Absence of Islet Autoantibodies and Modestly Raised Glucose Values at Diabetes Diagnosis Are Critical Features of MODY: Lessons from a 5-Year Paediatric Swedish National Cohort Study

Abstract

Background: Identifying monogenic diabetes in paediatric populations close to diabetes diagnosis is important but challenging. Misdiagnosis and unnecessary insulin treatment are common. Islet autoantibodies aid recognition of 'non Type 1' diabetes but are not universally advocated or comprehensively performed. This study aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with GCK, HNF1A and HNF4A MODY in the paediatric population. Methods: Patients (n=3933) aged between 1-18 years, with a new diagnosis of diabetes were recruited between May 2005 to December 2010 from the Swedish national consecutive prospective cohort 'Better Diabetes Diagnosis'(BDD). Clinical data, acute biochemistry, islet autoantibodies against GADA, IA-2A, ZnT8A and insulin, HLA type and C-peptide were collected at diagnosis. Monogenic diabetes was identified by sequencing, either through routine clinical or research testing. Findings: At least 1·2% of paediatric diabetes patients had MODY. Negativity to all 4 islet autoantibodies was the strongest discriminatory clinical feature of MODY (100% (46/46) vs 11% (416/3887) non-MODY; p=2x10-44) with MODY confirmed in 46/303 (15%) of autoantibody negative patients tested. Individuals with MODY had lower random plasma glucose (mean 11·7 vs 26·7mmol/L, p=3x10-19), lower HbA1c (53 vs 93 mmol/mol, p=1x10-20) and absent DKA (0/26 MODY vs 545/3342, p=0·02) compared to non-MODY patients. Testing the 100 autoantibody negative patients with the predefined HbA1c <58mmol/mol at diagnosis identified 36/46 (78%) MODY patients. On follow-up 42/46 (91%) MODY patients were not on insulin with excellent glycaemic control (mean HbA1c 47mmol/mol). Interpretation: At diagnosis of paediatric diabetes absence of islet autoantibodies and modest hyperglycaemia are key clinical features of MODY allowing differentiation from Type 1 diabetes. All paediatric patients negative for 4 islet autoantibodies and HbA1c <58mmol/mol at diabetes diagnosis should be tested for GCK, HNF1A and HNF4A MODY. This will improve treatment and allow excellent long term glycaemic control without insulin. Funding Statement: The Swedish Child Diabetes Foundation, the National Institutes of Health (DK063861) and the Wellcome Trust. Declaration of Interests: The authors state: There are no conflicts of interest to declare. Ethics Approval Statement: The Regional Ethics Board at the Karolinska Institute, Stockholm, Sweden approved the BDD study (Dnrs 2004-826/1, 2006/1082-32, 2009/1684-32). The study is written in line with STROBE guidelines for cohort studies.