Anti-GIP antibodies and future diabetes related risk: an eight-year prospective cohort study

Autoantibodies against metabolic regulators have been implicated in metabolic disorders; however, the clinical relevance of incretin-related autoantibodies in the development of hyperglycemia remains unclear. We investigated whether autoantibodies against glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are associated with future deterioration of glycemic status in a prospective cohort.

We analyzed 218 participants who underwent health checkups and were followed for a mean of 8.1 years. Individuals with diabetes or baseline HbA1c ≥ 6.5% were excluded. Baseline serum anti-GIP and anti-GLP-1 antibody (Ab) levels were measured using AlphaLISA. Incident diabetes-range glycemia was defined as fasting plasma glucose ≥ 126 mg/dL or HbA1c ≥ 6.5% without clinical confirmation, to avoid overestimation of incident diabetes in this cohort-based setting. Predictive performance was evaluated using receiver operating characteristic (ROC) analyses. To avoid overadjustment, HbA1c was excluded from the primary prediction models.

During follow-up, 21 participants developed diabetes-range glycemia. Baseline anti-GIP Ab levels were significantly higher in individuals who developed diabetes-range glycemia, whereas anti-GLP-1 Ab levels showed no association with risk. Anti-GIP Ab levels alone demonstrated modest but significant discriminative ability (AUC = 0.656). Although body mass index was a strong predictor (AUC = 0.799), adding anti-GIP Ab levels modestly improved model performance (AUC = 0.819).

Elevated baseline anti-GIP Ab levels were associated with the future development of diabetes-range glycemia and provided complementary predictive information beyond conventional metabolic risk factors. However, given the modest incremental improvement beyond BMI and the limited number of incident cases, the predictive contribution of anti-GIP antibody levels should be interpreted as exploratory and hypothesis-generating and requires validation in larger independent cohorts. These findings suggest that GIP-related immune responses may represent a distinct immunometabolic component involved in early glycemic deterioration.