Role of the cAMP Pathway in Glucose and Lipid Metabolism

  • Kim Ravnskjaer
  • Anila Madiraju
  • Marc MontminyEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 233)


3′–5′-Cyclic adenosine monophosphate (cyclic AMP or cAMP) was first described in 1957 as an intracellular second messenger mediating the effects of glucagon and epinephrine on hepatic glycogenolysis (Berthet et al., J Biol Chem 224(1):463–475, 1957). Since this initial characterization, cAMP has been firmly established as a versatile molecular signal involved in both central and peripheral regulation of energy homeostasis and nutrient partitioning. Many of these effects appear to be mediated at the transcriptional level, in part through the activation of the transcription factor CREB and its coactivators. Here we review current understanding of the mechanisms by which the cAMP signaling pathway triggers metabolic programs in insulin-responsive tissues.


CBP (CREB Binding Protein) CREB (cAMP Response Element Binding protein) CRTC (cAMP Regulated Transcriptional Coactivator) 


  1. Acin-Perez R et al (2009) Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab 9(3):265–276PubMedPubMedCentralCrossRefGoogle Scholar
  2. Adler ES et al (2012) Neurochemical characterization and sexual dimorphism of projections from the brain to abdominal and subcutaneous white adipose tissue in the rat. J Neurosci 32(45):15913–15921PubMedCrossRefGoogle Scholar
  3. Ahmad F et al (2009) Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta3-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes. Biochem J 424(3):399–410PubMedPubMedCentralCrossRefGoogle Scholar
  4. Ahn S et al (1998) A dominant-negative inhibitor of CREB reveals that it is a general mediator stimulus-dependent transcription of c-fos. Mol Cell Biol 18:967–977PubMedPubMedCentralCrossRefGoogle Scholar
  5. Altarejos JY, Montminy M (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12(3):141–151PubMedPubMedCentralCrossRefGoogle Scholar
  6. Ammälä C, Ashcroft F, Rorsman P (1993) Calcium-independent potentiation of insulin release by cyclic AMP in single beta-cells. Nature 363(6427):356–358PubMedCrossRefGoogle Scholar
  7. Anthonsen MW et al (1998) Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. J Biol Chem 273(1):215–221PubMedCrossRefGoogle Scholar
  8. Arner P et al (1990) Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clin Invest 85(3):893–898PubMedPubMedCentralCrossRefGoogle Scholar
  9. Arrojo E, Drigo R, Fonseca TL, Werneck-de-Castro JP, Bianco AC (2013) Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochim Biophys Acta 1830(7):3956–3964CrossRefGoogle Scholar
  10. Artner I, Hang Y, Mazur M, Yamamoto T, Guo M, Lindner J, Magnuson MA, Stein R (2010) MafA and MafB regulate genes critical to beta-cells in a unique temporal manner. Diabetes 59(10):2530–2539PubMedPubMedCentralCrossRefGoogle Scholar
  11. Barroso I, Benito B, Garcí-Jiménez C, Hernández A, Obregón MJ, Santisteban P (1999) Norepinephrine, tri-iodothyronine and insulin upregulate glyceraldehyde-3-phosphate dehydrogenase mRNA during Brown adipocyte differentiation. Eur J Endocrinol 141(2):169–179PubMedCrossRefGoogle Scholar
  12. Basit A, Hydrie M, Hakeem R, Ahmedani MY, Masood Q (2004) Frequency of chronic complications of type II diabetes. J Coll Physicians Surg Pak 14:79–83PubMedGoogle Scholar
  13. Ber I, Shternhall K, Perl S, Ohanuna Z, Goldberg I, Barshack I, Benvenisti-Zarum L, Meivar-Levy I, Ferber S (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. J Biol Chem 278(34):31950–31957PubMedCrossRefGoogle Scholar
  14. Berthet J, Rall TW, Sutherland EW (1957) The relationship of epinephrine and glucagon to liver phosphorylase. IV. Effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. J Biol Chem 224(1):463–475PubMedGoogle Scholar
  15. Birsoy K, Chen Z, Friedman J (2008) Transcriptional regulation of adipogenesis by KLF4. Cell Metab 7(4):339–347PubMedPubMedCentralCrossRefGoogle Scholar
  16. Blanchet E, Van de Velde S, Matsumura S, Hao E, LeLay J, Kaestner K, Montminy M (2015) Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Rep 10:1149–1157PubMedCrossRefGoogle Scholar
  17. Bogacka I, Ukropcova B, McNeil M, Gimble JM, Smith SR (2005) Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab 90(12):6650–6656PubMedCrossRefGoogle Scholar
  18. Borboni P, Porzio O, Pierucci D, Cicconi S, Magnaterra R, Federici M, Sesti G, Lauro D, D’Agata V, Cavallaro S, Marlier LN (1999) Molecular and functional characterization of pituitary adenylate cyclase-activating polypeptide (PACAP-38)/vasoactive intestinal polypeptide receptors in pancreatic beta-cells and effects of PACAP-38 on components of the insulin secretory system. Endocrinology 140(12):5530–5537PubMedGoogle Scholar
  19. Boyda HN et al (2013) Peripheral adrenoceptors: the impetus behind glucose dysregulation and insulin resistance. J Neuroendocrinol 25(3):217–228PubMedCrossRefGoogle Scholar
