Determinants of Glucose Tolerance in a Population Without Overt Diabetes: The Role of β-Cell Glucose Sensitivity, Insulin Sensitivity, and Insulin Clearance

Background/Objectives: To investigate how β-cell glucose sensitivity, insulin clearance, and insulin sensitivity interact to determine glucose tolerance in a population without overt diabetes. Methods: We analyzed data from 54 individuals without diabetes (age: 44 years, IQR: 27–56; 63% females; BMI: 24.5 kg/m2, IQR: 21.9–28.7; HbA1c 33.26 mmol/mol, IQR: 32.13–35.51) undergoing a 3-h OGTT. β-cell glucose sensitivity, insulin clearance, and insulin sensitivity were assessed via modeling of OGTT data. Their relationship with glucose tolerance was evaluated through linear regression models. Results: β-cell glucose sensitivity strongly predicted glucose tolerance during the OGTT (IQR increase effect: −87 mg/dL; 95% CI: −141, −32; p = 0.003) but not fasting glucose (p = 0.4). Patients with lower β-cell glucose sensitivity showed the widest range of glucose tolerance during the OGTT, some approaching diabetic levels whereas others tolerating glucose well; insulin sensitivity was the strongest determinant of this variance (IQR increase effect: −49 mg/dL; 95% CI: −68, −31; p < 0.001) significantly influencing the relationship between β-cell glucose sensitivity and glucose tolerance (interaction term p = 0.035). Conversely, insulin clearance did not show a statistically significant association with mean glucose levels during the OGTT (β: 4.2; 95% CI: −8.0, 16; p = 0.5). However, a non-linear relationship between insulin clearance and β-cell glucose sensitivity was identified, and three distinct metabolic subgroups were defined, highlighting the heterogeneity underlying the development of dysglycemia. Conclusions: β-cell glucose sensitivity is the primary determinant of glucose tolerance during an oral glucose challenge. While high β-cell glucose sensitivity often overcomes low insulin sensitivity, the latter becomes crucial when β-cell glucose sensitivity is low. The identification of distinct metabolic profiles, related to insulin secretion and clearance, highlights the heterogeneity of the transition from glucose tolerance to dysglycemia.