Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.

Metformin is a first-line antidiabetic agent taken by 150 million people across the world every year, yet its mechanism remains only partially understood and controversial. It was proposed that suppression of glucose production in hepatocytes by metformin is AMPK-independent; however, unachievably high concentrations of metformin were employed in these studies. In the current study, we find that metformin, via an AMP-activated protein kinase (AMPK)-dependent mechanism, suppresses glucose production and gluconeogenic gene expression in primary hepatocytes at concentrations found in the portal vein of animals (60–80 μm). Metformin also inhibits gluconeogenic gene expression in the liver of mice administered orally with metformin. Furthermore, the cAMP-PKA pathway negatively regulates AMPK activity through phosphorylation at Ser-485/497 on the α subunit, which in turn reduces net phosphorylation at Thr-172. Because diabetic patients often have hyperglucagonemia, AMPKα phosphorylation at Ser-485/497 is a therapeutic target to improve metformin efficacy.

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.

Metformin is the most widely prescribed oral anti-diabetic agent. Recently, we have shown that low metformin concentrations found in the portal vein suppress glucose production in hepatocytes through activation of AMPK. Moreover, low concentrations of metformin were found to activate AMPK by increasing the phosphorylation of AMPKα at Thr-172. However, the mechanism underlying the increase in AMPKα phosphorylation at Thr-172 and activation by metformin remains unknown. In the current study, we find that low concentrations of metformin promote the formation of the AMPK αβγ complex, resulting in an increase in net phosphorylation of the AMPK α catalytic subunit at Thr-172 by augmenting phosphorylation by LKB1 and antagonizing dephosphorylation by PP2C. Background: The mechanism underlying the activation of AMPK by metformin remains unclear. Results: Metformin promotes the formation of AMPK αβγ heterotrimeric complex. Conclusion: The formation of the AMPK αβγ heterotrimeric complex augments AMPKα phosphorylation by LKB1 and prevents dephosphorylation by protein phosphatase. Significance: Metformin-mediated formation of the AMPK αβγ heterotrimeric complex results in AMPK activation by elevating AMPK phosphorylation at Thr-172.

Diabetes and obesity are characterized by insulin resistance and chronic low-grade inflammation. An elevated plasma concentration of lipopolysaccharide (LPS) caused by increased intestinal permeability during diet-induced obesity promotes insulin resistance in mice. Here, we show that LPS induces endoplasmic reticulum (ER) stress and protein levels of P300, an acetyltransferase involved in glucose production. In high-fat diet fed and genetically obese ob/ob mice, P300 translocates from the nucleus into the cytoplasm of hepatocytes. We also demonstrate that LPS activates the transcription factor XBP1 via the ER stress sensor IRE1, resulting in the induction of P300 which, in turn, acetylates IRS1/2, inhibits its association with the insulin receptor, and disrupts insulin signaling. Pharmacological inhibition of P300 acetyltransferase activity by a specific inhibitor improves insulin sensitivity and decreases hyperglycemia in obese mice. We suggest that P300 acetyltransferase activity may be a promising therapeutic target for the treatment of obese patients.