The role of genetic modifiers, inflammation and CFTR in the pathogenesis of Cystic fibrosis related diabetes

Abstract

Cystic fibrosis related diabetes (CFRD) generally reflects insufficient and/or delayed production of insulin, developing slowly over years to decades. Multiple mechanisms have been implicated in the pathogenesis of CFRD. CFTR function itself is a strong determinant of CFRD risk. Variants in CFTR that result in residual CFTR function and exocrine pancreatic sufficiency reduce the risk of CFRD by ten to twenty fold. Two groups of hypotheses have been proposed for the mechanism of CFTR impairing insulin secretion in CFRD: (1) β-cell dysfunction results from β cell intrinsic CFTR-dependent mechanisms of insulin secretion. (2) β-cell dysfunction results from factors outside the β cell. Genome-wide association studies have identified multiple susceptibility genes for type 2 diabetes, including TCF7L2, CDKN2A/B, CDKAL1, and IGF2BP2, as containing genetic modifiers of CFRD. These findings support the presence of intrinsic β cell defects playing a role in CFRD pathogenesis. Oxidative stress and inflammation are β cell-extrinsic mechanisms involved with CFRD. CFTR mutations render β cells more susceptible to oxidative stress and also leads to defects in α-cell function, resulting in reduced suppression of glucagon secretion. Furthermore, CFRD is characterized by β cell loss secondary to intra-islet inflammation. Recent studies have demonstrated the presence of multiple inflammatory mediators within the human CF islet. This review presents a concise overview of the current understanding of genetic modifiers of CFRD, oxidative stress, islet inflammation, and the controversies about the role of CFTR in the islet.

Metabolic Syndrome and Tendon Disease: A Comprehensive Review

“…[82][83][84] Studies have also linked CFTR to DM. 85,86 One confirmed that high glucose levels inhibited TDSC proliferation and differentiation through the let-7b-5p/CFTR pathway, contributing to poor tendon healing in patients with DM (Figure 2A). 87 Under the high glucose levels present in cases of DM, CFTR may adversely impact TDSCs and consequently affect tendon healing.…”

ISPAD Clinical Practice Consensus Guidelines 2022: Management of cystic fibrosis‐related diabetes in children and adolescents

“…Pancreatic sufficient CF Individuals with PS are at lower risk for development of CFRD than those with PI. 153 The presence of exocrine defects have been shown to increase risk for insulin secretory defects 8,37 and therefore CFRD. Given this low risk, particularly with a normal 2-h glucose, it would be reasonable for PS individuals with normal glucose tolerance to reduce frequency of OGTT screening to every 3-5 years.…”

“…Individuals with PS are at lower risk for development of CFRD than those with PI 153 . The presence of exocrine defects have been shown to increase risk for insulin secretory defects 8,37 and therefore CFRD.…”