Browsing by Subject "Islet cells"

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    12-Lipoxygenase governs the innate immune pathogenesis of islet inflammation and autoimmune diabetes
    (The American Society for Clinical Investigation, 2021-07-22) Kulkarni, Abhishek; Pineros, Annie R.; Walsh, Melissa A.; Casimiro, Isabel; Ibrahim, Sara; Hernandez-Perez, Marimar; Orr, Kara S.; Glenn, Lindsey; Nadler, Jerry L.; Morris, Margaret A.; Tersey, Sarah A.; Mirmira, Raghavendra G.; Anderson, Ryan M.; Pediatrics, School of Medicine
    Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of proinflammatory eicosanoids, but its role and mechanisms in myeloid cells in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β cells and the subsequent development of hyperglycemia. The depletion or inhibition of 12-LOX in this model resulted in reduced macrophage infiltration into islets and the preservation of β cell mass. In NOD mice, the deletion of the gene encoding 12-LOX in the myeloid lineage resulted in reduced insulitis with reductions in proinflammatory macrophages, a suppressed T cell response, preserved β cell mass, and almost complete protection from the development of T1D. 12-LOX depletion caused a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration resulted from the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migratory defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune cells in the early pathogenesis of T1D and identify 12-LOX as an enzyme required to promote their prodiabetogenic phenotype in the context of autoimmunity.
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    High residual C-peptide likely contributes to glycemic control in type 1 diabetes
    (American Society for Clinical Investigation, 2020-01-02) Rickels, Michael R.; Evans-Molina, Carmella; Bahnson, Henry T.; Ylescupidez, Alyssa; Nadeau, Kristen J.; Hao, Wei; Clements, Mark A.; Sherr, Jennifer L.; Pratley, Richard E.; Hannon, Tamara S.; Shah, Viral N.; Miller, Kellee M.; Greenbaum, Carla J.; Medicine, School of Medicine
    BACKGROUND Residual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known. METHODS We studied 63 adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (<0.007 pmol/mL; n = 15), low (0.017–0.200; n = 16), intermediate (>0.200–0.400; n = 15), or high (>0.400; n = 17). We compared the groups’ glycemia from continuous glucose monitoring (CGM), β cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemic-euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp. RESULTS Low and intermediate MMTT C-peptide groups did not exhibit β cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤ 0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P < 0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared with the negative group (P ≤ 0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared with negative (P = 0.01). CGM demonstrated lower mean glucose and more time in range for the high C-peptide group. CONCLUSION These results indicate that in adults with type 1 diabetes, β cell responsiveness to hyperglycemia and α cell responsiveness to hypoglycemia are observed only at high levels of residual C-peptide that likely contribute to glycemic control. FUNDING Funding for this work was provided by the Leona M. and Harry B. Helmsley Charitable Trust, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.