| Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. | |
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MedLine Citation:
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PMID: 23292513 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glucose production by the liver is essential for providing a substrate for the brain during fasting. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type-2 diabetes mellitus and other diseases of insulin resistance. For fifty years, one of the few classes of therapeutics effective in reducing glucose production has been the biguanides, which include phenformin and metformin, the latter the most frequently prescribed drug for type-2 diabetes. Nonetheless, the mechanism of action of biguanides remains imperfectly understood. The suggestion a decade ago that metformin reduces glucose synthesis through activation of the enzyme AMP-activated protein kinase (AMPK) has recently been challenged by genetic loss-of-function experiments. Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. In mouse hepatocytes, metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinase A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. These data support a mechanism of action for metformin involving antagonism of glucagon, and suggest an approach for the development of antidiabetic drugs. |
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Authors:
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Russell A Miller; Qingwei Chu; Jianxin Xie; Marc Foretz; Benoit Viollet; Morris J Birnbaum |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2013-01-06 |
Journal Detail:
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Title: Nature Volume: 494 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2013 Feb |
Date Detail:
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Created Date: 2013-02-14 Completed Date: 2013-03-12 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 256-60 Citation Subset: IM |
Affiliation:
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Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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metabolism Adenylate Cyclase / metabolism Animals Biguanides / pharmacology* Cells, Cultured Cyclic AMP / biosynthesis, metabolism* Cyclic AMP-Dependent Protein Kinases / metabolism Diabetes Mellitus, Type 2 / drug therapy Enzyme Activation / drug effects Glucagon / antagonists & inhibitors*, metabolism* Glucose / metabolism Hepatocytes / drug effects*, metabolism* Hypoglycemic Agents Liver / cytology, drug effects, metabolism Metformin / pharmacology, therapeutic use Mice Phenformin / pharmacology Phosphorylation Signal Transduction / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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P01 DK049210/DK/NIDDK NIH HHS; P01 DK49210/DK/NIDDK NIH HHS; P30 DK19525/DK/NIDDK NIH HHS; R01 DK056886/DK/NIDDK NIH HHS; R01 DK56886/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Biguanides; 0/Hypoglycemic Agents; 114-86-3/Phenformin; 50-99-7/Glucose; 60-92-4/Cyclic AMP; 657-24-9/Metformin; 9007-92-5/Glucagon; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 4.6.1.1/Adenylate Cyclase |
| Comments/Corrections | |
Comment In:
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Nat Rev Endocrinol. 2013 Mar;9(3):132
[PMID:
23358356
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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