Pancreatic β-cell identity, glucose sensing and the control of insulin secretion

Biochemical Journal

Volumn 466, Issue , 2015, Pages 203-218

  Rutter, Guy A ^a   Pullen, Timothy J ^a   Hodson, David J ^a   Martinez Sanchez, Aida ^a  

^a IMPERIAL COLLEGE LONDON   (United Kingdom)

Author keywords

Beta cell; Diabetes; Electrophysiology; Glucose; Imaging; Insulin; Islet; Pancreas; Recombinant probe; Secretion

Indexed keywords

ADENOSINE TRIPHOSPHATE; GLUCOSE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; INSULIN; LACTATE DEHYDROGENASE; MONOCARBOXYLATE TRANSPORTER 1; REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FKHR; TRANSCRIPTION FACTOR MAFA; TRANSCRIPTION FACTOR NKX6.1; TRANSCRIPTION FACTOR PDX 1; TRANSCRIPTION FACTOR RFX6; UNCLASSIFIED DRUG; UNTRANSLATED RNA; GLUCOSE BLOOD LEVEL;

AEROBIC METABOLISM; BLOOD GLUCOSE MONITORING; CALCIUM SIGNALING; CELL DIFFERENTIATION; CELL FUNCTION; CELL MEMBRANE; ENZYMOLOGY; GENE SILENCING; GLUCOSE BLOOD LEVEL; GLUCOSE TOLERANCE; GLUCOSE TRANSPORT; HUMAN; HYPERGLYCEMIA; HYPOGLYCEMIA; IN VIVO STUDY; INSULIN BLOOD LEVEL; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN RELEASE; MITOCHONDRION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; NUCLEAR REPROGRAMMING; PANCREAS ISLET BETA CELL; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVIEW; STEM CELL TRANSPLANTATION; ANIMAL; BIOLOGICAL MODEL; BLOOD; CELL DEDIFFERENTIATION; CYTOLOGY; METABOLISM; PANCREAS ISLET; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY; SECRETION (PROCESS); SECRETORY PATHWAY;

ANIMALIA; RODENTIA;

ANIMALS; BLOOD GLUCOSE; CELL DEDIFFERENTIATION; DIABETES MELLITUS, TYPE 2; HUMANS; INSULIN; INSULIN-SECRETING CELLS; ISLETS OF LANGERHANS; MITOCHONDRIA; MODELS, BIOLOGICAL; SECRETORY PATHWAY;

EID: 84923148964     PISSN: 02646021     EISSN: 14708728     Source Type: Journal    
DOI: 10.1042/BJ20141384     Document Type: Review

References (223)

1. Guariguata, L., Whiting, D.R., Hambleton, I., Beagley, J., Linnenkamp, U. and Shaw, J.E. (2014) Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res. Clin. Pract. 103, 137-149 CrossRef PubMed
2. Scully, T. (2012) Diabetes in numbers. Nature 485, S2-S3 CrossRef PubMed
3. ADA (2013) Economic costs of diabetes in the U.S. in 2012. Diabetes Care 36, 1033-1046 CrossRef PubMed
4. McEvoy, R.C. (1981) Changes in the volumes of the A-, B-, and D-cell populations in the pancreatic islets during the postnatal development of the rat. Diabetes 30, 813-817 CrossRef PubMed
5. Rahier, J., Goebbels, R.M. and Henquin, J.C. (1983) Cellular composition of the human diabetic pancreas. Diabetologia 24, 366-371 CrossRef PubMed
6. Orci, L. and Unger, R.H. (1975) Functional subdivision of islets of Langerhans and possible role of D cells. Lancet 2, 1243-1244 CrossRef PubMed
7. Bosco, D., Armanet, M., Morel, P., Niclauss, N., Sgroi, A., Muller, Y.D., Giovannoni, L., Parnaud, G. and Berney, T. (2010) Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59, 1202-1210 CrossRef PubMed
8. Rodriguez-Diaz, R., Abdulreda, M.H., Formoso, A.L., Gans, I., Ricordi, C., Berggren, P.O. and Caicedo, A. (2011) Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab. 14, 45-54 CrossRef PubMed
9. Unger, R.H. and Orci, L. (1975) The essential role of glucagon in the pathogenesis of diabetes mellitus. Lancet 1, 14-16 CrossRef PubMed
10. UKPDS (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group [see comments]. Lancet 352, 837-853 CrossRef PubMed
11. Butler, A.E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R.A. and Butler, P.C. (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102-110 CrossRef PubMed
12. Marselli, L., Suleiman, M., Masini, M., Bugliani, M., Olimpico, F., Syed, F., Masiello, P., Filipponi, F., Boggi, U. and Marchetti, P. (2013) Are we overestimating the loss of beta cells in type 2 diabetes? Diabetologia 56, S212-S213
13. Rahier, J., Guiot, Y., Goebbels, R.M., Sempoux, C. and Henquin, J.C. (2008) Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes. Metab. 10, 32-42 CrossRef PubMed
14. Del Guerra, S., Lupi, R., Marselli, L., Masini, M., Bugliani, M., Sbrana, S., Torri, S., Pollera, M., Boggi, U., Mosca, F. et al. (2005) Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 54, 727-735 CrossRef PubMed
15. Rosengren, A.H., Braun, M., Mahdi, T., Andersson, S.A., Travers, M.E., Shigeto, M., Zhang, E., Almgren, P., Ladenvall, C., Axelsson, A.S. et al. (2012) Reduced insulin exocytosis in human pancreatic beta-cells with gene variants linked to type 2 diabetes. Diabetes 61, 1726-1733 CrossRef PubMed
16. Donath, M.Y. and Shoelson, S.E. (2011) Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98-107 CrossRef PubMed
17. Rutter, G.A. (2014) Understanding GWAS genes for Type 2 diabetes. Diabet. Med. 31, 1480-1487 CrossRef PubMed
18. Kahn, S.E., Zraika, S., Utzschneider, K.M. and Hull, R.L. (2009) The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia 52, 1003-1012 CrossRef PubMed
19. Rutter, G.A. and Parton, L.E. (2008) The beta-cell in type 2 diabetes and in obesity. Front. Horm. Res. 36, 118-134 CrossRef PubMed
20. Cnop, M., Hughes, S.J., Igoillo-Esteve, M., Hoppa, M.B., Sayyed, F., van de, L.L., Gunter, J.H., de Koning, E.J., Walls, G.V., Gray, D.W. et al. (2010) The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia 53, 321-330 CrossRef PubMed
21. Parsons, J.A., Brelje, T.C. and Sorenson, R.L. (1992) Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion. Endocrinology 130, 1459-1466 PubMed
22. Butler, A.E., Cao-Minh, L., Galasso, R., Rizza, R.A., Corradin, A., Cobelli, C. and Butler, P.C. (2010) Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 53, 2167-2176 CrossRef PubMed
