The importance of the AMPK gamma 1 subunit in metformin suppression of liver glucose production.

ABSTRACT: Metformin has been used to treat patients with type 2 diabetes for over 60 years, however, its mechanism of action is still not completely understood. Our previous reports showed that high-fat-diet (HFD)-fed mice with liver-specific knockout of both AMPK catalytic ?1 and ?2 subunits exhibited significantly higher fasting blood glucose levels and produced more glucose than floxed AMPK catalytic ?1 and ?2 mice after long-term metformin treatment, and that metformin promotes the formation of the functional AMPK ??? heterotrimeric complex. We tested the importance of each regulatory ? subunit isoform to metformin action in this current study. We found that depletion of ?1, but not ?2 or ?3, drastically reduced metformin activation of AMPK. HFD-fed mice with depletion of the ?1 subunit are resistant to metformin suppression of liver glucose production. Furthermore, we determined the role of each regulatory cystathionine-?-synthase (CBS) domain in the ?1 subunit in metformin action and found that deletion of either CBS1 or CBS4 negated metformin's effect on AMPK? phosphorylation at T172 and suppression of glucose production in hepatocytes. Our data indicate that the ?1 subunit is required for metformin's control of glucose metabolism in hepatocytes. Furthermore, in humans and animal models, metformin treatment leads to the loss of body weight, we found that the decrease in body weight gain in mice treated with metformin is not directly attributable to increased energy expenditure.

SUBMITTER: An H 

PROVIDER: S-EPMC7320014 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature