OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

Abstract

Background/Aims: Metformin treatment is reported to be associated with a lower incidence of and mortality from pancreatic cancer (PC) in type 2 diabetes patients. Activated pancreatic stellate cells (PSCs) are key stroma cells responsible for pancreatic fibrogenesis and PC progression. However, little research is about the influence of metformin on PSCs. Given the potential beneficial effects of metformin on PC, pancreatic tumour stroma is an important target for new therapeutics. We observed the effects of metformin on PSCs. We investigated the effects of metformin on human PSCs proliferation and the production of extracellular matrix (ECM) proteins. Methods: Cells were cultured with different concentrations of metformin (0-10 mmol/L). Cell proliferation was determined by immunofluorescence staining for nuclear Ki67 labelling. ECM production was studied by quantitative real-time polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Adenosine monophosphate–activated protein kinase (AMPK), an important regulatory molecule responsible for metformin action, and the organic cation transporter member 1 (OCT1), which is believed to be the most important transporter for the pharmacological action of metformin, were investigated for their possible involvements in metformin-induced proliferation and ECM production. Results: Our results showed that metformin inhibited PSCs proliferation and decreased the production of ECM proteins by activation of AMPK phosphorylation. Silencing of OCT1 expression resulted in a reduction in the effects of metformin on PSCs activity. Conclusions: Collectively, the data indicate that OCT1 may contribute to uptake metformin and regulate PSCs activity. OCT1 is a target of metformin in regulating PSCs activity.

Pharmacokinetic Interaction of Green Rooibos Extract With Atorvastatin and Metformin in Rats

“…In contrast to these findings, the concomitant administration of GRT with metformin in vivo did not affect the plasma concentration of metformin, suggesting that interaction of GRT (rooibos) with metformin is unlikely. Although metformin is not dependent on cytochrome P450 (CYP450) metabolism, drug transporting membrane proteins, such as the solute carrier family of transporters, including organic cation transporters (OCTs), and ATP-binding cassette transporters alters the extent of its pharmacological effects (Mato et al, 2018; Wu et al, 2018). GRT alone significantly increased Abcc2 mRNA expression, while in combination with metformin or atorvastatin, no significant effect was demonstrated.…”

Mitochondrial targets of metformin—Are they physiologically relevant?

“…Other transporters from SLC22 and SLC47 families, for example, organic cation transporters (OCT1‐3) or carnitine/organic cation transporter (OCTN1), which are expressed in intestine were also proposed to be involved in metformin uptake . In addition, OCTs have also been implicated to play important role in metformin distribution in cancer cells and other tissues like liver or kidney . High expression of OCTs explains profound metformin accumulation in mouse liver (~40 μmol/L) when compared to serum (~5 μmol/L) …”

Metformin in Reproductive Biology

“…The exact molecular mechanism of metformin's action remains unclear. In the first publications, metformin's actions at the cellular level have been attributed to inhibition of Complex I of the mitochondrial respiratory chain, albeit at relatively high concentrations (mM) ( 5 – 10 ). This inhibition results in a decline in ATP production by mitochondria and an increase in the [adenosine monophosphate to ATP ratio ([AMP]/[ATP]) leading to the activation of the AMP-activated protein kinase (AMPK) complex ( 11 ).…”