Enzymatically stable analogue of the gut-derived peptide xenin on beta-cell transdifferentiation in high fat fed and insulin-deficient Ins1Cre/+;Rosa26-eYFP mice
Neil Tanday
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Search for more papers by this authorR. Charlotte Moffett
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Search for more papers by this authorVictor A. Gault
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Search for more papers by this authorPeter R. Flatt
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Search for more papers by this authorCorresponding Author
Nigel Irwin
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Correspondence
Nigel Irwin, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
Email: [email protected]
Search for more papers by this authorNeil Tanday
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Search for more papers by this authorR. Charlotte Moffett
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Search for more papers by this authorVictor A. Gault
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Search for more papers by this authorPeter R. Flatt
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Search for more papers by this authorCorresponding Author
Nigel Irwin
SAAD Centre for Pharmacy and Diabetes, Ulster University, Coleraine, Northern Ireland, UK
Correspondence
Nigel Irwin, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
Email: [email protected]
Search for more papers by this authorFunding information: Department for the Economy, Northern Ireland; Invest Northern Ireland; European Foundation for the Study of Diabetes; Diabetes UK
Abstract
Background
The antidiabetic effects of the gut hormone xenin include augmenting insulin secretion and positively affecting pancreatic islet architecture.
Methods
The current study has further probed pancreatic effects through sub-chronic administration of the long-acting xenin analogue, xenin-25[Lys13PAL], in both high fat fed (HFF) and streptozotocin (STZ)-induced insulin-deficient Ins1Cre/+;Rosa26-eYFP transgenic mice. Parallel effects on metabolic control and pancreatic islet morphology, including islet beta-cell lineage tracing were also assessed.
Results
Xenin-25[Lys13PAL] treatment reversed body weight loss induced by STZ, increased plasma insulin and decreased blood glucose levels. There were less obvious effects on these parameters in HFF mice, but all xenin-25[Lys13PAL] treated mice exhibited decreased pancreatic alpha-cell areas and circulating glucagon. Xenin-25[Lys13PAL] treatment fully, or partially, returned overall islet and beta-cell areas in STZ- and HFF mice to those of lean control animals, respectively, and was consistently associated with decreased beta-cell apoptosis. Interestingly, xenin-25[Lys13PAL] also increased beta-cell proliferation and decreased alpha-cell apoptosis in STZ mice, with reduced alpha-cell growth noted in HFF mice. Lineage tracing studies revealed that xenin-25[Lys13PAL] reduced the number of insulin positive pancreatic islet cells that lost their beta-cell identity, in keeping with a decreased transition of insulin positive to glucagon positive cells. These beneficial effects on islet cell differentiation were linked to maintained expression of Pdx1 within beta-cells. Xenin-25[Lys13PAL] treatment was also associated with increased numbers of smaller sized islets in both models.
Conclusions
Benefits of xenin-25[Lys13PAL] on diabetes includes positive modulation of islet cell differentiation, in addition to promoting beta-cell growth and survival.
CONFLICT OF INTEREST
V.A.G., P.R.F. and N.I. are named on patents filed by the University of Ulster for exploitation of incretin-based drugs and other peptide therapeutics.
REFERENCES
- 1Feurle GE, Hamscher G, Kusiek R, Meyer HE, Metzger JW. Identification of xenin, a xenopsin-related peptide, in the human gastric mucosa and its effect on exocrine pancreatic secretion. J Biol Chem. 1992; 267: 22305-22309.
- 2Taylor AI, Irwin N, McKillop AM, Patterson S, Flatt PR, Gault VA. Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety. J Endocrinol. 2010; 207: 87-93.
- 3Wice BM, Wang S, Crimmins DL, et al. Xenin-25 potentiates glucose-dependent insulinotropic polypeptide action via a novel cholinergic relay mechanism. J Biol Chem. 2010; 285: 19842-19853.
