Alcohol ingestion induces pancreatic islet dysfunction and apoptosis via mediation of FGF21 resistance

Abstract

Background: Disruption of β-cell insulin secretion and viability caused by excessive ethanol consumption increases type 2 diabetes mellitus (T2DM) pathogenesis risk. Fibroblast growth factor 21 (FGF21) plays a significant role in regulating lipid and glucose homeostasis. Recently, FGF21, best known for its role in lipid and glucose homeostasis regulation, and its obligate co-receptor β-klotho have been shown to inhibit ethanol ingestion and metabolism. It remains unclear whether heavy ethanol intake modulates islet FGF21 expression and function. This study investigated the relationship between ethanol exposure, FGF21, and islet function in vivo/ex vivo islet and in vitro cell models.Methods: Mice were gavaged with 3.5 g/kg ethanol or saline for 1-3 weeks (long-term exposure). Human MIN6 cells and isolated islets were cultured and treated with 80 mM ethanol for 24 h (short-term exposure) to mimic excessive ethanol consumption. We applied the oral glucose tolerance test (OGTT), blood glucometry, enzyme-linked immunosorbent assay (ELISAs) for insulin and FGF21, glucose stimulated insulin secretion (GSIS) testing, reverse-transcription (RT)-polymerase chain reaction (PCR), and western blot experiments.Results: Long-term ethanol treatment induced FGF21 resistance in mouse pancreatic islets. Moreover, ethanol exposure damaged insulin secretory ability and glucose homeostasis. In vitro and ex vivo experiments showed that short-term ethanol treatment upregulated the expression of FGF21 signaling pathway-related genes and proteins, without affecting β-cell survival or function.Conclusions: Long-term ethanol consumption induces FGF21 resistance-mediated pancreatic β-cell dysfunction, and thus diabetes pathogenesis risk.

miR-155-5p upregulation ameliorates myocardial insulin resistance via mTOR signaling in chronic alcohol drinking rats

“…However, no significant changes were observed in LVIDs, EF and FS. In addition, our results confirm that long-term ethanol consumption induces insulin resistance and thus diabetes pathogenesis risk, which was consistent with Yang, Wu & Leung (2020) . In view of the heart dysfunction and myocardial insulin resistance caused by ethanol, reducing alcohol consumption might be metabolically favorable for human future glucose metabolism.…”

Lentinan protects against pancreatic β‐cell failure in chronic ethanol consumption‐induced diabetic mice via enhancing β‐cell antioxidant capacity

“…It is reported that excessive alcohol is a significant risk factor in β‐cell apoptosis 1‐3 . To examine whether LNT could prevent ethanol‐induced β‐cell apoptosis, MIN6 cells were pretreated with LNT for 2 hours and then exposed to ethanol for an additional 72 hours.…”

“…Chronic alcohol consumption is well established as a major risk factor to trigger the development of type 2 diabetes mellitus (T2DM), which is evidenced by impaired glucose metabolism and insulin resistance 1‐3 . Due to the key role of pancreatic β‐cell failure in the pathogenesis of T2DM, increasingly more attention has been paid to the understanding of β‐cell damage induced by excessive heavy ethanol in recent years 4,5 .…”

Alcohol and Metabolic-associated Fatty Liver Disease

“…Studies showed that alcohol intake of more than 3–5 drinks/day can dramatically increase the energy intake from alcohol. 7 , 8 More importantly, chronic heavy drinking has been proven to induce pancreatic β-cell dysfunction in human and animal models, 11 , 12 with decreased insulin-secretory ability and disrupted glucose homeostasis. Both increased energy intake and pancreatic β-cell dysfunction contribute to the pathogenesis of obesity in heavy drinkers.…”