Abstract
Recent evidence from serum metabolomics indicates that specific metabolic disturbances precede β-cell autoimmunity in humans and can be used to identify those children who subsequently progress to type 1 diabetes. The mechanisms behind these disturbances are unknown. Here we show the specificity of the pre-autoimmune metabolic changes, as indicated by their conservation in a murine model of type 1 diabetes. We performed a study in non-obese prediabetic (NOD) mice which recapitulated the design of the human study and derived the metabolic states from longitudinal lipidomics data. We show that female NOD mice who later progress to autoimmune diabetes exhibit the same lipidomic pattern as prediabetic children. These metabolic changes are accompanied by enhanced glucose-stimulated insulin secretion, normoglycemia, upregulation of insulinotropic amino acids in islets, elevated plasma leptin and adiponectin, and diminished gut microbial diversity of the Clostridium leptum group. Together, the findings indicate that autoimmune diabetes is preceded by a state of increased metabolic demands on the islets resulting in elevated insulin secretion and suggest alternative metabolic related pathways as therapeutic targets to prevent diabetes.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease that results from the selective destruction of insulin-producing b-cells in pancreatic islets
We have recently found that distinct metabolic disturbances precede b-cell autoimmunity in children who later progress to type 1 diabetes (T1D)
We performed a murine study using non-obese diabetic (NOD) mice that recapitulated the protocol used in human, followed up by independent studies where NOD mice were studied in relation to risk of diabetes progression
Summary
Type 1 diabetes (T1D) is an autoimmune disease that results from the selective destruction of insulin-producing b-cells in pancreatic islets. The incidence of T1D among children and adolescents has increased markedly in the Western countries during the recent decades [3] and is presently increasing at a faster rate than ever before [4,5]. This suggests an important role of environment and gene-environment interactions in T1D pathogenesis. Recent evidence from serum metabolomics suggests that metabolic disturbances precede early b-cell autoimmunity markers in children who subsequently progress to T1D [2]. In order to effectively prevent this disease it is fundamental to identify suitable experimental models that recapitulate findings from such large-scale clinical studies while being amenable to mechanistic studies at the systems level
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