Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis

Abstract

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in CF is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n=16) or GIP (n=16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions with either incretin or placebo infused by randomized, double-blind, cross-over fashion. Another 4 adults with PI-CF and normal glucose tolerance (NGT) and 4 matched non-CF controls underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion, but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in non-CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Early-phase insulin secretion during mixed-meal tolerance testing predicts β-cell function and secretory capacity in cystic fibrosis

“…A total of 89 CF participants and 5 non-CF controls were enrolled in studies that included baseline assessment of both MMTT and GPA during an approximate 10-year period ( 5 , 6 , 10 – 12 ). Four CF participants and one non-CF control were unable to complete one or both tests and were, therefore, excluded from the present analyses.…”

“…Inhibitors of dipeptidyl peptidase-4 (DPP-4) prevent inactivation of endogenous GLP-1 and GIP, and our group has shown that treatment of adults with PI-CF and abnormal glucose tolerance with the DPP-4 inhibitor sitagliptin for 6 months improved the rate and degree of postprandial insulin secretion during the MMTT, although did not improve post-prandial glucose tolerance ( 11 ). This favorable effect upon insulin secretion may be attributed to GLP-1 as infusion of GLP-1, but not of GIP, improves glucose-dependent β-cell insulin secretion in PI-CF ( 12 ).…”

“…Subjects ≥6 years of age with a confirmed clinical diagnosis of CF as per Cystic Fibrosis Foundation diagnostic criteria were included ( 14 ). Data from non-CF control participants from a study on the effects of incretin hormones on islet function in PI-CF were also included for comparison ( 12 ).…”

“…While multiple methodologies exist to quantify β-cell function, each has their own limitations due to varying routes of administration, stimuli and sampling ( 9 ). We have successfully used the glucose potentiated arginine (GPA) test, which provides validated measures of functional β-cell mass, across multiple studies to evaluate β-cell function and secretory capacity in PwCF ( 5 , 6 , 10 – 12 ). β-cell responses at basal (fasting) glucose and under hyperglycemic clamp conditions are calculated in response to arginine, a non-glucose insulin secretagogue.…”

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

“…There are ongoing studies ( NCT01851694 ) of incretin mimetic agents such as the glucagon‐like peptide‐1 (GLP‐1) agonists or the dipeptidyl peptidase‐4 (dpp‐4) inhibitors, and small studies show GLP‐1 agonists increased insulin secretion in PwCF with glucose intolerance. 168 However, an RCT on the effect of Sitagliptin (a DPP‐IV inhibitor) on islet function in pancreatic insufficient PwCF with abnormal glucose tolerance found no improvement in meal‐related glucose excursion or insulin response. 169 …”