23. Van Assche, F.A., Aerts, L. and De, P.F. (1978) A morphological study of the endocrine pancreas in human pregnancy. Br. J. Obstet. Gynaecol. 85, 818-820 CrossRef PubMed
24. Maclean, N. and Ogilvie, R.F. (1955) Quantitative estimation of the pancreatic islet tissue in diabetic subjects. Diabetes 4, 367-376 CrossRef PubMed
25. Kloppel, G., Lohr, M., Habich, K., Oberholzer, M. and Heitz, P.U. (1985) Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv. Synth. Pathol. Res. 4, 110-125 PubMed
26. Brunzell, J.D., Robertson, R.P., Lerner, R.L., Hazzard, W.R., Ensinck, J.W., Bierman, E.L. and Porte, D. (1976) Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J. Clin. Endocrinol. 42, 222-229 CrossRef
27. Yalow, R.S. and Berson, S.A. (1960) Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39, 1157-1175 CrossRef PubMed
28. Chera, S., Baronnier, D., Ghila, L., Cigliola, V., Jensen, J.N., Gu, G., Furuyama, K., Thorel, F., Gribble, F.M., Reimann, F. and Herrera, P.L. (2014) Diabetes recovery by age-dependent conversion of pancreatic delta-cells into insulin producers. Nature 514, 503-507 CrossRef PubMed
29. Thorel, F., Nepote, V., Avril, I., Kohno, K., Desgraz, R., Chera, S. and Herrera, P.L. (2010) Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss. Nature 464, 1149-1154 CrossRef PubMed
30. Turner, M.D. and Arvan, P. (2000) Protein traffic from the secretory pathway to the endosomal system in pancreatic beta-cells. J. Biol. Chem. 275, 14025-14030 CrossRef PubMed
31. Fava, E., Dehghany, J., Ouwendijk, J., Muller, A., Niederlein, A., Verkade, P., Meyer-Hermann, M. and Solimena, M. (2012) Novel standards in the measurement of rat insulin granules combining electron microscopy, high-content image analysis and in silico modelling. Diabetologia 55, 1013-1023 CrossRef PubMed
32. Pouli, A.E., Emmanouilidou, E., Zhao, C., Wasmeier, C., Hutton, J.C. and Rutter, G.A. (1998) Secretory granule dynamics visualised in vivo with a phogrin-green fluorescent protein chimaera. Biochem. J. 333, 193-199 PubMed
33. Rorsman, P. and Renstrom, E. (2003) Insulin granule dynamics in pancreatic beta cells. Diabetologia 46, 1029-1045 CrossRef PubMed
34. Panten, U. and Ishida, H. (1975) Fluorescence of oxidized flavoproteins from perifused isolated pancreatic islets. Diabetologia 11, 569-573 CrossRef PubMed
35. 2+ and secretion. EMBO J. 9, 53-60 PubMed
36. Ashcroft, S.J., Weerasinghe, L.C., Bassett, J.M. and Randle, P.J. (1972) The pentose cycle and insulin release in mouse pancreatic islets. Biochem. J. 126, 525-532 PubMed
37. Verspohl, E.J., Handel, M. and Ammon, H.P. (1979) Pentosephosphate shunt activity of rat pancreatic islets: its dependence on glucose concentration. Endocrinology 105, 1269-1274 CrossRef PubMed
38. Detimary, P., Dejonghe, S., Ling, Z.D., Pipeleers, D., Schuit, F. and Henquin, J.C. (1998) The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in beta cells but not in a cells and are also observed in human islets. J. Biol. Chem. 273, 33905-33908 CrossRef PubMed
39. 2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic β-cells. PLoS One 7, e39722 CrossRef
40. Kennedy, H.J., Pouli, A.E., Jouaville, L.S., Rizzuto, R. and Rutter, G.A. (1999) Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J. Biol. Chem. 274, 13281-13291 CrossRef PubMed
41. Ashcroft, F.M., Harrison, D.E. and Ashcroft, S.J. (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic B-cells. Nature Lond. 312, 446-448 CrossRef
42. Cook, D.L. and Hales, C.N. (1984) Intracellular ATP directly blocks K+ channels in pancreatic B-cells. Nature 311, 271-273 CrossRef PubMed
43. Meissner, H.P. and Schmelz, H. (1974) Membrane potential of beta-cells in pancreatic islets. Pflugers Arch. 351, 195-206 CrossRef PubMed
44. Yang, S.N. and Berggren, P.O. (2006) The role of voltage-gated calcium channels in pancreatic beta-cell physiology and pathophysiology. Endocr. Rev. 27, 621-676 CrossRef PubMed
45. Sudhof, T.C. and Rothman, J.E. (2009) Membrane fusion: grappling with SNARE and SM proteins. Science 323, 474-477 CrossRef PubMed
46. Jahn, R. and Fasshauer, D. (2012) Molecular machines governing exocytosis of synaptic vesicles. Nature 490, 201-207 CrossRef PubMed
47. 2+ microdomains and the control of insulin secretion. Cell Calcium 40, 539-551 CrossRef PubMed
48. Pinton, P., Tsuboi, T., Ainscow, E.K., Pozzan, T., Rizzuto, R. and Rutter, G.A. (2002) Dynamics of glucose-induced recruitment of protein kinase C bII in living panreatic islet β-cells. J. Biol. Chem. 277, 37702-37710 CrossRef PubMed
49. Hoppa, M.B., Collins, S., Ramracheya, R., Hodson, L., Amisten, S., Zhang, Q., Johnson, P., Ashcroft, F.M. and Rorsman, P. (2009) Chronic palmitate exposure inhibits insulin secretion by dissociation of Ca(2+) channels from secretory granules. Cell Metab. 10, 455-465 CrossRef PubMed
50. Emmanouilidou, E., Teschemacher, A., Pouli, A.E., Nicholls, L.I., Seward, E.P. and Rutter, G.A. (1999) Imaging [Ca2+] changes at the secretory vesicle surface with a recombinant targeted cameleon. Curr. Biol. 9, 915-918 CrossRef PubMed
51. 2+ signaling events in pancreatic beta-cells. FASEB J. 19, 301-303 PubMed
52. 2+ homeostasis revealed by RNA silencing. Diabetes 53, 393-400 CrossRef PubMed
53. 2+ store in neuroendocrine cells with a VAMP2.aequorin chimaera. J.Cell Biol. 155, 41-51 CrossRef PubMed
54. 2+ release from insulin-containing vesicles in living pancreatic beta-cells (MIN6). J. Biol. Chem. 278, 11057-11064 CrossRef PubMed
55. Masgrau, R., Churchill, G.C., Morgan, A.J., Ashcroft, S.J. and Galione, A. (2003) NAADP. A new second messenger for glucose-induced Ca(2+) responses in clonal pancreatic beta cells. Curr. Biol. 13, 247-251 CrossRef PubMed
56. Gilon, P., Chae, H.Y., Rutter, G.A. and Ravier, M.A. (2014) Calcium signaling in pancreatic beta-cells in health and in Type 2 diabetes. Cell Calcium 56, 340-361 CrossRef PubMed
