Hepatic and Pancreatic Cellular Response to Early Life Nutritional Mismatch

Abstract To determine the basis for perinatal nutritional mismatch causing metabolic dysfunction associated steatotic liver disease (MASLD) and diabetes mellitus, we examined adult phenotype, hepatic transcriptome, and pancreatic β-islet function. In prenatal caloric restricted rat with intrauterine growth restriction (IUGR) and postnatal exposure to high fat with fructose (HFhf) or high carbohydrate (RC), we investigated male and female IUGR-Hfhf and IUGR-RC, versus HFhf and CON offspring. Males more than females displayed adiposity, glucose intolerance, insulin resistance, hyperlipidemia, hepatomegaly with hepatic steatosis. Male hepatic triglyceride synthesis, de novo lipogenesis genes increased, while female lipolysis, β-oxidation, fatty acid efflux, and FGF21 genes increased. IUGR-HFhf males demonstrated reduced β-islets insulin and humanin, and type1 diabetes mellitus human amniotic fluid increased humanin. Humanin suppression disabled glucose stimulated insulin, ATP production, with apoptotic diminished β-islet viability. Humanin and FGF21 may reverse perinatal nutritional mismatched phenotype, by restoring functional β-islets and preventing MASLD and diabetes mellitus.