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Diabetologia
Published in: Diabetologia 2/2011

01-02-2011 | Article

Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells

Authors: B. Roger, J. Papin, P. Vacher, M. Raoux, A. Mulot, M. Dubois, J. Kerr-Conte, B. H. Voy, F. Pattou, G. Charpentier, J.-C. Jonas, N. Moustaïd-Moussa, J. Lang

Published in: Diabetologia | Issue 2/2011

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Abstract

Aims/hypothesis

Glucose and incretins regulate beta cell function, gene expression and insulin exocytosis via calcium and cAMP. Prolonged exposure to elevated glucose (also termed glucotoxicity) disturbs calcium homeostasis, but little is known about cAMP signalling. We therefore investigated long-term effects of glucose on this pathway with special regard to the incretin glucagon-like peptide 1 (GLP-1).

Methods

We exposed INS-1E cells and rat or human islets to different levels of glucose for 3 days and determined functional responses in terms of second messengers (cAMP, Ca2+), transcription profiles, activation of cAMP-responsive element (CRE) and secretion by measuring membrane capacitance. Moreover, we modulated directly the abundance of a calcium-sensitive adenylyl cyclase (ADCY8) and GLP-1 receptor (GLP1R).

Results

GLP-1- or forskolin-mediated increases in cytosolic calcium, cAMP-levels or insulin secretion were largely reduced in INS-1E cells cultured at elevated glucose (>5.5 mmol/l). Statistical analysis of transcription profiles identified cAMP pathways as major targets regulated by glucose. Quantitative PCR confirmed these findings and unravelled marked downregulation of the calcium-sensitive adenylyl cyclase ADCY8 also in rat and in human islets. Re-expression of ADCY8, but not of the GLP1R, recovered GLP-1 signalling in glucotoxicity in INS-1E cells and in rat islets. Moreover, knockdown of this adenylyl cyclase showed that GLP-1-induced cAMP generation, calcium signalling, activation of the downstream target CRE and direct amplification of exocytosis by cAMP-raising agents (evaluated by capacitance measurement) proceeds via ADCY8.

