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Blockade of glucagon signaling prevents or reverses diabetes onset only if residual ?-cells persist.

ABSTRACT: Glucagon secretion dysregulation in diabetes fosters hyperglycemia. Recent studies report that mice lacking glucagon receptor (Gcgr(-/-)) do not develop diabetes following streptozotocin (STZ)-mediated ablation of insulin-producing ?-cells. Here, we show that diabetes prevention in STZ-treated Gcgr(-/-) animals requires remnant insulin action originating from spared residual ?-cells: these mice indeed became hyperglycemic after insulin receptor blockade. Accordingly, Gcgr(-/-) mice developed hyperglycemia after induction of a more complete, diphtheria toxin (DT)-induced ?-cell loss, a situation of near-absolute insulin deficiency similar to type 1 diabetes. In addition, glucagon deficiency did not impair the natural capacity of ?-cells to reprogram into insulin production after extreme ?-cell loss. ?-to-?-cell conversion was improved in Gcgr(-/-) mice as a consequence of ?-cell hyperplasia. Collectively, these results indicate that glucagon antagonism could i) be a useful adjuvant therapy in diabetes only when residual insulin action persists, and ii) help devising future ?-cell regeneration therapies relying upon ?-cell reprogramming.

SUBMITTER: Damond N

PROVIDER: S-EPMC4871705 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist.

Damond Nicolas N Thorel Fabrizio F Moyers Julie S JS Charron Maureen J MJ Vuguin Patricia M PM Powers Alvin C AC Herrera Pedro L PL

eLife 20160419

Glucagon secretion dysregulation in diabetes fosters hyperglycemia. Recent studies report that mice lacking glucagon receptor (Gcgr(-/-)) do not develop diabetes following streptozotocin (STZ)-mediated ablation of insulin-producing β-cells. Here, we show that diabetes prevention in STZ-treated Gcgr(-/-) animals requires remnant insulin action originating from spared residual β-cells: these mice indeed became hyperglycemic after insulin receptor blockade. Accordingly, Gcgr(-/-) mice developed hyp ...[more]

PMID: 27092792

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Project description:BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

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Blockade of glucagon signaling prevents or reverses diabetes onset only if residual ?-cells persist.

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Blockade of glucagon signaling prevents or reverses diabetes onset only if residual β-cells persist.

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