Combined vitamin D, ibuprofen and glutamic acid decarboxylase-alum treatment in recent onset Type I diabetes: lessons from the DIABGAD randomized pilot trial

Abstract

Aim: Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D). Methods: 64 patients (T1D since <4 months, age 10–17.99, fasting sC-peptide ≥0.12 nmol/l, GADA-positive) were randomized into Day(D) 1–90 400 mg/day Ibuprofen, D1–450 vitamin D 2000 IU/day, D15, 45 sc. 20 μg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40 μg GAD-alum D15, 45; placebo. Results: Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24 h with change in C-peptide AUC at 15 months (r = -0.776, p < 0.0001). Conclusion: Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 ( ClinicalTrials.gov ).

Glutamic Acid Decarboxylase Injection Into Lymph Nodes: Beta Cell Function and Immune Responses in Recent Onset Type 1 Diabetes Patients

“…Our study suggests that GAD-alum administration directly into lymph-nodes of T1D patients in combination with oral vitamin D may result in better preservation of C-peptide than seen in T1D patients of similar age ( 2 , 15 ). Vitamin D is supposed to improve efficacy by its effect on the immune system, and the design of this study makes it impossible to discriminate the effect of GAD-alum from the effect of Vitamin D. However, in other studies with the same Vitamin D treatment, we have only seen some support for using Vitamin D, but no clear effect on beta cell preservation ( 16 ). The idea of a main effect due to GAD-alum is supported by the results showing that main changes after treatment are all antigen-specific, while non-specific immunomodulatory effects were not observed.…”

A century later, still fighting back: antigen‐specific immunotherapies for type 1 diabetes

“…In the DIAGNODE‐1 study, patients with newly diagnosed T1D received three low‐dose GAD‐alum injections directly into an inguinal lymph node and an oral vitD supplement 55 . In parallel, another group of recent‐onset patients received two higher doses of GAD‐alum subcutaneously, along with oral vitD and ibuprofen (DIABGAD study) 56 . Both exhibited overall safety, but the comparison between treatments highlighted the strong type 2 T‐helper cell‐like modulation achieved by intranodal administration after 6 months, because the aluminum adjuvant does preferentially induce type 2 T‐helper cell and humoral responses, and intralymphatic administration delivers more antigen to the desired site.…”

“…For instance, a first treatment with a nonspecific immunomodulating therapy could reduce the T1D proinflammatory environment so that the following antigen‐specific immunotherapy could “land swiftly” and have a greater possibility of success. However, these combinations require a thorough mechanistic analysis, as the nonspecific immunotherapy could override the pathways on which the antigen‐specific immunotherapy relies 56,89 . By contrast, the combination of strategies must be taken into consideration when aiming to revert the disease.…”

“…55 In parallel, another group of recent-onset patients received two higher doses of GAD-alum subcutaneously, along with oral vitD and ibuprofen (DIABGAD study). 56 Both exhibited overall safety, but the comparison between treatments highlighted the strong type 2 T-helper cell-like modulation achieved by intranodal administration after 6 months, because the aluminum adjuvant does preferentially induce type 2 T-helper cell and humoral responses, and intralymphatic administration delivers more antigen to the desired site. In fact, the immune responses of these patients were characterized by higher serum anti-GAD antibody titers and a shift of IgG subclasses-with a relative reduction of IgG1 and a shift toward IgG2, IgG3 and IgG4-as well as an increase in IL-13 secretion and lower proliferation rates in GAD65stimulated peripheral blood mononuclear cells.…”

“…However, these combinations require a thorough mechanistic analysis, as the nonspecific immunotherapy could override the pathways on which the antigenspecific immunotherapy relies. 56,89 By contrast, the combination of strategies must be taken into consideration when aiming to revert the disease. Antigenspecific immunotherapy coadministered with a regenerative strategy to recover b-cell fitness might be the only way of successfully re-establishing normoglycemia after T1D diagnosis.…”