Roles of insulin resistance and beta-cell dysfunction in the pathogenesis of glucose intolerance in cystic fibrosis.

Abstract

The roles of insulin deficiency and insulin resistance in the pathogenesis of glucose intolerance in cystic fibrosis (CF) were evaluated in eight patients (aged 16.5 +/- 1.9 yr), four with normal glucose tolerance (NGT) and four with impaired glucose tolerance (IGT), and in seven healthy control (CN) subjects. First and second phase insulin secretions were evaluated during a hyperglycemic clamp. Hepatic glucose production (HGP) and insulin-stimulated glucose disposal were measured using [6,6-2H2]glucose and a stepwise hyperinsulinemic-euglycemic clamp. First and second phase insulin levels were significantly lower in both groups of CF patients compared with control values. There was an inverse relationship between glycohemoglobin level and first phase insulin (r = -0.81; P = 0.015) and second phase insulin (r = -0.97; P < 0.001). During the hyperglycemic clamp, the insulin sensitivity index was lower in CF-IGT, but not CF-NGT, compared with control values (6.66 +/- 1.79, 12.82 +/- 1.61, and 13.02 +/- 1.78 mumol/kg.min/pmol.L, respectively; P < 0.05). Basal HGP and fasting plasma glucose were higher in CF vs. CN [24.8 +/- 2.9 vs. 16.9 +/- 1.4 mumol/kg.min (P = 0.036) and 5.8 +/- 0.2 vs. 5.4 +/- 0.1 mmol/L (P = 0.035), respectively]. During the hyperinsulinemic euglycemic clamp, insulin-stimulated glucose disposal was significantly lower in CF-IGT (45.68 +/- 4.87 mumol/kg.min) vs. CF-NGT (78.99 +/- 1.34 mumol/kg.min) and CN (71.74 +/- 6.88 mumol/kg.min). Insulin sensitivity was lower in CF-IGT vs. CF-NGT (7.04 +/- 0.86 and 14.38 +/- 0.84 mumol/kg.min/pmol.L; P < 0.05). We conclude that 1) glycohemoglobin is a strong correlate of insulin deficiency in CF; and 2) glucose intolerance in this group of CF patients occurred as a consequence of concomitant insulin deficiency and insulin resistance.

Conventional measures underestimate glycaemia in cystic fibrosis patients

“…The higher levels of glucose in the initial part of the OGTT may provide an increased stimulus to increased insulin secretion later in the OGTT and hence the normalization of the 2-h glucose value. Physiological studies looking at firstand second-phase insulin studies using intravenous glucose tolerance tests and hyperglycaemic clamps support this hypothesis [25,33,35,36].…”

Mechanisms of glucose intolerance in cystic fibrosis

“…Although studies in CF subjects with normal glucose tolerance (NGT) have shown normal insulin sensitivity, there are conflicting reports regarding its role in patients with impaired glucose tolerance (IGT) and CFRD since studies have shown increased [5,6], normal [7][8][9] or decreased insulin sensitivity [10][11][12][13][14]. The disagreement among previous studies relates to differences in inclusion criteria [7,11], age distribution [10,12], small patient numbers [6,10] and interpretation of results [12,14]. Another contributory factor to the discordant findings stems from a variety of methods used to measure insulin resistance [5,7,9].…”

Prior diabetes mellitus is associated with increased morbidity in cystic fibrosis patients undergoing bilateral lung transplantation: an ‘orphan’ area? A retrospective case–control study

“…1 Patients with CF are also susceptible to insulin resistance that may worsen with steroid therapy, pulmonary infections and poor nutrition. 2,3 The effect of hyperglycaemia on outcomes following bilateral lung transplantation in CF patients is not known, but is assumed to be associated with increased mortality as seen in the general medical setting. 4 More specifically, it is not known whether a prior diagnosis of CFRD affects outcomes over and above that of inpatient hyperglycaemia.…”