Hepatic insulin resistance and defects in substrate utilization in cystic fibrosis.

Abstract

Patients with cystic fibrosis (CF)-related diabetes (CFRD) have clinical features of both type 1 and type 2 diabetes. Past studies have documented peripheral 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 resistance. Cystic fibrosis is a catabolic condition, yet the etiology of catabolism is poorly understood. De novo lipogenesis is energy wasteful and precludes ketogenesis. Patients with CFRD rarely develop ketogenesis, despite insulin deficiency. We speculated that CF patients have de novo lipogenesis, and therefore evaluated substrate utilization in CF. Using [6,6-2H2]glucose and a three-step hyperinsulinemic-euglycemic clamp, we measured HGP in 29 adult CF subjects and 18 control volunteers. Using indirect calorimetry, we measured lipid oxidation, oxidative glucose metabolism, and resting energy expenditure at baseline and at high levels of insulin. All subjects were characterized by oral glucose tolerance testing (OGTT) and National Diabetes 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 x kg(-1) x h(-1); P = 0.002). Baseline HGP correlated with glucose levels obtained 2 h after 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 subjects at peripheral insulin levels of 16 and 29 microU/ml. At peripheral insulin levels of 100 microU/ml and 198 microU/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 lipid oxidation. During maximum insulin stimulation, there was a greater tendency for nonoxidative glucose metabolism in all CF subjects. The CF subjects with abnormal glucose tolerance also had de novo lipogenesis. Our results 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 the high incidence of abnormal glucose tolerance in CF.

Update on diagnosis and monitoring of cystic fibrosis-related diabetes mellitus (CFRD)

“…Peak insulin secretion in normal individuals occurs at 30 to 60 minutes, while in CFRD patients it is observed between 90 and 120 minutes. This delay in insulin secretion in the oGTT is related to the loss of the first phase of insulin secretion, which was found in CF patients, even in those who still presented normal glucose tolerance (44).…”

“…A clamp study found hepatic insulin resistance with elevated glucose production (in fasting, as well as in response to insulin infusion), occurring equally in diabetic patients and in those who had totally normal fasting glucose levels (44). It has been hypothesized that increased energy needs of CF patients create a physiological balance between elevated hepatic glucose production and high glucose demand (43,44).…”

Estudo da freqüência de diabetes mellitus e intolerância à glicose em pacientes com fibrose cística

“…Alterações na sensibilidade periférica e hepática à insulina vem sendo implicadas 8,[11][12][13][14][15] . Neste estudo encontramos uma correlação significativa entre a insulinemia, representada pela ASC de insulina, e o tempo de doença clinicamente manifesta (Figura 2), o que aponta para uma resistência insulínica progressiva nessa condição.…”

“…Vários estudos demonstraram claramente um comprometimento na secreção de insulina em pacientes mucoviscidóticos [5][6][7][8] , que decorreria da destruição das ilhotas pancreáticas por fibrose, infiltração gordurosa ou deposição de amilóide 2,9,10 . Alterações na sensibilidade à insulina também têm sido implicadas 8,[11][12][13][14][15] . A resistência insulínica nesse distúrbio tem sido justificada por vários mecanismos: infecções pulmonares recorrentes ou crônicas, fibrose hepática subclínica, elevação de hormônios contra-reguladores (cortisol e catecolaminas), níveis elevados de citocinas (interleucinas e TNFa) e, em pacientes com diabetes manifesto, a glicotoxicidade.…”

“…A resistência insulínica nesse distúrbio tem sido justificada por vários mecanismos: infecções pulmonares recorrentes ou crônicas, fibrose hepática subclínica, elevação de hormônios contra-reguladores (cortisol e catecolaminas), níveis elevados de citocinas (interleucinas e TNFa) e, em pacientes com diabetes manifesto, a glicotoxicidade. O aumento da produção hepática de glicose, secundária à resistência à insulina nesse orgão, foi demonstrada em pacientes, ainda não diabéticos, com mucoviscidose [13][14][15][16] . Estudos anteriores estabeleceram uma correlação direta do aparecimento do DM com a insuficiência exócrina 17,18 .…”