57. Campbell, J.E. and Drucker, D.J. (2013) Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17, 819-837 CrossRef PubMed
58. Holz, G.G. (2004) Epac: a new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell. Diabetes 53, 5-13 CrossRef PubMed
59. Seino, S. and Shibasaki, T. (2005) PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol. Rev. 85, 1303-1342 CrossRef PubMed
60. Dalle, S., Ravier, M.A. and Bertrand, G. (2011) Emerging roles for beta-arrestin-1 in the control of the pancreatic beta-cell function and mass: new therapeutic strategies and consequences for drug screening. Cell Signal. 23, 522-528 CrossRef PubMed
61. Ruiz de Azua, I., Gautam, D., Guettier, J.M. and Wess, J. (2011) Novel insights into the function of beta-cell M3 muscarinic acetylcholine receptors: therapeutic implications. Trends Endocrinol. Metab. 22, 74-80 CrossRef PubMed
62. Hillaire-Buys, D., Chapal, J., Bertrand, G., Petit, P. and Loubatieres-Mariani, M.M. (1994) Purinergic receptors on insulin-secreting cells. Fundam. Clin. Pharmacol. 8, 117-127 CrossRef PubMed
63. Diraison, F., Parton, L., Ferre, P., Foufelle, F., Briscoe, C.P., Leclerc, I. and Rutter, G.A. (2003) Over-expression of sterol response element binding protein-1c or culture with 5-aminoimidazole-4-carboxamide ribonucleoside induces lipogenesis and decresaes glucose-stimulated insulin secretion from rat pancreatic islets. Diabetic Med. 20, A77
64. Itoh, Y., Kawamata, Y., Harada, M., Kobayashi, M., Fujii, R., Fukusumi, S., Ogi, K., Hosoya, M., Tanaka, Y., Uejima, H. et al. (2003) Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40. Nature 422, 173-176 CrossRef PubMed
65. Wollheim, C.B., Kikuchi, M., Renold, A.E. and Sharp, G.W. (1977) Somatostatin- and epinephrine-induced modifications of 45Ca++ fluxes and insulin release in rat pancreatic islets maintained in tissue culture. J. Clin. Invest. 60, 1165-1173 CrossRef PubMed
66. Rorsman, P., Bokvist, K., Ammala, C., Arkhammar, P., Berggren, P.O., Larsson, O. and Wahlander, K. (1991) Activation by adrenaline of a low-conductance G protein-dependent K+ channel in mouse pancreatic B cells. Nature 349, 77-79 CrossRef PubMed
67. Hoelzer, D.R., Dalsky, G.P., Clutter, W.E., Shah, S.D., Holloszy, J.O. and Cryer, P.E. (1986) Glucoregulation during exercise: hypoglycemia is prevented by redundant glucoregulatory systems, sympathochromaffin activation, and changes in islet hormone secretion. J. Clin. Invest. 77, 212-221 CrossRef PubMed
68. Cerasi, E. and Luft, R. (1963) Plasma-insulin response to sustained hyperglycemia induced by glucose infusion in human subjects. Lancet 2, 1359-1361 CrossRef PubMed
69. Curry, D.L., Bennett, L.L. and Grodsky, G.M. (1968) Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology 83, 572-584 CrossRef PubMed
70. Nesher, R. and Cerasi, E. (2002) Modeling phasic insulin release: immediate and time-dependent effects of glucose. Diabetes 51, S53-S59 CrossRef PubMed
71. Rutter, G.A. (2004) Visualising insulin secretion. The Minkowski lecture 2004. Diabetologia 47, 1861-1872 CrossRef PubMed
72. Berthoud, H.R., Bereiter, D.A., Trimble, E.R., Siegel, E.G. and Jeanrenaud, B. (1981) Cephalic phase, reflex insulin secretion. Neuroanatomical and physiological characterization. Diabetologia 20, 393-401 CrossRef PubMed
73. Teff, K. (2000) Nutritional implications of the cephalic-phase reflexes: endocrine responses. Appetite 34, 206-213 CrossRef PubMed
74. Ahren, B. and Holst, J.J. (2001) The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia. Diabetes 50, 1030-1038 CrossRef PubMed
75. Donath, M.Y. and Burcelin, R. (2013) GLP-1 effects on islets: hormonal, neuronal, or paracrine? Diabetes Care 36, S145-S148 CrossRef PubMed
76. O'Rahilly, S., Turner, R.C. and Matthews, D.R. (1988) Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N. Engl. J. Med. 318, 1225-1230 CrossRef PubMed
77. Porksen, N., Munn, S., Steers, J., Vore, S., Veldhuis, J. and Butler, P. (1995) Pulsatile insulin secretion accounts for 70% of total insulin secretion during fasting. Am. J. Physiol. 269, E478-E488 PubMed
78. Bertram, R., Sherman, A. and Satin, L.S. (2010) Electrical bursting, calcium oscillations, and synchronization of pancreatic islets. Adv. Exp. Med. Biol. 65, 261-279 CrossRef
79. Zhang, M., Fendler, B., Peercy, B., Goel, P., Bertram, R., Sherman, A. and Satin, L. (2008) Long lasting synchronization of calcium oscillations by cholinergic stimulation in isolated pancreatic islets. Biophys. J. 95, 4676-4688 CrossRef PubMed
80. Matschinsky, F.M. and Ellerman, J.E. (1968) Metabolism of glucose in the islets of Langerhans. J. Biol. Chem. 243, 2730-2736 PubMed
81. Randle, P.J., Ashcroft, S. J. H. and Gill, J.R. (1968) Carbohydrate Metabolism and its Disorders, pp. 427-437, Academic Press, London
82. Ashcroft, S.J. (1980) Glucoreceptor mechanisms and the control of insulin release and biosynthesis. Diabetologia 18, 5-15 CrossRef PubMed
83. Hedeskov, C.J. (1980) Mechanisms of glucose-induced insulin secretion. Physiol. Rev. 60, 442-509 PubMed
84. Kyriazis, G.A., Soundarapandian, M.M. and Tyrberg, B. (2012) Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proc. Natl. Acad. Sci. U.S.A. 109, E524-E532 CrossRef PubMed
85. Nakagawa, Y., Ohtsu, Y., Nagasawa, M., Shibata, H. and Kojima, I. (2014) Glucose promotes its own metabolism by acting on the cell-surface glucose-sensing receptor T1R3. Endocr. J. 61, 119-131 CrossRef PubMed
86. Nie, Y., Vigues, S., Hobbs, J.R., Conn, G.L. and Munger, S.D. (2005) Distinct contributions of T1R2 and T1R3 taste receptor subunits to the detection of sweet stimuli. Curr. Biol. 15, 1948-1952 CrossRef PubMed