- 4Martin CM, Gault VA, McClean S, Flatt PR, Irwin N. Degradation, insulin secretion, glucose-lowering and GIP additive actions of a palmitate-derivatised analogue of xenin-25. Biochem Pharmacol. 2012; 84: 312-319.
- 5Martin C, Parthsarathy V, Pathak V, Gault VA, Irwin FPR. Characterisation of the biological activity of xenin-25 degradation fragment peptides. J Endocrinol. 2014; 221: 193-200.
- 6Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Investig. 1992; 91: 301-307.
- 7Gault VA, Martin C, Flatt PR, Parthsarathy V, Irwin N. Xenin-25 [Lys 13 PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential. Acta Diabetol. 2015; 52: 461-471.
- 8Parthsarathy V, Irwin N, Hasib A, et al. A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing properties. Biochim Biophys Acta. 2016; 1860: 757-764.
- 9Cooke JH, Patterson M, Patel SR, et al. Peripheral and central administration of xenin and neurotensin suppress food intake in rodents. Obesity. 2009; 17: 1135-1143.
- 10Hamscher G, Meyer HE, Metzger JW, Feurle GE. Distribution, formation, and molecular forms of the peptide xenin in various mammals. Peptides. 1995; 16: 791-797.
- 11Hamscher G, Meyer HE, Feurle GE. Identification of proxenin as a precursor of the peptide xenin with sequence homology to yeast and mammalian coat protein α. Peptides. 1996; 17: 889-893.
- 12Khan D, Vasu S, Moffett RC, Gault VA, Flatt PR, Irwin N. Locally produced xenin and the neurotensinergic system in pancreatic islet function and β-cell survival. Biol Chem. 2017; 399: 79-92.
- 13Craig SL, Gault VA, Irwin N. Emerging therapeutic potential for xenin and related peptides in obesity and diabetes. Diabetes Metab Res Rev. 2018; 34:e3006.
- 14Collombat P, Hecksher-Sorensen J, Krull J, et al. Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression. J Clin Investig. 2007; 117: 961-970.
- 15Collombat P, Xu X, Ravassard P, et al. The ectopic expression of Pax4 in the mouse pancreas converts progenitor cells into α and subsequently β cells. Cell. 2009; 138: 449-462.
- 16Thorel F, Népote V, Avril I, et al. Conversion of adult pancreatic α-cells to β-cells after extreme β-cell loss. Nature. 2010; 464: 1149-1154.
- 17Huising MO, Lee S, van der Meulen T. Evidence for a Neogenic niche at the periphery of pancreatic islets. Bioessays 2018; 40: 1800119, e1800119.
- 18Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell. 2012; 150: 1223-1234.
- 19Weir GC, Aguayo-Mazzucato C, Bonner-Weir S. β-Cell dedifferentiation in diabetes is important, but what is it? Islets. 2013; 5: 233-237.
- 20Fiori JL, Shin YK, Kim W, et al. Resveratrol prevents beta-cell dedifferentiation in nonhuman primates given a high-fat/high-sugar diet. Diabetes. 2013; 62: 3500-3513.
- 21Gao T, McKenna B, Li C, et al. Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab. 2014; 19: 259-271.
- 22Dor Y, Glaser B. Beta-cell dedifferentiation and type 2 diabetes. N Engl J Med. 2013; 368: 572-573.
- 23Cinti F, Bouchi R, Kim-Muller JY, et al. Evidence of β-cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016; 101: 1044-1054.
- 24Thorens B, Tarussio D, Maestro MA, Rovira M, Heikkilä E, Ferrer J. Ins1 Cre knock-in mice for beta cell-specific gene recombination. Diabetologia. 2015; 58: 558-565.
- 25Tanday N, Flatt PR, Irwin N, Moffett RC. Liraglutide and sitagliptin counter beta- to alpha-cell transdifferentiation in diabetes. J Endocrinol. 2020; 245: 53-64.
