Aims The goal of this study was to identify the glycaemic status and investigate the roles of peripheral insulin resistance (IR) and pancreatic β‐cell dysfunction in the pathogenesis of cystic fibrosis‐related diabetes (CFRD) in adult cystic fibrosis (CF) patients with no previous history of glycaemic disturbances.

Methods The glucose tolerance status of 68 CF patients was determined using 2‐h oral glucose tolerance tests (OGTTs). Peripheral IR was measured using the homeostasis model assessment for insulin resistance (HOMA‐IR) in the CF group and 46 normal healthy control subjects. Pancreatic β‐cell function, calculated as the ratio between the 30‐min increment in plasma insulin and the corresponding 30‐min post‐OGTT plasma glucose concentration, was also measured in a subset of 30 CF patients and 16 normal healthy controls. Extended 180‐min OGTTs, with frequent plasma glucose and insulin sampling, were also undertaken in 24 CF patients and eight normal healthy controls to determine glucose‐induced insulin response.

Results Of the 68 CF patients studied, 41, 18 and nine were found to have normal, impaired and diabetic glucose tolerances, respectively. The mean HOMA‐IR values (mU/mmol) in the CF patients, as a whole, were not significantly different compared with the normal healthy controls (CF 2.2 ± 1.1 vs. control 1.8 ± 0.9; NS). Within the CF group, glycaemic status had no impact on HOMA‐IR (mU/mmol): 2.2 ± 1.2 (normal glucose tolerance); 2.0 ± 1.0 (impaired glucose tolerance); and 2.3 ± 1.1 (diabetic glucose tolerance). β‐cell function (mU/mmol) was not only significantly lower in the CF group (CF 1.65 ± 1.8; P < 0.001) but also in the CF group with normal glucose tolerance (2.25 ± 2.10; P < 0.01) compared with healthy control (4.98 ± 2.38). Mean plasma glucose concentrations were generally higher and mean plasma insulin concentrations lower in the CF group as a whole when compared with normal healthy controls. Within the CF group, there was a progressive decline in glucose‐induced insulin release with worsening glycaemic status.

Conclusions A lack of difference in peripheral IR, measured using HOMA‐IR, in the CF group and healthy controls or within the CF group with differing glycaemic status suggests that IR does not have a significant role in the pathogenesis of CFRD. Pancreatic β‐cell function, already subnormal in CF patients with OGTT‐defined normal glucose tolerance status, deteriorated further with worsening glycaemic status. This suggests that insulinopenia plays a prominent role in the pathogenesis of glucose intolerance and subsequent development of CFRD.