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Metformin: An Update

Dmitri Kirpichnikov, MD; Samy I. McFarlane, MD; and James R. Sowers, MD
[+] Article and Author Information

From State University of New York Health Science Center at Brooklyn and Veterans Affairs Medical Center, Brooklyn, New York.


Acknowledgments: The authors thank Jun Ren, PhD; Amy Davidoff, PhD; and Jacob Peuler, PhD, for their seminal contribution to work on the cardiovascular effects of metformin.

Grant Support: By the National Institutes of Health (RO1-HL-63904-01), the Veterans Affairs Merit Review, and the American Diabetic Association.

Requests for Single Reprints: James R. Sowers, MD, State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 1205, Brooklyn, NY 11203; e-mail, jsowers@netmail.hscbklyn.edu.

Current Author Addresses: Drs. Kirpichnikov, McFarlane, and Sowers: State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 1205, Brooklyn, New York 11203.


Ann Intern Med. 2002;137(1):25-33. doi:10.7326/0003-4819-137-1-200207020-00009
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Insulin resistance contributes greatly to development of cardiovascular disease in patients with the metabolic syndrome and its extreme presentation, type 2 diabetes mellitus. Therefore, treatment with an insulin-sensitizing agent, such as metformin, in patients with type 2 diabetes mellitus may correct several of the primary pathophysiologic abnormalities of the metabolic syndrome. In diabetic patients, metformin appears to provide cardiovascular protection that cannot be attributed only to its antihyperglycemic effects. These additional cardioprotective effects in these patients may be related to the favorable actions of metformin on lipid metabolism, vascular smooth-muscle and cardiomyocyte intracellular calcium handling, endothelial function, hypercoagulation, and platelet hyperactivity. We discuss known mechanisms by which metformin exerts its beneficial glycemic and cardiovascular actions.

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Figure 1.
Mechanisms of metformin action on hepatic glucose production and muscle glucose consumption.++GLUT++

Metformin decreases hepatic gluconeogenesis by interfering with respiratory oxidation in mitochondria. It suppresses gluconeogenesis from several substrates, including lactate, pyruvate, glycerol, and amino acids. In addition, metformin increases intramitochondrial levels of calcium (Ca ), a modulator of mitochondrial respiration. In insulin-sensitive tissues (such as skeletal muscle), metformin facilitates glucose transport by increasing tyrosine kinase activity in insulin receptors and enhancing glucose transporter ( ) trafficking to the cell membrane. ADP = adenosine diphosphate; ATP = adenosine triphosphate; Ca = intracellular calcium levels; OAA = oxaloacetate; PEP = phosphoenolpyruvate; Pi = inorganic phosphate; TK = tyrosine kinase.

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Figure 2.
Metformin and fatty acids.FA

Metformin inhibits fatty acid ( ) production and oxidation, thereby reducing fatty acid–induced insulin resistance and hepatic glucose production. CoA = coenzyme A; CPT = carnitine palmitoyltransferase; FFA = free fatty acid; GLUT = glucose transporter; IGF-1 = insulin-like growth factor I; IRS-1 = insulin receptor substrate-1; OAA = oxaloacetate; PDH = pyruvate dehydrogenase; PFK = phosphofructokinase; PI-3 = phosphatidyl inositol-3.

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Figure 3.
Proposed cellular mechanisms of metformin action in the vascular smooth-muscle cells and cardiomyocytes.NOCa++

In vascular smooth-muscle cells, metformin decreases vasoconstriction by enhancing sodium pump activity and nitric oxide ( ) production, causing a decrease in intracellular calcium levels ( ). Metformin improves diastolic relaxation by enhancing calcium removal from cardiomyocytes after systole. ATP = adenosine triphosphate; cGMP = cyclic guanosine monophosphate; GTP = guanosine triphosphate; K-ATP = potassium-adenosine triphosphate.

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Summary for Patients

Metformin for Patients with Type 2 Diabetes Mellitus

The summary below is from the full report titled “Metformin: An Update.” It is in the 2 July 2002 issue of Annals of Internal Medicine (volume 137, pages 25-33). The authors are D Kirpichnikov, SI McFarlane, and JR Sowers.

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