  20. Brasaemle DL et al (2009) Perilipin A and the control of triacylglycerol metabolism. Mol Cell Biochem 326(1–2):15–21PubMedCrossRefGoogle Scholar
  21. Brown MS, Goldstein J (2008) Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 7:95–96PubMedCrossRefGoogle Scholar
  22. Buck J et al (1999) Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. Proc Natl Acad Sci U S A 96(1):79–84PubMedPubMedCentralCrossRefGoogle Scholar
  23. Cairns SP, Dulhunty A (1993) Beta-adrenergic potentiation of E-C coupling increases force in rat skeletal muscle. Muscle Nerve 16:1317–1325PubMedCrossRefGoogle Scholar
  24. Cameron IL, Smith RE (1964) Cytological responses of brown fat tissue in cold-exposed rats. J Cell Biol 23:89–100PubMedPubMedCentralCrossRefGoogle Scholar
  25. Cannon B, Hedin A, Nedergaard J (1982) Exclusive occurrence of thermogenin antigen in brown adipose tissue. FEBS Lett 150(1):129–132PubMedCrossRefGoogle Scholar
  26. Centers for Disease Control and Prevention (2015) Diabetes public health resource. Accessed June 2015
  27. Chen J et al (1995) A region of adenylyl cyclase 2 critical for regulation by G protein beta gamma subunits. Science 268(5214):1166–1169PubMedCrossRefGoogle Scholar
  28. Chen M, Feng H, Gupta D, Kelleher J, Dickerson KE, Wang J, Hunt D, Jou W, Gavrilova O, Jin JP, Weinstein LS (2009) G(s)alpha deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency. Am J Physiol Cell Physiol 296(4):C930–C940PubMedPubMedCentralCrossRefGoogle Scholar
  29. Chen M et al (2010) G(s)alpha deficiency in adipose tissue leads to a lean phenotype with divergent effects on cold tolerance and diet-induced thermogenesis. Cell Metab 11(4):320–330PubMedPubMedCentralCrossRefGoogle Scholar
  30. Choi YH et al (2006) Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice. J Clin Invest 116(12):3240–3251PubMedPubMedCentralCrossRefGoogle Scholar
  31. Chrivia JC et al (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365(6449):855–859PubMedCrossRefGoogle Scholar
  32. Clausen T (2003) Na + −K+ pump regulation and skeletal muscle contractility. Physiol Rev 83(4):1269–1324PubMedCrossRefGoogle Scholar
  33. Coppack SW, Jensen M, Miles JM (1994) In vivo regulation of lipolysis in humans. J Lipid Res 35(2):177–193PubMedGoogle Scholar
  34. Costes S, Vandewalle B, Tourrel-Cuzin C, Broca C, Linck N, Bertrand G, Kerr-Conte J, Portha B, Pattou F, Bockaert J, Dalle S (2009) Degradation of cAMP-responsive element-binding protein by the ubiquitin-proteasome pathway contributes to glucotoxicity in beta-cells and human pancreatic islets. Diabetes 58:1105–1115PubMedPubMedCentralCrossRefGoogle Scholar
  35. Cummings DE et al (1996) Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature 382(6592):622–626PubMedCrossRefGoogle Scholar
  36. Cypess AM et al (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360(15):1509–1517PubMedPubMedCentralCrossRefGoogle Scholar
  37. Dai XQ, Spigelman A, Khan S, Braun M, Manning Fox JE, MacDonald PE (2014) SUMO1 enhances cAMP-dependent exocytosis and glucagon secretion from pancreatic α-cells. J Physiol 592(Pt 17):3715–3726PubMedPubMedCentralCrossRefGoogle Scholar
  38. Dalle S, Quoyer J, Varin E, Costes S (2011) Roles and regulation of the transcription factor CREB in pancreatic β-cells. Curr Mol Pharmacol 4:187–195PubMedCrossRefGoogle Scholar
  39. de Jesus LA et al (2001) The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest 108(9):1379–1385PubMedPubMedCentralCrossRefGoogle Scholar
  40. de Rooij J et al (1998) Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396(6710):474–477PubMedCrossRefGoogle Scholar
  41. Defer N, Best-Belpomme M, Hanoune J (2000) Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol Renal Physiol 279(3):F400–F416PubMedGoogle Scholar
  42. Dempersmier J, Sambeat A, Gulyaeva O, Paul SM, Hudak CS, Raposo HF, Kwan HY, Kang C, Wong RH, Sul HS (2015) Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat. Mol Cell 57(2):235–246PubMedPubMedCentralCrossRefGoogle Scholar
  43. Dessauer CW (2009) Adenylyl cyclase--A-kinase anchoring protein complexes: the next dimension in cAMP signaling. Mol Pharmacol 76(5):935–941PubMedPubMedCentralCrossRefGoogle Scholar
  44. Di Benedetto G et al (2008) Protein kinase A type I and type II define distinct intracellular signaling compartments. Circ Res 103(8):836–844PubMedCrossRefGoogle Scholar
  45. DiFrancesco D, Tortora P (1991) Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351(6322):145–147PubMedCrossRefGoogle Scholar
  46. Ding WG, Gromada J (1997) Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide. Diabetes 46(4):615–621PubMedCrossRefGoogle Scholar
  47. Ding WG, Renström E, Rorsman P, Buschard K, Gromada J (1997) Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2 + −induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. Diabetes 46(5):792–800PubMedCrossRefGoogle Scholar