Conclusions/interpretation

cAMP-mediated pathways are modelled by glucose, and downregulation of the calcium-sensitive ADCY8 plays a central role herein, including signalling via the GLP1R.
Appendix
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Literature
1.
MacDonald PE, Rorsman P (2007) The ins and outs of secretion from pancreatic beta-cells: control of single-vesicle exo- and endocytosis. Physiology (Bethesda) 22:113–121
2.
Unger RH, Grundy S (1985) Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia 28:119–121CrossRefPubMed
3.
Poitout V, Robertson RP (2008) Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 29:351–366CrossRefPubMed
4.
Hojberg PV, Vilsboll T, Rabol R et al (2009) Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes. Diabetologia 52:199–207CrossRefPubMed
5.
Knop FK, Vilsboll T, Hojberg PV et al (2007) Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes 56:1951–1959CrossRefPubMed
6.
7.
Buteau J, Foisy S, Joly E, Prentki M (2003) Glucagon-like peptide 1 induces pancreatic beta-cell proliferation via transactivation of the epidermal growth factor receptor. Diabetes 52:124–132CrossRefPubMed
8.
MacDonald PE, Wang X, Xia F et al (2003) Antagonism of rat beta-cell voltage-dependent K+ currents by exendin 4 requires dual activation of the cAMP/protein kinase A and phosphatidylinositol 3-kinase signaling pathways. J Biol Chem 278:52446–52453CrossRefPubMed
9.
Holz GG, Kang G, Harbeck M, Roe MW, Chepurny OG (2006) Cell physiology of cAMP sensor Epac. J Physiol 577:5–15CrossRefPubMed
10.
Gromada J, Dissing S, Bokvist K et al (1995) Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting beta TC3-cells by enhancement of intracellular calcium mobilization. Diabetes 44:767–774CrossRefPubMed
11.
Tsuboi T, da Silva XG, Holz GG, Jouaville LS, Thomas AP, Rutter GA (2003) Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells. Biochem J 369:287–299CrossRefPubMed
12.
Lang J (1999) Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion. Eur J Biochem 259:3–17CrossRefPubMed
13.
Henquin JC (2009) Regulation of insulin secretion: a matter of phase control and amplitude modulation. Diabetologia 52:739–751CrossRefPubMed
14.
Kim SJ, Nian C, Widenmaier S, McIntosh CH (2008) Glucose-dependent insulinotropic polypeptide-mediated up-regulation of beta-cell antiapoptotic Bcl-2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2. Mol Cell Biol 28:1644–1656CrossRefPubMed
15.
Khaldi MZ, Guiot Y, Gilon P, Henquin JC, Jonas JC (2004) Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose. Am J Physiol Endocrinol Metab 287:E207–E217CrossRefPubMed
16.
Dubois M, Vacher P, Roger B et al (2007) Glucotoxicity inhibits late steps of insulin exocytosis. Endocrinology 148:1605–1614CrossRefPubMed
17.
Lajus S, Vacher P, Huber D et al (2006) Alpha-latrotoxin induces exocytosis by inhibition of voltage-dependent K+ channels and by stimulation of L-type Ca2+ channels via latrophilin in beta-cells. J Biol Chem 281:5522–5531CrossRefPubMed
18.
Dubois M, Kerr-Conte J, Gmyr V et al (2004) Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration. Diabetologia 47:463–469CrossRefPubMed
19.
Bensellam M, van Lommel L, Overbergh L, Schuit FC, Jonas JC (2009) Cluster analysis of rat pancreatic islet gene mRNA levels after culture in low-, intermediate- and high-glucose concentrations. Diabetologia 52:463–476CrossRefPubMed
20.
Patton C, Thompson S, Epel D (2004) Some precautions in using chelators to buffer metals in biological solutions. Cell Calcium 35:427–431CrossRefPubMed
21.
Dyachok O, Idevall-Hagren O, Sagetorp J et al (2008) Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion. Cell Metab 8:26–37CrossRefPubMed
22.
Siegel EG, Wollheim CB, Kikuchi M, Renold AE, Sharp GW (1980) Dependency of cyclic AMP-induced insulin release on intra- and extracellular calcium in rat islets of Langerhans. J Clin Invest 65:233–241CrossRefPubMed
23.
Roche E, Assimacopoulos-Jeannet F, Witters LA et al (1997) Induction by glucose of genes coding for glycolytic enzymes in a pancreatic beta-cell line (INS-1). J Biol Chem 272:3091–3098CrossRefPubMed
24.
Regard JB, Kataoka H, Cano DA et al (2007) Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest 117:4034–4043PubMed
25.
Abderrahmani A, Cheviet S, Ferdaoussi M, Coppola T, Waeber G, Regazzi R (2006) ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis. EMBO J 25:977–986CrossRefPubMed
26.
Tsuboi T, Ravier MA, Parton LE, Rutter GA (2006) Sustained exposure to high glucose concentrations modifies glucose signaling and the mechanics of secretory vesicle fusion in primary rat pancreatic beta-cells. Diabetes 55:1057–1065CrossRefPubMed
27.
Olofsson CS, Collins S, Bengtsson M et al (2007) Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane. Diabetes 56:1888–1897CrossRefPubMed
