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 Table of Contents  
HISTORICAL VIGNETTE
Year : 2014  |  Volume : 1  |  Issue : 2  |  Page : 127-130

Metformin: A Journey from countryside to the bedside


Department of Biochemistry and Biotechnology, Haffkine Institute for Training, Research and Testing, Parel, Mumbai, Maharashtra, India

Date of Submission22-Mar-2014
Date of Decision24-Mar-2014
Date of Acceptance25-Mar-2014
Date of Web Publication12-Jun-2014

Correspondence Address:
A. Rosalind Marita
Department of Biochemistry and Biotechnology, Haffkine Institute for Training, Research and Testing, Acharya Donde Marg, Parel, Mumbai 400 012, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2347-9906.134435

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  Abstract 

The discovery of metformin as an anti-diabetic drug spans three centuries-beginning in the herb, Galega officinalis in the 17 th century and ending in its launch as "Glucophage" in the 20 th century. Extract from the leaves of G. officinalis was used to treat many ailments such as fever, plague and symptoms of diabetes. The herbal extract contains guanidine and galegine as major chemical components. These compounds, although had an anti-diabetic effect, were too toxic for clinical use. Discovery of antimalarial drug, paludrine which also had blood glucose lowering activity, at the Imperial Chemical Industries, UK prompted evaluation of paludrine analogues, as potential anti-diabetic agents. This speculation was also based on the structure of paludrine, which partly resembled galegine, a compound present in the extract of G. officinalis. This development coupled with Garcia's positive results using flumamine, a guanidine analogue, on 'flu' fever accelerated the evaluation of guanidine and galegine analogues for anti-diabetic activity. These efforts culminated in the discovery of metformin, introduced as 'Glucophage', by Jean Sterne, in 1957. In this article, we have highlighted the journey of metformin from a common countryside herb to its present day status of a 'Wonder Drug' sitting at the bedside of diabetic patients.

Keywords: Anti-diabetic, guanidine, herbal extract, metformin


How to cite this article:
Patade GR, Marita AR. Metformin: A Journey from countryside to the bedside. J Obes Metab Res 2014;1:127-30

How to cite this URL:
Patade GR, Marita AR. Metformin: A Journey from countryside to the bedside. J Obes Metab Res [serial online] 2014 [cited 2018 Dec 18];1:127-30. Available from: http://www.jomrjournal.org/text.asp?2014/1/2/127/134435

'Nothing in Life is to be feared, it is only to be understood'. This quote by the famous physicist Marie Curie (1867-1934) aptly reflects the emergence of metformin from a poisonous herb to the most widely prescribed medicine for type 2 diabetes. Metformin is derived from the plant, Galega officinalis Linn. [Figure 1]. G. officinalis is commonly known as Goat's rue, French lilac, Italian fitch and Professor-weed. It is mainly found as bushes along the countryside of Britain, France and Europe. In medieval Europe, it was used to treat plague, fever, snake bites, miasma, dysuria and St. Vitus dance. [1],[2] Tea brewed from the leaves of the plant was used to treat frequent urination and halitosis. However, the plant is extremely toxic with the potential to induce hypotension, tracheal frothing, paralysis, and even death. [3]

The anti-diabetic property of the herb was first described in the 17 th century by Culpeper, an English Botanist and a Physician. [4],[5] In his work 'A Treatise on Aurum Potabile' published in 1656, he described the blood glucose lowering effect of G. officinalis and its effect on other symptoms of diabetes like polyuria. Although treatment with Goat's rue extract was known to lower blood glucose for a long time, it was not clear as to which ingredient in the extract was responsible for its anti-diabetic effect. The herb extract was rich in guanidine [Figure 2]a] and galegine [Figure 2]b]. Guanidine showed anti-diabetic effect in animals, [6],[7],[8] but it was too toxic for clinical use. On the other hand, galegine was found to be less toxic, but had a low anti-diabetic activity. [9],[10]
Figure 1. Flowering Galega officinalis Linn. Available at http://en.wikipedia.org/wiki/File:Galegaofficinalis03.jpg

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Figure 2. Structures of guanidine and analogues

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  Metformin and malaria Top


In the early 1920s, malaria had become a widespread disease in England. At that time, quinine was the only drug available to treat malaria. Quinine was extracted from the bark of the cinchona tree. Quinine was very expensive and some parasites became resistant to it. Furthermore, the drug was imported from Java and the supply was unpredictable. Due to this, chemists in UK were working to find cheaper alternatives to quinine for treating malaria. During the Second World War, a team led by the chemist, FHS Curd at the Imperial Chemical Industries Laboratories in UK decided to work on compounds derived from pyrimidine. [11] Curd and his team investigated pyrimidine series since it was a constituent of nucleic acids and it was a structural component of sulfadiazine drug, which has weak antimalarial activity. Their work led to the discovery of a potent antimalarial drug, paludrine in 1945. [12] The right hand portion of paludrine (proguanil) [Figure 2]c] had a distinct resemblance to galegine, a constituent of Goat's rue extract. Two years later, animal studies using paludrine revealed reduction in blood glucose levels. [13]


