Dataset Information

The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells.

ABSTRACT:

Aims

To understand the mechanism by which imeglimin (a new oral hypoglycemic agent whose phase 3 development program in Japan has now been completed) decreases hepatic glucose production.

Materials and methods

We compared the effect of imeglimin and metformin on glucose production, ATP/ADP ratio, oxygen consumption rate, mitochondrial redox potential and membrane potential in primary rat hepatocytes.

Results

We found that both imeglimin and metformin dose-dependently decreased glucose production and the ATP/ADP ratio. Moreover, they both increased mitochondrial redox potential (assessed by mitochondrial NAD(P)H fluorescence) and decreased membrane potential (assessed by TMRM fluorescence). However, contrary to metformin, which inhibits mitochondrial Complex I, imeglimin did not decrease the oxygen consumption rate in intact cells. By measuring the oxygen consumption of in situ respiratory chain as a function of the concentration of NADH, we observed that imeglimin decreased the affinity of NADH for the respiratory chain but did not affect its Vmax (ie competitive inhibition) whereas metformin decreased both the Vmax and the affinity (ie uncompetitive inhibition).

Conclusions

We conclude that imeglimin induces a kinetic constraint on the respiratory chain that does not affect its maximal activity. This kinetic constraint is offset by a decrease in the mitochondrial membrane potential, which induces a thermodynamic constraint on the ATPase responsible for a decrease in the ATP/ADP ratio.

SUBMITTER: Vial G

PROVIDER: S-EPMC8029524 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells.

Vial Guillaume G Lamarche Frédéric F Cottet-Rousselle Cécile C Hallakou-Bozec Sophie S Borel Anne-Laure AL Fontaine Eric E

Endocrinology, diabetes & metabolism 20210223 2

<h4>Aims</h4>To understand the mechanism by which imeglimin (a new oral hypoglycemic agent whose phase 3 development program in Japan has now been completed) decreases hepatic glucose production.<h4>Materials and methods</h4>We compared the effect of imeglimin and metformin on glucose production, ATP/ADP ratio, oxygen consumption rate, mitochondrial redox potential and membrane potential in primary rat hepatocytes.<h4>Results</h4>We found that both imeglimin and metformin dose-dependently decrea ...[more]

PMID: 33855213

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Project description:The regulation of hepatic gluconeogenesis is of great significance to improve insulin resistance and benefit diabetes therapy. cAMP-Regulated Transcriptional Co-activator 2 (CRTC2) plays a key role in regulating hepatic gluconeogenesis through controlling the expression of gluconeogenic rate-limiting enzymes such as glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Recently, salt-inducible kinase 1 (SIK1) has been identified to play an important role in glucose metabolism disorders, but whether and how SIK1 regulates the CTRC2 signaling in liver cells under high glucose conditions has rarely been intensively elucidated. Here, we show that high glucose stimulation resulted in time-dependent down-regulated expression of SIK1, phosphorylated SIK1 at T182 site, and phosphorylated CRTC2 at S171 site, as well as upregulated expression of total CRTC2 and its downstream targets G6Pase and PEPCK in the human liver cell line HepG2. The nuclear expression levels of SIK1 and CRTC2 were time-dependently upregulated upon high glucose challenge, which was accompanied by enhanced cytoplasm-to-nucleus translocation of SIK1. Manipulation of SIK1 activity using plasmid-mediated SIK1 over-expression and the use of the SIKs inhibitor HG-9-91-01 confirmed that SIK1 regulated the CRTC2 signaling pathway in HepG2 cells. Furthermore, in mouse primary hepatocytes, high glucose exposure down-regulated SIK1 expression, and promoted SIK1 nuclear accumulation. While HG-9-91-01 treatment suppressed SIK1 expression and released the inhibitory effects of SIK1 on the expressions of key molecules involved in the CRTC2 signaling pathway, additional ectopic expression of SIK1 using adenovirus infection reversed the impacts of HG-9-91-01 on the expressions of these molecules in mouse hepatocytes. Therefore, SIK1 regulates CRTC2-mediated gluconeogenesis signaling pathway under both physiological and high glucose-induced pathological conditions. The modulation of the SIK1-CRTC2 signaling axis could provide an attractive means for treating diabetes.

Dataset Information

The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells.

Aims

Materials and methods

Results

Conclusions

Publications

The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells.

Similar Datasets

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