Cystic Fibrosis-related Diabetes is Associated with Reduced Islet Protein Expression of GLP-1 Receptor and Perturbation of Cell-specific Transcriptional Programs

Overview

Journal Sci Rep

Specialty Science

Date 2024 Oct 28

PMID 39463434

Authors

Sina A Gharib

Rachna Vemireddy

Joseph J Castillo

Brendy S Fountaine

Theo K Bammler

James W MacDonald

Rebecca L Hull-Meichle

Sakeneh Zraika

Affiliations

Soon will be listed here.

Abstract

Insulin secretion is impaired in individuals with cystic fibrosis (CF), contributing to high rates of CF-related diabetes (CFRD) and substantially increasing disease burden. To develop improved therapies for CFRD, better knowledge of pancreatic pathology in CF is needed. Glucagon like peptide-1 (GLP-1) from islet α cells potentiates insulin secretion by binding GLP-1 receptors (GLP-1Rs) on β cells. We determined whether expression of GLP-1 and/or its signaling components are reduced in CFRD, thereby contributing to impaired insulin secretion. Immunohistochemistry of pancreas from humans with CFRD versus no-CF/no-diabetes revealed no difference in GLP-1 immunoreactivity per islet area, whereas GLP-1R immunoreactivity per islet area or per insulin-positive islet area was reduced in CFRD. Using spatial transcriptomics, we observed several differentially expressed α- and/or β-cell genes between CFRD and control pancreas. In CFRD, we found upregulation of α-cell PCSK1 which encodes the enzyme (PC1/3) that generates GLP-1, and downregulation of α-cell PCSK1N which inhibits PC1/3. Gene set enrichment analysis also revealed α and β cell-specific pathway dysregulation in CFRD. Together, our data suggest intra-islet GLP-1 is not limiting in CFRD, but its action may be restricted due to reduced GLP-1R protein levels. Thus, restoring β-cell GLP-1R protein expression may improve β-cell function in CFRD.

References

Moran A, Dunitz J, Nathan B, Saeed A, Holme B, Thomas W . Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care. 2009; 32(9):1626-31. PMC: 2732133. DOI: 10.2337/dc09-0586. View

Lewis C, Blackman S, Nelson A, Oberdorfer E, Wells D, Dunitz J . Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med. 2014; 191(2):194-200. PMC: 4347432. DOI: 10.1164/rccm.201403-0576OC. View

Merjaneh L, Hasan S, Kasim N, Ode K . The role of modulators in cystic fibrosis related diabetes. J Clin Transl Endocrinol. 2021; 27:100286. PMC: 8668978. DOI: 10.1016/j.jcte.2021.100286. View

Kelly A, Sheikh S, Stefanovski D, Peleckis A, Nyirjesy S, Eiel J . Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance. J Clin Endocrinol Metab. 2021; 106(9):2617-2634. PMC: 8660013. DOI: 10.1210/clinem/dgab365. View

Nyirjesy S, Peleckis A, Eiel J, Gallagher K, Doliba A, Tami A . Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis. Diabetes. 2022; 71(10):2153-2165. PMC: 9501647. DOI: 10.2337/db22-0399. View

Tornehave D, Kristensen P, Romer J, Knudsen L, Heller R . Expression of the GLP-1 receptor in mouse, rat, and human pancreas. J Histochem Cytochem. 2008; 56(9):841-51. PMC: 2516959. DOI: 10.1369/jhc.2008.951319. View

Waget A, Cabou C, Masseboeuf M, Cattan P, Armanet M, Karaca M . Physiological and pharmacological mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice. Endocrinology. 2011; 152(8):3018-29. DOI: 10.1210/en.2011-0286. View

Washington M, Raboin S, Thompson W, Larsen C, Sayegh A . Exenatide reduces food intake and activates the enteric nervous system of the gastrointestinal tract and the dorsal vagal complex of the hindbrain in the rat by a GLP-1 receptor. Brain Res. 2010; 1344:124-33. DOI: 10.1016/j.brainres.2010.05.002. View

Deacon C, Johnsen A, Holst J . Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J Clin Endocrinol Metab. 1995; 80(3):952-7. DOI: 10.1210/jcem.80.3.7883856. View

10.

Deacon C, Nauck M, Pridal L, Willms B, Holst J . Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995; 44(9):1126-31. DOI: 10.2337/diab.44.9.1126. View

11.

Goke R, Goke B, Thole H, Zimmermann B, Voigt K, McGregor G . Endoproteolysis of glucagon-like peptide (GLP)-1 (7-36) amide by ectopeptidases in RINm5F cells. Peptides. 1997; 18(5):625-32. DOI: 10.1016/s0196-9781(97)00123-x. View

12.

Kieffer T, McIntosh C, PEDERSON R . Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995; 136(8):3585-96. DOI: 10.1210/endo.136.8.7628397. View

13.

Holter M, Saikia M, Cummings B . Alpha-cell paracrine signaling in the regulation of beta-cell insulin secretion. Front Endocrinol (Lausanne). 2022; 13:934775. PMC: 9360487. DOI: 10.3389/fendo.2022.934775. View

14.

Huypens P, Ling Z, Pipeleers D, Schuit F . Glucagon receptors on human islet cells contribute to glucose competence of insulin release. Diabetologia. 2000; 43(8):1012-9. DOI: 10.1007/s001250051484. View

15.

Samols E, Marri G, Marks V . PROMOTION OF INSULIN SECRETION BY GLUCAGON. Lancet. 1965; 2(7409):415-6. DOI: 10.1016/s0140-6736(65)90761-0. View

16.

Masur K, Tibaduiza E, Chen C, Ligon B, Beinborn M . Basal receptor activation by locally produced glucagon-like peptide-1 contributes to maintaining beta-cell function. Mol Endocrinol. 2005; 19(5):1373-82. DOI: 10.1210/me.2004-0350. View

17.

Eissele R, Goke R, Willemer S, Harthus H, Vermeer H, Arnold R . Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest. 1992; 22(4):283-91. DOI: 10.1111/j.1365-2362.1992.tb01464.x. View

18.

Marchetti P, Lupi R, Bugliani M, Kirkpatrick C, Sebastiani G, Grieco F . A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia. 2012; 55(12):3262-72. DOI: 10.1007/s00125-012-2716-9. View

19.

Mojsov S, Kopczynski M, Habener J . Both amidated and nonamidated forms of glucagon-like peptide I are synthesized in the rat intestine and the pancreas. J Biol Chem. 1990; 265(14):8001-8. View

20.

Wideman R, Yu I, Webber T, Verchere C, Johnson J, Cheung A . Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1). Proc Natl Acad Sci U S A. 2006; 103(36):13468-73. PMC: 1569187. DOI: 10.1073/pnas.0600655103. View