Diabetes (CFRD) is a frequent and serious complication in cystic fibrosis (CF), caused by defects in insulin secretion. New modulator therapies raised the hope to prevent or treat CFRD. Current evidence does not support significant effects, but the natural history of insulin secretory defects is unclear in early life and therapy is now offered earlier.
The researchers hypothesized that CFTR modulators can ameliorate insulin secretory defects, but, in previous studies, the endocrine pancreas damage may have been too advanced for therapy to be effective.
In this context, they have assessed subjects 6-11 years old using repeated OGTTs to measure the insulin secretion parameters along with clinical parameters. Subjects who become eligible to CFTR modulators have been studied at therapy onset and after 1 yr.
Abnormal insulin secretion associated with high glucose response during OGTT in prepuberal people with CF predicts a decrease in adult height z-score, suggesting that insulin secretory defects in CF affect growth prior to the development of fasting hyperglycemia. It was also reported the distribution of OGTT-related variables in people with CF from puberty to adulthood. Data collected pre- and across puberty showed an increment in insulin secretory parameters during puberty that is not well described even in the general population.
During the project the researchers have also found no evidence of improvements in glucose tolerance mechanisms in people with CF after one-year treatment with the CFTR modulator lumacaftor/ivacaftor. Analysis is currently underway to describe the effect of different genotypes on glucose tolerance and insulin secretion. Preliminary results show that people with CF with at least one CFTR allele with residual function have better glucose tolerance associated with better beta-cell function. Analysis is currently underway to analyze prospectively the changes in parameter during the 1yr follow-up.
Parameters of insulin secretion are important determinants of adult height, glucose tolerance, are related to CF genotype, and are probably not easily affected by current modulator therapies.

Pubblications

• Battezzati A, Foppiani A et al. Prepuberal Insulin Secretory Indices Are Long-Term Predictors of Short Adult Stature in Cystic Fibrosis. Endocrine Connections 2022 May 10;11(5):e220056
• Foppiani A, Ciciriello F et al. Distribution of OGTT-Related Variables in Patients with Cystic Fibrosis from Puberty to Adulthood: An Italian Multicenter Study. Journal of personalized medicine 2023 Mar 3;13(3):469
• Colombo C, Foppiani A et al. Lumacaftor/Ivacaftor in Cystic Fibrosis: Effects on Glucose Metabolism and Insulin Secretion. Journal of endocrinological investigation 2021 Oct;44(10):2213-2218