Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 19  |  Issue : 2  |  Page : 81-86

Metformin: a review on its ethnobotanical source and versatile uses


1 Department of Pharmaceutical Chemistry, Himalayan Institute of Pharmacy Research, Dehradun, Uttarakhand, India
2 Gopiballavpur Multi Super Specialty Hospital, Gopiballavpur, Jhargram, West Bengal, India
3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Northern Border University, Rafha, Saudi Arabia

Date of Submission26-Sep-2019
Date of Acceptance19-Dec-2019
Date of Web Publication06-May-2020

Correspondence Address:
Professor & HOD Mohammad Asif
Department of Pharmaceutical Chemistry, Himalayan Institute of Pharmacy Research, Dehradun, Uttarakhand, 248009
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/epj.epj_50_19

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  Abstract 

At present metformin is the core for the management of type-2 diabetes mellitus. The key clue of metformin as a hypoglycemic drug was collected from the traditional utilization of Galega officinalis for the management of diabetes. Modern study recommends several valuable activities of Metformin other than the hypoglycemic effect such as type-1 diabetes mellitus, polycystic ovary syndrome, cholesterol-lowering effect, avoidance of heart disease, age, cancer, and neuroprotection. In the present review, we are discussing about the source and versatile utilization of metformin and its outcome.

Keywords: cancer, diabetes mellitus, metformin, neuroprotective, polycystic ovary syndrome, traditional use, type-1 diabetes mellitus, type-2 diabetes mellitus


How to cite this article:
Asif M, Acharya M, Imran M. Metformin: a review on its ethnobotanical source and versatile uses. Egypt Pharmaceut J 2020;19:81-6

How to cite this URL:
Asif M, Acharya M, Imran M. Metformin: a review on its ethnobotanical source and versatile uses. Egypt Pharmaceut J [serial online] 2020 [cited 2020 Aug 14];19:81-6. Available from: http://www.epj.eg.net/text.asp?2020/19/2/81/283857


  Introduction Top


Currently, metformin is a biguanide derivative (dimethylbiguanide), which becomes the first-line drug for type-2 diabetes mellitus (T2-DM) treatment. In the modern time, metformin becomes a well-accepted drug due to its low cost, lesser side effects, and multiple benefits in different disease states along with both types of diabetes mellitus (T1-DM and T2-DM). Traditionally, Galega officinalis (galega, goat’s rue, Italian fitch or professor-weed, French lilac) is recognized to treat diabetes in Europe and found to be well-off in Guanidine. Guanidine analogs (metformin and several non-Metformin drugs) were used for the treatment of diabetes in 1920s–1930s, but those drugs were withdrawn due to its toxicities (mainly lactic acidosis) and the better accessibility of insulin in the market. Metformin was revived in the investigation for antimalarial drugs (proguanil and chloroproguanil) in 1940s and for the duration of clinical trial, it is proved useful to treat influenza infection when it occasionally lowered the blood glucose level. Jean Sterne a French physician was first precisely used and reported metformin as an oral hypoglycemic agent to treat diabetes in 1957. But metformin get less awareness due to its less potency in comparison to other biguanide derivatives, which were progressively discontinued in the late 1970 due to their toxic effects like lactic acidosis. Metformin opposes insulin resistance and tackles hyperglycemia without weight gain or higher risk of hypoglycemia and after concentrated analysis metformin was introduced in 1995 in the USA. The UK Prospective Diabetes Study (UKPDS) in 1998 reported that long use of metformin give cardiovascular benefits, and provided a justification to accept metformin as an initial therapy to treat hyperglycemia in T2-DM [1] ([Figure 1]).
Figure 1 Galega officinalis, a natural source of galegine. Metformin (a) structurally is a biguanide and it has link with guanidine (b) and galegine (c), which can both be extracted from the plant goat’s rue.

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Versatile use of metformin

Metformin is mainly used for the cure of T-2DM, but is also used in polycystic ovary syndrome (PCOS). Outcomes emerge to be improved even in those with some extent of kidney disease, heart failure, or liver problems [2].

Metformin for the treatment of persons at risk for diabetes

Salpeter et al. [3] have reported the use of metformin in persons at risk for diabetes in The American Journal of Medicine in 2008, They observed that metformin treatment recovered weight, lipid profiles, and insulin resistance and reduces newer inception of diabetes by 40%.

Metformin for the management of type-1 diabetes mellitus

Beysel et al. [4] have reported that beneficial actions of metformin for the treatment of T1-DM in a BMC Endocrine Disorders Journal in 2018 reported that metformin reduced glucose level, reduced metabolic syndrome, and insulin dose necessity more than insulin treatment alone. The result was free of blood lipid enhancement or weight loss, while on average weight stay reduced with metformin–insulin remedy, whereas the average weight raised with insulin therapy alone.

Metformin for the management of type-2 diabetes mellitus

Metformin is the core of T-2DM therapy for many years. It is used for its glucose-lowering effect since 1957 in Europe and 1995 in USA. In addition, being highly efficient in improving glycemic control, metformin has also lowered the risk of hypoglycemia. Metformin remains at the top of treatment protocol for T-2DM, either as monotherapy or in combination with thiazolidinediones, sulfonylureas, and insulin. The molecular mechanism of metformin behind its valuable effect is complex and not completely recognized. Physiologically, metformin has reduced hepatic glucose production (gluconeogenesis). Gluconeogenesis is an energy-dependent course which need ATP to be brought from the mitochondria. Metformin accumulates within the mitochondria to concentrate up to 1000-fold higher than in the extracellular medium, because metformin bears a positive charge. Inside the mitochondria, metformin blocks complex I of the respiratory chain thereby inhibiting ATP formation and finally reducing gluconeogenesis [5].

