Metformin instigates cellular autophagy to ameliorate high-fat diet-induced pancreatic inflammation and fibrosis/EMT in mice

Chronic pancreatic dysfunction is frequently observed as a consequence of prolonged high-fat diet consumption and is a serious public health concern. This pro-diabetic insult aggravates inflammation-influenced fibrotic lesions and is associated with deregulated autophagy. Metformin, a conventional anti-hyperglycemic drug, might be beneficial for pancreatic health, but the complex molecular regulations are not clarified. Considering the worldwide prevalence of chronic pancreatic dysfunction in obese individuals, we aimed to unwind the molecular intricacies explaining the involvement of oxidative stress, inflammation and fibrosis and to approbate metformin as a plausible intervention in this crossroad. Age-matched Swiss Albino mice were exposed to high-fat diet (60 kcal%) against control diet (10 kcal%) to establish diet-induced stress model. Metformin treatment was introduced after 4 weeks to metformin-control and HFD-exposed metformin groups. After 8 weeks, metabolic and molecular outcomes were assessed to establish the impact of metformin on chronic consequences of HFD-mediated injury. High-fat diet administration to healthy mice primes oxidative stress-mediated chronic inflammation through Nrf2/Keap1/NF-κB interplay. Besides, pro-inflammatory cytokine bias leading to fibrotic (increased TGF-β, α-SMA, and MMP9) and pro-EMT (Twist1, Slug, Vimentin, E-cadherin) repercussions in pancreatic lobules were evident. Metformin distinctly rescues high-fat diet-induced remodeling of pancreatic pro-diabetic alterations and cellular survival/death switch. Further, metformin abrogates the p62-Twist1 crosstalk in an autophagy-dependent manner (elevated beclin1, LC3-II/I, Lamp2) to restore pancreatic homeostasis. Our research validates the therapeutic potential of metformin in the inflammation-fibrosis nexus to ameliorate high-fat diet-induced pancreatic dysfunction and related metabolic alterations. [Display omitted] •Metformin salvages metabolic insufficiency in high-fat diet-induced diabetic mice.•Metformin attenuates oxidative stress-mediated cell death in diabetic mouse pancreas.•Inflammation-associated fibrosis is recouped by metformin in high fat diet-exposed mouse pancreas.•Metformin disrupts p62-Twist1 interaction to allay fibrosis-initiated EMT in diabetic mice.•Metformin triggers cellular autophagy to mitigate high-fat diet-induced pancreatic dysfunction.