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Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog

Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeuti...

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Autores principales: Edgerton, Dale S., Moore, Mary C., Winnick, Jason J., Scott, Melanie, Farmer, Ben, Naver, Helle, Jeppesen, Claus B., Madsen, Peter, Kjeldsen, Thomas B., Nishimura, Erica, Brand, Christian L., Cherrington, Alan D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392933/
https://www.ncbi.nlm.nih.gov/pubmed/24947349
http://dx.doi.org/10.2337/db14-0266
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author Edgerton, Dale S.
Moore, Mary C.
Winnick, Jason J.
Scott, Melanie
Farmer, Ben
Naver, Helle
Jeppesen, Claus B.
Madsen, Peter
Kjeldsen, Thomas B.
Nishimura, Erica
Brand, Christian L.
Cherrington, Alan D.
author_facet Edgerton, Dale S.
Moore, Mary C.
Winnick, Jason J.
Scott, Melanie
Farmer, Ben
Naver, Helle
Jeppesen, Claus B.
Madsen, Peter
Kjeldsen, Thomas B.
Nishimura, Erica
Brand, Christian L.
Cherrington, Alan D.
author_sort Edgerton, Dale S.
collection PubMed
description Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally or peripherally were compared with an acylated insulin model compound (insulin-327) in dogs. During somatostatin and basal portal vein glucagon infusion, insulin was infused portally (PoHI; 1.8 pmol/kg/min; n = 7) or peripherally (PeHI; 1.8 pmol/kg/min; n = 8) and insulin-327 (Pe327; 7.2 pmol/kg/min; n = 5) was infused peripherally. Euglycemia was maintained by glucose infusion. While the effects on liver glucose metabolism were greatest in the PoHI and Pe327 groups, nonhepatic glucose uptake increased most in the PeHI group. Suppression of lipolysis was greater during PeHI than PoHI and was delayed in Pe327 infusion. Thus small increments in portal vein insulin have major consequences on the liver, with little effect on nonhepatic glucose metabolism, whereas insulin delivered peripherally cannot act on the liver without also affecting nonhepatic tissues. Pe327 functionally restored the physiologic portal–arterial gradient and thereby produced hepato-preferential effects.
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spelling pubmed-43929332015-11-01 Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog Edgerton, Dale S. Moore, Mary C. Winnick, Jason J. Scott, Melanie Farmer, Ben Naver, Helle Jeppesen, Claus B. Madsen, Peter Kjeldsen, Thomas B. Nishimura, Erica Brand, Christian L. Cherrington, Alan D. Diabetes Pharmacology and Therapeutics Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally or peripherally were compared with an acylated insulin model compound (insulin-327) in dogs. During somatostatin and basal portal vein glucagon infusion, insulin was infused portally (PoHI; 1.8 pmol/kg/min; n = 7) or peripherally (PeHI; 1.8 pmol/kg/min; n = 8) and insulin-327 (Pe327; 7.2 pmol/kg/min; n = 5) was infused peripherally. Euglycemia was maintained by glucose infusion. While the effects on liver glucose metabolism were greatest in the PoHI and Pe327 groups, nonhepatic glucose uptake increased most in the PeHI group. Suppression of lipolysis was greater during PeHI than PoHI and was delayed in Pe327 infusion. Thus small increments in portal vein insulin have major consequences on the liver, with little effect on nonhepatic glucose metabolism, whereas insulin delivered peripherally cannot act on the liver without also affecting nonhepatic tissues. Pe327 functionally restored the physiologic portal–arterial gradient and thereby produced hepato-preferential effects. American Diabetes Association 2014-11 2014-10-13 /pmc/articles/PMC4392933/ /pubmed/24947349 http://dx.doi.org/10.2337/db14-0266 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
spellingShingle Pharmacology and Therapeutics
Edgerton, Dale S.
Moore, Mary C.
Winnick, Jason J.
Scott, Melanie
Farmer, Ben
Naver, Helle
Jeppesen, Claus B.
Madsen, Peter
Kjeldsen, Thomas B.
Nishimura, Erica
Brand, Christian L.
Cherrington, Alan D.
Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog
title Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog
title_full Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog
title_fullStr Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog
title_full_unstemmed Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog
title_short Changes in Glucose and Fat Metabolism in Response to the Administration of a Hepato-Preferential Insulin Analog
title_sort changes in glucose and fat metabolism in response to the administration of a hepato-preferential insulin analog
topic Pharmacology and Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392933/
https://www.ncbi.nlm.nih.gov/pubmed/24947349
http://dx.doi.org/10.2337/db14-0266
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