  48. Dodt C et al (1999) Intraneural stimulation elicits an increase in subcutaneous interstitial glycerol levels in humans. J Physiol 521(Pt 2):545–552PubMedPubMedCentralCrossRefGoogle Scholar
  49. Dowse GK, Qin H, Collins VR, Zimmet PZ, Alberti KG, Gareeboo H (1990) Determinants of estimated insulin resistance and beta-cell function in Indian, Creole and Chinese Mauritians. The Mauritius NCD Study Group. Diabetes Res Clin Pract 10:265–279PubMedCrossRefGoogle Scholar
  50. Eberhard CE, Fu A, Reeks C, Screaton RA (2013) CRTC2 is required for β-cell function and proliferation. Endocrinology 154:2308–2317PubMedCrossRefGoogle Scholar
  51. Eckert B, Schwaninger M, Knepel W (1996) Calcium-mobilizing insulin secretagogues stimulate transcription that is directed by the cyclic adenosine 3′,5′-monophosphate/calcium response element in a pancreatic islet beta-cell line. Endocrinology 137:225–233PubMedGoogle Scholar
  52. Eckner R et al (1994) Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev 8(8):869–884PubMedCrossRefGoogle Scholar
  53. Ehses JA, Casilla V, Doty T, Pospisilik JA, Winter KD, Demuth HU, Pederson RA, McIntosh CH (2003) Glucose-dependent insulinotropic polypeptide promotes beta-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase. Endocrinology 144(10):4433–4445PubMedCrossRefGoogle Scholar
  54. Elliott AD, Ustione A, Piston DW (2015) Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP. Am J Physiol Endocrinol Metab 308(2):E130–E143PubMedPubMedCentralCrossRefGoogle Scholar
  55. El-Maghrabi MR, Claus T, Pilkis J, Pilkis SJ (1982) Regulation of 6-phosphfructo-2-kinase activity by cyclic AMP-dependent phosphorylation. Proc Natl Acad Sci U S A 79:315–319PubMedPubMedCentralCrossRefGoogle Scholar
  56. Enerback S et al (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387(6628):90–94PubMedCrossRefGoogle Scholar
  57. Ezrailson EG, Entman M, Garber AJ (1983) Adrenergic and serotonergic regulation of skeletal muscle metabolism in rat. I. The effects of adrenergic and serotonergic antagonists on the regulation of muscle amino acid release, glycogenolysis, and cyclic nucleotide levels. J Biol Chem 258(20):12494–12498PubMedGoogle Scholar
  58. Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151(2):400–413PubMedPubMedCentralCrossRefGoogle Scholar
  59. Fox KE et al (2006) Depletion of cAMP-response element-binding protein/ATF1 inhibits adipogenic conversion of 3T3-L1 cells ectopically expressing CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBP beta, or PPAR gamma 2. J Biol Chem 281(52):40341–40353PubMedCrossRefGoogle Scholar
  60. Francis SH, Blount MA, Corbin JD (2011) Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 91(2):651–690PubMedCrossRefGoogle Scholar
  61. Frayn KN (2002) Adipose tissue as a buffer for daily lipid flux. Diabetologia 45(9):1201–1210PubMedCrossRefGoogle Scholar
  62. Froese A et al (2012) Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. J Clin Invest 122(3):1119–1130PubMedPubMedCentralCrossRefGoogle Scholar
  63. Furman B, Ong W, Pyne NJ (2010) Cyclic AMP signaling in pancreatic islets. Adv Exp Med Biol 654:281–304PubMedCrossRefGoogle Scholar
  64. Gao T, McKenna B, Li C, Reichert M, Nguyen J, Singh T, Yang C, Pannikar A, Doliba N, Zhang T, Stoffers DA, Edlund H, Matschinsky F, Stein R, Stanger BZ (2014) Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab 19(2):259–271PubMedPubMedCentralCrossRefGoogle Scholar
  65. George M, Ayuso E, Casellas A, Costa C, Devedjian JC, Bosch F (2002) Beta cell expression of IGF-I leads to recovery from type 1 diabetes. J Clin Invest 109:1153–1163PubMedPubMedCentralCrossRefGoogle Scholar
  66. Gerhardstein BL, Puri T, Chien AJ, Hosey MM (1999) Identification of the sites phosphorylated by cyclic AMP-dependent protein kinase on the beta 2 subunit of L-type voltage-dependent calcium channels. Biochemistry 38(32):10361–10370PubMedCrossRefGoogle Scholar
  67. Gettys TW et al (1987) Short-term feedback regulation of cAMP by accelerated degradation in rat tissues. J Biol Chem 262(1):333–339PubMedGoogle Scholar
  68. Gromada J, Bokvist K, Ding WG, Barg S, Buschard K, Renström E, Rorsman P (1997) Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. J Gen Physiol 110(3):217–228PubMedPubMedCentralCrossRefGoogle Scholar
  69. Guirguis E, Hockman S, Chung YW, Ahmad F, Gavrilova O, Raghavachari N, Yang Y, Niu G, Chen X, Yu ZX, Liu S, Degerman E, Manganiello V (2013) A role for phosphodiesterase 3B in acquisition of brown fat characteristics by white adipose tissue in male mice. Endocrinology 154(9):3152–3167PubMedPubMedCentralCrossRefGoogle Scholar
  70. Gujral UP, Narayan K, Kahn SE, Kanaya AM (2014) The relative associations of β-cell function and insulin sensitivity with glycemic status and incident glycemic progression in migrant Asian Indians in the United States: the MASALA study. J Diabetes Complications 28:45–50PubMedCrossRefGoogle Scholar