  Metformin and influenza Top


During this period, Garcia, a prominent Philippine physician, used synthetic guanidine analogues, including biguanides, to treat influenza and endemic malaria. [14] Garcia reported that treatment with a compound referred to as 'flumamine' relieved the symptoms of flu and fever within 24 h. From these findings, he speculated that flumamine could act in malaria patients by reducing blood glucose and thus reduce the survival of the malarial parasite. Flumamine is structurally similar to polymethylene diguanide [Figure 2]d], a synthetic biguanide. Polymethylene diguanides were synthesised and analysed for efficacy and toxicity. However, they were found to be toxic for human use.


  Discovery of Metformin (Glucophage) Top


The real breakthrough came with the work of French diabetologist, Jean Sterne [Figure 3]. Sterne (1909-1997) was a physician and clinical pharmacologist who trained in diabetology at the Hτpital de la Pitie in Paris. While working at Aron Laboratories in Paris, he was prompted by Garcia's report on flumamine. In collaboration with Denise Duval and others he evaluated the anti-diabetic effect of flumamine in animals. Flumamine, now known as metformin, showed a powerful glucose-lowering effect. Inspired by his results in animals, Sterne conducted animal studies on several biguanides. From these efforts, he selected metformin for clinical development. He coined the name 'Glucophage' meaning 'glucose eater' for metformin and published his results in 1957. [15] Thus, 'Glucophage' or metformin, now virtually a medical household name, was born.
Figure 3. Dr. Jean Sterne: Medicinal chemist who coined the term 'Glucophage'. Available at https://ds-pharma.jp/literature/ goldstandard/article/issue01/07.html

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  Rise of metformin Top


The first systematic evaluation of Sterne's work appeared in 1962. [16] Thirty nine patients were given metformin for a period of 6 months. Out of the 39 patients, 14 showed satisfactory control of the disease with metformin, another six showed some improvement if metformin was combined with low doses of insulin. In 1929, several glucose-lowering biguanides were synthesised, along with metformin. [17] In 1957, Ungar published trials with phenformin [18] and in 1958; Mehnert reported the effect of buformin. [19] Phenformin and buformin were found to be more potent than metformin. However, they were soon withdrawn from clinical use due to their toxicity, especially lactic acidosis. [20] These reports affected the widespread use of metformin, since it also belonged to the biguanide class. However, studies demonstrating the anti-hyperglycaemic effects of metformin, without causing overt hypoglycaemia or weight gain, [21],[22] regained confidence in the drug. Strongest evidence for the superior actions of metformin came from the United Kingdom Prospective Diabetes Study (UKPDS) which revealed the benefits of metformin in reducing cardiovascular mortality and increasing overall survival rate of obese diabetic patients. [23]

Metformin became available in the British National Formulary in 1958. It was sold in the UK by Rona, a subsidiary of Aron Laboratories. Metformin was approved in Canada in 1972 but did not receive approval by the US FDA until 1994. Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the United States, in 1995. Generic formulations are now available in several countries.


  Metformin: The Wonder Drug! Top


The biological actions of metformin are numerous. It reduces insulin resistance, lowers gluconeogenesis and thereby relieves the metabolic defects in type 2 diabetes. [24],[25] Recent studies indicate that metformin has a strong cardioprotective effect. [26],[27] It also has anti-atherothrombotic and anti-inflammatory activity. [28],[29],[30] Cancer prevention is an interesting potential future application of metformin. UKPDS revealed that metformin treatment reduced the risk of death from cancer by 29%. Other studies also observed significantly lower cancer mortality rate in patients treated with metformin. [31] Metformin is also being prescribed for polycystic ovary syndrome [32] and HIV infection, [33] among others.


  Conclusion Top


Started as a humble herb along the countryside, metformin has progressed to be the bedside cure of each and every diabetic patient. However, unlike many drugs of the same era which have fallen by the wayside, it has endured, and indeed flourished. It is now the most preferred drug of choice worldwide. Jean Sterne noted in the first publication on metformin that "It [metformin] is well-tolerated in man, at therapeutic doses, but its mechanism of action and its ultimate place in the management of diabetes requires further study". It holds true even today when despite detailed investigations we still have not found the exact mechanism of action of the drug. It seems that more than 50 years of research on metformin have set the scene for more advances in the understanding and therapeutic use of this remarkable drug.

