Current understanding of metformin effect on the control of hyperglycemia in diabetes

Abstract

Metformin is a first-line oral anti-diabetic agent that has been used clinically to treat patients with type 2 diabetes for over 60 years. Due to its efficacy in therapy and affordable price, metformin is taken by more than 150 million people each year. Metformin improves hyperglycemia mainly through the suppression of hepatic gluconeogenesis along with the improvement of insulin signaling. However, its mechanism of action remains partially understood and controversial, especially in regard to the role of AMPK in metformin's action and the mechanism of AMPK activation. In this review, we discuss recent advances in the understanding of metformin's suppression of hepatic glucose production and the mechanism related to the improvement of insulin signaling.

Keywords: glucose metabolism; insulin action; liver; metabolism.

Figure 1. Metformin Suppression of Hepatic Glucose Production by Promoting the Formation of the AMPKαβγ Heterotrimeric Complex

Metformin increases the phosphorylation of AMPK by promoting the formation of the AMPK heterotrimeric complex. Activated AMPK leads to the phosphorylation of CREB co-activators and the inhibition of gluconeogenic gene expression.

Figure 2. Direct Suppression of Hepatic Glucose Production by Metformin through the Inhibition of Mitochondrial Respiratory Chain Complex 1, AMP Deaminase, and Mitochondrial Glycerol 3-Phosphate Dehydrogenase

Inhibition of mitochondrial complex 1 also leads to an increase in AMP levels or the AMP/ATP ratio, as does the inhibition of AMP deaminase, resulting in the activation of AMPK. However, high metformin concentrations are needed to inhibit the mitochondrial complex and AMP deaminase. Metformin inhibition of mitochondrial glycerol 3-phosphate dehydrogenase (G3PDH) will increase NADH levels in the cytoplasm and suppress the conversion of lactate from pyruvate. This mechanism of metformin action is important for patients with high levels of serum lactate.

Figure 3. Metformin Improves Insulin Signaling in the Liver

Metformin can alter the microbiota in the intestine, resulting a reduction in LPS production and translocation across the intestinal barrier. Activation of AMPK by metformin also blocks LPS-mediated activation of the NF-κB signaling pathway and PTEN induction.