Insulin Gene Mutations are Found in Children with Diabetes and Negative to T1D Autoantibodies

Results: Heterozygous mutations of insulin (INS) gene are found in patients with neonatal/infancy-onset diabetes. We have evidence that INS gene mutations cause permanent diabetes by endoplasmic reticulum stress-induced apoptosis of the beta cells. Probands of the Italian series who carry insulin mutations show diabetes in isolation with onset between 1 to 6 months from birth. However, 2 affected parents of familial cases bearing the R65C (or R89C) mutation presented with diabetes at 1 and 4 years of age, respectively. We screened the INS gene in 4 patients with diabetes onset above 1 year of age, who were negative to the search of ICA, GAD, IA-A2, IAA and zinc transporter 8 (ZnT8) autoantibodies. We detected 2 INS gene mutations: the already described GB8S (or G32S) and the novel ASignal23S. The GB8S mutant had diabetes onset at 2 years, 10 months of age with detectable C peptide at outset (0.49 ng/ml), and after 2 years (0.34 ng/ml); presently, his insulin dose is 0.5 U Kg-1 d-1. The individual with the ASignal23S mutation presented with typical symptoms of diabetes (polyuria, polydipsia) when he was 6 years 8 months old (HBA1c= 11%). Insulin was started and continued for 6 months; during the following 2 years the patient went off/on insulin several times. Currently, he is on insulin at the dose of 0.2 U Kg-1 d-1. C-peptide measured 11 and 24 months after onset of hyperglycemia was 1.32 and 0.7 ng/ml, respectively. We conclude that: 1) INS gene mutations can be found in children previuosly classified as T1D; 2) the clinical presentation of diabetes in these patients, who do not show any associated feature, is indistinguishable from common T1D diabetes.