Metformin for the management of polycystic ovary syndrome

PCOS is the common hormonal disorder among women of reproductive period and has a range of metabolic and reproductive consequences. Metformin is the first insulin sensitizing drug (ISD) that is used in PCOS to examine the responsibility of insulin resistance in the pathogenesis of the syndrome. Significant improvements in menstrual regularity and decrease in circulating androgen levels reduced the body weight [6]. Another ISD, troglitazone was used in the development of cycle regularity and serum androgen levels in spite of lack of change in body weight [7]. Numerous studies have reported contradictory facts concerning the effect of metformin in PCOS. In several meta-analyses, the available facts have been reported with contradictory results [8]. ISD acts in PCOS by lowering the moving insulin levels in the body. But, some contradictory facts as metformin be able to directly influence ovarian steroidogenesis [9],[10]. Numerous results have exhibited the advantages of metformin in PCOS patients together with restoring ovulation, reducing weight, circulating androgen levels, risk of miscarriage, and risk of gestational diabetes mellitus. Metformin in ovarian stimulation regime in in-vitro reproduction gives better pregnancy results.

Effect of metformin on cholesterol level

Metformin is the preferential treatment for diabetes because it appears to be the most efficient drug of all FDA-approved diabetes drugs for reducing unhealthy low-density lipoprotein cholesterol level [11].

Role of metformin on the prevention of heart disease

Metformin reduced the risk of coronary heart disease in individuals with metabolic syndrome or T-2 DM; some studies have reported that metformin reduces heart disease risk as regular exercise. It also established its efficacy in avoiding heart disease in people without metabolic syndrome [12].

Prevention of cancer and cancer recurrence

Various epidemiological studies have reported associations between metformin, used to treat T-2DM, and reduced cancer occurrence and mortality [2]. Some studies reported that smokers with diabetes who takes metformin are less expected to produce lung cancer. Oral use of metformin reduced tumor incidence in mice by 40-50 percent, and injected metformin reduced tumor incidence by 72% [13].

Fights fat in the womb

Some morbidly obese pregnant women are taking metformin to avoid their babies from being born overweight. The drug safely reduced the quantity of food going to the unborn babies, although it will not assist the mother to lose weight. This type of barrier is vital because critically overweight pregnant women often produce obese babies, which can cause troubles during labor and delivery and life-long health for the child [14].

Metformin improving aging outcomes

Metformin also affect ageing other than glycemic control. Like inflammatory markers, interleukins and tumor necrosis factor can activate different cellular processes that lead to cellular and tissue damage. The interleukin-6 can persuade fibroblast proliferation and collagen formation, leading to cardiac remodeling. It can promote depressed contractility, myocyte hypertrophy and apoptosis [15]. Metformin changes inflammatory responses via inhibition of nuclear factor-kB via AMP-activated protein kinase (AMPK)-dependent pathways [16]. Metformin also reduces the formation of reactive oxygen species via reverse electron flux [17] and via the mechanistic target of rapamycin, leading to a drop in in superoxide, which may guide to DNA damage and mutations [18]. High levels of ceramides in the skeletal muscle are concerned in the aging process. This decreases myoblast proliferation, aberrant cell-cycle regulation, and a senescent myoblast phenotype. Cell studies have exhibited that metformin can reserve the negative result of ceramides, thus potentially avoiding myoblast senescence [19]. This may be helpful for the rising population of older adults with sarcopenic obesity, while possibly improving tissue fitness and functions.

Neuroprotective role of metformin

Some studies have exhibited that metformin exhibited neuroprotective actions, reducing neuronal damage and enhancing oxygen and glucose deficiency, ensuing in improved neuronal survival and avoiding etoposide-induced apoptosis in the key neurons [20],[21] ([Table 1],[Table 2],[Table 3],[Table 4],[Table 5]).
Table 1 Roles and mechanisms of metformin in different uses

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Table 2 Metformin improved nonalcoholic fatty liver disease [31],[32],[33],[34],[35],[36]

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Table 3 Beneficial effects of metformin on energy metabolism and white-adipose-tissue remodeling [37],[38],[39]

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Table 4 Metformin reduces inflammation [2],[40],[41]

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Table 5 Cardiovascular protective effect of metformin [2],[42],[43],[44],[45],[46],[47]

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  Conclusion Top


Metformin is not completely free from side effects. Most often caused side effects are nausea, vomiting, and headache. Rarely, in few individuals, it causes an increase of lactic acid in the blood (lactic acidosis), a very severe side effect. Individuals with kidney problems are more vulnerable to lactic acidosis and should not take metformin. Hence, although there are a variety of assumed applications of metformin in an enormous spectrum of diseases, many mechanisms remain to be understood. More clinical data are needed before the beneficial application of metformin which can be wide-ranging to treat those diseases other than of diabetes [47].

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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