In this article, metformin is introduced from the development history, pharmacological properties, molecular mechanism of action and its clinical application.

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Metformin, The Next "Miracle Drug" After Aspirin
Metformin, a guanidine derivative originally extracted from the plant Galega
officinalis (French clove), has been used as a human hypoglycemic drug for
over 60 years. According to American Diabetes Association (ADA)
guidelines, metformin is the recommended first-line drug for the
treatment of type 2 diabetes (T2D). In recent years, studies have found that
metformin can also be used to treat cancer, obesity, non-alcoholic fatty liver
disease (NAFLD), polycystic ovary syndrome (PCOS) and metabolic
syndrome, and has certain anti-aging and bone protection effects. The various
effects of metformin may be the result of its interaction with various
enzymes. In this article, metformin is introduced from the development history,
pharmacological properties, molecular mechanism of action and its clinical
application.
Development History of Metformin
The history of metformin dates back to the 17th century, when it was
discovered that the leaf extract of Galega officinalis, a French clove, can be
used to treat plague, fever, snake bites and other ailments. In 1653, Culpeper
proposed in Complete Herbal that G.FFicinalis had hypoglycemic properties in
animals, but it was not suitable for human beings because of its toxicity. The
chemical synthesis of guanidin was first described by German chemist Adolph
Strecker in 1844 -- 1861. The synthesis of biguanides was carried out in 1878
-- 1879 by the German chemist Bernhard Rathke. In 1922, Werner and Bell
achieved the synthesis of metformin and metformin. In 1929, researchers
demonstrated that metformin injected into rabbits effectively lowered
blood sugar, paving the way for metformin to be used as a first-line
treatment for type 2 diabetes (T2D) in humans. In 1957, French doctor Jean
Sterne took the milestone step of using metformin to treat diabetes. However,
due to the risk of lactic acidosis, the FDA announced the discontinuation of
metformin on November 15, 1978. Metformin was officially approved for
use in the United States in 1995.

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Figure 1 The development history of metformin
Pharmacological Properties of Metformin
The structural formula of metformin is C4H11N5 and its molecular weight is
129.16 g/mol. Metformin for clinical use is synthesized from dimethylamine
chloride and dicyandiamide. Metformin hydrochloride is a white powder at
room temperature with a melting point of 223-226℃, and its solubility in water
can be up to 200g/L. After oral administration, metformin is absorbed mainly
in the proximal small intestine (duodenum and jejunum). The absolute
bioavailability of metformin hydrochloride orally is relatively low (about
50-60%), and ingestion reduces the degree of drug absorption and slightly
delays its rate of absorption. Notably, metformin is not metabolized by the liver.
The primary method of elimination of metformin is rapid excretion through the
kidneys. Therefore, patients with renal impairment need to adjust the dosage
of metformin. The most common side effect of metformin is its
gastrointestinal reaction, which can cause flatulence, diarrhea, nausea,
vomiting and cramps. These symptoms are most common when metformin
is used for the first time or at high doses. This side effect can be avoided by
starting at a low dose and gradually increasing the dose or by using a
sustained-release formulation. The most serious adverse effect of metformin is
lactic acidosis, a rare complication that appears to be associated with liver and
kidney damage in the vast majority of cases. In addition, high dose and
long-term use of metformin can increase the incidence of vitamin B12
deficiency.

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Figure 2 Chemical structure, pharmacological properties and side effects of
metformin
Molecular Mechanism of Metformin Action
1. Mechanism of hypoglycemic action
Mitochondrial dysfunction is associated with many chronic diseases,
including diabetes. Metformin has weak mitochondrial toxicity and can inhibit
complex I, thereby reducing the ATP/AMP ratio, which in turn increases AMP
levels leading to the activation of AMPK. Zhou et al. (2001) first demonstrated
that metformin activated AMPK in rat hepatocytes at concentrations of 10 and
20μM. AMPK is a key regulator of many metabolic functions, including
enhanced glucose uptake, increased glycolysis, fatty acid oxidation and
mitochondrial biogenesis, while reducing gluconeogenesis, glycogen synthesis,
protein synthesis and proliferation, and reduced fatty acid and cholesterol
synthesis. Many studies have confirmed that metformin releases GLP-1
through AMPK-dependent action, promotes insulin secretion, and
inhibits glucagon secretion.

