Early Impairment of Insulin Sensitivity, β-Cell Responsiveness, and Insulin Clearance in Youth with Stage 1 Type 1 Diabetes

Abstract

Context: Clinical onset of type 1 diabetes (Stage 3 T1D) is preceded by a presymptomatic phase characterized by multiple islet autoantibodies with normal glucose tolerance (Stage 1 T1D).

Objective: The aim was to explore the metabolic phenotypes of β-cell function and insulin sensitivity and clearance in normoglycemic youth with Stage 1 T1D and compare them with healthy nonrelated peers during a 3-hour oral glucose tolerance test (OGTT).

Methods: Twenty-eight lean youth, 14 with ≥2 islet autoantibodies (cases) and 14 healthy controls underwent a 3-hour 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×SI). Fasting insulin clearance (CL0) was calculated as the ratio between the fasting insulin secretion rate (ISR) and plasma insulin levels (ISR0/I0), while postload clearance (CL180) was estimated by the ratio of AUC of ISR over the plasma insulin AUC for the 3-hour OGTT (ISRAUC/IAUC). Participants with impaired fasting glucose, impaired glucose tolerance, or any OGTT glucose concentration ≥200 mg/dL were excluded.

Results: Cases (10.5 years [8, 15]) exhibited reduced DI (P < .001) due to a simultaneous reduction in both φtotal (P < 0.001) and SI (P = .008) compared with controls (11.5 years [10.4, 14.9]). CL0 and CL180 were lower in cases than in controls (P = .005 and P = .019).

Conclusion: Presymptomatic Stage 1 T1D in youth is associated with reduced insulin sensitivity and lower β-cell responsiveness, and the presence of blunted insulin clearance.

Keywords: Prediabetes; insulin sensitivity; islet autoimmunity; oral minimal model; type 1 diabetes; β-cell function.

Figure 1.

Glucose (A), Insulin (B), and C-peptide (C) during oral glucose tolerance test (OGTT) by time in controls (blue) and cases (red). Data are expressed as mean ± SD.

Figure 2.

Disposition index (DI) (A), ${\phi }_{\mathrm{t}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l}}$ (B) and insulin sensitivity (SI) (C), ${\phi }_{\mathrm{s}\mathrm{t}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{c}}$ (D) and ${\phi }_{\mathrm{d}\mathrm{y}\mathrm{n}\mathrm{a}\mathrm{m}\mathrm{i}\mathrm{c}}$ (E), baseline (F) and 180-min (G) insulin clearance for controls (blue) and cases (red). CL_0, baseline clearance; CL₁₈₀, 180-minute clearance; ISR_AUC/I_AUC, area under the curve (AUC) for insulin secretion rate over AUC of insulin over 180 minutes; ISR₀/I₀ , baseline insulin secretion rate over baseline insulin. Data are expressed as median (25th, 75th centile).

Figure 3.

β-cell responsiveness (${\phi }_{\mathrm{t}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l}}$) and insulin sensitivity (SI) for controls (blue circles) and cases with 2 or 3 antibodies (empty red triangle) or 4 or 5 antibodies (filled red triangle). The red and blue dashed fit-lines represent the relationship between ${\phi }_{\mathrm{t}\mathrm{o}\mathrm{t}\mathrm{a}\mathrm{l}}$ and SI for cases and controls, respectively. Data are expressed as naturally log-transformed values.