Endocrine Abstracts

Background: Cystic fibrosis (CF) is a genetic disorder in which a dysfunctional cystic fibrosis transmembrane regulator (CFTR) chloride channel can result in multimorbidity, including severe respiratory disease and reduced pancreatic exocrine secretion and diabetes. Recently, CFTR modulator therapy, has emerged with the potential of improving respiratory function and remission of diabetes. The effect of CFTR modulator therapy on pancreatic function in patients without preexisting diabetes remains unclear.

Case presentation: An 18-year old female with longstanding CF based on F508del/F508del genotype, was admitted for feeling generally unwell and recurring episodes of nausea, trembling and tinnitus usually 1 hour postprandially. She had been taking tezacaftor 50mg, ivacaftor 75mg, elaxacaftor 100mg daily for 6 months with a clear beneficial effect on respiratory symptoms. However, she associated the onset of neuroglycopenic symptoms with initiation of CFTR modulator therapy, and she had noted an increasing frequency of the episodes. A brief interruption of the tezacaftor-ivacaftor-elaxacaftor had not improved her complaints. Biochemical testing revealed a low venous blood level (63 mg/dl) at the time of nausea, in the presence of unadapted high insulin (141 pmol/l) and c-peptide (1.27 nmol/l) levels. Further clinical and biochemical evaluation did not show underlying infection nor any other significant alteration in comorbidities. The glycated hemoglobin level (HbA1c) had dropped from 6.2% before the initiation of tezacaftor-ivacaftor-elaxacaftor to 5.8 %, without the use of any exogenous insulin, nor any other glucose lowering therapy. The patient was advised to limit the intake of simple carbohydates and monitor the glycemia closely and symptoms improved.

Discussion: This case supports the preliminary notion that CFTR modulator therapy has the potential to affect glucose homeostasis in patients with CF. The underlying mechanism remains uncertain, as it could be that insulin resistance or beta-cell function or both might be affected. Indeed, relief of chronic inflammation, especially in the respiratory tract and the lungs might yield reduced insulin resistance and thus improved glucose homeostasis. But it is also possible that reduction of pancreatic inflammation directly affects the beta cells insulin secretory capacity. In the current case neuroglycopenic symptoms were present postprandially, resembling reactive hypoglycemia in patients with exaggerated insulin secretion in response to simple carbohydrates. This observation might indicate there is a (temporary) improvement in insulin secretion, and not only reduction of insulin resistance.

Conclusion: This case report describes recurrent hypoglycemic episodes after initiation of CFTR modulator therapy in the absence of prior antidiabetic medication use.