Aims: Subclinical systemic inflammation may contribute to the development of type 2 diabetes, but its association with early progression of glycaemic deterioration in persons without diabetes has not been fully investigated. Our primary aim was to assess longitudinal associations of changes in pro-inflammatory (leukocytes, high-sensitivity C-reactive protein (hsCRP)) and anti-inflammatory (adiponectin) markers with changes in markers that assessed glycaemia, insulin resistance, and secretion (HbA1c, HOMA-IR, and HOMA-ß). Furthermore, we aimed to directly compare longitudinal with cross-sectional associations. Materials and methods: This study includes 819 initially nondiabetic individuals with repeated measurements from the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 cohort study (median follow-up: 7.1 years). Longitudinal and cross-sectional associations were simultaneously examined using linear mixed growth models. Changes in markers of inflammation were used as independent and changes in markers of glycaemia/insulin resistance/insulin secretion as dependent variables. Models were adjusted for age, sex, major lifestyle and metabolic risk factors for diabetes using time-varying variables in the final model. Results: Changes of leukocyte count were positively associated with changes in HbA1c and HOMA-ß while changes in adiponectin were inversely associated with changes in HbA1c. All examined cross-sectional associations were statistically significant; they were generally stronger and mostly directionally consistent to the longitudinal association estimates. Conclusions: Adverse changes in low-grade systemic inflammation go along with glycaemic deterioration and increased insulin secretion independently of changes in other risk factors, suggesting that low-grade inflammation may contribute to the development of hyperglycaemia and a compensatory increase in insulin secretion.