  71. Handa N et al (2008) Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP. J Biol Chem 283(28):19657–19664PubMedCrossRefGoogle Scholar
  72. Hang Y, Stein R (2011) MafA and MafB activity in pancreatic β cells. Trends Endocrinol Metab 22(9):364–373PubMedPubMedCentralCrossRefGoogle Scholar
  73. Harcourt LJ, Schertzer J, Ryall JG, Lynch GS (2007) Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue. Neuromuscul Disord 17:47–55PubMedCrossRefGoogle Scholar
  74. Härndahl L, Jing X, Ivarsson R, Degerman E, Ahrén B, Manganiello VC, Renström E, Holst LS (2002) Important role of phosphodiesterase 3B for the stimulatory action of cAMP on pancreatic beta-cell exocytosis and release of insulin. J Biol Chem 277(40):37446–37455PubMedCrossRefGoogle Scholar
  75. Hauge-Evans AC, King A, Carmignac D, Richardson CC, Robinson IC, Low MJ, Christie MR, Persaud SJ, Jones PM (2009) Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58(2):403–411PubMedPubMedCentralCrossRefGoogle Scholar
  76. Hayes JS, Brunton LL, Mayer SE (1980) Selective activation of particulate cAMP-dependent protein kinase by isoproterenol and prostaglandin E1. J Biol Chem 255(11):5113–5119PubMedGoogle Scholar
  77. Heaton GM et al (1978) Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. Eur J Biochem 82(2):515–521PubMedCrossRefGoogle Scholar
  78. Heimann E, Jones H, Resjö S, Manganiello VC, Stenson L, Degerman E (2010) Expression and regulation of cyclic nucleotide phosphodiesterases in human and rat pancreatic islets. PLoS One 5(12):e14191PubMedPubMedCentralCrossRefGoogle Scholar
  79. Henquin JC, Nenquin M (2014) Activators of PKA and Epac distinctly influence insulin secretion and cytosolic Ca2+ in female mouse islets stimulated by glucose and tolbutamide. Endocrinology 155(9):3274–3287PubMedPubMedCentralCrossRefGoogle Scholar
  80. Herzig S et al (2001) CREB regulates hepatic gluconeogenesis via the co-activator PGC-1. Nature 413:179–183PubMedCrossRefGoogle Scholar
  81. Hinkle RT, Lefever F, Dolan ET, Reichart DL, Dietrich JA, Gropp KE, Thacker RI, Demuth JP, Stevens PJ, Qu XA, Varbanov AR, Wang F, Isfort RJ (2007) Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice. BMC Med 5:18PubMedPubMedCentralCrossRefGoogle Scholar
  82. Hollenberg CH, Raben MS, Astwood EB (1961) The lipolytic response to corticotropin. Endocrinology 68:589–598PubMedCrossRefGoogle Scholar
  83. Houslay MD (2010) Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 35(2):91–100PubMedCrossRefGoogle Scholar
  84. 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(4):1444–1455PubMedCrossRefGoogle Scholar
  85. Huttunen P, Hirvonen J, Kinnula V (1981) The occurrence of brown adipose tissue in outdoor workers. Eur J Appl Physiol Occup Physiol 46(4):339–345PubMedCrossRefGoogle Scholar
  86. Insel PA (1996) Seminars in medicine of the Beth Israel Hospital, Boston. Adrenergic receptors – evolving concepts and clinical implications. N Engl J Med 334(9):580–585PubMedCrossRefGoogle Scholar
  87. Ishibashi K, Sasaki S, Akiba T, Marumo F (1993) Expression of bone morphogenic protein 7 mRNA in MDCK cells. Biochem Biophys Res Commun 193(1):235–239PubMedCrossRefGoogle Scholar
  88. Ishihara H, Asano T, Tsukuda K, Katagiri H, Inukai K, Anai M, Kikuchi M, Yazaki Y, Miyazaki J, Oka Y (1994) Overexpression of hexokinase I but not GLUT1 glucose transporter alters concentration dependence of glucose-stimulated insulin secretion in pancreatic beta-cell line MIN6. J Biol Chem 269(4):3081–3087PubMedGoogle Scholar
  89. Islam D, Zhang N, Wang P, Li H, Brubaker PL, Gaisano HY, Wang Q, Jin T (2009) Epac is involved in cAMP-stimulated proglucagon expression and hormone production but not hormone secretion in pancreatic alpha- and intestinal L-cell lines. Am J Physiol Endocrinol Metab 296(1):E174–E181PubMedCrossRefGoogle Scholar
  90. Iwami G et al (1995) Regulation of adenylyl cyclase by protein kinase A. J Biol Chem 270(21):12481–12484PubMedCrossRefGoogle Scholar
  91. Jambal P, Masterson S, Nesterova A, Bouchard R, Bergman B, Hutton JC, Boxer LM, Reusch JE, Pugazhenthi S (2003) Cytokine-mediated down-regulation of the transcription factor cAMP-response element-binding protein in pancreatic beta-cells. J Biol Chem 278:23055–23065PubMedCrossRefGoogle Scholar
  92. Jhala US, Canettieri G, Screaton RA, Kulkarni RN, Krajewski S, Reed J, Walker J, Lin X, White M, Montminy M (2003) cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev 17:1575–1580PubMedPubMedCentralCrossRefGoogle Scholar
  93. Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46:3–19PubMedCrossRefGoogle Scholar
  94. Kai AK, Lam A, Chen Y, Tai AC, Zhang X, Lai AK, Yeung PK, Tam S, Wang J, Lam KS, Vanhoutte PM, Bos JL, Chung SS, Xu A, Chung SK (2013) Exchange protein activated by cAMP 1 (Epac1)-deficient mice develop β-cell dysfunction and metabolic syndrome. FASEB J 27(10):4122–4135PubMedCrossRefGoogle Scholar
