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Wasner, H. Metformin’s Mechanism of Action. Encyclopedia. Available online: https://encyclopedia.pub/entry/20103 (accessed on 13 August 2024).
Wasner H. Metformin’s Mechanism of Action. Encyclopedia. Available at: https://encyclopedia.pub/entry/20103. Accessed August 13, 2024.
Wasner, Heinrich. "Metformin’s Mechanism of Action" Encyclopedia, https://encyclopedia.pub/entry/20103 (accessed August 13, 2024).
Wasner, H. (2022, March 02). Metformin’s Mechanism of Action. In Encyclopedia. https://encyclopedia.pub/entry/20103
Wasner, Heinrich. "Metformin’s Mechanism of Action." Encyclopedia. Web. 02 March, 2022.
Metformin’s Mechanism of Action
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This entry is adapted from the peer-reviewed paper 10.3390/ijms23042200

Metformin is the leading drug for treating type 2 diabetics, but the mechanism of action of metformin, despite some suggested mechanisms such as the activation of the AMP-kinase, is largely unknown. Among its many positive effects are the reduction of blood glucose levels, the inhibition of cyclic AMP synthesis, gluconeogenesis and an increase in sensitivity to insulin. Recent studies have described the natural antagonist of cyclic AMP, prostaglandylinositol cyclic phosphate. The parallels between the beneficial effects of metformin and the regulations triggered by cyclic PIP suggest that the mechanism of action of this key drug may well be explained by its stimulation of the synthesis of prostaglandylinositol cyclic phosphate (cyclic PIP).

Metformin diabetics cyclic PIP

1. The Biguanide Metformin

Metformin was identified in 1922 and was used as an oral antidiabetic drug beginning in the 1950’s. In the 1970’s, increased lactate levels after biguanide treatments, causing lactic acidosis, led to the decision to take the biguanides buformin and phenformin off the market. Metformin has remained available. Its beneficial effects for treating type 2 diabetic patients are accepted worldwide. It is the 4th most frequently prescribed drug in the USA today. Metformin is not only beneficial for type 2 diabetics. It is beneficial also for type 1 diabetics [1], it may help various cancer patients [2], and it can improve aging problems [3]. A proposed mechanism of action of metformin is that it inhibits the respiratory chain in the mitochondria leading to increased AMP levels. These activate the AMP kinase, leading to most of the needed effects [4]. Nonetheless, most discussions on this topic conclude that the molecular mechanism of metformin’s action is “complicated and not completely understood” [5][6]. However, in studies of well-understood metabolic pathways, actions of metformin have been characterized. It increases sensitivity to insulin, decreases elevated blood glucose levels, and inhibits gluconeogenesis and the synthesis of cyclic AMP [7].

