Here we demonstrate using multiple preclinical models of MASH that pancreas- and liver-targeted IL-22 beneficially modulates multiple pathways, including reducing hyperglycemia by improving beta cell function and quality of secreted insulin (decrease in proinsulin); reducing hepatocyte ER stress, inflammation, and oxidative stress; reducing hepatic fat accumulation; and reducing hepatic fibrosis. This evidence concerns the gene INS and metabolic dysfunction-associated steatohepatitis.