87. Iynedjian, P.B. (1993) Mammalian glucokinase and its gene. Biochem. J. 293, 1-13 PubMed
88. McCulloch, L.J., van de Bunt, M., Braun, M., Frayn, K.N., Clark, A. and Gloyn, A.L. (2011) GLUT2 (SLC2A2) is not the principal glucose transporter in human pancreatic beta cells: implications for understanding genetic association signals at this locus. Mol. Genet. Metab. 104, 648-653 CrossRef PubMed
89. Gerber, P.A., Bellomo, E.A., Hodson, D.J., Meur, G., Solomou, A., Mitchell, R.K., Hollinshead, M., Chimienti, F., Bosco, D., Hughes, S.J. et al. (2014) Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Diabetologia 57, 1635-1644 CrossRef PubMed
90. Niemeyer, H., de la Luz, C.M., Rabajille, E., Ureta, T., Clark-Turri, L. and Penaranda, J. (1975) Sigmoidal kinetics of glucokinase. Enzyme 20, 321-333 PubMed
91. Sekine, N., Cirulli, V., Regazzi, R., Brown, L.J., Gine, E., Tamarit-Rodriguez, J., Girotti, M., Marie, S., MacDonald, M.J., Wollheim, C.B. and Rutter, G.A. (1994) Low lactate dehydrogenase and high mitochondrial glycerol phosphate dehydrogease in pancreatic β-cell. Potential role in nutrient sensing. J. Biol. Chem. 269, 4895-4902 PubMed
92. Froguel, P., Vaxillaire, M., Sun, F., Velho, G., Zouali, H., Butel, M.O., Lesage, S., Vionnet, N., Clement, K., Fougerousse, F. et al. (1992) Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356, 162-164 CrossRef PubMed
93. Reardon, W., Ross, R. J. M., Sweeney, M.G., Luxon, L.M., Pembrey, M.E., Harding, A.E. and Trembeth, R.C. (1992) Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 340, 1376-1379 CrossRef PubMed
94. van den Ouweland, J.M., Lemkes, H.H., Ruitenbeek, W., Sandkuijl, L.A., de Vijlder, M.F., Struyvenberg, P.A., van de Kamp, J.J. and Maassen, J.A. (1992) Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat.Genet. 1, 368-371 CrossRef PubMed
95. Koeck, T., Olsson, A.H., Nitert, M.D., Sharoyko, V.V., Ladenvall, C., Kotova, O., Reiling, E., Ronn, T., Parikh, H., Taneera, J. et al. (2011) A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes. Cell Metab. 13, 80-91 CrossRef PubMed
96. Hutton, J.C., Sener, A., Herchuelz, A., Atwater, I., Kawazu, S., Boschero, A.C., Somers, G., Devis, G. and Malaisse, W.J. (1980) Similarities in the stimulus-secretion coupling mechanisms of glucose- and 2-keto acid-induced insulin release. Endocrinology 106, 203-219 CrossRef PubMed
97. Matschinsky, F.M., Meglasson, M., Ghosh, A., Appel, M., Bedoya, F., Prentki, M., Corkey, B., Shimizu, T., Berner, D., Najafi, H. et al. (1986) Biochemical design features of the pancreatic islet cell glucose- sensory system. Adv. Exp. Med. Biol. 211, 459-469 CrossRef PubMed
98. Leclercq-Meyer, V., Garcia-Martinez, J.A., Villanueva-Penacarrillo, M.L., Valverde, I. and Malaisse, W.J. (1995) In vitro and in vivo insulinotropic action of methyl pyruvate. Horm. Metab. Res. 27, 477-481 CrossRef PubMed
99. Henquin, J.C., Dufrane, D. and Nenquin, M. (2006) Nutrient control of insulin secretion in isolated normal human islets. Diabetes 55, 3470-3477 CrossRef PubMed
100. Hutton, J.C., Sener, A., Herchuelz, A., Atwater, I., Kawazu, S., Boschero, A.C., Somers, G., Devis, G. and Malaisse, W.J. (1980) Similarities in the stimulus-secretion coupling mechanisms of glucose- and 2-keto acid-induced insulin release. Endocrinology 106, 203-219 CrossRef PubMed
101. Denton, R.M. and McCormack, J.G. (1980) On the role of the calcium transport cycle in the heart and other mammalian mitochondria. FEBS Lett. 119, 1-8 CrossRef PubMed
102. 2+ in aequorin-expressing INS-1 cells. J. Clin. Invest. 98, 2524-2538 CrossRef PubMed
103. 2+ to supramicromolar levels in a pancreatic β-cell line: possible role in glucose and agonist-induced insulin secretion. J. Biol. Chem. 268, 22385-22390 PubMed
104. Wiederkehr, A., Szanda, G., Akhmedov, D., Mataki, C., Heizmann, C.W., Schoonjans, K., Pozzan, T., Spat, A. and Wollheim, C.B. (2011) Mitochondrial matrix calcium is an activating signal for hormone secretion. Cell Metab. 13, 601-611 CrossRef PubMed
105. 2+ uniporter (MCU) contribute to metabolism-secretion coupling in clonal pancreatic beta-cells. J. Biol. Chem. 287, 34445-34454 CrossRef PubMed
106. 2+ responses that are propagated into mitochondria. FASEB J. 28, 3301-3312 CrossRef PubMed
107. Gopel, S.O., Kanno, T., Barg, S., Eliasson, L., Galvanovskis, J., Renstrom, E. and Rorsman, P. (1999) Activation of Ca(2+)-dependent K(+) channels contributes to rhythmic firing of action potentials in mouse pancreatic beta cells. J. Gen. Physiol. 114, 759-770 CrossRef PubMed
108. 2+-dependent mechanism. Diabetes 51, S162-S170 CrossRef PubMed
109. Li, J., Shuai, H.Y., Gylfe, E. and Tengholm, A. (2013) Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca(2+). Diabetologia 56, 1577-1586 CrossRef PubMed
110. Cunningham, B.A., Deeney, J.T., Bliss, C.R., Corkey, B.E. and Tornheim, K. (1996) Glucose-induced oscillatory insulin secretion in perifused rat pancreatic islets and clonal beta-cells (HIT). Am. J. Physiol. Endocrinol. Metab. 34, E702-E710
111. Detimary, P., Gilon, P. and Henquin, J.C. (1998) Interplay between cytoplasmic Ca2+ and the ATP/ADP ratio: a feedback control mechanism in mouse pancreatic islets. Biochem. J. 333, 269-274 PubMed
112. Dufer, M., Haspel, D., Krippeit-Drews, P., Aguilar-Bryan, L., Bryan, J. and Drews, G. (2004) Oscillations of membrane potential and cytosolic Ca(2+) concentration in SUR1(-/-) beta cells. Diabetologia 47, 488-498 CrossRef PubMed
113. + channels owing to a knockout of the pore-forming subunit Kir6.2. Endocrinology 150, 33-45 CrossRef PubMed
114. Ren, J., Sherman, A., Bertram, R., Goforth, P.B., Nunemaker, C.S., Waters, C.D. and Satin, L.S. (2013) Slow oscillations of KATP conductance in mouse pancreatic islets provide support for electrical bursting driven by metabolic oscillations. Am. J. Physiol. Endocrinol. Metab. 305, E805-E817 CrossRef PubMed