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Figure 3 Regulatory effects of metformin on mitochondrial function and
gluconeogenesis genes
2. Mechanism of endothelial vascular protection
Mather et al. (2001) found that metformin reduced insulin resistance and
improved endothelium-dependent vasodilation (EDV). Another study showed
that six months of treatment with 850mg/day metformin improved vascular
dilatation in patients with peripheral artery disease. These data suggest that
metformin may improve vascular function in addition to improving blood
glucose control. Orphan nuclear receptor NR4A1 is critical for mediating the
protective effect of metformin against hyperglycemia induced endothelial
dysfunction. NR4A1 can directly bind to metformin and regulate the
localization of LCB1, thereby activating AMPK and reducing inflammatory
signals and intracellular ROS production. In addition, metformin inhibits
high-glucose-induced NF-κB activation, which is also associated with
increased AMPK phosphorylation.

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Figure 4 Metformin interacts with multiple protein targets
3. Mechanism of anti-cancer action
In a meta-analysis, metformin-treated diabetics were found to have a 31%
reduction in cancer incidence and a 34% reduction in cancer mortality after
adjusting for body mass index. Further evidence suggests that metformin may
also have an adjunctive effect in patients undergoing chemotherapy. Insulin
and IGF-1 are both potential growth factors that stimulate cell survival and
mitosis, and their receptors are expressed in many cancer cells, including
breast, liver, colon, pancreatic, and skin cancers. Treatment with metformin
may reduce serum insulin and IGF-1 levels, thus reducing the stimulation of
tumor growth. In addition, the activation of LKB1/AMPK signaling by metformin
inhibited aerobic glycolysis and induced tumor cell death. The risk of malignant
transformation of cancer cells can be reduced by regulating AMPK activation
dependent fatty acid synthesis. It can target pro-inflammatory cytokines in the
tumor microenvironment and regulate the immune microenvironment of cancer
cells.

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Figure 5 Mechanism of action of metformin in cancer
4. Anti-aging mechanism of action
The lifespan-extending effects of metformin in Caenorhabditis elegans (C.
elegans) were first reported in 2010. This study shows that metformin
extends the life of C. elegans by activating AMPK/LKB1/Nrf2 signaling.
SIRT1 plays a crucial role in the regulation of growth, stress response and
aging, and metformin can prolong lifespan by activating SIRT1. Metformin may
also indirectly affect the epigenome by regulating metabolite levels, altering
histone and DNA-regulating enzyme activities, thus regulating the aging
process. Lysosomes and lysosome-related organelles play an important role in
regulating aging and longevity, and metformin appears to have the potential to
affect mitochondrial, lysosomal function, cell signaling, and inflammatory
responses by regulating lysosomal metal homeostasis (e.g., copper, zinc, and
iron).
Figure 6. Effects of metformin on model organisms and human lifespan

