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The Mechanism of Metformin's (Glucophage) Lowering Fasting Glucose Levels and Hepatogluconeogenesis

Summary:

  • It is well known that patients with type 2 diabetes mellitus are characterized as having insulin resistance, a decrease in insulin mediated glucose uptake by peripheral tissues, and excessive basal rates of hepatic glucose production.
  • Impairment in peripheral glucose uptake and suppression of gluconeogenesis both contribute to worsening postprandial (post-meal) hyperglycemia whereas excessive basal rates of hepatic glucose production primarily contributes to the worsening of fasting glucose levels.
  • The most common biguanide, metformin, has been shown to "slow down" the accelerated basal rates of hepatic gluconeogenesis by inhibiting 2 key enzymes in hepatic gluconeogenesis (glucose 6-phosphate and phosphoenolpyruvate carboxykinase) without an apparent effect on lactate turnover for gluconeogenesis or increases in insulin secretion.  Thus fasting blood sugars are most affected.
  • The average reductions in fasting blood glucose levels and hemoglobin A1c while on metformin are approximately 44 to 53 mg/dL (2.4-2.9 mmol/L) and 1.4-2%, respectively.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers:
Jon D. Herrington, PharmD, BCPS, BCOP and Donald S. Nuzum, PharmD, BCACP, CDE
Last Reviewed:
October 2015

Explanation

  • It is well known that patients with type 2 diabetes mellitus (T2DM) are characterized as having insulin resistance, a decrease in insulin mediated glucose uptake by peripheral tissues (despite elevated insulin levels) and excessive basal rates of hepatic gluconeogenesis.1,2  An impairment in peripheral glucose uptake and suppression of gluconeogenesis both contribute to worsening postprandial (post-meal) hyperglycemia whereas excessive basal rates of hepatic gluconeogenesis primarily contributes to the worsening of fasting glucose levels.  To date, the biguanide class of medications primarily suppresses the excessive basal rates of gluconeogenesis which includes primarily metformin (Glucophage).3,4  The other biguanide, phenformin (Azucaps, Insoral, Fenformin), is no longer FDA approved in the United States because of unacceptable rates of lactic acidosis but can still be used and/or purchased by clinicians/patients in other countries.5 

    Why do type 2 diabetics have excessive rates in basal hepatic glucose production?
    Normally, the breakdown of glycogen and gluconeogenesis in the liver are both in part regulated by the presence of insulin and have a direct impact on fasting blood glucose levels.1  However, with T2DM being in a state of insulin resistance, the ability of insulin to activate protein phosphatases, which dephosphorylates glycogen phosphorylase a and glycogen synthase b that shut off glycogen breakdown, is decreased, thereby allowing a greater amount of glycogen to be converted to Glucose 1-phosphate.  In addition, the state of insulin resistance may also not be as efficient at regulating or "slowing down" the two critical steps in gluconeogenesis that also puts more glucose into the blood.  The first enzyme lacking regulation in insulin resistance is phosphoenolpyruvate carboxykinase ((PEPCK); which converts oxaloacetate to phosphoenolpyruvate) and the second is a reduction in the amount of fructose 2,6-bisphosphate (F-2,6-P) produced by insulin which can then inhibit the enzyme fructose 1,6-bisphosphatase.  All of the above abnormally regulated processes lead to a greater amount of glucose 6-phospate that can then be converted back to glucose in the blood via glucose 6-phosphatase (an enzyme only found in the liver). 

                   Metformins Mechanism of Action on Hepatogluconeogenesis 

    How then does metformin affect one or both of these abnormally regulated processes in hepatic gluconeogenesis?
    Metformin's primary benefit in T2DM has been in its ability to "slow down" the accelerated basal rates of hepatic gluconeogenesis without an apparent effect on lactate turnover for gluconeogenesis or increases in insulin secretion.3,4  Metformin does this by decreasing the amount of enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (see figure).6  

    How does it do this?
    Metformin can activate an upstream primary kinase called LKB1 thereby resulting in the phosphorylation of  AMP-activated protein kinase (AMPK).7   The phosphorylated AMPK will then result in the cytosolic sequestering of the CREB transcription factor named transducer of regulated CREB activity 2 (TORC2).7 With TORC2 now trapped in the cytosol of the hepatocyte (liver cell) CREB within the nucleus is now notas efficient at transcribing a transcriptional cofactor named peroxisome proliferator-activated receptor-g co-activator 1a (PGC1a).7 With lower amounts of PGC1a there is less transcriptional activation of glucose 6-phosphatase and PEPCK thereby leading to a "slowing down" of the excessive basal rates of hepatic gluconeogeneis.7  Interestingly, metformin's activation of AMPK also contributes to overall glucose control by increasing AMPK mediated increases in translocation of GLUT-4 transporters in muscle.8

    Therefore, metformin improves fasting blood sugars by slowing down the "excessive" basal hepatic gluconeogenesis without significant changes in insulin levels that would be known to cause hypoglycemia.3,4,9  The average reductions in fasting blood glucose levels and hemoglobin A1c while on metformin are approximately 44-53 mg/dL (2.4-2.9 mmol/L)and 1.4-2%, respectively.3,4,9

    References:

    1. Monnier L, Colette C, Owens DR.  Type 2 diabetes: a well-characterised but suboptimally controlled disease.  Can we bridge the divide?  Diabetes Metab.  2008;34(3):207-216.   
    2. Leiberman M, Marks AD, eds. Mark's Basic Medical Biochemistry A Clinical Approach.  3rd Ed.  Philadelphia, PA: Lippincott Williams & Wilkins; 2009:479-566.
    3. Bristol-Myers Squibb Co.  Glucophage (metformin hydrochloride) package insert. Princeton, NJ; August 2008.  Link obtained on 11/24/2008: Package Insert
    4. Cusi K, Consoli A, DeFronzo RA.  Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus.  J Clin Endocrinol Metab 1996;81:4059-4067.   
    5. Kumar A, Nugent K, Kalakunja A, Pirtle F.  Severe acidosis in a patient with type 2 diabetes mellitus, hypertension and renal failure.  CHEST  2003;123:1726-1729.  
    6. Mithieux G, Guignot L, Bordet J, Wiernsperger N.  Intrahepatic mechanisms underlying the effect of metformin in decreasing basal glucose production in rats fed a high fat diet.  Diabetes  2002;51:139-143.   
    7. Shaw RJ, Lamia KA, Vasquez D et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutics effects of metformin.  Science  2005;310(5754):1642-1646.  
    8. Yamaguchi S. Katahira H, Ozawa S et al. Activators of AMP-activated protein kinase enhance GLUT4 translocation and its glucose transport activity in 3T3-LI adipocytes.  Am J Physiol Endocrinol Metab  2005;289(4):E643-E649.  
    9. DeFronzo RA, Goodman  AM, The Multicenter Metformin Study Group.  Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus.  N Engl J Med 1995;333:541-549.   
    10. Nathan DM, Buse JB, Davidson MB et al.  Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes.  Diabetes Care  2006;29(8):1963-1972.

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MESH Terms & Keywords

  • Glucophage, Metformin, Metformin's Mechanism of Action, Hepatic Gluconeogenesis