Search

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.

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.

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 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.

Impaired incretin secretion may contribute to insulin secretion defects in pancreatic insufficient cystic fibrosis (PI-CF). We hypothesized that dipeptidyl peptidase-4 (DPP-4) inhibitor therapy would increase glucagon-like peptide-1 (GLP-1) and improve insulin secretion in glucose intolerant CF. We conducted a randomized, double blind, placebo-controlled trial in 24 subjects with PI-CF and abnormal glucose tolerance who received the DPP-4 inhibitor sitagliptin 100 mg (n = 12) or matched-placebo (n = 12) for 6 months. Randomization was stratified by oral glucose tolerance. Mixed-meal tolerance tests (MMTT) and glucose-potentiated arginine (GPA) tests were performed at baseline and after 6 months intervention. Incremental area-under-the-curves were calculated for GLP-1 (AUCGLP-1) post meal. Insulin secretory rates (ISR), derived by parametric deconvolution of C-peptide kinetics, were modeled using linear mixed effects models. Acute insulin and glucagon response to arginine were calculated under fasting, 230, and 340 mg/dL hyperglycemic clamp conditions. Subjects in the sitagliptin vs. placebo groups were similar in age (median 24 [range 18-43] vs. 28 [18-43] years), sex (5 females each), and BMI (24 [19-34] vs. 22 [17-24] kg/m2). HbA1c, similar at baseline (5.6 [4.8-6.1] vs. 5.7 [5.4-5.9] %), improved after 3 months of sitagliptin (-0.2 %, 95% CI -0.4- -0.2, P = 0.02). AUCGLP-1 was higher after sitagliptin vs. placebo (1400 pmol·min/L, 95% CI 750-2050, P < 0.001). ISR after sitagliptin showed a faster rise through 60 min post meal (9.1 µU·mL-1·min-1, 95% CI 4.4-13.9, P < 0.001) and returned to baseline faster vs. placebo (-12.0 µU·mL-1·min-1, 95% CI -16.9- -7.2, P < 0.001). Acute insulin responses did not differ between groups, but acute glucagon responses were lower after sitagliptin vs. placebo (P = 0.03). In glucose intolerant CF, six-month therapy with sitagliptin resulted in modest improvement in glycemic control and islet function. Disclosure S. Sheikh: None. A. Kelly: None. D. Stefanovski: None. A.J. Peleckis: None. S. Nyirjesy: None. J.N. Eiel: None. A. Sidhaye: None. D.D. De Leon: Consultant; Self; Crinetics, Novartis Pharmaceuticals Corporation, Soleno Therapeutics, Zealand Pharma A/S. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; Crinetics, Zealand Pharma A/S. Stock/Shareholder; Self; Merck & Co., Inc. D. Hadjiliadis: Other Relationship; Self; AstraZeneca. R.C. Rubenstein: None. M.R. Rickels: Consultant; Self; Semma Therapeutics, Inc. Research Support; Self; Xeris Pharmaceuticals, Inc. Funding National Institutes of Health (R01DK97830, K23DK107937, UL1TR001878, P30DK19525, T32 DK007314); Merck & Co., Inc. (MISP50512)

Individuals with pancreatic insufficient cystic fibrosis (PI-CF) and glucose intolerance demonstrate impaired incretin and insulin secretion. The goal of this study was to assess β-cell responsiveness to the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) during glucose potentiated arginine (GPA) testing in adults with PI-CF and abnormal glucose tolerance. Participants were randomized to receive either GLP-1 (n=15) or GIP (n=15) and then underwent GPA testing during either incretin or placebo infusion in a randomized, cross-over fashion. OGTT was similar between groups (1hr: 214±8 vs. 208±7 mg/dL; 2hr: 141±18 vs. 150±18 mg/dL). During GPL-1 infusion, fasting glucose was lower after 30 min vs. placebo (p Disclosure J.N. Eiel: None. S. Nyirjesy: None. A.J. Peleckis: None. D. De Leon: Employee; Spouse/Partner; Merck & Co., Inc.. Research Support; Self; Zealand Pharma A/S. Consultant; Self; XOMA Corporation, ProSciento. Research Support; Self; Biomarin Corporation. D. Hadjiliadis: None. C. Kubrak: None. A. Tami: None. S. Sheikh: None. R.C. Rubenstein: None. A. Kelly: None. M.R. Rickels: Consultant; Self; Hua Medicine, Xeris Pharmaceuticals, Inc..

Background: Few young adults (YA) with type 1 diabetes (T1D) achieve national glycemic targets, and even fewer of low socioeconomic status (SES) meet these goals. Inconsistent clinic attendance is thought to contribute to this disparity in glycemic control but has not been studied. Methods: We evaluated clinic attendance in YA with T1D, 18-25 years, seen in a young adult diabetes clinic. We extracted data from medical charts and used insurance status to identify low and higher SES YA, comparing individuals with federal/state-sponsored (public) insurance to commercial (private) insurance. Glycemic control was defined as the difference between the last documented A1c and the baseline first appointment A1c. There were 2 outcomes representing inconsistent attendance: 1) missing ≥1 scheduled quarterly visit per year and 2) gap in care >6 months. We used multilevel mixed effects linear and logistic regression models to examine relationships between insurance status, inconsistent attendance, and glycemic control, adjusting for demographic, clinical, social, and health system factors. Results: 312 YA were seen in the clinic (mean age 23.5 years) totaling 2376 care visits. Forty-six percent (n=147) had public insurance. Publicly insured YA were more frequently black (42% vs. 11%, p6 months (OR 1.96, p=0.008). In addition, missed appointments worsened glycemic control from baseline (A1c +0.57%, p Conclusions: Low SES YA with T1D are a particularly high-risk subset who are more likely to miss appointments and have gaps in care, which is associated with worse glycemic control. Our results highlight the need to refocus on improving follow-up rates in vulnerable populations to address disparities in glycemic outcomes. Disclosure S. Agarwal: None. H.L. Viroslav: None. J.N. Eiel: None. J.A. Long: None.

BACKGROUND Patients with pancreatic insufficient cystic fibrosis (PI-CF) meeting standard criteria for normal glucose tolerance display impaired β-cell secretory capacity and early-phase insulin secretion defects. We sought evidence of impaired β-cell secretory capacity, a measure of functional β-cell mass, among those with early glucose intolerance (EGI), defined as 1-hour oral glucose tolerance test (OGTT) glucose ≥155 mg/dL (8.6 mmol/L). METHODS A cross-sectional study was conducted in the Penn and CHOP Clinical & Translational Research Centers. PI-CF categorized by OGTT as normal (PI-NGT: 1-hour glucose