2. Stimulation of  Prostaglandylinositol Cyclic Phosphate (cyclic PIP) Synthesis by Metformin

All biguanides tested (metformin, buformin and phenformin) activated cyclic PIP synthase [8]. Metformin increased it by 1.9 to 2-fold; buformin 3.0 to 3.2-fold and phenformin 3.5 to 4.2-fold (Table 1). The most likely action of the biguanides is the activation of the insulin receptor tyrosine kinase [9], which then activates cyclic PIP synthase by tyrosine phosphorylation [10], leading to elevated cyclic PIP synthesis. Interestingly, this activation is additive to the activation of cyclic PIP synthase by fluoride [11][10], which was suggested to activate G proteins comparably to the activation of adenylate cyclase via G-proteins. Fluoride may also act as a protein tyrosine phosphatase inhibitor. In this case, fluoride inhibits the dephosphorylation of the, by tyrosine phosphorylation, activated cyclic PIP synthase [10]. However, the activation of basal cyclic PIP synthase by fluoride in the absence of ATP can best be explained by the action of a G protein (Table 1), suggesting that fluoride may exert two independent effects on cyclic PIP synthase.
Table 1. Activation of particular cyclic PIP synthase by various chemicals and drugs.
  Cyclic PIP Synthase Activity  
Addition Activation (x-fold) Inhibition (%)
Experiment 1    
No Additions (basal activity) 1.0  
Fluoride (10mM) 3.2  
ATP (10mM) 10.6  
ATP + Fluoride 14.4  
Experiment 2    
Metformin (0.5mM) 2.1  
Buformin (1.0 mM) 3.05  
Phenformin (1.0 mM) 4.2  
Glibenclamide (0.1 mM)   66
       (1.0 mM)   99
Chloropropamide (1.0 mM)   95
Tolbutamide (1.0 mM)   97
The activation of cyclic PIP synthase by tyrosine phosphorylation [10] predicts that it is inactivated by dephosphorylation (Figure 1). Consequently, a further way to keep cyclic PIP synthase active is to inhibit this protein tyrosine phosphatase. The antihypertensive drug captopril was shown to inhibit protein tyrosine phosphatase [12] and it was shown that captopril and other antihypertensive drugs increase the synthesis of cyclic PIP [8]. This suggests that a more efficient treatment of type 2 diabetics should be to treat these patients with a combination of these 2 drugs or their alternatives.
/media/item_content/202203/6220224a428bfijms-23-02200-g002.png
Figure 1. Regulation of the activity of cyclic PIP synthase by protein tyrosine and protein ser-ine/threonine phosphorylation and dephosphorylation. On insulin stimulation, the insulin receptor protein tyrosine kinase is activated and activates by tyrosine phosphorylation cyclic PIP synthase. Increased cyclic AMP levels activate P ser/thr kinases, which then inhibit cyclic PIP synthase. Abbreviations: P tyr K, protein tyrosine kinase; P tyr P, protein tyrosine phosphatase; P ser/thr K, protein serine/threonine kinase; P ser/thr P, protein serine/threonine phosphatase.
Past experience has shown that metformin loses its efficacy to help type 2 diabetics within five to ten years of treatment. A more recent observation is that metformin helps diabetics for a longer time [13]. Metformin appears to act intracellularly on the insulin receptor (Figure 2), activating down-stream signaling [14]. The progression of insulin resistance is connected to a decreasing receptor density [15][16]. Thus, the primary site of action of metformin and the location where effects of insulin resistance begin are closely located. It is of interest to ask whether the efficacy of metformin is affected by the decreasing receptor density. The two regulators, cyclic AMP and cyclic PIP, inhibit the synthesis and action of each other [17]. There are at least two ways by which cyclic PIP synthesis is inhibited. Metformin activates cyclic PIP synthesis very well, but it is not yet known whether it shuts off the inhibitory mechanisms, such as (a) inactivation of cyclic PIP synthase by protein tyrosine dephosphorylation [10] and (b) inhibition by protein serine/threonine phosphorylation, which is triggered by cyclic AMP [8]. Better understanding of the interplay of the inhibitory mechanisms on cyclic PIP synthase will further improve the treatment of diabetics.
/media/item_content/202203/6220225e5142cijms-23-02200-g003.png
Figure 2. Signal transduction of insulin and the activation of cyclic PIP synthase by tyrosine phosphorylation, and regulatory effects of cyclic PIP. The points of action of metformin are indicated. (used abbreviations: Tyr Kinase is the insulin receptor tyrosine kinase; Prot Phosph the protein ser/thr phosphatase; act InsP the activated inositol cyclic phosphate; Cyclase the adenylate cyclase; Prot Tyr Phosph a protein tyr phosphatase; PDH the pyruvate dehydrogenase and PKA protein kinase A).
A rare but serious side effect of the biguanides is that they can cause lactic acidosis [18][19]. A puzzling point is that the biguanides buformin and phenformin are more efficient in stimulating cyclic PIP synthase than metformin and one would expect that these biguanides would be more beneficiary for diabetics. It is rather peculiar that these more efficient biguanides are the ones with the greater risk to cause lactic acidosis. Could this problem of lactic acidosis be connected to overdosage of these drugs, especially as overdosing of insulin results in hypo-glycemia? The same problem is expected in cases of excess levels of cyclic PIP. Cyclic PIP stimulates the pyruvate dehydrogenase complex up to 5-fold [17]. This means that the intracellularly produced pyruvate should not be converted to lactate but to acetyl-CoA, and the question remains why is pyruvate transformed in high amounts to lactate. One possibility is that in these patients the biguanide could not increase cyclic PIP synthesis. This could result, for instance, from consumption of easily accessible, non-steroidal-anti-inflammatory drugs, which inhibit prostaglandin synthesis preventing cyclic PIP synthesis [20]. Furthermore, type 1 and type 2 diabetes have a tendency to develop lactic acidosis, and a large study showed an incidence rate of 3% for the patients with diabetes mellitus compared to an incidence rate of 0.1% in the non-diabetic control group [21]. Other studies came to the conclusion that the use of metformin did not increase the risk of lactic acidosis [22][23]. However, the well-recognized risk of lactic acidosis is feared because of its high mortality rate [24]. Though risk-factors for the development of lactic acidosis, such as hypoxia, sepsis, dehydration, and worsening of renal and cardiac failure, are recognized, more studies are needed to fully understand the problem at a molecular level and to further reduce/prevent the occurrence of lactic acidosis in type 2 diabetic patients on treatment with metformin. A question that needs to be answered is: Is the development of lactic acidosis more the result of other risk factors in the diabetic patient or does it solely result from the treatment with biguanides? All biguanides stimulate the synthesis of cyclic PIP, which activates pyruvate dehydrogenase, preventing the overproduction of lactate. Thus, it should not be a biguanide that initiates overproduction of lactate leading to lactic acidosis.
The goal of research should be to ask for a more effective drug than metformin. One can remember phenformin, which activates the biosynthesis of cyclic PIP twice as effectively as metformin, though phenformin was taken from the market because of the lactic acidosis problem. If causes of lactic acidosis become better understood and found not to be the result of the action of the biguanides, a drug such as phenformin might be reconsidered.
The regulation of the activity of cyclic PIP synthase appears to be modulated by many drugs. For instance, antidiabetic drugs of the sulfonylurea group inhibit cyclic PIP synthase (Table 1) [8]. These drugs are known to increase insulin secretion and one may ask if this can be beneficiary, especially when one takes into consideration that insulin and cyclic PIP switch off the secretion of insulin [17]. Further, it is known that in the early stage of type 2 diabetes patients have elevated serum insulin levels, most likely as a result of the reduced or lost switch off mechanism. Certainly, one can see the increase in insulin secretion as positive and helpful, but one needs to be aware that these drugs inhibit cyclic PIP synthase not only in the β-cells of the pancreas but in all cells of a body [8] and this inhibition will decrease the efficacy of insulin.