 
  References Top

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2.Mori A, Cohen BD, Lowenthal A. Guanidines - Historical, biological, biochemical and clinical aspects of the naturally occurring guanidine compounds. London: Plenum Press; 1985.  Back to cited text no. 2
    
3.Bailey CJ, Campbell IW, Chan JC, Davidson JA, Howlett HC, Ritz P. Galegine and anti-diabetic plants. Metformin: The gold standard. A scientific handbook. Ch. 1. Chichester: Wiley; 2007.  Back to cited text no. 3
    
4.Culpeper N. In: Potterton D, editor. Culpeper's colour herbal. London: Foulsham and Co. Ltd.; 1983.  Back to cited text no. 4
    
5.Culpeper N. The English Physitian or an astrologo-physical discourse on the vulgar herbs of this nation. London: Peter Cole; 1652.  Back to cited text no. 5
    
6.Watanabe CK. Studies in the metabolic changes induced by administration of guanidine bases. J Biol Chem 1918;33:253-65.  Back to cited text no. 6
    
7.Sterne J. Pharmacology and mode of action of the hypoglycaemic guanidine derivatives. In: Campbell GD, editor. Oral hypoglycaemic agents. London: Academic Press; 1969. p. 193-245.  Back to cited text no. 7
    
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9.Muller H, Rheinwein H. Pharmacology of galegin. Arch Exp Path Pharmacol 1927;125:212-28.  Back to cited text no. 9
    
10.Simonnet H, Tanret G. On hypoglycemic properties sulfate galegine. Bull soc chem boil 1927;8:8.  Back to cited text no. 10
    
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13.Chen KK, Anderson RC. The toxicity and general pharmacology of N1-p-chlorophenyl-N5-isopropyl biguanide. J Pharmacol Exp Ther 1947;91:157-60.  Back to cited text no. 13
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14.Garcia E. 1949 Flumamine. Untraced publication from the Philippines. Cited by Sterne J in an interview [April 4, 1996] for Merck-Lipha published in Glucophage. In: Pasik C, editor. Serving diabetology for 40 years. Lyon: GroupeLipha; 1997. p. 21, 29.  Back to cited text no. 14
    
15.Sterne J. Innovations in antidiabetics. nn dimethylamine guanyl guanidine  [N.N.D.G.]. Maroc Med 1957;36:1295-6.  Back to cited text no. 15
    
16.Gottlieb B, Auld WH. Metformin in treatment of diabetes mellitus. Br Med J 1962;1:680-2.  Back to cited text no. 16
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17.Hesse G, Taubmann G. The effect of biguanide and its derivatives on glucose metabolism. Arch Exp Path Pharmacol 1929;142:290-308.  Back to cited text no. 17
    
18.Ungar G, Freedman L, Shapiro SL. Pharmacological studies of a new oral hypoglycemic drug. Proc Soc Exp Biol Med 1957;95:190-2.  Back to cited text no. 18
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19.Mehnert H, Seitz W. Further results of diabetes therapy with blood sugar lowering biguanides. Munch Med Wochenschr. 1958;100:1849-51.  Back to cited text no. 19
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21.Hermann LS. Metformin: A review of its pharmacological properties and therapeutic use. Diabete Metab 1979;5:233-45.  Back to cited text no. 21
    
22.Campbell IW, Howlett HC. Worldwide experience of metformin as an effective glucose-lowering agent: A meta-analysis. Diabetes Metab Rev 1995;11 Suppl 1:S57-62.  Back to cited text no. 22
    
23.Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-65.  Back to cited text no. 23
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26.Eurich DT, Majumdar SR, McAlister FA, Tsuyuki RT, Johnson JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005;28:2345-51.  Back to cited text no. 26
    
27.Montaguti U, Celin D, Ceredi C, Descovitch GC. Efficacy of the long-term administration of metformin in hyperlipidaemic patients. Res Clin Forums 1979;1:95-103.  Back to cited text no. 27
    
28.De Jager J, Kooy A, Lehert P, Bets D, Wulffelé MG, Teerlink T, et al. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: A randomized, placebo-controlled trial. J Intern Med 2005;257:100-9.  Back to cited text no. 28
    
29.Carter AM, Bennett CE, Bostock JA, Grant PJ. Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with Type 2 diabetes mellitus. Diabet Med 2005;22:1282-4.  Back to cited text no. 29
    
30.Hattori Y, Suzuki K, Hattori S, Kasai K. Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension 2006;47:1183-8.  Back to cited text no. 30
    
31.Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 2010;33:322-6.  Back to cited text no. 31
    
32.American Association of Clinical Endocrinologists. Position statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Available from: http://www.aace.com/pub/pdf/guidelines/PCOSpositionstatement.pdf. [Last accessed on 2014 Feb 20].  Back to cited text no. 32
    
33.Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S. Metformin in the treatment of HIV lipodystrophy syndrome: A randomized controlled trial. JAMA 2000;284:472-7.  Back to cited text no. 33
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]


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