β-cell dysfunction is a crucial factor of glycaemic deterioration in type 2 diabetes (T2D), but the role of circulating proteins in its progression is currently not understood. We studied the potential associations between β-cell glucose sensitivity progression over 3 years and baseline proteomics in a cohort of recently diagnosed T2D patients (N = 653) from the IMI-DIRECT project, through linear regression analysis. We found that forty-six proteins have a significant association to β-cell glucose sensitivity progression. Subsequent functional analysis showed these proteins belong to functional modules linked to insulin secretion and T2D pathophysiology. These findings, along with further investigation in longitudinal studies, may point to novel protein markers and processes of β-cell function deterioration.