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Abstract

Background: Type 2 diabetes (T2D) in children has increased over the past two decades. Strategies to mitigate disease progression often focus on macronutrients, overlooking micronutrients despite evidence of deficiency in children with T2D. Riboflavin, as flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), is crucial for metabolism and oxidative stress management, mainly through FAD-dependent glutathione reductase. Given that insulin-producing β-cells are vulnerable to oxidative stress, they may have unique riboflavin requirements, especially during puberty, a period characterized by β-cell expansion. The objective of my thesis was to investigate the role of riboflavin in glucose homeostasis in an adolescent mouse model. Methods: Male and female C57BL/6J mice were fed for 8-12 weeks from weaning one of the following diets: control (6mg riboflavin/kg diet), low riboflavin (1mg riboflavin/kg diet), western (45% energy fat, 6mg riboflavin/kg diet), or western low riboflavin (45% energy fat, 1mg riboflavin/kg diet). Physiological assessments of adiposity and glucose homeostasis were performed. Serum, liver, gonadal fat, and pancreatic islets were collected for metabolite analyses and functional assessment of β-cells. Results: The low riboflavin diets lowered (p<0.01) serum riboflavin and hepatic FMN/FAD concentrations. Male mice had lower (p=0.064) pancreatic islet FAD, while female mice showed lower (p<0.05) pancreatic islet riboflavin and FMN concentrations. No effect of the diet on metabolites was observed in gonadal fat. In male mice, serum and liver vitamin B6 metabolites were consistently lowered (p<0.05). Female mice on the western low riboflavin diet had reduced adiposity (p<0.05) and smaller gonadal fat pads (p<0.05) Additionally, these females showed elevated (p<0.05) serum advanced glycation end-products (AGEs) and lower (p<0.05) ketone levels, alongside lower (p<0.05) pancreatic islets concentrations of ornithine, asparagine, and proline. Both sexes had lower (p<0.05) liver TCA metabolites in response to the low riboflavin diet. Riboflavin deficiency did not alter glucose tolerance, insulin sensitivity, or β-cell function. Conclusion: A low riboflavin diet exerts a sex- and tissue-specific effect, without altering glucose tolerance and β-cell function. These findings suggest that riboflavin deficiency may influence early metabolic pathways linked to glucose homeostasis and inflammation, particularly in female mice.