  95. Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM (2009) Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 460(7259):1154–1158PubMedPubMedCentralCrossRefGoogle Scholar
  96. Kamenetsky M et al (2006) Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol 362(4):623–639PubMedPubMedCentralCrossRefGoogle Scholar
  97. Kaneto H, Miyatsuka T, Kawamori D, Yamamoto K, Kato K, Shiraiwa T, Katakami N, Yamasaki Y, Matsuhisa M, Matsuoka TA (2008) PDX-1 and MafA play a crucial role in pancreatic beta-cell differentiation and maintenance of mature beta-cell function. Endocr J 55(2):235–252PubMedCrossRefGoogle Scholar
  98. Kang G, Chepurny O, Malester B, Rindler MJ, Rehmann H, Bos JL, Schwede F, Coetzee WA, Holz GG (2006) cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic beta cells and rat INS-1 cells. J Physiol 573(Pt 3):595–609PubMedPubMedCentralCrossRefGoogle Scholar
  99. Kashima Y, Miki T, Shibasaki T, Ozaki N, Miyazaki M, Yano H, Seino S (2001) Critical role of cAMP-GEFII––Rim2 complex in incretin-potentiated insulin secretion. J Biol Chem 276:46046–46053PubMedCrossRefGoogle Scholar
  100. Keravis T, Lugnier C (2010) Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs. Curr Pharm Des 16(9):1114–1125PubMedCrossRefGoogle Scholar
  101. Kim MJ, Kang J, Park YG, Ryu GR, Ko SH, Jeong IK, Koh KH, Rhie DJ, Yoon SH, Hahn SJ, Kim MS, Jo YH (2006) Exendin-4 induction of cyclin D1 expression in INS-1 beta-cells: involvement of cAMP-responsive element. J Endocrinol 188(3):623–633PubMedCrossRefGoogle Scholar
  102. 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(5):1644–1656PubMedPubMedCentralCrossRefGoogle Scholar
  103. Kimple ME, Keller M, Rabaglia MR, Pasker RL, Neuman JC, Truchan NA, Brar HK, Attie AD (2013) Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes 62(6):1904–1912PubMedPubMedCentralCrossRefGoogle Scholar
  104. Kolditz CI, Langin D (2010) Adipose tissue lipolysis. Curr Opin Clin Nutr Metab Care 13(4):377–381PubMedCrossRefGoogle Scholar
  105. Kong X, Banks A, Liu T, Kazak L, Rao RR, Cohen P, Wang X, Yu S, Lo JC, Tseng YH, Cypess AM, Xue R, Kleiner S, Kang S, Spiegelman BM, Rosen ED (2014) IRF4 is a key thermogenic transcriptional partner of PGC-1α. Cell 158(1):69–83PubMedPubMedCentralCrossRefGoogle Scholar
  106. Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, Takemori H, Montminy M (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437(7062):1109–1111PubMedCrossRefGoogle Scholar
  107. Leiser M, Fleischer N (1996) cAMP-dependent phosphorylation of the cardiac-type alpha 1 subunit of the voltage-dependent Ca2+ channel in a murine pancreatic beta-cell line. Diabetes 45(10):1412–1418PubMedCrossRefGoogle Scholar
  108. Lidell ME et al (2013) Evidence for two types of brown adipose tissue in humans. Nat Med 19(5):631–634PubMedCrossRefGoogle Scholar
  109. Light PE, Manning Fox J, Riedel MJ, Wheeler MB (2002) Glucagon-like peptide-1 inhibits pancreatic ATP-sensitive potassium channels via a protein kinase A- and ADP-dependent mechanism. Mol Endocrinol 16(9):2135–2144PubMedCrossRefGoogle Scholar
  110. Lin B, Morris D, Chou JY (1997) The role of HNF1alpha, HNF3gamma, and cyclic AMP in glucose-6-phosphatase gene activation. Biochemistry 36(46):14096–14106PubMedCrossRefGoogle Scholar
  111. Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates J 3rd, Olefsky J, Guarente L, Montminy M (2008) A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456(7219):269–273PubMedPubMedCentralCrossRefGoogle Scholar
  112. Love JA, Richards N, Owyang C, Dawson DC (1998) Muscarinic modulation of voltage-dependent Ca2+ channels in insulin-secreting HIT-T15 cells. Am J Physiol 274(2 Pt 1):G397–G405PubMedGoogle Scholar
  113. Maltin CA, Hay S, Delday MI, Lobley GE, Reeds PJ (1989) The action of the beta-agonist clenbuterol on protein metabolism in innervated and denervated phasic muscles. Biochem J 261:965–971PubMedPubMedCentralCrossRefGoogle Scholar
  114. Mattsson CL, Csikasz R, Chernogubova E, Yamamoto DL, Hogberg HT, Amri EZ, Hutchinson DS, Bengtsson T (2011) β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor-knockout mice via nonshivering thermogenesis. Am J Physiol Endocrinol Metab 301(6):E1108–E1118PubMedCrossRefGoogle Scholar
  115. McKinnon CM, Docherty K (2001) Pancreatic duodenal homeobox-1, PDX-1, a major regulator of beta cell identity and function. Diabetologia 44(10):1203–1214PubMedCrossRefGoogle Scholar
  116. Metz SA (1988) Epinephrine impairs insulin release by a mechanism distal to calcium mobilization. Similarity to lipoxygenase inhibitors. Diabetes 37(1):65–73PubMedCrossRefGoogle Scholar
  117. Monroe MB et al (2001) Direct evidence for tonic sympathetic support of resting metabolic rate in healthy adult humans. Am J Physiol Endocrinol Metab 280(5):E740–E744PubMedGoogle Scholar
