulin was unaltered. Neither arterial nor portal insulin changed from basal in the CONT group. With a selective rise in peripheral insulin, the net hepatic glucose output (NHGO; basal, 11.8 +/- 0.7 micromol x kg-1 x min-1) did not change initially (11.8 +/- 2.1 micromol x kg-1 x min-1, 30 min after the insulin increase), but eventually fell (P < 0.05 ) to 6.1 +/- 0.9 micromol x kg-1 x min-1 (last 30 min). With a selective rise in portal insulin, NHGO dropped quickly (P < 0.05) from 10.0 +/- 0.9 to 5.6 +/- 0.6 micromol x kg-1 x min-1 (30 min after the insulin increase) and eventually reached 3.1 +/- 1.1 micromol x kg-1 x min-1 (last 30 min). When insulin levels were not increased (CONT group), NHGO dropped progressively from 10.1 +/- 0.6 to 8.3 +/- 0.6 micromol x kg-1 x min-1 (last 30 min). Conclusions drawn from the net hepatic glucose balance data were confirmed by the tracer data. Net hepatic gluconeogenic substrate uptake (three carbon precursors) fell 2.0 micromol x kg-1 x min-1 in the PERI group, but rose 1.2 micromol x kg-1 x min-1 in the PORT group and 1.2 micromol x kg-1 x min-1 in the CONT group. A selective 84 pmol/l rise in arterial insulin was thus associated with a fall in NHGO of approximately 50%, which took 1 h to manifest. Conversely, a selective 84 pmol/l rise in portal insulin was associated with a 50% fall in NHGO, which occurred quickly (15 min). From the control data, it is evident that in either case approximately 30% of the fall in NHGO was due to a drift down in baseline and that 70% was due to the rise in insulin. In conclusion, an increment in portal insulin had a rapid inhibitory effect on NHGO, caused by the suppression of glycogenolysis, while an equal increment in arterial insulin produced an equally potent but slower effect that resulted from a small increase in hepatic sinusoidal insulin, from a suppression of gluconeogenic precursor uptake by the liver, and from a redirection of glycogenolytic carbon to lactate rather than glucose.
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Insulin modulates hepatic glycogen degradation in canines and humans, although the sensitivity of glycogenolysis and gluconeogenesis to insulin concentration may differ substantially.
“This is evidenced by the modulating influence of insulin on hepatic glycogen degradation in both canines [109] and humans [110], although the sensitivity of glycogenolysis and gluconeogenesis to insulin concentration may differ substantially [110].”
From Regulation of Energy Substrate Metabolism in Endurance Exercise (2021) · cites this paper as [109]
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Self-citationEffects of portal free fatty acid elevation on insulin clearance and hepatic glucose flux
Yoshii, H., Lam, T. K. T., Gupta, N., Goh, T. T., Haber, C. A., Uchino, H., Kim, T. T. Y., Chong, V. Z., Shah, K. B., Fantus, I. G., et al. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00306.2005 · Cited by 40 · see citing works
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“Data from several studies suggest that the short-term effect of insulin on glucose production is primarily via suppression of glycogenolysis and not gluconeogenesis [20-23].”
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“The phenomenon of insulindependent receptor internalization is best documented in liver: insulin concentrations in the portal vein are about fourfold higher than in the hepatic vein owing to receptormediated clearance (8).”
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Pancreatic Response to Mild Non–Insulin-Induced Hypoglycemia Does Not Involve Extrinsic Neural Input
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“These correction factors were used because the gut has been shown to destroy some of the insulin (25) and glucagon (26) in blood as the organ is perfused.”
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Self-citationJackson, P. A., Cardin, S., Coffey, C. S., Neal, D. W., Allen, E. J., Penaloza, A. R., Snead, W. L., & Cherrington, A. D. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.6.e1249 · Cited by 31 · see citing works
“Plasma [3-(3)H]glucose was determined by liquid scintillation counting after Somogyi-Nelson deproteinization and a (3)H2O exclusion procedure (24).”
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“The collection and processing of blood samples have been described previously (21).”
