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Published on: July 3, 2018
Reduced β-cell function in early preclinical type 1 diabetes
Maarit K Koskinen1, Olli Helminen1, Jaakko Matomäki2
1Department of PaediatricsUniversity of Turku and Turku University Hospital, Turku, FinlandMediCity LaboratoriesDepartment of Clinical Medicine, University of Turku, Lemminkäisenkatu 3, 20520 Turku, FinlandPEDEGO Research UnitDepartment of Paediatrics, Medical Research Centre Oulu, University of Oulu, Oulu, FinlandDepartment of Children and AdolescentsOulu University Hospital, Oulu, FinlandClinical Research CentreTurku University Hospital, Turku, FinlandDepartment of PaediatricsTampere University Hospital, Tampere, FinlandNovo Nordisk Farma OyCMR Department, Espoo, FinlandDiabetes Outpatient ClinicTampere, FinlandDepartment of PaediatricsTurku University Hospital, Turku, FinlandResearch Centre of Applied and Preventive Cardiovascular MedicineUniversity of Turku, Turku, FinlandImmunogenetics LaboratoryUniversity of Turku, Turku, FinlandDepartment of Clinical MicrobiologyUniversity of Eastern Finland, Kuopio, FinlandChildren's HospitalUniversity of Helsinki and Helsinki University Hospital, Helsinki, FinlandResearch Programs UnitDiabetes and Obesity, University of Helsinki, Helsinki, FinlandFolkhälsan Research CentreUniversity of Helsinki, Helsinki, FinlandDepartment of PhysiologyInstitute of Biomedicine, University of Turku, Turku, Finland Department of PaediatricsUniversity of Turku and Turku University Hospital, Turku, FinlandMediCity LaboratoriesDepartment of Clinical Medicine, University of Turku, Lemminkäisenkatu 3, 20520 Turku, FinlandPEDEGO Research UnitDepartment of Paediatrics, Medical Research Centre Oulu, University of Oulu, Oulu, FinlandDepartment of Children and AdolescentsOulu University Hospital, Oulu, FinlandClinical Research CentreTurku University Hospital, Turku, FinlandDepartment of PaediatricsTampere University Hospital, Tampere, FinlandNovo Nordisk Farma OyCMR Department, Espoo, FinlandDiabetes Outpatient ClinicTampere, FinlandDepartment of PaediatricsTurku University Hospital, Turku, FinlandResearch Centre of Applied and Preventive Cardiovascu
Insights
Children progressing to type 1 diabetes show reduced first phase insulin response (FPIR) years before diagnosis. This indicates an early defect in pancreatic beta-cell function or mass.
Area of Science:
- Endocrinology
- Immunology
- Metabolic Disorders
Background:
- Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic beta cells.
- Early detection of T1D pathogenesis is crucial for developing preventative strategies.
- Islet autoimmunity precedes clinical diagnosis by several years.
Purpose of the Study:
- To investigate insulin secretion patterns during the preclinical phase of type 1 diabetes.
- To characterize changes in glucose metabolism preceding T1D diagnosis.
- To identify early markers of beta-cell dysfunction in individuals at high risk for T1D.
Main Methods:
- Longitudinal observation of a population-based cohort of children with HLA-conferred T1D susceptibility.
- Regular screening for islet autoantibodies.
- Sequential intravenous glucose tolerance tests (IVGTTs) to assess glucose metabolism and insulin response.
Main Results:
- Children progressing to T1D (progressors) exhibited significantly decreased first phase insulin response (FPIR) 4-6 years before diagnosis compared to non-progressors.
- The reduction in FPIR was evident across all age groups studied and increased with age.
- Insulin sensitivity remained comparable between progressors and non-progressors, suggesting a specific defect in insulin secretion.
Conclusions:
- Decreased FPIR is an early indicator of preclinical type 1 diabetes, detectable years before diagnosis.
- This finding suggests an intrinsic defect in pancreatic beta-cell mass and/or function in individuals who will develop T1D.
- FPIR may serve as a valuable biomarker for monitoring disease progression and evaluating interventions in at-risk populations.
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.
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