- 26Martin CM, Parthsarathy V, Hasib A, et al. Biological activity and antidiabetic potential of C-terminal octapeptide fragments of the gut-derived hormone xenin. PLOS ONE. 2016; 11:e0152818.
- 27Pathak V, Vasu S, Gault VA, Flatt PR, Irwin N. Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJ db/db mice. Diabetologia. 2015; 58: 2144-2153.
- 28Vasu S, Moffett RC, Thorens B, Flatt PR. Role of endogenous GLP-1 and GIP in beta cell compensatory responses to insulin resistance and cellular stress. PLOS ONE. 2014; 9:e101005.
- 29Flatt P, Bailey C. Abnormal plasma glucose and insulin responses in heterozygous lean (Ob/ ) mice. Diabetologia. 1981; 20: 573-577.
- 30Vasu S, Moffett RC, McClenaghan NH, Flatt PR. Responses of GLP1-secreting L-cells to cytotoxicity resemble pancreatic β-cells but not α-cells. J Mol Endocrinol. 2015; 54: 91-104.
- 31Butler PC, Meier JJ, Butler AE, Bhushan A. The replication of β cells in normal physiology, in disease and for therapy. Nat Rev Endocrinol. 2007; 3: 758-768.
- 32Bollheimer L, Wobser H, Wrede C, et al. Glucagon under high fat diet induced obesity. Exp Clin Endocrinol Diabetes. 2007; 115: P01_062.
- 33Ellingsgaard H, Ehses JA, Hammar EB, et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci U S A. 2008; 105: 13163-13168.
- 34Weir GC, Knowlton SD, Atkins RF, McKennan KX, Martin DB. Glucagon secretion from the perfused pancreas of streptozotocin-treated rats. Diabetes. 1976; 25: 275-282.
- 35Irwin N, Franklin ZJ, O'Harte FP. desHis1Glu9-glucagon-[mPEG] and desHis1Glu9 (Lys30PAL)-glucagon: long-acting peptide-based PEGylated and acylated glucagon receptor antagonists with potential antidiabetic activity. Eur J Pharmacol. 2013; 709: 43-51.
- 36O'Harte F, Franklin Z, Rafferty E, Irwin N. Characterisation of structurally modified analogues of glucagon as potential glucagon receptor antagonists. Mol Cell Endocrinol. 2013; 381: 26-34.
- 37O'Harte F, Franklin Z, Irwin N. Two novel glucagon receptor antagonists prove effective therapeutic agents in high-fat-fed and obese diabetic mice. Diabetes Obes Metab. 2014; 16: 1214-1222.
- 38McShane LM, Franklin ZJ, O'Harte FP, Irwin N. Ablation of glucagon receptor signaling by peptide-based glucagon antagonists improves glucose tolerance in high fat fed mice. Peptides. 2014; 60: 95-101.
- 39Kelly R, Garhyan P, Raddad E, et al. Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes Metab. 2015; 17: 414-422.
- 40Kazda CM, Ding Y, Kelly RP, et al. Evaluation of efficacy and safety of the glucagon receptor antagonist LY2409021 in patients with type 2 diabetes: 12- and 24-week phase 2 studies. Diabetes Care. 2016; 39: 1241-1249.
- 41Silvestre RA, Rodrı́guez-Gallardo J, Egido EM, Hernández R, Marco J. Stimulatory effect of xenin-8 on insulin and glucagon secretion in the perfused rat pancreas. Regul Pept. 2003; 115: 25-29.
- 42Craig S, Gault V, McClean S, Hamscher G, Irwin N. Effects of an enzymatically stable C-terminal hexapseudopeptide fragment peptide of xenin-25, ψ-xenin-6, on pancreatic islet function and metabolism. Mol Cell Endocrinol. 2019; 496:110523.
- 43Cassidy RS, Irwin N, Flatt PR. Effects of gastric inhibitory polypeptide (GIP) and related analogues on glucagon release at normo-and hyperglycaemia in Wistar rats and isolated islets. Biol Chem. 2008; 389: 189-193.
