ESPE Abstracts (2014) 82 FC3.4

Genetics of Paediatric Type 2 Diabetes: ABCC8 Mutation in Obesity-Associated Insulin Secretion Defects

Susanna Wieganda, Deimante Simaiteb, Almut Dannemannc, Peter Kühnena, Heiko Krudea, Maolian Gongb & Klemens Raileb


aInstitute of Experimental Paediatric Endocrinology, Charité, Berlin, Germany; bExperimental and Clinical Research Center, Charité, Berlin, Germany; cInterdisciplinary Social Paediatric Center, Charité, Berlin, Germany


Background: Type 2 diabetes in children and adolescents is a rare disease with an estimated incidence (age 0–20 years) of below 5/100 000 in Germany.

Objective and Hypotheses: We hypothesize that monogenic alterations might contribute to early-onset insulin secretion defects, if islet function was challenged by obesity-associated insulin resistance.

Method: We follow more than 1500 children and adolescents with obesity. Patients are initially screened for impaired fasting glucose, insulin, or HOMA >95th percentile. Overall 264 children with abnormal lab-tests (glucose or HOMA-index) or extreme obesity (BMI>+2.5 SDS) are currently followed by annual oGTTs. Patients that display impaired glucose tolerance or diabetes (IGT/DM) and have an overall maximum insulin level below 130 mU/ml (during 0–120 min oGTT) are categorized as being at risk for defective insulin secretion. All cases were auto antibody-negative. In total, 32 patients with lowest insulin secretion were selected for genetic testing in this project. All coding exons and exon-intron boundaries of ATP-dependent potassium channel (KATP) genes KCNJ11 and ABCC8 were screened by Sanger sequencing.

Results: We identified two unrelated individuals with the same heterozygous mutation c.1616A>G/p.Tyr539Cys in exon 10 of ABCC8. The tyrosine at position 539 is highly conserved among vertebrates and this functionally uncharacterized variant is reported in dbSNP (rs193922397) as observed in one child with neonatal diabetes. Patient one (girl, 11.5 years) was obese (BMI 27.7 kg/m2) and had polyurea, hyperglycemia and increased HbA1c (8.9%). Her diabetes was initially treated with insulin but recovered completely under weight reduction. Patient two (boy, 12.8 years, BMI 26.8 kg/m2) had abnormal fasting glucose and impaired glucose tolerance but his glucose levels normalized as he reduced weight.

Conclusion: Pathogenic variants of genes involved in insulin secretion, like ABCC8 might contribute to early-onset type 2 diabetes in a monogenic or oligogenic fashion, especially if insulin secretion was challenged by obesity-associated insulin resistance.

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