  118. Morgan DG, Kulkarni R, Hurley JD, Wang ZL, Wang RM, Ghatei MA, Karlsen AE, Bloom SR, Smith DM (1998) Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells. Diabetologia 41(12):1482–1491PubMedCrossRefGoogle Scholar
  119. Mullur R, Liu Y, Brent GA (2014) Thyroid hormone regulation of metabolism. Physiol Rev 94(2):355–382PubMedPubMedCentralCrossRefGoogle Scholar
  120. Murakami T, Nishiyama T, Shirotani T, Shinohara Y, Kan M, Ishii K, Kanai F, Nakazuru S, Ebina Y (1992) Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes. J Biol Chem 267:9300–9306PubMedGoogle Scholar
  121. Niehof M, Manns MP, Trautwein C (1997) CREB controls LAP/C/EBP beta transcription. Mol Cell Biol 17(7):3600–3613PubMedPubMedCentralCrossRefGoogle Scholar
  122. Nishizawa Y, Bray GA (1978) Ventromedial hypothalamic lesions and the mobilization of fatty acids. J Clin Invest 61(3):714–721PubMedPubMedCentralCrossRefGoogle Scholar
  123. Niwa T, Matsukawa Y, Senda T, Nimura Y, Hidaka H, Niki I (1998) Acetylcholine activates intracellular movement of insulin granules in pancreatic beta-cells via inositol trisphosphate-dependent [correction of triphosphate-dependent] mobilization of intracellular Ca2+. Diabetes 47(11):1699–1706PubMedCrossRefGoogle Scholar
  124. Offield MF, Jetton T, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CV (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122(3):983–995PubMedGoogle Scholar
  125. Okla M, Ha J, Temel RE, Chung S (2015) BMP7 drives human adipogenic stem cells into metabolically active beige adipocytes. Lipids 50(2):111–120PubMedPubMedCentralCrossRefGoogle Scholar
  126. Olefsky JM (1977) Insensitivity of large rat adipocytes to the antilipolytic effects of insulin. J Lipid Res 18(4):459–464PubMedGoogle Scholar
  127. Pagnon J et al (2012) Identification and functional characterization of protein kinase A phosphorylation sites in the major lipolytic protein, adipose triglyceride lipase. Endocrinology 153(9):4278–4289PubMedCrossRefGoogle Scholar
  128. Park BO, Ahrends R, Teruel MN (2012) Consecutive positive feedback loops create a bistable switch that controls preadipocyte-to-adipocyte conversion. Cell Rep 2(4):976–990PubMedCrossRefGoogle Scholar
  129. Perfetti R, Zhou J, Doyle ME, Egan JM (2000) Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 141(12):4600–4605PubMedCrossRefGoogle Scholar
  130. Petersen RK et al (2008) Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes. Mol Cell Biol 28(11):3804–3816PubMedPubMedCentralCrossRefGoogle Scholar
  131. Poitout V, Robertson R (2008) Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 29:351–366PubMedPubMedCentralCrossRefGoogle Scholar
  132. Puddu A, Sanguineti R, Montecucco F, Viviani GL (2015) Effects of high glucose levels and glycated serum on GIP responsiveness in the pancreatic beta cell line HIT-T15. J Diabetes Res 2015:326359PubMedPubMedCentralCrossRefGoogle Scholar
  133. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92(6):829–839PubMedCrossRefGoogle Scholar
  134. Purwana I, Zheng J, Li X, Deurloo M, Son DO, Zhang Z, Liang C, Shen E, Tadkase A, Feng ZP, Li Y, Hasilo C, Paraskevas S, Bortell R, Greiner DL, Atkinson M, Prud’homme GJ, Wang Q (2014) GABA promotes human β-cell proliferation and modulates glucose homeostasis. Diabetes 63:4197–4205PubMedCrossRefGoogle Scholar
  135. Quinn PG, Granner DK (1990) Cyclic AMP-dependent protein kinase regulates transcription of the phosphoenolpyruvate carboxykinase gene but not binding of nuclear factors to the cyclic AMP regulatory element. Mol Cell Biol 10:3357–3364PubMedPubMedCentralCrossRefGoogle Scholar
  136. Richards CS, Yokoyama M, Furuya E, Uyeda K (1982) Reciprocal changes in fructose-2,6-bisphosphate, 2-kinase and fructose-2,6-bisphosphatase activity in response to glucagon and epinephrine. Biochem Biophys Res Commun 104:1073–1079PubMedCrossRefGoogle Scholar
  137. Richelsen B, Pedersen O (1985) Beta-adrenergic regulation of prostaglandin E2 receptors in human and rat adipocytes. Endocrinology 116(3):1182–1188PubMedCrossRefGoogle Scholar
  138. Rim JS, Kozak L (2002) Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene. J Biol Chem 277(37):34589–34600PubMedCrossRefGoogle Scholar
  139. Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156(1–2):20–44PubMedPubMedCentralCrossRefGoogle Scholar
  140. Russell TR, Ho R (1976) Conversion of 3T3 fibroblasts into adipose cells: triggering of differentiation by prostaglandin F2alpha and 1-methyl-3-isobutyl xanthine. Proc Natl Acad Sci U S A 73(12):4516–4520PubMedPubMedCentralCrossRefGoogle Scholar
  141. Ryall JG, Schertzer J, Alabakis TM, Gehrig SM, Plant DR, Lynch GS (2008) Intramuscular beta2-agonist administration enhances early regeneration and functional repair in rat skeletal muscle after myotoxic injury. J Appl Physiol 105:165–172PubMedCrossRefGoogle Scholar
