Hepatic insulin resistance and defects in substrate utilization in cystic fibrosis

Patients with cystic fibrosis (CF)-related diabetes (CFRD) have clinical fe atures of both type 1 and type 2 diabetes. Past studies have documented per ipheral insulin resistance in CF, and some studies have noted high hepatic glucose production (HGP) in CF patients. We hypothesized that patients with CF, similar to patients with type 2 diabetes, have hepatic insulin resista nce. Cystic fibrosis is a catabolic condition, yet the etiology of cataboli sm is poorly understood. De novo lipogenesis is energy wasteful and preclud es ketogenesis. Patients with CFRD rarely develop ketogenesis, despite insu lin deficiency. We speculated that CF patients have de novo Lipogenesis, an d therefore evaluated substrate utilization in CF. Using [6,6-H-2(2)]glucos e and a three-step hyperinsulinemic-euglycemic clamp, me measured HGP in 29 adult CF subjects and 18 control volunteers. Using indirect calorimetry, m e measured lipid oxidation, oxidative glucose metabolism, and resting energ y expenditure at baseline and at high levels of insulin. All subjects were characterized by oral glucose tolerance testing (OGTT) and National Diabete s Data Group criteria. The CF subjects had increased HGP when compared with control subjects (CF, 3.5 +/- 0.6; control, 2.5 +/- 0.5 mg . kg(-1) . h(-1 ); P = 0.002). Baseline HGP correlated with glucose levels obtained 2 h aft er a glucose load given for OGTT (r = 0.69, P = 0.001). Suppression of HGP by insulin was significantly less in all CF subgroups than in control subje cts at peripheral insulin levels of 16 and 29 mu U/ml. At peripheral insuli n levels of 100 mu U/ml and 198 mu U/ml, there was no difference in insulin suppression of HGP between CF and control subjects. At baseline, there was no significant difference between control and CF subjects for glucose or l ipid oxidation. During maximum insulin stimulation, there was a greater ten dency for nonoxidative glucose metabolism in all CF subjects. The CF subjec ts with abnormal glucose tolerance also had de novo lipogenesis. Our result s indicate that CF patients have several defects in substrate utilization, including de novo lipogenesis. Furthermore, these results suggest that high hepatic glucose production and hepatic insulin resistance contribute to th e high incidence of abnormal glucose tolerance in CF.