Type 1 diabetes can present before the age of 6 months and is characterised by autoimmunity and rapid loss of beta cells

Abstract

Aims/hypothesis: Diabetes diagnosed at <6 months of age is usually monogenic. However, 10-15% of affected infants do not have a pathogenic variant in one of the 26 known neonatal diabetes genes. We characterised infants diagnosed at <6 months of age without a pathogenic variant to assess whether polygenic type 1 diabetes could arise at early ages.

Methods: We studied 166 infants diagnosed with type 1 diabetes at <6 months of age in whom pathogenic variants in all 26 known genes had been excluded and compared them with infants with monogenic neonatal diabetes (n = 164) or children with type 1 diabetes diagnosed at 6-24 months of age (n = 152). We assessed the type 1 diabetes genetic risk score (T1D-GRS), islet autoantibodies, C-peptide and clinical features.

Results: We found an excess of infants with high T1D-GRS: 38% (63/166) had a T1D-GRS >95th centile of healthy individuals, whereas 5% (8/166) would be expected if all were monogenic (p < 0.0001). Individuals with a high T1D-GRS had a similar rate of autoantibody positivity to that seen in individuals with type 1 diabetes diagnosed at 6-24 months of age (41% vs 58%, p = 0.2), and had markedly reduced C-peptide levels (median <3 pmol/l within 1 year of diagnosis), reflecting rapid loss of insulin secretion. These individuals also had reduced birthweights (median z score -0.89), which were lowest in those diagnosed with type 1 diabetes at <3 months of age (median z score -1.98).

Conclusions/interpretation: We provide strong evidence that type 1 diabetes can present before the age of 6 months based on individuals with this extremely early-onset diabetes subtype having the classic features of childhood type 1 diabetes: high genetic risk, autoimmunity and rapid beta cell loss. The early-onset association with reduced birthweight raises the possibility that for some individuals there was reduced insulin secretion in utero. Comprehensive genetic testing for all neonatal diabetes genes remains essential for all individuals diagnosed with diabetes at <6 months of age. Graphical abstract.

Keywords: Autoimmunity; Genetic risk score; Neonatal diabetes; Type 1 diabetes.

Graphical abstract

Fig. 1

Distribution of T1D-GRS in control population (individuals without diabetes) (black line, n = 2938) and individuals with diabetes diagnosed at <6 months of age without a known genetic cause (grey bars, n = 166). Hatched bars represent the enrichment of individuals with high T1D-GRS, above the control population distribution. The dashed line represents the 95th centile of the control population (0.280)

Fig. 2

Proportion of infants positive for anti-islet autoantibodies in those with diabetes of a known monogenic cause (n = 93, control group), diabetes with an unknown cause diagnosed before the age of 6 months with a low T1D-GRS (n = 33) and with a high T1D-GRS (n = 22), and type 1 diabetes diagnosed between the ages of 6 months and 2 years (n = 88). Dark blue bars, positive for at least one of GADA, IA2A or ZnT8A; purple bars, GADA positive; red bars, IA2A positive; light blue bars, ZnT8A positive. GRS, genetic risk score; T1D, type 1 diabetes

Fig. 3

Serum C-peptide (pmol/l) in infants with diabetes of a known monogenic cause (n = 63, control group), diabetes with an unknown cause diagnosed before the age of 6 months with a low T1D-GRS (n = 15) and with a high T1D-GRS (n = 7), and type 1 diabetes diagnosed between the ages of 6 months and 2 years (n = 28). C-peptide is plotted on a log scale. The dashed horizontal line represents 200 pmol/l, with C-peptide values below this considered low. All samples were taken within 1 year of the diagnosis of diabetes. The central line within the box represents the median and the upper and lower limits of the box represent the IQR. The whiskers are the most extreme values within 1.5× the IQR from the first and second quartiles. GRS, genetic risk score

Fig. 4

Scatter plot of adjusted birthweight z score and age at diagnosis of diabetes in weeks in children with high T1D-GRS (n = 48). The fitted line is the predicted linear regression (r² = 0.18, p = 0.001) with grey shading representing the 95% CI. Black circles, islet autoantibody positive; white circles, islet autoantibody tested; grey crosses, islet autoantibody testing unavailable