MethodSelf-citationImportance of the route of insulin delivery to its control of glucose metabolism
Edgerton, D. S., Moore, M. C., Gregory, J. M., Kraft, G., & Cherrington, A. D. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00628.2020 · Cited by 30 · see citing works
Self-citationEdgerton, D. S., Cardin, S., Pan, C., Neal, D. W., Farmer, B., Converse, M., & Cherrington, A. D. (2002) · Diabetes · doi:10.2337/diabetes.51.11.3151 · Cited by 29 · see citing works
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Control of Glucose Production in vivo by Insulin and Glucagon
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“It is being debated whether insulin exerts different effects on EGP when delivered through the hepatic artery (23) or through the portal vein (24,25) and which of these routes is more important for the regulation of EGP.”
BackgroundFructose augments infection-impaired net hepatic glucose uptake during TPN administration
Donmoyer, C. M., Ejiofor, J., Lacy, D. B., et al. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.5.e703 · Cited by 28 · see citing works
“In the case of insulin, the equation was modified to account for the extraction of insulin by the nonhepatic splanchnic tissues (28).”
BackgroundSindelar, D. K., Chu, C. A., Neal, D. W., & Cherrington, A. D. (1997) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1997.273.5.e972 · Cited by 28 · see citing works
Self-citationHepatic glucose disposition during concomitant portal glucose and amino acid infusions in the dog
Moore, M. C., Flakoll, P. J., Hsieh, P., Pagliassotti, M. J., Neal, D. W., Monohan, M., Venable, C. L., & Cherrington, A. D. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.274.5.e893 · Cited by 27 · see citing works
“In the presence of a euglycemic, hyperinsulinemic (,120 pM) clamp, the fractional extraction of gluconeogenic amino acids did not change compared with basal conditions (28).”
BackgroundSelf-citationCanavan, J. P., New, J. P., Alberti, K. G. M. M., et al. (1997) · Diabetologia · doi:10.1007/s001250050797 · Cited by 26 · see citing works
Pancreatic Islet Cell Transplantation
Ridgway, D. M., White, S. A., Nicholson, M. L., & Kimber, R. M. (2003) · Treatments in Endocrinology · doi:10.2165/00024677-200302030-00004 · Cited by 23 · see citing works
Prior Exercise and Postprandial Incretin Responses in Lean and Obese Individuals
Heden, T. D., Liu, Y., Kearney, M. L., Park, Y., Dellsperger, K. C., Thomas, T. R., & Kanaley, J. A. (2013) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e318294b225 · Cited by 24 · see citing works
Impact of continuous and pulsatile insulin delivery on net hepatic glucose uptake
Grubert, J., Lautz, M., Lacy, D. B., Moore, M. C., Farmer, B., Penaloza, A. R., Cherrington, A. D., & McGuinness, O. P. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00567.2004 · Cited by 24 · see citing works
“This observation is consistent with previous studies in which plasma glucose concentrations 190 mg/dl in the presence of elevated insulin levels (4 basal) were shown to effectively suppress glucose production by the liver (23, 26).”
BackgroundResultSelf-citationCardin, S., Jackson, P. A., Edgerton, D. S., Neal, D. W., Coffey, C. S., & Cherrington, A. D. (2001) · Diabetes · doi:10.2337/diabetes.50.3.558 · Cited by 24 · see citing works
“The collection and processing of blood samples have been described previously (15).”
MethodSelf-citationEffects of Long-Term Cranberry Supplementation on Endocrine Pancreas in Aging Rats
Zhu, M., Hu, J., Perez, E., et al. (2011) · The Journals of Gerontology Series A · doi:10.1093/gerona/glr105 · Cited by 23 · see citing works
Peripheral glucose homeostasis: does brain insulin matter?
Levin, B. E., & Sherwin, R. S. (2011) · Journal of Clinical Investigation · doi:10.1172/jci59653 · Cited by 22 · see citing works
Chokkalingam, K., Tsintzas, K., Snaar, J. E. M., Norton, L., Solanky, B., Leverton, E., Morris, P. G., Mansell, P., & Macdonald, I. A. (2007) · Diabetologia · doi:10.1007/s00125-007-0747-4 · Cited by 22 · see citing works
“A large body of evidence concerning hepatic glucose metabolism during exercise in diabetes has been derived from animal experiments [18–22] but there is a lack of in vivo human data.”
BackgroundMason, T. M., Gupta, N., Goh, T. T., et al. (2000) · Metabolism · doi:10.1053/meta.2000.17731 · Cited by 21 · see citing works
Impact of acute epinephrine removal on hepatic glucose metabolism during stress hormone infusion.
