Reduced β-cell function in early preclinical type 1 diabetes

Abstract

Objective: We aimed to characterize insulin responses to i.v. glucose during the preclinical period of type 1 diabetes starting from the emergence of islet autoimmunity.

Design and methods: A large population-based cohort of children with HLA-conferred susceptibility to type 1 diabetes was observed from birth. During regular follow-up visits islet autoantibodies were analysed. We compared markers of glucose metabolism in sequential intravenous glucose tolerance tests between 210 children who were positive for multiple (≥2) islet autoantibodies and progressed to type 1 diabetes (progressors) and 192 children testing positive for classical islet-cell antibodies only and remained healthy (non-progressors).

Results: In the progressors, the first phase insulin response (FPIR) was decreased as early as 4-6 years before the diagnosis when compared to the non-progressors (P=0.001). The difference in FPIR between the progressors and non-progressors was significant (P<0.001) in all age groups, increasing with age (at 2 years: difference 50% (95% CI 28-75%) and at 10 years: difference 172% (95% CI 128-224%)). The area under the 10-min insulin curve showed a similar difference between the groups (P<0.001; at 2 years: difference 36% (95% CI 17-58%) and at 10 years: difference 186% (95% CI 143-237%)). Insulin sensitivity did not differ between the groups.

Conclusions: FPIR is decreased several years before the diagnosis of type 1 diabetes, implying an intrinsic defect in β-cell mass and/or function.

Figure 1

Median values of the study variables ((A) FPIR, (B) AUC_0–10 min for insulin, (C) fasting insulin, (D) fasting glucose, (E) HOMA-IR index and (F) HOMA-IR to FPIR ratio) before the diagnosis of type 1 diabetes in the progressors (black line) and in the non-progressors until the last IVGTT (dotted line). Point 0 indicates the time of the diagnosis or the last IVGTT. The x axis indicates years before the diagnosis or the last IVGTT. (A and B) The y axis indicates the unit for the study variable. FPIR and AUC_0–10 min for insulin were decreased 0–2 and 2–4 years (P<0.001 for both variables and time periods) and up to the time period of 4–6 years before the diagnosis as compared to the non-progressors (P=0.001 and P=0.002 respectively). (C) Fasting insulin did not differ between the groups before the diagnosis. (D) Fasting glucose differed between the groups 0–2 years before the diagnosis (P=0.008). (E) HOMA-IR index did not differ between the groups before the diagnosis. (F) HOMA-IR to FPIR ratio was increased in the progressors during the time periods 0–2, 2–4 and 4–6 years prior to diagnosis (P<0.001, P<0.001 and P=0.005 respectively).

Figure 2

Mean values of the study variables ((A) FPIR, (B) AUC_0–10 min for insulin, (C) fasting insulin, (D) fasting glucose, (E) HOMA-IR index and (F) HOMA-IR to FPIR ratio) in cubic splines between the non-progressors and progressors as a function of age (years). The solid line shows the values of the progressors. The black line represents the values when the last 2 years prior to diagnosis were excluded. The grey line represents the values when the last 2 years prior to diagnosis were included. The black dotted line represents the non-progressors. (C, D and E) Fasting insulin increased 3.9%/year, fasting glucose 0.50%/year and HOMA-IR index increased 4.4%/year (P<0.001, P=0.0024 and P<0.001 respectively).

Figure 3

(A) Median 60-min values of glucose before the diagnosis of type 1 diabetes in the progressors (black line) and in the non-progressors until the last IVGTT (dotted line). Point 0 indicates the time of the diagnosis or the last IVGTT. The x axis indicates years before the diagnosis or the last IVGTT. The y axis indicates plasma glucose concentration at 60 minutes. (B) The median, upper and lower quartile for 60-min glucose values before the diagnosis of type 1 diabetes. Point 0 indicates the time of diagnosis. The x axis indicates years before the diagnosis. The y axis indicates plasma glucose concentration at 60 minutes. For other variables in this study, the quartiles before the diagnosis of type 1 diabetes are seen in the Supplementary File. (C) Mean values of glucose at 60 min in cubic splines among the non-progressors and progressors as a function of age (years). The solid line shows the values of the progressors. The black line represents the values when the last 2 years prior to diagnosis were excluded. The grey line represents the values when the last 2 years prior to diagnosis were included. The black dotted line represents the non-progressors. Glucose values at 60 min were obtained from the Turku data set (299 samples from non-progressors and 325 samples from progressors).