  142. Saida K, Van Breemen C (1984) Cyclic AMP modulation of adrenoreceptor-mediated arterial smooth muscle contraction. J Gen Physiol 84(2):307–318PubMedCrossRefGoogle Scholar
  143. Screaton RA, Conkright M, Katoh Y, Best JL, Canettieri G, Jeffries S, Guzman E, Niessen S, Yates JR 3rd, Takemori H, Okamoto M, Montminy M (2004) The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119:61–74PubMedCrossRefGoogle Scholar
  144. Sculptoreanu A, Scheuer T, Catterall WA (1993) Voltage-dependent potentiation of L-type Ca2+ channels due to phosphorylation by cAMP-dependent protein kinase. Nature 364(6434):240–243PubMedCrossRefGoogle Scholar
  145. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6(1):38–54PubMedPubMedCentralCrossRefGoogle Scholar
  146. Seematter G et al (2004) Relationship between stress, inflammation and metabolism. Curr Opin Clin Nutr Metab Care 7(2):169–173PubMedCrossRefGoogle Scholar
  147. Semple RK, Crowley V, Sewter CP, Laudes M, Christodoulides C, Considine RV, Vidal-Puig A, O’Rahilly S (2004) Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord 28(1):176–179PubMedCrossRefGoogle Scholar
  148. Sette C, Iona S, Conti M (1994) The short-term activation of a rolipram-sensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL-5 cells is mediated by a cAMP-dependent phosphorylation. J Biol Chem 269(12):9245–9252PubMedGoogle Scholar
  149. Shimizu Y, Satoh S, Yano H, Minokoshi Y, Cushman SW, Shimazu T (1998) Effects of noradrenaline on the cell-surface glucose transporters in cultured brown adipocytes: novel mechanism for selective activation of GLUT1 glucose transporters. Biochem J 330(Pt 1):397–403PubMedPubMedCentralCrossRefGoogle Scholar
  150. Siersbaek R et al (2014) Molecular architecture of transcription factor hotspots in early adipogenesis. Cell Rep 7(5):1434–1442PubMedCrossRefGoogle Scholar
  151. Silva JE (2006) Thermogenic mechanisms and their hormonal regulation. Physiol Rev 86(2):435–464PubMedCrossRefGoogle Scholar
  152. Silva JE, Larsen PR (1983) Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature 305(5936):712–713PubMedCrossRefGoogle Scholar
  153. Sinnarajah S et al (2001) RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III. Nature 409(6823):1051–1055PubMedCrossRefGoogle Scholar
  154. Skala JP, Knight BL (1977) Protein kinases in brown adipose tissue of developing rats. State of activation of protein kinase during development and cold exposure and its relationship to adenosine 3′:5′-monophosphate, lipolysis, and heat production. J Biol Chem 252(3):1064–1070PubMedGoogle Scholar
  155. Smith FD et al (2013) Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation. Elife 2:e01319PubMedPubMedCentralGoogle Scholar
  156. Soderling TR, Hickenbottom J, Reimann EM, Hunkeler FL, Walsh DA, Krebs EG (1970) Inactivation of glycogen synthetase and activation of phosphorylase kinase by muscle adenosine 3′,5′-monophosphate-dependent protein kinases. J Biol Chem 245:6317–6328PubMedGoogle Scholar
  157. Song WJ, Schreiber W, Zhong E, Liu FF, Kornfeld BD, Wondisford FE, Hussain MA (2008) Exendin-4 stimulation of cyclin A2 in beta-cell proliferation. Diabetes 57(9):2371–2381PubMedPubMedCentralCrossRefGoogle Scholar
  158. Staimez LR, Weber M, Ranjani H, Ali MK, Echouffo-Tcheugui JB, Phillips LS, Mohan V, Narayan KM (2013) Evidence of reduced β-cell function in Asian Indians with mild dysglycemia. Diabetes Care 36:2772–2778PubMedPubMedCentralCrossRefGoogle Scholar
  159. Studer RK, Borle AB (1982) Differences between male and female rats in the regulation of hepatic glycogenolysis. The relative role of calcium and cAMP in phosphorylase activation by catecholamines. J Biol Chem 257(14):7987–7993PubMedGoogle Scholar
  160. Studer RK, Snowdowne KW, Borle AB (1984) Regulation of hepatic glycogenolysis by glucagon in male and female rats. Role of cAMP and Ca2+ and interactions between epinephrine and glucagon. J Biol Chem 259(6):3596–3604PubMedGoogle Scholar
  161. Sun X, Dang F, Zhang D, Yuan Y, Zhang C, Wu Y, Wang Y, Liu Y (2015) Glucagon-CREB/CRTC2 signaling cascade regulates hepatic BMAL1 protein. J Biol Chem 290(4):2189–2197PubMedPubMedCentralCrossRefGoogle Scholar
  162. Tang QQ, Lane MD (2012) Adipogenesis: from stem cell to adipocyte. Annu Rev Biochem 81:715–736PubMedCrossRefGoogle Scholar
  163. Thomas SA, Palmiter RD (1997) Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline. Nature 387(6628):94–97PubMedCrossRefGoogle Scholar
  164. Thorens B, Guillam M, Beermann F, Burcelin R, Jaquet M (2000) Transgenic reexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion. J Biol Chem 275(31):23751–23758PubMedCrossRefGoogle Scholar
  165. Tourrel C, Bailbé D, Meile MJ, Kergoat M, Portha B (2001) Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 50:1562–1570PubMedCrossRefGoogle Scholar
