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Molecular Mechanism by which Guanide...

Madiraju, Anila Kanchan.

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Molecular Mechanism by which Guanide Compounds Inhibit Hepatic Gluconeogenesis.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Molecular Mechanism by which Guanide Compounds Inhibit Hepatic Gluconeogenesis./
作者:	Madiraju, Anila Kanchan.
面頁冊數:	150 p.
附註:	Source: Dissertation Abstracts International, Volume: 75-09(E), Section: B.
Contained By:	Dissertation Abstracts International75-09B(E).
標題:	Physiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3580760
ISBN:	9781321054019

Molecular Mechanism by which Guanide Compounds Inhibit Hepatic Gluconeogenesis.
Madiraju, Anila Kanchan.

Molecular Mechanism by which Guanide Compounds Inhibit Hepatic Gluconeogenesis. - 150 p.

Source: Dissertation Abstracts International, Volume: 75-09(E), Section: B.

Thesis (Ph.D.)--Yale University, 2014.

This item is not available from ProQuest Dissertations & Theses.

Metformin is considered to be one of the most effective therapeutics for the treatment of type 2 diabetes (T2D) since it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain, or posing a risk of hypoglycemia. For over half a century, this agent has been prescribed to T2D patients worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. In this study, we demonstrate that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase (mGPD), increasing the cytosolic redox state of the liver. This altered hepatocellular redox state leads to decreased hepatic gluconeogenesis as a result of reduced conversion of lactate and glycerol to glucose. To ascertain that redox modulation is important to the mechanism of metformin action in vivo, we performed studies in rats administered acute and chronic low-dose metformin treatment, which effectively reduced endogenous glucose production (EGP), while increasing cytosolic redox and decreasing mitochondrial redox states. To verify the role of mGPD inhibition in metformin's therapeutic effects, we used antisense oligonucleotide (ASO) to knockdown hepatic mGPD expression in rats, which resulted in a phenotype akin to chronic metformin treatment. Furthermore, mGPD ASO treatment abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations and inhibition of EGP. These findings were replicated in whole-body mGPD knockout mice. Computational modeling proposes energetically favorable binding of metformin to the FAD + pocket of mGPD. These results have significant implications for understanding one of metformin's therapeutic mechanisms of action, and provide a novel therapeutic target for T2D.

ISBN: 9781321054019Subjects--Topical Terms:

518431
Physiology.

Molecular Mechanism by which Guanide Compounds Inhibit Hepatic Gluconeogenesis.
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520 $a Metformin is considered to be one of the most effective therapeutics for the treatment of type 2 diabetes (T2D) since it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain, or posing a risk of hypoglycemia. For over half a century, this agent has been prescribed to T2D patients worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. In this study, we demonstrate that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase (mGPD), increasing the cytosolic redox state of the liver. This altered hepatocellular redox state leads to decreased hepatic gluconeogenesis as a result of reduced conversion of lactate and glycerol to glucose. To ascertain that redox modulation is important to the mechanism of metformin action in vivo, we performed studies in rats administered acute and chronic low-dose metformin treatment, which effectively reduced endogenous glucose production (EGP), while increasing cytosolic redox and decreasing mitochondrial redox states. To verify the role of mGPD inhibition in metformin's therapeutic effects, we used antisense oligonucleotide (ASO) to knockdown hepatic mGPD expression in rats, which resulted in a phenotype akin to chronic metformin treatment. Furthermore, mGPD ASO treatment abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations and inhibition of EGP. These findings were replicated in whole-body mGPD knockout mice. Computational modeling proposes energetically favorable binding of metformin to the FAD + pocket of mGPD. These results have significant implications for understanding one of metformin's therapeutic mechanisms of action, and provide a novel therapeutic target for T2D.
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