The main mechanism associated with progression of glucose intolerance in older patients with cystic fibrosis is insulin resistance and not reduced insulin secretion capacity

Abstract

Background: Aging cystic fibrosis (CF) patients are at high risk of developing CF-related diabetes (CFRD). Decrease in insulin secretion over time is the main hypothesis to explain this increasing prevalence but mechanisms are still not well elucidated. The objective is to assess evolution of glucose tolerance and insulin secretion/sensitivity in aging CF patients. Methods: This is a retro-prospective observational analysis in the older adult CF patients from the Montreal Cystic Fibrosis Cohort (n = 46; at least 35 years old at follow-up) and followed for at least 4 years. Baseline and followup (last visit to date) 2-h oral glucose tolerance test (OGTT with glucose and insulin measurements every 30 min) were performed. Pulmonary function test (FEV 1 ) and anthropometric data were measured the same day. Insulin sensitivity was measured by the Stumvoll index. Results: After a mean follow-up of 9.9 ± 2.6 years, mean age at follow-up was 43.5 ± 8.1 years old. An increase of body weight (+2.6 ± 6.5 kg, p = 0.01) and a decrease in pulmonary function (FEV 1 ; 73.4 ± 21.2% to 64.5 ± 22.4%, p ≤ 0.001) were observed. Overall, insulin secretion is maintained at follow-up but all OGTT glucose values increased (for all values, p ≤ 0.028). At follow-up, 28.3% of patients had a normal glucose tolerance while 71.7% had abnormal glucose tolerance (AGT). AGT patients decreased their insulin sensitivity over time (p = 0.029) while it remained the same in NGT patients (p = 0.917). Conclusion:In older CF patients, the progression of impaired glucose tolerance is occurring with stable insulin secretion but reduced insulin sensitivity.

Polymorphism of clinical manifestations of cystic fibrosis-related diabetes

“…Последние исследования показывают, что ген CFTR непосредственно не регулирует секрецию инсулина или глюкагона, и в основном МЗСД вызван повреждением поджелудочной железы хроническим воспалением, фиброзом, дисфункцией и гибелью β-клеток в условиях прогрессирующего полиорганного заболевания, при котором поражение экзокринной функции поджелудочной железы наблюдается с рождения у около 85 % пациентов [6]. В нескольких исследованиях анализировалась взаимосвязь фенотипов, обусловленных МВ заболеваний поджелудочной железы, с вариантами гена CFTR [7][8][9]. Показано, что нарушения метаболизма глюкозы являются частым коморбидным состоянием у пациентов, которые имеют генетический вариант c.1521_1523delCTT (p.Phe508del, F508del) [9,10].…”

“…В нескольких исследованиях анализировалась взаимосвязь фенотипов, обусловленных МВ заболеваний поджелудочной железы, с вариантами гена CFTR [7][8][9]. Показано, что нарушения метаболизма глюкозы являются частым коморбидным состоянием у пациентов, которые имеют генетический вариант c.1521_1523delCTT (p.Phe508del, F508del) [9,10].…”

Cystic fibrosis related diabetes: Medical management

“…Scheuing et al carefully delineated insulin doses in CFRD compared with T1DM and found that those with CFRD needed more [20]. Although there is increasing literature that insulin sensitivity declines as the CF population ages [24], it is still recommended to initiate insulin at lower doses and then adjust based on the patient's response. Insulin dosing needs in CFRD typically average <0.5À0.8 units/kg/ day, and typically do not differ between adolescents and adults [25].…”

Hepatic enzyme ALT as a marker of glucose abnormality in men with cystic fibrosis

“…The role of insulin resistance is currently debated, but there is evidence to suggest its contribution to the development of dysglycemia in CF patients, particularly in certain states, such as the use of steroids and acute pulmonary infections [11, 14]. Furthermore, it has been shown that in the context of low insulin secretion, insulin resistance can modulate glucose tolerance changes over time [15, 16] and in response to exercise [17].…”