115. Henquin, J.C., Nenquin, M., Ravier, M.A. and Szollosi, A. (2009) Shortcomings of current models of glucose-induced insulin secretion. Diabetes Obes. Metab. 11, 168-179 CrossRef PubMed
116. 2+ in rat pancreatic islets. Proc. Natl. Acad. Sci. U.S.A. 92, 10728-10732 CrossRef PubMed
117. + channels in mouse B cells. J. Clin. Invest. 89, 1288-1295 CrossRef PubMed
118. Hodson, D.J., Mitchell, R.K., Bellomo, E.A., Sun, G., Vinet, L., Meda, P., Li, D., Li, W.H., Bugliani, M., Marchetti, P. et al. (2013) Lipotoxicity disrupts incretin-regulated human beta cell connectivity. J. Clin. Invest. 123, 4182-4194 CrossRef PubMed
119. Hodson, D.J., Tarasov, A.I., Gimeno, B.S., Mitchell, R.K., Johnston, N.R., Haghollahi, S., Cane, M.C., Bugliani, M., Marchetti, P., Bosco, D. et al. (2014) Incretin-modulated beta cell energetics in intact islets of Langerhans. Mol. Endocrinol. 28, 860-871 CrossRef PubMed
120. Hodson, D.J., Mitchell, R.K., Marselli, L., Pullen, T.J., Brias, S.G., Semplici, F., Everett, K.L., Cooper, D.M., Bugliani, M., Marchetti, P. et al. (2014) ADCY5 couples glucose to insulin secretion in human islets. Diabetes 63, 3009-3021 CrossRef PubMed
121. Holz, G.G., Kuhtreiber, W.M. and Habener, J.F. (1993) Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7-37). Nature 361, 362-365 CrossRef PubMed
122. Park, J.H., Kim, S.J., Park, S.H., Son, D.G., Bae, J.H., Kim, H.K., Han, J. and Song, D.K. (2012) Glucagon-like peptide-1 enhances glucokinase activity in pancreatic beta-cells through the association of Epac2 with Rim2 and Rab3A. Endocrinology 153, 574-582 CrossRef PubMed
123. Jitrapakdee, S. and Wallace, J.C. (1999) Structure, function and regulation of pyruvate carboxylase. Biochem. J. 340, 1-16 CrossRef PubMed
124. Denton, R.M. and Randle, P.J. (1966) Citrate and the regulation of adipose-tissue phosphofructokinase. Biochem. J. 100, 420-423 PubMed
125. Ammala, C., Eliasson, L., Bokvist, K., Berggren, P.O., Honkanen, R.E., Sjoholm, A. and Rorsman, P. (1994) Activation of protein kinases and inhibition of protein phosphatases play a central role in the regulation of exocytosis in mouse pancreatic beta cells. Proc. Natl. Acad. Sci. U.S.A. 91, 4343-4347 CrossRef PubMed
126. Newsholme, P., Cruzat, V., Arfuso, F. and Keane, K. (2014) Nutrient regulation of insulin secretion and action. J. Endocrinol. 221, R105-R120 CrossRef PubMed
127. Prentki, M., Matschinsky, F.M. and Madiraju, S.R. (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab. 18, 162-185 CrossRef PubMed
128. Khan, A., Ling, Z.C. and Landau, B.R. (1996) Quantifying the carboxylation of pyruvate in pancreatic islets. J. Biol. Chem. 271, 2539-2542 CrossRef PubMed
129. MacDonald, M.J. (1993) Glucose enters mitochondrial metabolism via both carboxylation and decarboxylation of pyruvate in pancreatic islets. Metabolism 42, 1229-1231 CrossRef PubMed
130. Ivarsson, R., Quintens, R., Dejonghe, S., Tsukamoto, K., In 't Veld, P., Renstrom, E. and Schuit, F.C. (2005) Redox control of exocytosis: regulatory role of NADPH, thioredoxin, and glutaredoxin. Diabetes 54, 2132-2142 CrossRef PubMed
131. Newsholme, P., Rebelato, E., Abdulkader, F., Krause, M., Carpinelli, A. and Curi, R. (2012) Reactive oxygen and nitrogen species generation, antioxidant defenses, and beta-cell function: a critical role for amino acids. J. Endocrinol. 214, 11-20 CrossRef PubMed
132. Hoy, M., Maechler, P., Efanov, A.M., Wollheim, C.B., Berggren, P.O. and Gromada, J. (2002) Increase in cellular glutamate levels stimulates exocytosis in pancreatic beta-cells. FEBS Lett. 531, 199-203 CrossRef PubMed
133. Maechler, P. and Wollheim, C.B. (1999) Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature 402, 685-689 CrossRef PubMed
134. MacDonald, M.J. (2003) Export of metabolites from pancreatic islet mitochondria as a means to study anaplerosis in insulin secretion. Metabolism 52, 993-998 CrossRef PubMed
135. Bertrand, G., Ishiyama, N., Nenquin, M., Ravier, M.A. and Henquin, J.C. (2002) The elevation of glutamate content and the amplification of insulin secretion in glucose-stimulated pancreatic islets are not causally related. J. Biol. Chem. 277, 32883-32891 CrossRef PubMed
136. Storto, M., Capobianco, L., Battaglia, G., Molinaro, G., Gradini, R., Riozzi, B., Di, M.A., Mitchell, K.J., Bruno, V., Vairetti, M.P. et al. (2006) Insulin secretion is controlled by mGlu5 metabotropic glutamate receptors. Mol. Pharmacol. 69, 1234-1241 CrossRef PubMed
137. Gheni, G., Ogura, M., Iwasaki, M., Yokoi, N., Minami, K., Nakayama, Y., Harada, K., Hastoy, B., Wu, X., Takahashi, H. et al. (2014) Glutamate acts as a key signal linking glucose metabolism to incretin/cAMP action to amplify insulin secretion. Cell Rep. 9, 661-673 CrossRef PubMed
138. Roduit, R., Nolan, C., Alarcon, C., Moore, P., Barbeau, A., Delghingaro-Augusto, V., Przybykowski, E., Morin, J., Masse, F., Massie, B. et al. (2004) A role for the malonyl-CoA/long-chain acyl-CoA pathway of lipid signaling in the regulation of insulin secretion in response to both fuel and nonfuel stimuli. Diabetes 53, 1007-1019 CrossRef PubMed
139. Brun, T., Roche, E., AssimacopoulosJeannet, F., Corkey, B.E., Kim, K.H. and Prentki, M. (1996) Evidence for an anaplerotic/malonyl-CoA pathway in pancreatic beta-cell nutrient signaling. Diabetes 45, 190-198 CrossRef PubMed
140. Corkey, B.E., Glennon, M.C., Chen, K.S., Deeney, J.T., Matschinsky, F.M. and Prentki, M. (1989) A role for malonyl-CoA in glucose-stimulated insulin secretion from clonal pancreatic beta-cells. J. Biol. Chem. 264, 21608-21612 PubMed
