Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA
Authors: Martinez Maria Månsson , Spiliopoulos Lampros , Salami Falastin , Agardh Daniel , Toppari Jorma , Lernmark Åke , Kero Jukka , Veijola Riitta , Tossavainen Päivi , Palmu Sauli , Lundgren Markus , Borg Henrik , Katsarou Anastasia , Larsson Helena Elding , Knip Mikael , Maziarz Marlena , Törn Carina ,   and the TEDDY-Family (TEFA) Study Group, Ramelius Anita , Jönsson Ida , Bennet Rasmus , Sjöberg Birgitta , Wimar Åsa , Melin Jessica , Ask Maria , Wallin Anne , Hansen Monika , Hyberg Susanne , Ottosson Karin , Bremer Jenny , Carlsson Ulla-Marie , Ulvenhag Ulrika , Sjöberg Anette , Lindström Marielle , Fransson Lina , Johansen Fredrik , Rahmati Kobra , Mestan Zeliha , Tekum-Amboh Evelyn , Jovic Silvija , Gerardsson Joanna , Ericson-Hallström Emelie , Åberg Sofie , Sibthorpe Sara , Mäntymäki Elina , Vainionpää Sini , Romo Minna , Othmani Zhian , Varjonen Eeva , Jokipuu Sanna , Ruohonen Satu , Leppänen Laura , Rajala Petra , Riski Eija , Kähönen Miia , Koivikko Minna-Liisa , Joensuu Tea , Alanen Heidi , Mykkänen Teija , Latva-aho Tiina , Koivikko Minna-Liisa , Stenius Aino , Ollikainen Paula , Korpela Marika , Multasuo Katja , Salmijärvi Päivi , Kemppainen Pieta , Runtti Merja , Päkkilä Riitta , Viinikangas Irene , Pietikäinen Sinikka , Arkkola Tuula 
Published: January 2022

Background

Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.

Methods

Subjects (n = 57) at 2–50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24).

Results

Autoantibodies against GAD65 (GADA;n = 52), ZnT8 (ZnT8A;n = 40), IA-2 (IA-2A;n = 38) and insulin (IAA;n = 28) were present in 9 different combinations of 2–4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was − 1.88 (− 2.71, − 1.05)p = 3.49 × 10–5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (− 0.80 (− 1.58, − 0.02),p = 0.046).

Conclusions

The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account.

Trial registration

ClinicalTrials.govidentifier:NCT02605148, November 16, 2015