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20.05.2017 | Article

GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice

verfasst von: Dan Kawamori, Jun Shirakawa, Chong Wee Liew, Jiang Hu, Tomoaki Morioka, Alokesh Duttaroy, Bryan Burkey, Rohit N. Kulkarni

Erschienen in: Diabetologia | Ausgabe 8/2017

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Abstract

Aims/hypothesis

We aimed to investigate potential interactions between insulin and glucagon-like peptide (GLP)-1 signalling pathways in the regulation of beta cell-cycle dynamics in vivo, in the context of the therapeutic potential of GLP-1 to modulate impaired beta cell function.

Methods

Beta cell-specific insulin receptor knockout (βIRKO) mice, which exhibit beta cell dysfunction and an age-dependent decrease in beta cell mass, were treated with the dipeptidyl peptidase-4 inhibitor vildagliptin. Following this, glucose homeostasis and beta cell proliferation were evaluated and underlying molecular mechanisms were investigated.

Results

The sustained elevation in circulating GLP-1 levels, caused by treatment of the knockout mice with vildagliptin for 6 weeks, significantly improved glucose tolerance secondary to enhanced insulin secretion and proliferation of beta cells. Treating βIRKO beta cell lines with the GLP-1 analogue, exendin-4, promoted Akt phosphorylation and protein expression of cyclins A, D1 and E two- to threefold, in addition to cyclin D2. Pancreases from the vildagliptin-treated βIRKO mice exhibited increased cyclin D1 expression, while cyclin D2 expression was impaired.

Conclusions/interpretation

Activation of GLP-1 signalling compensates for impaired growth factor (insulin) signalling and enhances expression of cyclins to promote beta cell proliferation. Together, these data indicate the potential of GLP-1-related therapies to enhance beta cell proliferation and promote beneficial outcomes in models with dysfunctional beta cells.

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Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ (2005) Diabetes mellitus. Lippincott, Williams and Wilkins, New York

Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110CrossRefPubMed

Drucker DJ (2006) The biology of incretin hormones. Cell Metab 3:153–165CrossRefPubMed

Stoffers DA, Kieffer TJ, Hussain MA et al (2000) Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. Diabetes 49:741–748CrossRefPubMed

Habener JF, Stoffers DA (1998) A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus. Proc Assoc Am Physicians 110:12–21PubMed

Farilla L, Bulotta A, Hirshberg B et al (2003) Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 144:5149–5158CrossRefPubMed

Hui H, Nourparvar A, Zhao X, Perfetti R (2003) Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway. Endocrinology 144:1444–1455CrossRefPubMed

Jhala US, Canettieri G, Screaton RA et al (2003) cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2. Genes Dev 17:1575–1580CrossRefPubMedPubMedCentral

Ranta F, Avram D, Berchtold S et al (2006) Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes 55:1380–1390CrossRefPubMed

10.

Assmann A, Hinault C, Kulkarni RN (2009) Growth factor control of pancreatic islet regeneration and function. Pediatr Diabetes 10:14–32CrossRefPubMed

11.

Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR (1999) Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96:329–339CrossRefPubMed

12.

Kulkarni RN, Holzenberger M, Shih DQ et al (2002) β-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter β-cell mass. Nat Genet 31:111–115PubMed

13.

Xuan S, Kitamura T, Nakae J et al (2002) Defective insulin secretion in pancreatic β cells lacking type 1 IGF receptor. J Clin Invest 110:1011–1019CrossRefPubMedPubMedCentral

14.

Shirakawa J, Fernandez M, Takatani T et al (2017) Insulin signaling regulates the FoxM1/PLK1/CENP-A pathway to promote adaptive pancreatic β cell proliferation. Cell Metab 25:868–882CrossRefPubMed

15.

Cornu M, Modi H, Kawamori D, Kulkarni RN, Joffraud M, Thorens B (2010) Glucagon-like peptide-1 increases β-cell glucose competence and proliferation by translational induction of insulin-like growth factor-1 receptor expression. J Biol Chem 285:10538–10545CrossRefPubMedPubMedCentral

16.