28.
Renstrom E, Eliasson L, Rorsman P (1997) Protein kinase A-dependent and -independent stimulation of exocytosis by cAMP in mouse pancreatic B cells. J Physiol 502(Pt 1):105–118CrossRefPubMed
29.
Delmeire D, Flamez D, Hinke SA, Cali JJ, Pipeleers D, Schuit F (2003) Type VIII adenylyl cyclase in rat beta cells: coincidence signal detector/generator for glucose and GLP-1. Diabetologia 46:1383–1393CrossRefPubMed
30.
Fridlyand LE, Harbeck MC, Roe MW, Philipson LH (2007) Regulation of cAMP dynamics by Ca2+ and G protein-coupled receptors in the pancreatic beta-cell: a computational approach. Am J Physiol Cell Physiol 293:C1924–C1933CrossRefPubMed
31.
Waddleton D, Wu W, Feng Y et al (2008) Phosphodiesterase 3 and 4 comprise the major cAMP metabolizing enzymes responsible for insulin secretion in INS-1 (832/13) cells and rat islets. Biochem Pharmacol 76:884–893CrossRefPubMed
32.
Choi YH, Park S, Hockman S et al (2006) Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice. J Clin Invest 116:3240–3251CrossRefPubMed
33.
Kutlu B, Burdick D, Baxter D et al (2009) Detailed transcriptome atlas of the pancreatic b-cell. BMC Med Genomics 2:3CrossRefPubMed
34.
Willoughby D, Cooper DM (2007) Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol Rev 87:965–1010CrossRefPubMed
35.
Masada N, Ciruela A, MacDougall DA, Cooper DMF (2009) Distinct mechanisms of regulation by Ca2+/calmodulin of type 1 and 8 adenylyl cyclases support their different physiological roles. J Biol Chem 284:4451–4463CrossRefPubMed
36.
Takeshita S, Moritani M, Kunika K, Inoue H, Itakura M (2006) Diabetic modifier QTLs identified in F2 intercrosses between Akita and A/J mice. Mamm Genome 17:927–940CrossRefPubMed
37.
de Mooij-van Malsen AJ, van Lith HA, Oppelaar H et al (2009) Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder. Biol Psychiatry 66:1123–1130CrossRefPubMed
38.
Xu G, Kaneto H, Laybutt DR et al (2007) Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes. Diabetes 56:1551–1558CrossRefPubMed
39.
Zhou J, Livak MF, Bernier M et al (2007) Ubiquitination is involved in glucose-mediated downregulation of GIP receptors in islets. Am J Physiol Endocrinol Metab 293:E538–E547CrossRefPubMed
40.
Briaud I, Lingohr MK, Dickson LM, Wrede CE, Rhodes CJ (2003) Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells. Diabetes 52:974–983CrossRefPubMed
41.
Costes S, Broca C, Bertrand G et al (2006) ERK1/2 control phosphorylation and protein level of cAMP-responsive element-binding protein: a key role in glucose-mediated pancreatic beta-cell survival. Diabetes 55:2220–2230CrossRefPubMed
42.
Klinger S, Poussin C, Debril MB, Dolci W, Halban PA, Thorens B (2008) Increasing GLP-1-induced beta-cell proliferation by silencing the negative regulators of signaling cAMP response element modulator-alpha and DUSP14. Diabetes 57:584–593CrossRefPubMed
43.
Jansson D, Ng AC, Fu A, Depatie C, Al Azzabi M, Screaton RA (2008) Glucose controls CREB activity in islet cells via regulated phosphorylation of TORC2. Proc Natl Acad Sci U S A 105:10161–10166CrossRefPubMed
44.
Inada A, Hamamoto Y, Tsuura Y et al (2004) Overexpression of inducible cyclic AMP early repressor inhibits transactivation of genes and cell proliferation in pancreatic beta cells. Mol Cell Biol 24:2831–2841CrossRefPubMed
45.
Faruque OM, Le-Nguyen D, Lajoix AD et al (2009) Cell-permeable peptide-based disruption of endogenous PKA-AKAP complexes: a tool for studying the molecular roles of AKAP-mediated PKA subcellular anchoring. Am J Physiol Cell Physiol 296:C306–C316CrossRefPubMed
46.
Ramos LS, Zippin JH, Kamenetsky M, Buck J, Levin LR (2008) Glucose and GLP-1 stimulate cAMP production via distinct adenylyl cyclases in INS-1E insulinoma cells. J Gen Physiol 132:329–338CrossRefPubMed
47.
Moulder KL, Jiang X, Chang C et al (2008) A specific role for Ca2+-dependent adenylyl cyclases in recovery from adaptive presynaptic silencing. J Neurosci 28:5159–5168CrossRefPubMed
48.
Saxena R, Hivert MF, Langenberg C et al (2010) Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42:142–148CrossRefPubMed
49.
Dupuis J, Langenberg C, Prokopenko I et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105–116CrossRefPubMed
50.
Rosengren AH, Jokubka R, Tojjar D et al (2010) Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 327:217–220CrossRefPubMed
Metadata
Title
Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells
Authors
B. Roger
J. Papin
P. Vacher
M. Raoux
A. Mulot
M. Dubois
J. Kerr-Conte
B. H. Voy
F. Pattou
G. Charpentier
J.-C. Jonas
N. Moustaïd-Moussa
J. Lang
Publication date
01-02-2011
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 2/2011
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-010-1955-x

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