141. Leloup, C., Tourrel-Cuzin, C., Magnan, C., Karaca, M., Castel, J., Carneiro, L., Colombani, A.L., Ktorza, A., Casteilla, L. and Penicaud, L. (2009) Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion. Diabetes 58, 673-681 CrossRef PubMed
142. Newsholme, P., Morgan, D., Rebelato, E., Oliveira-Emilio, H.C., Procopio, J., Curi, R. and Carpinelli, A. (2009) Insights into the critical role of NADPH oxidase(s) in the normal and dysregulated pancreatic beta cell. Diabetologia 52, 2489-2498 CrossRef PubMed
143. Pi, J., Bai, Y., Zhang, Q., Wong, V., Floering, L.M., Daniel, K., Reece, J.M., Deeney, J.T., Andersen, M.E., Corkey, B.E. and Collins, S. (2007) Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes 56, 1783-1791 CrossRef PubMed
144. Pullen, T.J., Khan, A.M., Barton, G., Butcher, S.A., Sun, G. and Rutter, G.A. (2010) Identification of genes selectively disallowed in the pancreatic islet. Islets 2, 89-95 CrossRef PubMed
145. Thorrez, L., Laudadio, I., Van, D.K., Quintens, R., Hendrickx, N., Granvik, M., Lemaire, K., Schraenen, A., Van, L.L., Lehnert, S. et al. (2011) Tissue-specific disallowance of housekeeping genes: the other face of cell differentiation. Genome Res. 21, 95-105 CrossRef PubMed
146. Lortz, S., Gurgul-Convey, E., Naujok, O. and Lenzen, S. (2013) Overexpression of the antioxidant enzyme catalase does not interfere with the glucose responsiveness of insulin-secreting INS-1E cells and rat islets. Diabetologia 56, 774-782 CrossRef PubMed
147. Fu, A., Eberhard, C. and Screaton, R.A. (2013) Role of AMPK in pancreatic beta cell function. Mol. Cell Endocrinol. 366, 127-134 CrossRef PubMed
148. Hardie, D.G. (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 25, 1895-1908 CrossRef PubMed
149. Salt, I.P., Johnson, G., Ashcroft, S.J. and Hardie, D.G. (1998) AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. Biochem. J. 335, 533-539 PubMed
150. da Silva Xavier, G., Leclerc, I., Varadi, A., Tsuboi, T., Moule, S.K. and Rutter, G.A. (2003) Role for AMP-activated protein kinase in glucose-stimulated insulin secretion and preproinsulin gene expression. Biochem. J. 371, 761-774 CrossRef PubMed
151. Sun, G., Tarasov, A.I., McGinty, J., McDonald, A., DaSilva Xavier, G., Gorman, T., Marley, A., French, P.M., Parker, H., Gribble, F. et al. (2010) Ablation of AMP-activated protein kinase alpha1 and alpha2 from pancreatic beta-cells and RIP.Cre neurons suppresses insulin release in vivo. Diabetologia 53, 924-936 CrossRef PubMed
152. Tsuboi, T., daSilvaXavier, G., Leclerc, I. and Rutter, G.A. (2003) 5′ AMP-activated protein kinase controls insulin-containing secretory vesicle dynamics. J. Biol. Chem. 278, 52042-52051 CrossRef PubMed
153. MacDonald, P.E., Braun, M., Galvanovskis, J. and Rorsman, P. (2006) Selective release of low molecular-weight transmitters through kiss-and-run fusion pores in rat pancreatic β-cells. Cell Metab. 4, 283-290 CrossRef PubMed
154. Richards, S.K., Parton, L.E., Leclerc, I., Rutter, G.A. and Smith, R.M. (2006) Over-expression of AMP-activated protein kinase impairs pancreatic beta-cell function in vivo. J. Endocrinol. 187, 225-235 CrossRef
155. Beall, C., Piipari, K., Al-Qassab, H., Smith, M.A., Parker, N., Carling, D., Viollet, B., Withers, D.J. and Ashford, M.L. (2010) Loss of AMP-activated protein kinase alpha2 subunit in mouse beta-cells impairs glucose-stimulated insulin secretion and inhibits their sensitivity to hypoglycaemia. Biochem. J. 429, 323-333 CrossRef PubMed
156. Kone, M., Pullen, T.J., Sun, G., Ibberson, M., Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.S., Kantor, C., Swisa, A., Dor, Y. et al. (2014) LKB1 and AMPK differentially regulate pancreatic beta-cell identity. FASEB J. 28, 4972-4985 CrossRef PubMed
157. Gleason, C.E., Lu, D., Witters, L.A., Newgard, C.B. and Birnbaum, M.J. (2007) The role of AMPK and mTOR in nutrient sensing in pancreatic beta-cells. J. Biol. Chem. 282, 10341-10351 CrossRef PubMed
158. Rutter, G.A. and Hodson, D.J. (2013) Minireview: intraislet regulation of insulin secretion in humans. Mol. Endocrinol. 27, 1984-1995 CrossRef PubMed
159. Rutter, G.A. and Hodson, D.J. (2014) Beta cell connectivity in pancreatic islets: a type 2 diabetes target? Cell. Mol. Life Sci., Epub ahead of print
160. Salomon, D. and Meda, P. (1986) Heterogeneity and contact-dependent regulation of hormone secretion by individual B-cells. Exp. Cell Res. 162, 507-520 CrossRef PubMed
161. 2+ and insulin oscillations, and basal insulin release. Diabetes 54, 1798-1807 CrossRef PubMed
162. Head, W.S., Orseth, M.L., Nunemaker, C.S., Satin, L.S., Piston, D.W. and Benninger, R.K. (2012) Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse. Diabetes 61, 1700-1707 CrossRef PubMed
163. Hodson, D.J., Schaeffer, M., Romano, N., Fontanaud, P., Lafont, C., Birkenstock, J., Molino, F., Christian, H., Lockey, J., Carmignac, D. et al. (2012) Existence of long-lasting experience-dependent plasticity in endocrine cell networks. Nat. Commun. 3, 605 CrossRef PubMed
164. Stozer, A., Gosak, M., Dolensek, J., Perc, M., Marhl, M., Rupnik, M.S. and Korosak, D. (2013) Functional connectivity in islets of Langerhans from mouse pancreas tissue slices. PLoS Comput. Biol. 9, e1002923 CrossRef PubMed
165. da Silva Xavier, G., Loder, M.K., McDonald, A., Tarasov, A.I., Carzaniga, R., Kronenberger, K., Barg, S. and Rutter, G.A. (2009) TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes 58, 894-905 CrossRef PubMed
166. Mitchell, R.K., Mondragon, A., Chen, L., McGinty, J.A., French, P.M., Ferrer, J., Thorens, B., Hodson, D.J., Rutter, G.A. and da Silva Xavier, G. (2014) Selective disruption of Tcf7l2 in the pancreatic beta cell impairs secretory function and lowers beta cell mass. Hum. Mol. Genet., in the press