Cornu M, Yang JY, Jaccard E, Poussin C, Widmann C, Thorens B (2009) Glucagon-like peptide-1 protects β-cells against apoptosis by increasing the activity of an IGF-2/IGF-1 receptor autocrine loop. Diabetes 58:1816–1825CrossRefPubMedPubMedCentral

17.

Cozar-Castellano I, Fiaschi-Taesch N, Bigatel TA et al (2006) Molecular control of cell cycle progression in the pancreatic β-cell. Endocr Rev 27:356–370CrossRefPubMed

18.

Georgia S, Bhushan A (2004) β cell replication is the primary mechanism for maintaining postnatal β cell mass. J Clin Invest 114:963–968CrossRefPubMedPubMedCentral

19.

Kushner JA, Ciemerych MA, Sicinska E et al (2005) Cyclins D2 and D1 are essential for postnatal pancreatic β-cell growth. Mol Cell Biol 25:3752–3762CrossRefPubMedPubMedCentral

20.

Georgia S, Hinault C, Kawamori D et al (2010) Cyclin D2 is essential for the compensatory β-cell hyperplastic response to insulin resistance in rodents. Diabetes 59:987–996CrossRefPubMedPubMedCentral

21.

Zhang X, Gaspard JP, Mizukami Y, Li J, Graeme-Cook F, Chung DC (2005) Overexpression of cyclin D1 in pancreatic beta-cells in vivo results in islet hyperplasia without hypoglycemia. Diabetes 54:712–719CrossRefPubMed

22.

Friedrichsen BN, Neubauer N, Lee YC et al (2006) Stimulation of pancreatic β-cell replication by incretins involves transcriptional induction of cyclin D1 via multiple signalling pathways. J Endocrinol 188:481–492CrossRefPubMed

23.

Liu Z, Habener JF (2008) Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem 283:8723–8735CrossRefPubMedPubMedCentral

24.

Song WJ, Schreiber WE, Zhong E et al (2008) Exendin-4 stimulation of cyclin A2 in β-cell proliferation. Diabetes 57:2371–2381CrossRefPubMedPubMedCentral

25.

Xie T, Chen M, Zhang QH, Ma Z, Weinstein LS (2007) β cell-specific deficiency of the stimulatory G protein α-subunit Gsα leads to reduced beta cell mass and insulin-deficient diabetes. Proc Natl Acad Sci U S A 104:19601–19606CrossRefPubMedPubMedCentral

26.

Folli F, Okada T, Perego C et al (2011) Altered insulin receptor signalling and β-cell cycle dynamics in type 2 diabetes mellitus. PLoS One 6:e28050CrossRefPubMedPubMedCentral

27.

Gunton JE, Kulkarni RN, Yim S et al (2005) Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 122:337–349CrossRefPubMed

28.

Winzell MS, Ahren B (2004) The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 53(Suppl 3):S215–S219CrossRefPubMed

29.

Assmann A, Ueki K, Winnay JN, Kadowaki T, Kulkarni RN (2009) Glucose effects on β-cell growth and survival require activation of insulin receptors and insulin receptor substrate 2. Mol Cell Biol 29:3219–3228CrossRefPubMedPubMedCentral

30.

Liu S, Okada T, Assmann A et al (2009) Insulin signaling regulates mitochondrial function in pancreatic β-cells. PLoS One 4:e7983CrossRefPubMedPubMedCentral

31.

Kawamori D, Kaneto H, Nakatani Y et al (2006) The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J Biol Chem 281:1091–1098CrossRefPubMed

32.

Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705CrossRefPubMed

33.

Yang J, Robert CE, Burkhardt BR et al (2005) Mechanisms of glucose-induced secretion of pancreatic-derived factor (PANDER or FAM3B) in pancreatic β-cells. Diabetes 54:3217–3228CrossRefPubMed

34.

Kim W, Egan JM (2008) The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 60:470–512CrossRefPubMedPubMedCentral

35.