McGuinness, O. P., Snowden, R. T., Moran, C., Neal, D., Fujiwara, T., & Cherrington, A. (1999) · Metabolism: Clinical and Experimental · doi:10.1016/s0026-0495(99)90228-7 · Cited by 19 · see citing works
Self-citationEthnicity affects the postprandial regulation of glycogenolysis
Balasubramanyam, A., McKay, S. V., Nadkarni, P., Rajan, A. S., Garza, A., Pavlik, V., Herd, J. A., Jahoor, F., & Reeds, P. J. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.5.e905 · Cited by 20 · see citing works
Sekigami, T., Shimoda, S., Nishida, K., et al. (2004) · Journal of Artificial Organs · doi:10.1007/s10047-004-0251-2 · Cited by 20 · see citing works
“HGP is suppressed by both the direct and indirect actions of insulin.(27) The direct action can inhibit glycogenolysis and gluconeogenesis by directly controlling some key regulatory enzymes in the liver, and the indirect action decreases the supply of free fatty acids and glycerol from peripheral tissues to the liver…”
BackgroundInsulin action during late pregnancy in the conscious dog
Connolly, C. C., Aglione, L. N., Smith, M. S., Lacy, D. B., & Moore, M. C. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00143.2003 · Cited by 20 · see citing works
“However, the insulin levels used in the present study to assess the magnitude of peripheral insulin resistance may have masked pregnancy-induced alterations in hepatic insulin action, since the liver of the nonpregnant dog (and the human as well) is quite sensitive to slight increases in insulin (31, 36).”
BackgroundInsulin acutely suppresses glucose production by both peripheral and hepatic effects in normal dogs
McCall, R. H., Wiesenthal, S. R., Shi, Z. Q., Polonsky, K. S., & Giacca, A. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.274.2.e346 · Cited by 19 · see citing works
Johnson, K., Edgerton, D. S., Rodewald, T., Scott, M. F., Farmer, B., Neal, D. W., & Cherrington, A. D. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00642.2007 · Cited by 18 · see citing works
“Plasma insulin and glucagon concentrations were determined by RIA, as previously described (24).”
MethodSelf-citationRates of glucagon activation and deactivation of hepatic glucose production in conscious dogs
Dobbins, R. L., Davis, S. N., Neal, D. W., Caumo, A., Cobelli, C., & Cherrington, A. D. (1998) · Metabolism · doi:10.1016/s0026-0495(98)90209-8 · Cited by 19 · see citing works
Self-citationCamacho, R. C., Pencek, R., Lacy, D. B., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.2.285 · Cited by 18 · see citing works
“(12) found that insulin’s direct inhibitory effect (suppression of glycogenolysis) on Ra was more rapid.”
BackgroundMethodInfluentialIs Brain Insulin Action Relevant to the Control of Plasma Glucose in Humans?
Edgerton, D. S., & Cherrington, A. D. (2015) · Diabetes · doi:10.2337/db14-1666 · Cited by 17 · see citing works
“On the other hand, in another study a selective increase in insulin at the liver (but not brain) suppressed EGP within 15 min (22).”
BackgroundSelf-citationThe effects of HDV-insulin on carbohydrate metabolism in Type 1 diabetic patients
Davis, S. N., Geho, B., Tate, D. B., et al. (2001) · Journal of Diabetes and its Complications · doi:10.1016/s1056-8727(01)00154-4 · Cited by 16 · see citing works
Yoshimura, K., Hirano, S., Takata, H., et al. (2017) · Journal of Diabetes Investigation · doi:10.1111/jdi.12622 · Cited by 16 · see citing works
Insulin’s effect on glucose production: direct or indirect?
Barrett, E. J. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17881 · Cited by 14 · see citing works
“However, carefully designed experiments in which portal or peripheral insulin concentrations were selectively and independently varied convincingly demonstrated an indirect or peripheral effect of insulin to lower hepatic glucose production (13).”
BackgroundInfection impairs insulin-dependent hepatic glucose uptake during total parenteral nutrition
Donmoyer, C. M., Chen, S., Lacy, D. B., et al. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00035.2002 · Cited by 14 · see citing works
“8 in the equation accounts for the 20% extraction of circulating insulin that is degraded as blood flows through the gastrointestinal tract (23).”