167. Schuit, F., DeVos, A., Farfari, S., Moens, K., Pipeleers, D., Brun, T. and Prentki, M. (1997) Metabolic fate of glucose in purified islet cells - glucose-regulated anaplerosis in beta cells. J. Biol. Chem. 272, 18572-18579 CrossRef PubMed
168. Chippendale, G.M. (1978) The functions of carbohydrates in insect life processes. In Biochemistry of insects. (Rockstein, M., ed.), Academic Press, New York
169. Hellman, B., Idahl, L.-A., Sehlin, J. and Taljedal, I.-B. (1975) Influence of anoxia on glucose metabolism in pancreatic islets: lack of correlation between fructose-1,6-diphosphate and apparent glycolytic flux. Diabetologia 11, 495-500 CrossRef PubMed
170. Sener, A., Blachier, F. and Malaisse, W.J. (1988) Crabtree effect in tumoral pancreatic islet cells. J. Biol. Chem. 263, 1904-1909 PubMed
171. Hellman, B. and Taljedal, I.-B. (1967) Quantitative studies on isolated pancreatic islets of mammals. Activity and heterogeneity of lactate dehydrogenase in obese-hypreglycaemic mice. Endocrinology 81, 125-131 CrossRef PubMed
172. Liang, Y., Bai, G., Doliba, N., Buettger, C., Wang, L., Berner, D.K. and Matschinsky, F.M. (1996) Glucose metabolism and insulin release in mouse betaHC9 cells, as model for wild-type pancreatic beta-cells. Am. Physiol. 270, E846-E857
173. Malaisse, W.J., Kawazu, S., Hercheulz, A., Hutton, J.C., Somers, G., Devis, G. and Sener, A. (1979) The stimulus secretion coupling of glucose-induced insulin release: effect of lactate upon islet function. Arch. Biochem. Biophys. 194, 49-62 CrossRef PubMed
174. Casimir, M., Rubi, B., Frigerio, F., Chaffard, G. and Maechler, P. (2009) Silencing of the mitochondrial NADH shuttle component aspartate-glutamate carrier AGC1/Aralar1 in INS-1E cells and rat islets. Biochem. J. 424, 459-466 CrossRef PubMed
175. 2+ within electropermeabilized insulin secreting cells (INS-1). Biochim. Biophys. Acta 1175, 107-113 CrossRef PubMed
176. Pullen, T.J. and Rutter, G.A. (2013) When less is more: the forbidden fruits of gene repression in the adult beta-cell. Diabetes Obes. Metab. 15, 503-512 CrossRef PubMed
177. Halestrap, A.P. and Meredith, D. (2004) The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch. 447, 619-628 CrossRef PubMed
178. Otonkoski, T., Jiao, H., Kaminen-Ahola, N., Tapia-Piaz, I., Ullah, M.S., Parton, L.E., Schuit, F.C., Quintens, R., Sipila, I., Mayatepek, E. et al. (2007) Physical exercise-induced hyperinsulinemic hypoglycemia caused by failure of monocarboxylate transporter 1 silencing in pancreatic beta cells. Am. J. Hum. Genet. 81, 467-474 CrossRef PubMed
179. Pullen, T.J., Sylow, L, Sun, G., Halestrap, A.P., Richter, E.A. and Rutter, G.A. (2012) Over-expression of Monocarboxylate Transporter-1 (Slc16a1) in the pancreatic beta-cell leads to relative hyperinsulinism during exercise. Diabetes 61, 1719-1725 CrossRef PubMed
180. Ishihara, H., Wang, H. and Wollheim, C.B. (1999) Engineering of pyruvate or lactate-stimulated insulin secretion in pancreatic islets. Diabetologia 42, A128 CrossRef
181. Prentki, M., Joly, E., El Assaad, W. and Roduit, R. (2002) Malonyl-CoA signaling, lipid partitioning, and glucolipotoxicity: role in beta-cell adaptation and failure in the etiology of diabetes. Diabetes 51, S405-S413 CrossRef PubMed
182. Lenzen, S. (2008) Oxidative stress: the vulnerable beta cell. Biochem. Soc. Trans. 36, 343-347 CrossRef PubMed
183. Jonas, J.C., Sharma, A., Hasenkamp, W., Ilkova, H., Patane, G., Laybutt, R., Bonner-Weir, S. and Weir, G.C. (1999) Chronic hyperglycemia triggers loss of pancreatic beta cell differentiation in an animal model of diabetes. J. Biol. Chem. 274, 14112-14121 CrossRef PubMed
184. Talchai, C., Xuan, S., Lin, H.V., Sussel, L. and Accili, D. (2012) Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150, 1223-1234 CrossRef PubMed
185. Guo, S., Dai, C., Guo, M., Taylor, B., Harmon, J.S., Sander, M., Robertson, R.P., Powers, A.C. and Stein, R. (2013) Inactivation of specific beta cell transcription factors in type 2 diabetes. J. Clin. Invest. 123, 3305-3316 CrossRef PubMed
186. Gu, C., Stein, G.H., Pan, N., Goebbels, S., Hornberg, H., Nave, K.A., Herrera, P., White, P., Kaestner, K.H., Sussel, L. and Lee, J.E. (2010) Pancreatic beta cells require NeuroD to achieve and maintain functional maturity. Cell Metab. 11, 298-310 CrossRef PubMed
187. Taylor, B.L., Benthuysen, J. and Sander, M. (2014) Postnatal beta cell proliferation and mass expansion is dependent on the transcription factor Nkx6.1. Diabetes DB
188. Hart, A.W., Mella, S., Mendrychowski, J., van Heyningen, V. and Kleinjan, D.A. (2013) The developmental regulator Pax6 is essential for maintenance of islet cell function in the adult mouse pancreas. PLoS One 8, e54173 CrossRef PubMed
189. Gao, T., McKenna, B., Li, C., Reichert, M., Nguyen, J., Singh, T., Yang, C., Pannikar, A., Doliba, N., Zhang, T. et al. (2014) Pdx1 maintains beta cell identity and function by repressing an alpha cell program. Cell Metab. 19, 259-271 CrossRef PubMed
190. Piccand, J., Strasser, P., Hodson, D.J., Meunier, A., Ye, T., Keime, C., Birling, M.-C., Rutter, G.A. and Gradwohl, G. (2014) Rfx6 maintains the functional identity of adult pancreatic β-cells. Cell Rep, in the press
191. Smith, S.B., Qu, H.Q., Taleb, N., Kishimoto, N.Y., Scheel, D.W., Lu, Y., Patch, A.M., Grabs, R., Wang, J., Lynn, F.C. et al. (2010) Rfx6 directs islet formation and insulin production in mice and humans. Nature 463, 775-780 CrossRef PubMed
192. Pullen, T.J., da Silva Xavier, G., Kelsey, G. and Rutter, G.A. (2011) miR-29a and miR-29b contribute to pancreatic {beta}-cell specific silencing of Monocarboxylate Transporter 1 (Mct1/slc16a1). Mol. Cell Biol. 31, 3182-3194 CrossRef PubMed
