Interaction of B0AT1 Deficiency and Diet on Metabolic Function and Diabetes Incidence in Male Nonobese Diabetic Mice

Abstract

Context: The obesity epidemic parallels an increasing type 1 diabetes incidence, such that westernized diets, containing high fat, sugar, and/or protein, through inducing nutrient-induced islet β-cell stress, have been proposed as contributing factors. The broad-spectrum neutral amino acid transporter (B0AT1), encoded by Slc6a19, is the major neutral amino acids transporter in intestine and kidney. B0AT1 deficiency in C567Bl/6J mice causes aminoaciduria, lowers insulinemia, and improves glucose tolerance. Objective: We investigated the effects of standard rodent chow (chow), high-fat high-sucrose (HFHS), and high-fat high-protein (HFHP) diets, in addition to B0AT1 deficiency, on the diabetes incidence of male nonobese diabetic (NOD/ShiLtJArc (NOD)) mice. Methods: Male NOD.Slc6a19+/+ and NOD.Slc6a19-/- mice were fed chow, HFHS and HFHP diets from 6 to 24 weeks of age. A separate cohort of male NOD mice were fed the three diets from 6-30 weeks of age. Body weight and fed-state blood glucose and plasma insulin were monitored, and urinary amino-acid profiles, intraperitoneal glucose tolerance, diabetes incidence, pancreatic islet number, insulitis scores and beta-cell mass were measured. Results: The incidence of diabetes and severe glucose intolerance was 3.8% in HFHS-fed, 25.0% in HFHP-fed, and 14.7% in chow-fed mice, with higher pancreatic islet number and lower insulitis scores in HFHS-fed mice. B0AT1 deficiency had no effect on diabetes incidence, but curtailed HFHS-induced excessive weight gain, adipose tissue expansion, and hyperinsulinemia. In HFHP-fed mice, B0AT1 deficiency significantly increased pancreatic β-cell clusters and small islets. Male NOD mice that did not develop autoimmune diabetes were resistant to diet-induced hyperglycemia. Conclusion: Dietary composition does, but B0AT1 deficiency does not, affect autoimmune diabetes incidence in male NOD mice. B0AT1 deficiency, however, reduces diet-induced metabolic dysfunction and in HFHP-fed mice increases pancreatic β-cell clusters and small islets. Show more