Prevention of Catch-Up Growth by Early-Life Postnatal Undernutrition causes Impaired Insulin Secretion and Glucose Metabolism on HFD

Abstract

Type 2 Diabetes (T2D) is a metabolic disease characterized by chronic elevation in plasma glucose levels.T2D affects millions of people worldwide. One risk factor for developing T2D is accelerated postnatal growth, or “catch-up growth” (CUG), in early life. Consequences of interventions to prevent CUG, including early-postnatal undernutrition (UN), on adaptation to environmental stress have not been investigated. I hypothesize that mice exposed to postnatal UN are protected from weight gain and glucose intolerance, but have decreased pancreatic plasticity and gut-intrinsic factors. An ICR/CD1 mouse model for CUG prevention using early postnatal caloric restriction was generated and challenged with high fat diet (HFD). Postnatal UN mice are unable to adapt to HFD resulting in decreased insulin secretion and worsened glucose tolerance. Pancreatic islet area and number were quantified using H&E staining. Mice with postnatal UN had decreased islet area and number on chow but not on HFD. Islet composition was not different in postnatal UN mice. Insulin secretion is restored during an oGTT. Therefore, regulatory genes for incretin and bile acid synthesis, lipogenesis, and gluconeogenesis were investigated. This showed that lipogenesis and intestinal bile acid regulatory genes were reduced on HFD when CUG is prevented. This study shows that prevention of CUG using postnatal UN results in reduced glucose-stimulated insulin secretion and islet area on chow as well as reduced expression of lipogenesis and bile acid regulatory genes and worsened glucose metabolism when challenged with HFD.