Abstract
High protein feeding has been shown to accelerate the development of type 1 diabetes in female non-obese diabetic (NOD) mice. Here, we investigated whether reducing systemic amino acid availability via knockout of the Slc6a19 gene encoding the system B(0) neutral amino acid transporter AT1 would reduce the incidence or delay the onset of type 1 diabetes in female NOD mice. Slc6a19 gene deficient NOD mice were generated using the CRISPR-Cas9 system which resulted in marked aminoaciduria. The incidence of diabetes by week 30 was 59.5% (22/37) and 69.0% (20/29) in NOD.Slc6a19+/+ and NOD.Slc6a19−/− mice, respectively (hazard ratio 0.77, 95% confidence interval 0.41–1.42; Mantel-Cox log rank test: p = 0.37). The median survival time without diabetes was 28 and 25 weeks for NOD.Slc6a19+/+ and NOD.Slc6a19−/− mice, respectively (ratio 1.1, 95% confidence interval 0.6–2.0). Histological analysis did not show differences in islet number or the degree of insulitis between wild type and Slc6a19 deficient NOD mice. We conclude that Slc6a19 deficiency does not prevent or delay the development of type 1 diabetes in female NOD mice.
Highlights
Islet beta cell metabolic stress in response to nutrient overload has been proposed to increase the susceptibility of islet beta cells to immune destruction, accelerating the development of type 1 diabetes in genetically at risk individuals [1,2]
There is pre-clinical evidence in situations of chronic beta cell stress, including endoplasmic reticulum stress, which shows transport of amino acids into beta cells is increased and this contributes to beta cell loss through apoptosis [10]
The abundance in urine of alanine, glycine, isoleucine, leucine, methionine, phenylalanine, serine, threonine and valine were all markedly increased in 6–8 week old female non-obese diabetic (NOD).Slc6a19−/− compared to NOD.Slc6a19+/+ mice, consistent with successful construction of Slc6a19 deficient NOD mice (Figure 1a)
Summary
Islet beta cell metabolic stress in response to nutrient overload has been proposed to increase the susceptibility of islet beta cells to immune destruction, accelerating the development of type 1 diabetes in genetically at risk individuals [1,2]. Islet beta cell stress leads to activation of beta cell neoantigen production and stimulation of HLA class I expression on the cell surface [3,4,5]. This could underlie, at least in part, the increasing incidence of type 1 diabetes within older children and adolescents [6,7]. Approaches to limit islet beta cell metabolic stress through pharmacological means, such as by using metformin, or reducing availability of nutrient secretagogues, could prevent type 1 diabetes [8,9]. Amino acids augment glucose-stimulated insulin secretion and have the potential to increase beta cell nutrient-induced stress [8]. There is pre-clinical evidence in situations of chronic beta cell stress, including endoplasmic reticulum stress, which shows transport of amino acids into beta cells is increased and this contributes to beta cell loss through apoptosis [10]
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