The age of onset of Type 1 Diabetes (T1D) presents considerable variation from patient to patient. Some become insulin dependent in a just few weeks, while others may take months or years. In either, immune system-β-cell interactions conspire to lead to loss of β-cells and insulin secretion. The molecular and cellular events involved have been the focus of intense research efforts, but most longitudinal studies during the onset of T1D have been limited to biomarkers (circulating autoantibodies, C-peptide⋯), without direct β-cell assessment. Despite data indicating that patients can retain functional β-cells years after the onset of the disease, one school of thought is that there is a precipitous loss of β-cells just preceding the time of clinical onset, triggering the hyperglycemia observed in T1D patients. A counter-view supported by recent studies suggests that insulin secretion is reduced even before β-cell loss. These assessments are traditionally performed through histo-morphometry. The process is time-consuming, prone to errors and costly. Using an NOD line with a SfGFP reporter attached to the C-peptide, we have designed a platform allowing the in toto imaging of β-cell mass in a model of T1D. After a 15-minute IPGTT to capture the peak of insulin secretion, pancreata were harvested and imaged on a cohort of animals at a time of early onset of T1D. A comparison of classical histo-morphometry and in toto imaging revealed a tight correlation between both approaches. Using the new platform allowed the rapid classification of large cohorts of animals based on the β-cell mass and glucose response. The results highlighted a significant disconnect between mass and function in a subset of mice: Some animals presenting near-normal mass while being glucose intolerant while others displaying a drastically reduced mass but still responding normally to a glucose challenge. These findings emphasize the role of islet dysfunction during the onset of T1D even before β-cell death.


C.Cras-méneur: None. R.J.Seeley: Board Member; Fractyl Health, Inc., Consultant; Novo Nordisk, Eli Lilly and Company, Research Support; Novo Nordisk, Fractyl Health, Inc., AstraZeneca, Eli Lilly and Company. P.Arvan: None.


National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)

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