The Role of PANDER and Its Interplay with IL-6 in the Regulation of GLP-1 Secretion

Overview

Journal Endocr Connect

Specialty Endocrinology

Date 2024 Sep 5

PMID 39235859

Authors

Zeting Li

Ling Pei

Huangmeng Xiao

Nan Chen

Fenghua Lai

Shufang Yue

Changliu Xu

Yanbing Li

Haipeng Xiao

Xiaopei Cao

Affiliations

Soon will be listed here.

Abstract

Glucose-like peptide-1 (GLP-1) is a vital hormone in the intestines that regulates glucose metabolism. Although pancreatic-derived factor (PANDER) overexpression is known to suppress GLP-1, the underlying mechanisms are unclear. Our study aims to uncover how PANDER influences GLP-1 synthesis and secretion. We established a PANDER overexpression model in STC-1 intestinal cells, confirming its inhibitory effect on GLP-1 secretion. This effect was reversed in PANDER-knockout cells. Additionally, a negative correlation between PANDER and GLP-1 was observed in patients with a history of gestational diabetes. Subsequently, through whole transcriptome gene sequencing in PANDER-overexpressed STC-1 cells, we discovered that the activation of IL-6 and its related STAT3 signaling pathway was significantly inhibited, and this finding was validated by Western blotting and quantitative reverse transcription PCR. Finally, rescue experiments confirmed that the IL-6-related STAT3/Akt/GSK3β/β-catenin signaling pathway mediates the negative regulatory effect of PANDER on GLP-1. Taken together, our data identify IL-6 as a bridge connecting PANDER and GLP-1 in the STC-1 cells, demonstrating potential therapeutic targets for diabetes treatment by targeting the PANDER-IL-6-GLP-1 axis.

References

Bell G, Laybourn P, Najarian R . Exon duplication and divergence in the human preproglucagon gene. Nature. 1983; 304(5924):368-71. DOI: 10.1038/304368a0. View

Tanaka T, Narazaki M, Kishimoto T . IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol. 2014; 6(10):a016295. PMC: 4176007. DOI: 10.1101/cshperspect.a016295. View

Yang J, Wang C, Li J, Burkhardt B, Robert-Cooperman C, Wilson C . PANDER binds to the liver cell membrane and inhibits insulin signaling in HepG2 cells. FEBS Lett. 2009; 583(18):3009-15. DOI: 10.1016/j.febslet.2009.08.008. View

Metzger B, Gabbe S, Persson B, Buchanan T, Catalano P, Damm P . International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010; 33(3):676-82. PMC: 2827530. DOI: 10.2337/dc09-1848. View

Sanjana N, Shalem O, Zhang F . Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014; 11(8):783-784. PMC: 4486245. DOI: 10.1038/nmeth.3047. View

Timper K, Dalmas E, Dror E, Rutti S, Thienel C, Sauter N . Glucose-Dependent Insulinotropic Peptide Stimulates Glucagon-Like Peptide 1 Production by Pancreatic Islets via Interleukin 6, Produced by α Cells. Gastroenterology. 2016; 151(1):165-79. DOI: 10.1053/j.gastro.2016.03.003. View

Shehata M, Kamal M, El-Hefnawy M, El-Mesallamy H . Association of serum pancreatic derived factor (PANDER) with beta-cell dysfunction in type 2 diabetes mellitus. J Diabetes Complications. 2017; 31(4):748-752. DOI: 10.1016/j.jdiacomp.2017.01.001. View

Liu Y, He T, Li H, Jiang P . Liraglutide improves pancreatic islet β cell apoptosis in rats with type 2 diabetes mellitus by inhibiting the IKKε/NF-κB pathway. Eur Rev Med Pharmacol Sci. 2021; 25(14):4818-4828. DOI: 10.26355/eurrev_202107_26395. View

Lai F, Chen Y, Lin H, Wang X, Zhu X, Li Y . Pancreatic-derived factor impaired glucagon-like Peptide-1 production from GLUTag enterendorine L-cell line and intestines. Mol Cell Endocrinol. 2017; 452:110-119. DOI: 10.1016/j.mce.2017.05.021. View

10.

Cao X, Yang C, Lai F, Hong Z, Lin H, Liu J . Elevated circulating level of a cytokine, pancreatic-derived factor, is associated with metabolic syndrome components in a Chinese population. J Diabetes Investig. 2016; 7(4):581-6. PMC: 4931209. DOI: 10.1111/jdi.12437. View

11.

Helmstadter J, Keppeler K, Aust F, Kuster L, Frenis K, Filippou K . GLP-1 Analog Liraglutide Improves Vascular Function in Polymicrobial Sepsis by Reduction of Oxidative Stress and Inflammation. Antioxidants (Basel). 2021; 10(8). PMC: 8388926. DOI: 10.3390/antiox10081175. View

12.

Cao X, Gao Z, Robert C, Greene S, Xu G, Xu W . Pancreatic-derived factor (FAM3B), a novel islet cytokine, induces apoptosis of insulin-secreting beta-cells. Diabetes. 2003; 52(9):2296-303. DOI: 10.2337/diabetes.52.9.2296. View

13.

Kahles F, Meyer C, Mollmann J, Diebold S, Findeisen H, Lebherz C . GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes. 2014; 63(10):3221-9. DOI: 10.2337/db14-0100. View

14.

Cao X, Yang J, Burkhardt B, Gao Z, Wong R, Greene S . Effects of overexpression of pancreatic derived factor (FAM3B) in isolated mouse islets and insulin-secreting betaTC3 cells. Am J Physiol Endocrinol Metab. 2005; 289(4):E543-50. DOI: 10.1152/ajpendo.00113.2005. View

15.

Wueest S, Laesser C, Boni-Schnetzler M, Item F, Lucchini F, Borsigova M . IL-6-Type Cytokine Signaling in Adipocytes Induces Intestinal GLP-1 Secretion. Diabetes. 2017; 67(1):36-45. DOI: 10.2337/db17-0637. View

16.

Shalem O, Sanjana N, Hartenian E, Shi X, Scott D, Mikkelson T . Genome-scale CRISPR-Cas9 knockout screening in human cells. Science. 2013; 343(6166):84-87. PMC: 4089965. DOI: 10.1126/science.1247005. View

17.

Sandoval D, DAlessio D . Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015; 95(2):513-48. DOI: 10.1152/physrev.00013.2014. View

18.

Yang J, Robert C, Burkhardt B, Young R, Wu J, Gao Z . Mechanisms of glucose-induced secretion of pancreatic-derived factor (PANDER or FAM3B) in pancreatic beta-cells. Diabetes. 2005; 54(11):3217-28. DOI: 10.2337/diabetes.54.11.3217. View

19.

Guarnotta V, Bianco M, Vigneri E, Panto F, Lo Sasso B, Ciaccio M . Effects of GLP-1 receptor agonists on myokine levels and pro-inflammatory cytokines in patients with type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis. 2021; 31(11):3193-3201. DOI: 10.1016/j.numecd.2021.07.015. View

20.

MarElia C, Kuehl M, Shemwell T, Alman A, Burkhardt B . Circulating PANDER concentration is associated with increased HbA1c and fasting blood glucose in Type 2 diabetic subjects. J Clin Transl Endocrinol. 2018; 11:26-30. PMC: 5910510. DOI: 10.1016/j.jcte.2018.02.003. View