Metformin, the Preferred Drug For T2DM, How Does It Achieve Rapid Hypoglycemic Effect?

Metformin is very familiar to diabetic. It is a basic oral hypoglycemic agents. Hepatic glucose output is reduced primarily by mild inhibition of the mitochondrial respiratory chain complex I, which in turn agitates adenylate-activated protein kinase (AMPK). At present, authoritative experts at home and abroad have unanimously recommended that metformin be the first choice for the treatment of T2DM and the combination therapy of hypoglycemic.

How was metformin discovered?

Metformin was first discovered in the composition of goat beans in the 20th century, because its guanidine have hypoglycemic effects. At that time, it was mainly used as a traditional plant medicine for treating diabetes. Since its first use in the treatment of T2DM in 1957, it has undergone long-term clinical practice. It has become the first-line treatment of T2DM recommended by many diabetes guidelines because of its good hypoglycemic effect and its weight loss and other cardiovascular risk factors.

The hypoglycemic mechanism of metformin

(1) Lowering blood glucose by adenylate-activated protein kinase (AMPK). AMPK is a heterotrimer composed of catalytic subunit α and regulatory subunits β, γ. It is a cellular energy receptor that protects cell function when energy is limited. AMPK can be activated by upstream kinases such as LKB1/STK11 and Ca2+/calmodulin kinase β (CaMKKβ) when intracellular adenosine triphosphate (ATP) production and consumption imbalance leads to an increase in adenosine triphosphate/adenosine monophosphate (AMP/ATP) ratio. Studies have shown that changes in adenosine diphosphate (ADP) or ADP/ATP ratios can also bind to γ subunits, which in turn regulate AMPK. When AMPKK is activated, it can inhibit cell anabolism, promote catabolism, shut down the signaling pathway that consumes ATP, and restore cell energy balance. A breakthrough in the molecular mechanism of metformin is that in the early 21st century, two independent research groups reported that metformin can mildly and specifically inhibit mitochondrial respiratory chain complex I, selectively blocking the reverse electron flow of respiratory chain complex I, inhibition of mitochondrial reactive oxygen species (ROS) production. Metformin inhibits the mitochondrial respiratory chain complex I mildly and specifically, resulting in a decrease in intracellular transient energy reserve, activates AMPK, thereby inhibiting glycogen output and lowering blood glucose.

The possible mechanism by which AMPK mediates metformin reduces hepatic glucose export is:

1) to reduce the cyclic adenosine monophosphate (c-Amp) response factor binding protein 2 (CRTC2) by LKB1/AMPK signaling pathway, inhibit gene expression related to gluconeogenesis, and reduce Hepatic glucose output;

2) AMPK can increase liver deacetylase Sirtuin SIRT1) activity and down-regulates CRTC2, thereby inhibiting downstream gluconeogenesis gene transcription;

3) AMPK can reduce gluconeogenesis gene transcription by activating orphan nuclear receptor (SHP) or inhibiting krüpple-like factor 15 (KLF15).

Therefore, metformin can reduce hepatic gluconeogenesis and inhibits hepatic glucose output by various means (Fig. 1).

(2) Lower blood sugar by incretin. Studies have shown that in mice, metformin can increase glucagon-like peptide-1 (GLP-1) levels without glucose uptake, but does not affect other intestinal peptides, such as tyrosin (YY ), gastric inhibitory peptide (GIP) levels. Metformin has not been shown to affect dipeptidyl peptidase-4 (DPP-4) activity. In addition, metformin can increase gene expression of the islet cell GLP-1 receptor via the PPAR-α-mediated AMPK-independent pathway.

Figure 1. The hypoglycemic mechanism of metformin

Adverse reactions of metformin

1. Lactic acidosis: Although lactic acidosis of metformin is very rare, it is one of the most serious adverse reactions due to its serious consequences of lethality. At present, large-scale clinical trials and meta-analytical studies at home and abroad have shown that there is no evidence that metformin has an increased risk of lactic acidosis. Most cases of lactic acidosis reported in the case did not meet the clinical diagnostic criteria for metformin-related lactic acidosis, and were mostly caused by lax control of metformin and lack of dose adjustment.

2. Nephrotoxicity: Metformin itself is not nephrotoxic, but it is generally considered to be excreted by the kidneys as a prototype. If the patient's renal function is impaired, the drug may accumulate in the body and increase the risk of lactic acidosis. Therefore, most guidelines recommend that patients with impaired renal function should be treated with caution.

Edited by Suzhou Yacoo Science Co., Ltd.