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Clinical Applications
1. Diabetes
As the most widely used T2D drug in the world, metformin has been used in
clinical practice for more than 60 years. Numerous studies and clinical trials
have shown that metformin alone or in combination with other
hypoglycemic agents can effectively treat T2D. In 1991, Hermann and
colleagues reported that metformin restored fasting blood glucose (FBG) in
patients with non-insulin-dependent diabetes mellitus (NIDDM). In a 1995
study by Ra DeFronzo, metformin monotherapy was shown to improve
glycemic control and lipid concentrations and to reduce fasting glucose and
glycosylated hemoglobin in a dose-dependent manner in patients with NIDDM.
In recent years, several studies have shown that the combination of metformin
with other drugs is superior to that of metformin alone. Drugs used in
combination with metformin include glibenclamide, troglitazone, insulin,
dipeptidyl peptidase 4 (DPP4) inhibitors, sodium-glucose cotransporter-2
(SGLT2) inhibitors, and glucagon-like peptide 1 (GLP1) receptor agonists.
2. Degenerative Bone Diseases
Osteoporosis (OP), osteoarthritis (OA) and intervertebral disc degeneration
(IVDD) are the major degenerative bone diseases, all associated with aging.
There is growing evidence that metformin plays a beneficial role in the
treatment of degenerative bone diseases. Metformin improves bone
metabolism caused by glucocorticoid overexposure by inhibiting bone
resorption and stimulating bone formation in trabecular bone. It protects
articular cartilage by activating AMPK pathway, delays the onset and
progression of OA, and reduces OA-related pain sensitivity in injury-induced
OA models in mice and primates. By inhibiting cell senescence and
inflammatory response in nucleus pulposus and annulus fibrosus, the
intervertebral disc degeneration in rats was improved and local mechanical
hyperalgesia was reduced.
3. Cardiovascular Disease
Current clinical studies on the cardioprotective effects of metformin have
focused on coronary heart disease, heart failure, and heart attack
combined with pulmonary hypertension. Sardu et al. reported that
metformin reduced the risk of coronary heart disease by reducing coronary
endothelial dysfunction. In addition, metformin mitigated the early progression
of coronary plaque in men with prediabetes. Zhang et al. reported that
metformin changed the composition of serum lipids, which indirectly reduced
the probability of cardiovascular events in patients. In addition, metformin

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protected the heart by reducing myocardial oxygen consumption and
significantly lowering left ventricular mass index (LVMI), left ventricular mass
(LVM), left ventricular systolic pressure, and oxidative stress in patients with
coronary artery disease, and preserved ejection fraction to some extent.
4. Cancer
A study by Bodmer et al. showed that long-term use of metformin reduced
the risk of breast cancer in women with T2D, and this protective effect was
related to the type of breast cancer and the patient's hormone levels.
Metformin reduced the level of serum estradiol and inhibited the development
of breast cancer. Multiple clinical studies have reported that the use
of metformin in patients with T2D not only reduces the risk of colorectal cancer,
but also improves survival in patients with colorectal cancer. In addition,
metformin has been shown to reshape the methylation signature of colon
cancer cells, which may contribute to its anti-colon cancer effect. A regression
study showed a negative association between metformin use and lung cancer
incidence and mortality in lung cancer patients.
5. Non-alcoholic Fatty Liver Disease
NAFLD includes a variety of liver lesions, including steatosis, non-alcoholic
steatohepatitis (NASH), cirrhosis, and may progress to hepatocellular
carcinoma (HCC). Obesity, insulin resistance, and especially T2D are major
factors in the development of NAFLD and NASH. For this reason, NASH is
called "diabetic liver disease." The benefits of metformin in inhibiting liver
gluconogenesis, altering liver fatty acid metabolism (including inhibition of
adipose tissue liposolysis), improving fatty acid oxidation, inhibiting lipogenesis
and enhancing insulin sensitivity have been well recognized. The beneficial
effects of metformin on liver histology in NAFLD/NASH patients have been
reported in recent years.
6. Polycystic Ovary Syndrome
Polycystic ovary syndrome (PCOS) is one of the most common endocrine
disorders associated with reproductive and metabolic disorders, affecting 9%
to 18% of women. Manifestations of PCOS include infertility, obesity,
inappropriate gonadotropin secretion, pregnancy complications,
cardiovascular disease, and psychological problems. Studies in the 1990s
have shown that metformin can reduce insulin resistance, increase ovulation,
and improve the prognosis of women with PCOS undergoing assisted
reproductive technology. When combined with lifestyle interventions,
metformin can be more effective in treating PCOS.

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Conclusion
Metformin is an old drug with miraculous effects, acting differently in a
variety of tissues, but many mechanisms remain to be elucidated. More
clinical evidence is needed before the therapeutic application of metformin can
be expanded to treat diseases other than diabetes.
Metformin is the first-line drug that used to treat type 2 diabetes (T2DM) for 60
years. Huateng Pharma, a leading API & pharmaceutical intermediate supplier
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