- 44Hasib A, Ng MT, Tanday N, et al. Exendin-4(Lys27PAL)/gastrin/xenin-8-Gln: a novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (Ob/Ob) mice. Diabetes Metab Res Rev. 2019; 35:e3106.
- 45Mathis D, Vence L, Benoist C. β-Cell death during progression to diabetes. Nature. 2001; 414: 792-798.
- 46Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes. 2004; 53: S16-S21.
- 47Parker JC, Lavery KS, Irwin N, et al. Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP (3–42) and GLP-1 (9–36) amide, on insulin secretion and glucose homeostasis in Ob/Ob mice. J Endocrinol. 2006; 191: 93-100.
- 48Moffett RC, Vasu S, Thorens B, Drucker DJ, Flatt PR. Incretin receptor null mice reveal key role of GLP-1 but not GIP in pancreatic beta cell adaptation to pregnancy. PLOS ONE. 2014; 9:e96863.
- 49Trümper A, Trümper K, Trusheim H, Arnold R, Göke B, Hörsch D. Glucose-dependent insulinotropic polypeptide is a growth factor for β (INS-1) cells by pleiotropic signalling. Mol Endocrinol. 2001; 15: 1559-1570.
- 50Trümper A, Trümper K, Horsch D. Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in beta (INS-1)-cells. J Endocrinol. 2002; 174: 233-246.
- 51Ehses JA, Pelech SL, Pederson RA, McIntosh CH. Glucose-dependent insulinotropic polypeptide activates the Raf-Mek1/2-ERK1/2 module via a cyclic AMP/cAMP-dependent protein kinase/Rap1-mediated pathway. J Biol Chem. 2002; 277: 37088-37097.
- 52Karakose E, Ackeifi C, Wang P, Stewart AF. Advances in drug discovery for human beta cell regeneration. Diabetologia. 2018; 61: 1693-1699.
- 53Rutti S, Sauter NS, Bouzakri K, Prazak R, Halban PA, Donath MY. In vitro proliferation of adult human beta-cells. PLOS ONE. 2012; 7: e35801.
- 54Lee YS, Lee C, Choung JS, Jung HS, Jun HS. Glucagon-like peptide 1 increases β-cell regeneration by promoting α-to β-cell transdifferentiation. Diabetes. 2018; 67: 2601-2614.
- 55Sarnobat D, Moffett RC, Gault VA, et al. Effects of long-acting GIP, xenin and oxyntomodulin peptide analogues on alpha-cell transdifferentiation in insulin-deficient diabetic GluCreERT2; ROSA26-eYFP mice. Peptides. 2020; 125:170205.
- 56Ye L, Robertson MA, Hesselson D, Stainier DY, Anderson RM. Glucagon is essential for alpha cell transdifferentiation and beta cell neogenesis. Development. 2015; 142: 1407-1417.
- 57Sharon N, Chawla R, Mueller J, et al. A peninsular structure coordinates asynchronous differentiation with morphogenesis to generate pancreatic islets. Cell. 2019; 176: 790-804.
- 58Yang YP, Thorel F, Boyer DF, Herrera PL, Wright CV. Context-specific alpha- to-beta-cell reprogramming by forced Pdx1 expression. Genes Dev. 2011; 25: 1680-1685.
- 59Guo S, Dai C, Guo M, et al. Inactivation of specific β cell transcription factors in type 2 diabetes. J Clin Investig. 2013; 123: 3305-3316.
- 60Maryanovich AT, Kormilets DY, Polyanovsky AD. Xenin: the oldest after insulin? Mol Biol Rep. 2018; 45: 143-150.
- 61Kyrylkova K, Kyryachenko S, Leid M, Kioussi C. Detection of apoptosis by TUNEL assay. Odontogenesis. 2012; 227: 41-47.
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