Abstract
BackgroundIndividuals 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.MethodsSubjects (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).ResultsAutoantibodies 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).ConclusionsThe 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 registrationClinicalTrials.gov identifier: NCT02605148, November 16, 2015
Highlights
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
Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account
The ten measures of glucose metabolism we considered were (A) oral glucose tolerance test (OGTT) 2 h glucose, (B) log2transformed OGTT glucose area under the OGTT glucose curve (AUC), (C) log2-transformed OGTT C-peptide AUC, (D) log2-transformed OGTT insulin AUC, (E) the median glucose value based on a continuous glucose monitoring (CGM) from a 7-day sampling every 5 min, or (F) the difference between the 75th and 25th percentiles of glucose values based on a CGM from a 7-day sampling every 5 min, (G) HbA1c, (H) log2-transformed first phase insulin response (FPIR), as well as two measures of homeostasis model assessment (HOMA): (I) log2-transformed HOMA2-%B quantifying beta cell function, and (J) log2-transformed HOMA2-%S
Summary
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). As well as adults, with two or more islet autoantibodies proceed to develop diabetes but it may take up to 20 years before the clinical onset [7]. The sub-clinical autoimmune process resulting in the destruction and dysfunction of beta-cells begins months (in very young children) or years before the appearance of the classical clinical symptoms of type 1 diabetes and is reflected in a decreased first phase insulin response (FPIR) [[8] related to the number of islet autoantibodies and genetic factors other than HLA [9, 10]]. At the onset of clinical symptoms, only a small fraction of the functional beta-cell mass is thought to be left
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