Methyl succinate antagonises biguanide‐induced AMPK‐activation and death of pancreatic <i>β</i>‐cells through restoration of mitochondrial electron transfer
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.
The three-model screen
all 1,000 screened works →All three models called this out of scope.
Pharmacology experiment on biguanide-induced AMPK activation in beta-cells; the object is cell metabolism.
The study investigates metformin effects on pancreatic beta cells.
Biomedical pharmacology of biguanides on pancreatic beta cells.
Abstract
BACKGROUND AND PURPOSE: Two mechanisms have been proposed to explain the insulin-sensitising properties of metformin in peripheral tissues: (a) inhibition of electron transport chain complex I, and (b) activation of the AMP activated protein kinase (AMPK). However the relationship between these mechanisms and their contribution to beta-cell death and dysfunction in vitro, are currently unclear. EXPERIMENTAL APPROACH: The effects of biguanides (metformin and phenformin) were tested on MIN6 beta-cells and primary FACS-purified rat beta-cells. Cell metabolism was assessed biochemically and by FACS analysis, and correlated with AMPK phosphorylation state and cell viability, with or without fuel substrates. KEY RESULTS: In MIN6 cells, metformin reduced mitochondrial complex I activity by up to 44% and a 25% net reduction in mitochondrial reducing potential. In rat beta-cells, metformin caused NAD(P)H accumulation above maximal glucose-inducible levels, mimicking the effect of rotenone. Drug exposure caused phosphorylation of AMPK on Thr(172) in MIN6 cell extracts, indicative of kinase activation. Methyl succinate, a complex II substrate, appeared to bypass metformin blockade of complex I. This resulted in reduced phosphorylation of AMPK, establishing a link between biguanide-induced mitochondrial inhibition and AMPK activation. Corresponding assessment of cell death indicated that methyl succinate decreased biguanide toxicity to beta-cells in vitro. CONCLUSIONS AND IMPLICATIONS: AMPK activation can partly be attributed to metformin's inhibitory action on mitochondrial complex I. Anaplerotic fuel metabolism via complex II rescued beta-cells from metformin-associated toxicity. We propose that utilisation of anaplerotic nutrients may reconcile in vitro and in vivo effects of metformin on the pancreatic beta-cell.
Stored with the screening record, where it is evidence for the labels above.
The record
- Venue
- British Journal of Pharmacology
- Topic
- Metabolism, Diabetes, and Cancer
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- —
- Funders
- Canadian Institutes of Health ResearchVlaamse regeringFonds Wetenschappelijk Onderzoek
- Keywords
- AMPKBiguanideMetforminPhenforminAMP-activated protein kinaseMitochondrionProtein kinase ACell biologyBeta cellChemistryBiologyPhosphorylationPharmacologyBiochemistryEndocrinologyInsulinIslet
- Has abstract in OpenAlex
- yes