Fat accumulation in the pancreas has been associated with increased risk of type 2 diabetes mellitus (T2DM), although mechanisms linking fatty pancreas disease (FPD) and metabolic dysfunction remain incompletely understood. A cohort study published in Frontiers in Endocrinology evaluated whether genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels modify T2DM risk associated with FPD in participants from the UK Biobank.

The analysis included participants of White ethnicity without diabetes at the time of magnetic resonance imaging (MRI) assessment. The loss-of-function GIPR variant E354Q was used to estimate fasting GIP levels, while a polygenic risk score (PRS) for 2-hour postprandial GIP was used to estimate postprandial GIP levels. FPD was identified using MRI findings, and incident T2DM was defined using ICD-10-CM diagnosis code E11. During a median follow-up of 51 months, 276 participants developed incident T2DM.

Findings

• Significant interaction was observed between FPD and E354Q carrier status in relation to incident T2DM risk (P for interaction=0.018).
• Significant interaction was also observed between FPD and genetically predicted postprandial GIP levels assessed by 2-hour GIP PRS (P for interaction=0.015).
• Among participants without the E354Q variant, FPD was associated with a higher risk of incident T2DM (hazard ratio [HR] 2.44; 95% CI 1.78-3.34).
• Participants with higher genetically predicted postprandial GIP levels and FPD also demonstrated greater T2DM risk (HR 2.64; 95% CI 1.86-3.76).

This UK Biobank analysis suggested that genetically predicted GIP levels may modify the association between FPD and incident T2DM. The findings support further evaluation of incretin-related pathways in pancreatic fat accumulation and metabolic dysfunction, although conclusions remain limited to genetically predicted rather than measured GIP levels.