Early impairment of insulin sensitivity, β-cell responsiveness, and insulin clearance in youth with Stage 1 type 1 diabetes.
Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a pre-symptomatic phase characterized by multiple islet autoantibodies with normal glucose tolerance (Stage 1 T1D). The metabolic phenotypes of beta-cell function and insulin sensitivity and clearance were explored in normoglycemic youth with Stage 1 T1D and compared to healthy non-related peers during a 3-h oral glucose tolerance test (OGTT).Twenty-eight lean youth, 14 with ≥2 islet autoantibodies (cases) and 14 healthy controls underwent a 3-h 9-point OGTT with measurement of glucose, C-peptide and insulin. The oral minimal model was used to quantitate β-cell responsiveness (φtotal) and insulin sensitivity (SI), allowing assessment of β-cell function by the disposition index (DI= φtotal x SI). Fasting insulin clearance (CL0) was calculated as the ratio between the fasting insulin secretion rate (ISR) and plasma insulin levels (ISR0/I0), while post-load clearance (CL180) was estimated by the ratio of AUC of ISR over the plasma insulin AUC for the 3-h OGTT (ISRAUC/IAUC). Subjects with impaired fasting glucose, impaired glucose tolerance or any OGTT glucose concentration ≥200mg/dL were excluded.Cases (10.5y [8, 15]) exhibited reduced DI (p<0.001) due to a simultaneous reduction in both φtotal (p<0.001) and SI (p=0.008) compared to controls (11.5y [10.4, 14.9]). CL0 and CL180 were lower in cases than controls (p=0.005 and p=0.019).Pre-symptomatic Stage 1 T1D in youth is associated with reduced insulin sensitivity and lower β-cell responsiveness, and the presence of blunted insulin clearance.
Authors: Alfonso Galderisi, Antoinette Moran, Carmella Evans-Molina, Mariangela Martino, Nicola Santoro, Sonia Caprio, Claudio Cobelli