References

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  2. Feng, J.L.; Qin, X. Metformin and cancer-specific survival among breast, colorectal, or endometrial cancer patients: A nationwide data linkage study. Diabetes Res. Clin. Pract. 2021.
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  4. Agius, L.; Ford, B.E.; Chachra, S.S. The metformin mechanism on gluconeogenesis and AMPK activation: The metabolic perspective. Int. J. Mol. Sci. 2020, 21, 3240.
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  7. Giaccari, A.; Solini, A.; Frontoni, S.; Del Prato, S. Metformin benefits: Another example for alternative energy substrate mechanism? Diabetes Care 2021, 44, 647–654.
  8. Wasner, H.K.; Salge, U.; Psarakis, E.; Niktopoulos, A. Insulin resistance, a result of reduced synthesis of prostaglandylinositol cyclic phosphate, a mediator of insulin action? Regulation of cyclic PIP synthase activity by oral antidiabetic and antihypertensive drugs. Acta Diabetol. 1997, 34, 257–264.
  9. Dominguez, L.; Davidoff, A.; Srinivas, P.; Standley, P.; Walsh, M.; Sowers, J. Effects of metformin on tyrosine kinase activity, glucose transport, and intracellular calcium in rat vascular muscle. Endocrinology 1996, 137, 113–121.
  10. Wasner, H.K.; Gebel, M.; Hucken, S.; Schaefer, M.; Kincses, M. Two different mechanisms for activation of cyclic PIP synthase: By a G protein or by protein tyrosine phosphorylation. Biol. Chem. 2000, 382, 145–153.
  11. Wasner, H.K.; Lessmann, M.; Conrad, M.; Amini, H.; Psarakis, E.; Mir-Mohamad-Sadegh, A. Biosynthesis of the endogenous cyclic adenosine monophosphate (AMP) antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP), from prostaglandin E and activated inositol polyphosphate in rat liver plasma membranes. Acta Diabetol. 1996, 33, 126–138.
  12. Ruddraraju, K.V.; Zhan, Z.Y. Covalent inhibition of protein tyrosine phosphatases. Mol. Biosyst. 2017, 13, 1257–1279.
  13. Aroda, V.R.; Ratman, R.E. Metformin and type 2 diabetes prevention. Diabetes Spectr. 2018, 31, 336–342.
  14. Zhou, Z.Y.; Ren, L.W.; Zhan, P.; Yang, H.Y.; Chai, D.D.; Yu, Z.W. Metformin exerts glucose-lowering action in high-fat fed mice via attenuating endotoxemia and enhancing insulin signaling. Acta Pharmacol. Sin. 2016, 37, 1063–1075.
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  16. Galicia-Garcia, U.; Benito-Vincente, A.; Jebari, S.; Larrea-Sebal, A.; Siddiqi, H.; Uribe, K.B.; Ostolaza, H.; Martin, C. Pathophysiology of type 2 diabetes mellitus. Int. J. Mol. Sci. 2020, 21, 6275.
  17. Wasner, H.K. Prostaglandylinositol cyclic phosphate, the natural antagonist of cyclic AMP. IUBMB Life 2020, 72, 2282–2289.
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  20. Wasner, H.K.; Weber, S.; Partke, H.J.; Amini-Hadi-Kiashar, H. Indomethacin treatment causes loss of insulin action in rats: Involvement of prostaglandins in the mechanism of insulin action. Acta Diabetol. 1994, 31, 175–182.
  21. Weisberg, L.S. Lactic acidosis in a patient with type 2 diabetes mellitus. Clin. J. Am. Soc. Nephrol. 2015, 10, 1476–1483.
  22. Alvarez, C.A.; Halm, E.A.; Pugh, M.J.V.; McGuire, D.K.; Hennessy, S.; Miller, R.T.; Lingvay, I.; Vouri, S.M.; Zullo, A.R.; Yang, H.; et al. Lactic acidosis incidence with metformin in patients with type 2 diabetes and chronic kidney disease: A retrospective nested case-control study. Endocrinol. Diab. Metab. 2021, 4, e00170.
  23. Aharaz, A.; Pottegard, A.; Pilsgaard Henriksen, D.; Hallas, J.; Beck-Nielsen, H.; Touborg Lassen, A. Risk of lactic acidosis in type 2 diabetes patients using metformin: A case control study. PLoS ONE 2018, 13, 3019622.
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Heinrich Wasner
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