Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase

Abstract

Metformin is considered to be one of the most effective therapeutics for the treatment of type 2 diabetes (T2D) since it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain, or posing a risk of hypoglycemia1,2. For over half a century, this agent has been prescribed to T2D patients worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase (mGPD), resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production (EGP), while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide (ASO) knockdown of hepatic mGPD in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decrease in plasma glucose concentrations and inhibition of EGP. These findings were replicated in whole-body mGPD knockout mice. These results have significant implications for understanding the mechanism of metformin’s blood glucose lowering effects and provide a novel therapeutic target for T2D.

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial

“…However, our study does not exclude that the glucose-lowering effect of metformin in patients with type 2 diabetes is mainly due to inhibition of HGP, e.g. by blocking glucagon-dependent hepatic glucose output [7,8]. In patients with type 2 diabetes this could involve increased circulating glucagon levels and enhanced hepatic sensitivity to glucagon, which is believed to contribute to an elevated HGP [27][28][29].…”

“…The latter has been shown to abrogate activation of protein kinase A and by this mechanism antagonise glucagon-dependent glucose output in hepatocytes in mice [7]. Most recently, it was reported that metformin suppresses gluconeogenesis by inhibiting the hepatic redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase (mGPD) in rodents [8]. Thus, metformin indirectly decreases the substrate fluxes of lactate and glycerol to the gluconeogenesis and the flux of electrons to the mitochondrial respiratory chain [8].…”

“…Most recently, it was reported that metformin suppresses gluconeogenesis by inhibiting the hepatic redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase (mGPD) in rodents [8]. Thus, metformin indirectly decreases the substrate fluxes of lactate and glycerol to the gluconeogenesis and the flux of electrons to the mitochondrial respiratory chain [8]. It remains to be elucidated to what extent metformin continues to block HGP by these mechanisms under conditions in which glucose counter-regulatory mechanisms are activated to avoid hypoglycaemia.…”

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

“…Metformin enhances insulin sensitivity and lowers blood glucose levels by inhibiting gluconeogenesis in the liver. Metformin elicits these effects by inhibiting the mitochondrial respiratory‐chain complex I and glycerophosphate dehydrogenase (mGPD) and also by activating adenosine monophosphate‐activated protein kinase (AMPK) (Foretz et al ., 2014; Madiraju et al ., 2014). Activation of AMPK, in turn, leads to a plethora of signaling cascades that regulate energy homeostasis and metabolism (Hardie et al ., 2012).…”

Metformin: clinical topics and new mechanisms of action

“…Miller et al reported a suppressing effect of hepatic glucagon signaling via inhibition of adenylyl cyclase activity that participates in metformin action [11]. Madiraju et al reported that metformin inhibits mitochondrial glycerophosphate dehydrogenase (mGPD), a glycerophosphate shuttle enzyme, to exert a suppressing effect on hepatic gluconeogenesis [12].…”