Estimated insulin sensitivity, cardiovascular risk, and hepatic steatosis after 12 years from the onset of T1D.

AIM: To test the hypothesis that intensive insulin treatment and optimal glycaemic control are not fully protective against reduction of insulin sensitivity in children with type 1 diabetes. MATERIAL AND METHODS: Cohort study of 78 normal-weight patients with prepubertal onset (T0 ) and follow-up waves at 1 (T1 ), 5 (T5 ), 10 (T10 ), and 12 (T12 ) years; matched for age and sex to 30 controls at T12 . Estimated insulin sensitivity (eIS) by three formulae; ultrasound evaluation of para and perirenal fat thickness; hepatic steatosis (HS); carotid intima media thickness (cIMT) at T12 . RESULTS: At T12, the 36 patients (46%) who had constantly or prevalently haemoglobin A1c (HbA1c) < 58 mmol/l during follow-up showed better eIS indexes (p = 0.049 to <0.0001); lipid profile (p = 0.042 to <0.0001), reduced fat mass (p = 0.012) and required lower insulin dose (p = 0.032) than the 42 patients (54%) with HbA1c ≥ 58 at T12. Patients (N = 25) with eISEDC  < 8.77 mg kg-1  min-1 showed higher cIMT (p < 0.0001). HS was found in 6 patients (∼8%). In patients and normal-weight controls, fat mass (p = 0.03), age (p = 0.03), cIMT (p = 0.05) predicted HS; eIS indexes (p from 0.04 to <0.0001) predicted cIMT. Body mass index, perirenal fat, fat mass, and triglycerides to high density lipoprotein cholesterol ratio were associated with eIS indexes (p from 0.03 to <0.0001). CONCLUSIONS: Young T1D patients have reduced insulin sensitivity and higher cIMT. Adiposity, glucose, and lipid control over follow-up are likely to influence both. Enhanced adiposity seems of paramount relevance for the onset of HS in T1D patients alike in healthy youths.

A variable degree of autoimmunity in the pedigree of a patient with type 1 diabetes homozygous for the PTPN22 1858T variant.

We investigated whether the PTPN22 C1858T polymorphism is associated with the autoimmune conditions present in the family of a child affected by type 1 diabetes (T1D) carrying the TT genotype (index patient) and the potential immunological effect of the variant. We found that nine family members carried the CT genotype and five suffered from autoimmunity. Interestingly, anti-ZnT8 antibodies were detected in T1D patients and in three healthy relatives. In the TT patient, we showed diminished T-cell proliferation and reduced interleukin-2 (IL-2) and interferon-gamma (IFN-γ) production. A marked reduction of IL-2 was also observed for all CT relatives with autoimmunity and a lack of IFN-γ production was observed for the younger brother of the index patient, heterozygous for the polymorphism. In this family, the C1858T variant might confer a high risk of autoimmunity. Moreover, our data confirm that impaired IL-2 production upon T-cell receptor stimulation is associated with autoimmunity in the carriers of the polymorphism. This study might prompt to extend the panel of risk markers in relatives of subjects affected by T1D.

Genotypes of p53 codon 72 correlate with age at onset of type 1 diabetes in a sex-specific manner.

In type 1 diabetes mellitus (T1D) p53 pathways are up-regulated and there is an increased susceptibility to apoptosis. The hypothesis is that p53 codon 72 polymorphism could be associated with T1D. A total of 286 children with T1D and a control sample of 730 subjects were studied. p53 codon 72 polymorphism was analysed by polymerase chain reaction. A large increase of p53 *Arg/*Arg was observed in T1D patients with age at onset < 6 years. A strong linear correlation between *Arg/*Arg genotype and age at onset was observed in females. The involvement of the *Arg/*Arg genotype in apoptosis suggests that during the autoimmune process leading to T1D, genetic factors that favor apoptosis may contribute to the onset of overt disease.