Holst JJ, Vilsboll T, Deacon CF (2009) The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 297:127–136CrossRefPubMed

36.

Marchetti P, Lupi R, Del Guerra S, Bugliani M, Marselli L, Boggi U (2010) The β-cell in human type 2 diabetes. Adv Exp Med Biol 654:501–514CrossRefPubMed

37.

Flock G, Baggio LL, Longuet C, Drucker DJ (2007) Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes 56:3006–3013CrossRefPubMed

38.

Buteau J, Foisy S, Joly E, Prentki M (2003) Glucagon-like peptide 1 induces pancreatic β-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 52:124–132CrossRefPubMed

39.

Li Y, Cao X, Li LX, Brubaker PL, Edlund H, Drucker DJ (2005) β-Cell Pdx1 expression is essential for the glucoregulatory, proliferative, and cytoprotective actions of glucagon-like peptide-1. Diabetes 54:482–491CrossRefPubMed

40.

Campbell JE, Ussher JR, Mulvihill EE et al (2016) TCF1 links GIPR signaling to the control of beta cell function and survival. Nat Med 22:84–90CrossRefPubMed

41.

Drucker DJ (2007) Dipeptidyl peptidase-4 inhibition and the treatment of type 2 diabetes: preclinical biology and mechanisms of action. Diabetes Care 30:1335–1343CrossRefPubMed

42.

Itou M, Kawaguchi T, Taniguchi E, Sata M (2013) Dipeptidyl peptidase-4: a key player in chronic liver disease. World J Gastroenterol 19:2298–2306CrossRefPubMedPubMedCentral

43.

Lamers D, Famulla S, Wronkowitz N et al (2011) Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 60:1917–1925CrossRefPubMedPubMedCentral

44.

Ryskjaer J, Deacon CF, Carr RD et al (2006) Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake. Eur J Endocrinol 155:485–493CrossRefPubMed

45.

Fadini GP, Albiero M, Menegazzo L, de Kreutzenberg SV, Avogaro A (2012) The increased dipeptidyl peptidase-4 activity is not counteracted by optimized glucose control in type 2 diabetes, but is lower in metformin-treated patients. Diabetes Obes Metab 14:518–522CrossRefPubMed

46.

Sell H, Bluher M, Kloting N et al (2013) Adipose dipeptidyl peptidase-4 and obesity: correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro. Diabetes Care 36:4083–4090CrossRefPubMedPubMedCentral

47.

Shirakawa J, Amo K, Ohminami H et al (2011) Protective effects of dipeptidyl peptidase-4 (DPP-4) inhibitor against increased beta cell apoptosis induced by dietary sucrose and linoleic acid in mice with diabetes. J Biol Chem 286:25467–25476CrossRefPubMedPubMedCentral

48.

Shirakawa J, Okuyama T, Kyohara M et al (2016) DPP-4 inhibition improves early mortality, β cell function, and adipose tissue inflammation in db/db mice fed a diet containing sucrose and linoleic acid. Diabetol Metab Syndr 8:16CrossRefPubMedPubMedCentral

49.

He LM, Sartori DJ, Teta M et al (2009) Cyclin D2 protein stability is regulated in pancreatic β-cells. Mol Endocrinol 23:1865–1875CrossRefPubMedPubMedCentral

50.

Susaki E, Nakayama K, Nakayama KI (2007) Cyclin D2 translocates p27 out of the nucleus and promotes its degradation at the G0-G1 transition. Mol Cell Biol 27:4626–4640CrossRefPubMedPubMedCentral

Titel: GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice
verfasst von: Dan Kawamori
Jun Shirakawa
Chong Wee Liew
Jiang Hu
Tomoaki Morioka
Alokesh Duttaroy
Bryan Burkey
Rohit N. Kulkarni
Publikationsdatum: 20.05.2017
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 8/2017
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-017-4303-6

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GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice

Abstract

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Methods

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Abstract

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Conclusions/interpretation

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