Cystic fibrosis-related diabetes: the role of peripheral insulin resistance and beta-cell dysfunction.

Abstract

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