  166. Valverde I et al (1979) Calmodulin activation of adenylate cyclase in pancreatic islets. Science 206(4415):225–227PubMedCrossRefGoogle Scholar
  167. van Marken Lichtenbelt WD et al (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360(15):1500–1508PubMedCrossRefGoogle Scholar
  168. Virtanen KA et al (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360(15):1518–1525PubMedCrossRefGoogle Scholar
  169. Walsh DA, Perkins JP, Krebs EG (1968) An adenosine 3′,5′-monophosphate-dependant protein kinase from rabbit skeletal muscle. J Biol Chem 243(13):3763–3765PubMedGoogle Scholar
  170. Wang Y, Perfetti R, Greig NH, Holloway HW, DeOre KA, Montrose-Rafizadeh C, Elahi D, Egan JM (1997) Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats. J Clin Invest 99:2883–2889PubMedPubMedCentralCrossRefGoogle Scholar
  171. Wang H, Iezzi M, Theander S, Antinozzi PA, Gauthier BR, Halban PA, Wollheim CB (2005) Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells. Diabetologia 48(4):720–731PubMedCrossRefGoogle Scholar
  172. Wang Y, Inoue H, Ravnskjaer K, Viste K, Miller N, Liu Y, Hedrick S, Vera L, Montminy M (2010) Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity. Proc Natl Acad Sci U S A 107(7):3087–3092PubMedPubMedCentralCrossRefGoogle Scholar
  173. Welters HJ, Diakogiannaki E, Mordue JM, Tadayyon M, Smith SA, Morgan NG (2006) Differential protective effects of palmitoleic acid and cAMP on caspase activation and cell viability in pancreatic beta-cells exposed to palmitate. Apoptosis 11(7):1231–1238PubMedCrossRefGoogle Scholar
  174. White JE, Engel FL (1958) Lipolytic action of corticotropin on rat adipose tissue in vitro. J Clin Invest 37(11):1556–1563PubMedPubMedCentralCrossRefGoogle Scholar
  175. Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vázquez MJ, Morgan D, Csikasz RI, Gallego R, Rodriguez-Cuenca S, Dale M, Virtue S, Villarroya F, Cannon B, Rahmouni K, López M, Vidal-Puig A (2012) BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149(4):871–885PubMedPubMedCentralCrossRefGoogle Scholar
  176. Withers DJ, Burks D, Towery HH, Altamuro SL, Flint CL, White MF (1999) Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 23:32–40PubMedGoogle Scholar
  177. Wynshaw-Boris A, Short J, Loose DS, Hanson RW (1986) Characterization of the phosphoenolpyruvate carboxykinase (GTP) promoter-regulatory region. I. Multiple hormone regulatory elements and the effects of enhancers. J Biol Chem 261:9714–9720PubMedGoogle Scholar
  178. Yabe D, Seino Y (2011) Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation. Prog Biophys Mol Biol 107(2):248–256PubMedCrossRefGoogle Scholar
  179. Yasuda K et al (2006) Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity. Trends Endocrinol Metab 17(7):269–275PubMedCrossRefGoogle Scholar
  180. Yokomori N, Tawata M, Hosaka Y, Onaya T (1992) Transcriptional regulation of hexokinase I mRNA levels by TSH in cultured rat thyroid FRTL5 cells. Life Sci 51(20):1613–1619PubMedCrossRefGoogle Scholar
  181. Yoshimasa T et al (1987) Cross-talk between cellular signalling pathways suggested by phorbol-ester-induced adenylate cyclase phosphorylation. Nature 327(6117):67–70PubMedCrossRefGoogle Scholar
  182. Yosida M, Dezaki K, Uchida K, Kodera S, Lam NV, Ito K, Rita RS, Yamada H, Shimomura K, Ishikawa SE, Sugawara H, Kawakami M, Tominaga M, Yada T, Kakei M (2014) Involvement of cAMP/EPAC/TRPM2 activation in glucose- and incretin-induced insulin secretion. Diabetes 63(10):3394–3403PubMedCrossRefGoogle Scholar
  183. Zaccolo M (2011) Spatial control of cAMP signalling in health and disease. Curr Opin Pharmacol 11(6):649–655PubMedPubMedCentralCrossRefGoogle Scholar
  184. Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295(5560):1711–1715PubMedCrossRefGoogle Scholar
  185. Zhang JW et al (2004) Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis. J Biol Chem 279(6):4471–4478PubMedCrossRefGoogle Scholar
  186. Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy M, Kay SA (2010) Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med 16(10):1152–1156PubMedPubMedCentralCrossRefGoogle Scholar
  187. Zhao AZ, Zhao H, Teague J, Fujimoto W, Beavo JA (1997) Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B. Proc Natl Acad Sci U S A 94(7):3223–3228PubMedPubMedCentralCrossRefGoogle Scholar
  188. Zhou J, Pineyro M, Wang X, Doyle ME, Egan JM (2002) Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. J Cell Physiol 192(3):304–314PubMedCrossRefGoogle Scholar
  189. Ziegler MG et al (2012) Epinephrine and the metabolic syndrome. Curr Hypertens Rep 14(1):1–7PubMedCrossRefGoogle Scholar
  190. Zippin JH et al (2004) Bicarbonate-responsive “soluble” adenylyl cyclase defines a nuclear cAMP microdomain. J Cell Biol 164(4):527–534PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Salk InstituteLa JollaUSA

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