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 cystic fibrosis (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, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF 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 control participants without 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.

Trial registration: ClinicalTrials.gov NCT01851694.

Figure 1

Study design and participant flow. A: Eligible participants with PI-CF and AGT were randomized to receive either intervention with either GLP-1 or GIP and underwent GPA testing of islet function on two occasions with either incretin or placebo infused in a randomized, double-blind, cross-over fashion. B: Eligible participants with PI-CF and NGT and matched control participants without CF received intervention with GIP and underwent GPA testing with either GIP or placebo infused in a randomized, double-blind, cross-over fashion. Plasma levels of active GLP-1 during infusion of GLP-1 or placebo in participants with PI-CF and AGT (C), and plasma levels of GIP during infusion of GIP or placebo in participants with PI-CF and AGT (D), in participants with PI-CF and NGT (E), and in control participants without CF (F). Data are reported as mean ± SE. IV, intravenous.

Figure 2

Glucose and islet hormone concentrations in response to incretin infusion. Plasma glucose (A and B), insulin (C and D), and glucagon (E and F) before and 30 min after infusion of incretin (lined box plots) or placebo (open box plots), and at the end of the ∼230 mg/dL hyperglycemic clamp in participants with PI-CF and AGT in the GLP-1 (left) and GIP (right) groups. On the opposite y-axis (A and B), M represents the requisite glucose infusion rate during the hyperglycemic clamp. Box plots give the median and interquartile range.

Figure 3

C-peptide, proinsulin, and proinsulin secretory ratios in response to GPA testing. Islet β-cell release of processed C-peptide (A and B), unprocessed proinsulin (C and D), and PISRs (E and F) of the acute proinsulin and C-peptide responses to arginine under fasting and ∼230 mg/dL hyperglycemic clamp conditions during incretin or placebo infusion, and again under ∼340 mg/dL hyperglycemic clamp conditions without incretin or placebo infusion in participants with PI-CF and AGT in the GLP-1 (left) and GIP (right) groups. Data are reported as mean ± SE or in box plots giving the median and interquartile range.

Figure 4

Glucose and islet hormone levels in response to GIP infusion in NGT patients with PI-CF and control participants without CF. Plasma glucose (A and B), insulin (C and D), and glucagon (E and F) levels before and 30 min after infusion of GIP (marked/filled diamonds) or placebo (open diamonds), and at the end of the ∼230 mg/dL hyperglycemic clamp in participants with PI-CF and NGT (left) and in control participants without CF (right). On the opposite y-axis (A and B), M represents the requisite glucose infusion rate during the hyperglycemic clamp. Box plots give the median and interquartile range.

Figure 5

C-peptide, proinsulin, and proinsulin secretory ratios in response to GPA testing with GIP or placebo infusion in patients with PI-CF and control participants without CF. Islet β-cell release of processed C-peptide (A and B), unprocessed proinsulin (C and D), and PISRs (E and F) of the acute proinsulin and C-peptide responses to arginine under fasting and ∼230 mg/dL hyperglycemic clamp conditions during GIP or placebo infusion in participants with PI-CF and NGT (left) and in control participants without CF (right). Data are reported as mean ± SE or box plots giving the median and interquartile range.