Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance

Abstract

Purpose: Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT.

Methods: 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function.

Results: Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found.

Conclusions: In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.

Trial registration: ClinicalTrials.gov NCT01879228.

Keywords: DPP-4; abnormal glucose tolerance; cystic fibrosis; dipeptidyl peptidase-4 inhibitor; glucagon; glucagon-like peptide-1; glucose dependent insulinotropic polypeptide; incretin; insulin.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

CONSORT flow diagram. Eligibility was assessed at a screening visit, and double-blind randomization occurred following completion of baseline mixed-meal tolerance and glucose-potentiated arginine test visits. One subject randomized to placebo provided additional medical history at the randomization visit that met an exclusion criterion (history of angioedema) and so was removed from the study prior to initiating intervention. One subject randomized to sitagliptin developed a pruritic maculopapular rash affecting both arms after 1 week of intervention and was withdrawn from the study. All remaining subjects completed the 6-month intervention and follow-up mixed-meal tolerance and glucose-potentiated arginine test visits and are included in the analysis.

Figure 2.

(A) Adherence as assessed by pill count at 1, 3, and 6 months following randomization to sitagliptin 100 mg daily or matched placebo. (B) Glycemic control as assessed by HbA1c at baseline and at 3 and 6 months following randomization to sitagliptin 100 mg daily or matched placebo. HbA1c was slightly lower in the sitagliptin group at 3 months (−0.05; 95% CI: −0.17 to 0.08), a difference that largely reflected a nonsustained increase in the placebo group (0.16; 95% CI: 0.04 to 0.30; P = 0.023); no differences were present at 6 months (P = 0.89).

Figure 3.

Plasma levels of intact GLP-1 and intact GIP prior to (-●-) and 6 months following (-o-) intervention with sitagliptin 100 mg daily (A and C) or matched-placebo (B and D) in response to the mixed-meal tolerance test in subjects with pancreatic insufficient CF. Responses for intact GLP-1 (AUCGLP-1) and intact GIP (AUCGIP) increased after 6 months of sitagliptin vs placebo over the first 30 and 180 min (P < 0.01 for all comparisons). Data are given as mean ± SE.

Figure 4.

Plasma glucose and insulin secretory rates prior to (-●-) and 6 months following (-o-) intervention with sitagliptin 100 mg daily (A and C) or matched placebo (B and D) in response to the mixed-meal tolerance test in subjects with pancreatic insufficient CF. No differences in glucose excursion were found between sitagliptin (A) and placebo (B). While there was no difference in the ISR response assessed by 30- or 180-min AUCISR, ISR during the first 60 min was faster (P = 0.049) and declined more rapidly in the subsequent 60 min (P < 0.0001) following 6 months of sitagliptin (C) vs placebo (D). Data are given as mean ± SE.

Figure 5.

Plasma glucagon and free fatty acids prior to (-●-) and 6 months following (-o-) intervention with sitagliptin 100 mg daily (A and C) or matched-placebo (B and D) in response to the mixed-meal tolerance test in subjects with pancreatic insufficient CF. Postprandial glucagon suppression was greater over 180 min (AUCgln; P = 0.025) following 6 months of sitagliptin (A) vs placebo (B). There were no differences in free fatty acid suppression between sitagliptin (C) and placebo (D). Data are given as mean ± SE.

Figure 6.

Acute insulin responses to arginine under fasting, 230-mg/dL hyperglycemic clamp, and 340-mg/dL hyperglycemic clamp conditions prior to (-●-) and 6 months following (-o-) intervention with sitagliptin 100 mg daily (A) or matched-placebo (B) identify no augmentation of insulin secretion. Acute glucagon responses to arginine were lower under fasting (AGRarg; P = 0.016), trended lower under 230-mg/dL hyperglycemic clamp (AGRinh; P = 0.12), and were lower under 340-mg/dL hyperglycemic clamp (AGRmin; P = 0.049) conditions following 6 months of sitagliptin (C) vs placebo (D). Data are given as mean ± SE.

Figure 7.

Acute proinsulin and C-peptide responses to arginine prior to (-●-) and 6 months following (-o-) intervention with sitagliptin 100 mg daily or matched placebo. Acute proinsulin responses were not different under fasting but trended lower under 230-mg/dL hyperglycemic clamp, and 340-mg/dL hyperglycemic clamp conditions prior to (-●-) and 6 months following (-o-) intervention with sitagliptin 100 mg daily (A) or matched-placebo (B) identify no augmentation of insulin secretion. Acute C-peptide responses to arginine under fasting, 230-mg/dL hyperglycemic clamp, and 340-mg/dL hyperglycemic clamp conditions prior to (-●-) and 6 months following (-o-) intervention were not different after sitagliptin 100 mg PO daily (A) or matched-placebo (B). Data are given as mean ± SE.