Pediatr Diabetes. 2014 Aug;15(5):345-54.

Disease progression among 446 children with newly diagnosed type 1 diabetes located in Scandinavia, Europe and North America during the last 27 years.

Max Andersen ML, Nielsen LB, Svensson J, Pörksen S, Hougaard P, Beam C, Greenbaum C, Becker D, Petersen JS, Hansen L, Mortensen HB.

Department of Pediatrics, Herlev Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Herlev, Denmark.

 

Abstract

Objective – To clarify whether the rate of decline in stimulated C-peptide (SCP) from 2-15 months after diagnosis has changed over an interval of 27 years.

Research design and methods – The rate of decline in SCP levels at 1, 2, 3, 6, 9, 12 and 15 months after diagnosis was compared in four paediatric cohorts from Scandinavian and European countries including 446 children with new onset T1D (1982-2004). Findings were evaluated against 78 children (2004-2009) from the TrialNet studies.

Results – The mean rate of decline (%/month (±SEM)) in SCP for a 10 year old child was 7.7 %/month (±1.5) in the 1982-1985 Cohort, 6.3 %/month (±1.7) in the 1995-1998 Cohort, 7.8 %/month (±0.7) in the 1999-2000 Cohort, and 10.7 %/month (±0.9) in the latest 2004-2005 Cohort (P = 0.05). Including the TrialNet Cohort with a rate of decline in SCP of 10.0 %/month (±0.9) the differences between the cohorts are still significant (P=0.039). The rate of decline in SCP was negatively associated with age (P<0.0001), IA (P=0.003), GAD65A (P=0.03) initially with no statistically significant effect of BMI Z-score at 3 months. Also, at 3 months the time around partial remission, the effect of age on SCP was significantly greater in children ≤ 5 years compared to older children (P ≤ 0.0001)

Conclusions – During the past 27 years, initial C-peptide as well as the rate of C-peptide decline seem to have increased. The rate of decline was affected significantly by age, GAD65A and IA, but not BMI Z-score or initial C-peptide.

Key words: Diabetes mellitus, Type 1, C-peptide, Rate of decline, Children

PMID: 24731251

 

Supplement

T1D disease progression seems to have changed with a more pronounced rate of decline in SCP the first 15 months after diagnosis in the latest Danish cohort and TrialNet even when the initial higher C-peptide level was accounted for in statistical analyses. In addition the study showed that age has a stronger influence on stimulated C-peptide in the very young children compared with the older. Several studies have shown that the highest increase in T1D incidence is occurring among the youngest individuals ( <5 years of age) with stable or decreasing rates later in life, suggesting that the increasing incidence of T1D in youth is the result of an ‘acceleration’ of disease onset rather than an increased lifetime risk. This could explain the shift in rate of decline in stimulated C-peptide in the more recent cohorts as the decline is more pronounced in the very young children. There was no significant effect of BMI Z score on the rate of decline in SCP, however BMI Z score was positively associated with the level of SCP indicating decreased insulin sensitivity with increased body mass index. Positivity for GAD and IAA showed a significant negative effect on the rate of decline in SCP. Thus it’s the specific type of autoantibody profile which is associated with the clinical progression. After 3 months of disease duration, around the time of maximal residual beta cell function and peak in partial remission rate there was a non-linear effect of age on stimulated C-peptide levels. In the very young children (≤5 yr) SCP increased 44 per cent per year of age while the level of 3 months SCP only increased 3% per yr in children 5-10 yr and 9% in children above 10 yr. Thus the regenerative/proliferative potential of beta-cells in human is maximal ≤ 5 years. Yet, practically no children ≤ 5 years enter remission clinically while more children in the older age groups reach remission clinically. Therefore new onset intervention studies should target the young age group and older age cohorts with different strategies, i.e. primarily support beta-cell proliferation in the young age group and beta-cell preservation/protection in the older age group. Intervention should be initiated as early as possible after diagnosis and no later than 3 months post diagnosis.

 

 

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