BackgroundLevi Spear Parmly: the apostle of dental hygiene.
Sanoudos, M., & Christen, A. G. (1999) · PubMed · Cited by 15 · see citing works
The kinetics of glucagon action on the liver during insulin-induced hypoglycemia
Pedersen, C., Kraft, G., Edgerton, D. S., Scott, M. F., Farmer, B., Smith, M. S., LaNeve, D. C., Williams, P. E., Moore, L. M., & Cherrington, A. D. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00466.2019 · Cited by 13 · see citing works
Self-citationInsulin Sensitively Controls the Glucagon Response to Mild Hypoglycemia in the Dog
Igawa, K., Mugavero, M., Shiota, M., Neal, D. W., & Cherrington, A. D. (2002) · Diabetes · doi:10.2337/diabetes.51.10.3033 · Cited by 13 · see citing works
“7 because the gut fractional extraction of insulin is 30% (25).”
BackgroundSelf-citationFisher, S. E., Shi, Z., Lickley, H. L. A., et al. (2001) · Journal of Endocrinology · doi:10.1677/joe.0.1680049 · Cited by 12 · see citing works
“Since insulin’s direct effect on suppressing GP consists primarily of inhibiting glycogenolysis (Sindelar et al. 1996), the www.endocrinology.org Journal of Endocrinology (2001) 168, 49–58 Downloaded from Bioscientifica.com at 06/07/2022 03:01:40PM via free access diminished rates of glycogenolysis…”
BackgroundInfluentialMason, T. M., Chan, B., El-Bahrani, B., et al. (2002) · Atherosclerosis · doi:10.1016/s0021-9150(01)00659-1 · Cited by 10 · see citing works
Bedinger, D., Kieffer, D. A., Goldfine, I. D., Roell, M. K., & Adams, S. H. (2015) · Journal of Cellular Biochemistry · doi:10.1002/jcb.25168 · Cited by 8 · see citing works
“The systemically-elevated insulin levels resulting from peripheral insulin therapy acts on the muscle and adipose tissue to both increase glucose uptake and decrease the availability of gluconeogenic substrates coming to the liver [Sindelar et al., 1996].”
BackgroundEndogenously released GLP-1 is not sufficient to alter postprandial glucose regulation in the dog
Johnson, K., Farmer, T. E., Schurr, K., Donahue, E. P., Farmer, B., Neal, D. W., & Cherrington, A. D. (2011) · Endocrine · doi:10.1007/s12020-011-9441-x · Cited by 9 · see citing works
Self-citationGupta, N., Sandhu, H., Goh, T. T., Shah, K. B., Wiesenthal, S. R., Yoshii, H., Chong, V. Z., Lam, T. K. T., Haber, C. A., Williams, W. G., et al. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00091.2002 · Cited by 9 · see citing works
“, due to hepatic sinusoidal insulin’s interaction with the hepatocyte insulin receptor (18, 19, 28, 29, 31, 32), and in part indirect, due to peripheral insulin’s actions on extrahepatic tissues (1, 18, 19, 23, 28, 29, 31, 32).”
Background
- Authors
- Sindelar, D. K., Balcom, J. H., Chu, C. A., Neal, D. W., & Cherrington, A. D.
- Affiliations
- Vanderbilt University (US)
- ORCID
- Cherrington, Alan D
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1996-11-01
- Volume
- 45
- Issue
- 11
- Pages
- 1594-1604
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2122611589
- Cited by
- 134
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 2 · 2018: 2 · 2017: 5 · 2016: 2 · 2015: 5 · 2014: 5 · 2013: 6 · 2012: 1
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institute of Diabetes and Digestive and Kidney Diseases (2RO1DK-18243, 5P60 DK 2059, R01DK018243)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- glucose production, hepatic glucose production, hepatic glucose metabolism, glucagon, conscious dogs, normoglycemia, glucose infusion
- MeSH terms
- Acetoacetates, Amino Acids, Animals, Arteries, Blood Glucose, Dogs, Fatty Acids, Nonesterified, Female, Gluconeogenesis, Glycerol, Hindlimb, Hydroxybutyrates, Infusions, Intravenous, Insulin, Islets of Langerhans, Liver, Male, Portal Vein, Somatostatin, Veins, 3-Hydroxybutyric Acid
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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