193. van Arensbergen, J., Garcia-Hurtado, J., Maestro, M.A., Correa-Tapia, M., Rutter, G.A., Vidal, M. and Ferrer, J. (2013) Ring1b bookmarks genes in pancreatic embryonic progenitors for repression in adult beta cells. Genes Dev. 27, 52-63 CrossRef PubMed
194. Cantley, J., Selman, C., Shukla, D., Abramov, A.Y., Forstreuter, F., Esteban, M.A., Claret, M., Lingard, S.J., Clements, M., Harten, S.K. et al. (2009) Deletion of the von Hippel-Lindau gene in pancreatic beta cells impairs glucose homeostasis in mice. J. Clin. Invest. 119, 125-135 PubMed
195. Bailey, C.J. and Turner, R.C. (1996) Metformin. N. Engl. J. Med. 334, 574-579 CrossRef PubMed
196. DeFronzo, R.A. and Goodman, A.M. (1995) Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N. Engl. J. Med. 333, 541-549 CrossRef PubMed
197. Owen, M.R., Doran, E. and Halestrap, A.P. (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607-614 CrossRef PubMed
198. Avnit-Sagi, T., Kantorovich, L., Kredo-Russo, S., Hornstein, E. and Walker, M.D. (2009) The promoter of the pri-miR-375 gene directs expression selectively to the endocrine pancreas. PLoS One 4, e5033 CrossRef PubMed
199. Francis, N., Moore, M., Rutter, G.A. and Burns, C. (2014) The role of microRNAs in the pancreatic differentiation of pluripotent stem cells. Microrna 3, 54-63 CrossRef PubMed
200. Poy, M.N., Eliasson, L., Krutzfeldt, J., Kuwajima, S., Ma, X., MacDonald, P.E., Pfeffer, S., Tuschl, T., Rajewsky, N., Rorsman, P. and Stoffel, M. (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226-230 CrossRef PubMed
201. Moran, I., Akerman, I., van de Bunt, M., Xie, R., Benazra, M., Nammo, T., Arnes, L., Nakic, N., Garcia-Hurtado, J., Rodriguez-Segui, S. et al. (2012) Human beta cell transcriptome analysis uncovers lncRNAs that are tissue-specific, dynamically regulated, and abnormally expressed in type 2 diabetes. Cell Metab. 16, 435-448 CrossRef PubMed
202. Dumortier, O. and Van, O.E. (2012) MicroRNAs in pancreas development. Diabetes Obes. Metab. 14, 22-28 CrossRef PubMed
203. Lynn, F.C., Skewes-Cox, P., Kosaka, Y., McManus, M.T., Harfe, B.D. and German, M.S. (2007) MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes 56, 2938-2945 CrossRef PubMed
204. Kalis, M., Bolmeson, C., Esguerra, J.L., Gupta, S., Edlund, A., Tormo-Badia, N., Speidel, D., Holmberg, D., Mayans, S., Khoo, N.K. et al. (2011) Beta-cell specific deletion of Dicer1 leads to defective insulin secretion and diabetes mellitus. PLoS One 6, e29166 CrossRef PubMed
205. Mandelbaum, A.D., Melkman-Zehavi, T., Oren, R., Kredo-Russo, S., Nir, T., Dor, Y. and Hornstein, E. (2012) Dysregulation of Dicer1 in beta cells impairs islet architecture and glucose metabolism. Exp. Diabetes Res. 2012, 470302, Epub ahead of print CrossRef PubMed
206. Guay, C., Jacovetti, C., Nesca, V., Motterle, A., Tugay, K. and Regazzi, R. (2012) Emerging roles of non-coding RNAs in pancreatic beta-cell function and dysfunction. Diabetes Obes. Metab. 14, 12-21 CrossRef PubMed
207. Kameswaran, V., Bramswig, N.C., McKenna, L.B., Penn, M., Schug, J., Hand, N.J., Chen, Y., Choi, I., Vourekas, A., Won, K.J. et al. (2014) Epigenetic regulation of the DLK1-MEG3 microRNA cluster in human type 2 diabetic islets. Cell Metab. 19, 135-145 CrossRef PubMed
208. Locke, J.M., da, S.X., Dawe, H.R., Rutter, G.A. and Harries, L.W. (2014) Increased expression of miR-187 in human islets from individuals with type 2 diabetes is associated with reduced glucose-stimulated insulin secretion. Diabetologia 57, 122-128 CrossRef PubMed
209. Roggli, E., Gattesco, S., Caille, D., Briet, C., Boitard, C., Meda, P. and Regazzi, R. (2012) Changes in microRNA expression contribute to pancreatic beta-cell dysfunction in prediabetic NOD mice. Diabetes 61, 1742-1751 CrossRef PubMed
210. Esguerra, J.L., Bolmeson, C., Cilio, C.M. and Eliasson, L. (2011) Differential glucose-regulation of MicroRNAs in pancreatic islets of non-obese type 2 diabetes model goto-kakizaki rat. PLoS One 6, e18613 CrossRef PubMed
211. Nesca, V., Guay, C., Jacovetti, C., Menoud, V., Peyot, M.L., Laybutt, D.R., Prentki, M. and Regazzi, R. (2013) Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia 56, 2203-2212 CrossRef PubMed
212. Kaspi, H., Pasvolsky, R. and Hornstein, E. (2014) Could microRNAs contribute to the maintenance of beta cell identity? Trends Endocrinol. Metab. 25, 285-292 CrossRef PubMed
213. Kanji, M.S., Martin, M.G. and Bhushan, A. (2013) Dicer1 is required to repress neuronal fate during endocrine cell maturation. Diabetes 62, 1602-1611 CrossRef PubMed
214. Pullen, T.J. and Rutter, G.A. (2014) Roles of lncRNAs in pancreatic beta cell identity and diabetes susceptibility. Front Genet. 5, 193, doi:10.3389/fgene.2014.00193 CrossRef PubMed
215. Courtney, M., Gjernes, E., Druelle, N., Ravaud, C., Vieira, A., Ben-Othman, N., Pfeifer, A., Avolio, F., Leuckx, G., Lacas-Gervais, S. et al. (2013) The inactivation of Arx in pancreatic alpha-cells triggers their neogenesis and conversion into functional beta-like cells. PLoS Genet. 9, e1003934 CrossRef PubMed
216. Sancho, R., Gruber, R., Gu, G. and Behrens, A. (2014) Loss of Fbw7 reprograms adult pancreatic ductal cells into alpha, delta, and beta cells. Cell Stem. Cell 15, 139-153 CrossRef PubMed
217. Ferber, S., Halkin, A., Cohen, H., Ber, I., Einav, Y., Goldberg, I., Barshack, I., Seijffers, R., Kopolovic, J., Kaiser, N. and Karasik, A. (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat. Med. 6, 568-572 CrossRef PubMed
218. Cheung, A.T., Dayanandan, B., Lewis, J.T., Korbutt, G.S., Rajotte, R.V., Bryer-Ash, M., Boylan, M.O., Wolfe, M.M. and Kieffer, T.J. (2000) Glucose-dependent insulin release from genetically engineered K cells. Science 290, 1959-1962 CrossRef PubMed
219. Okita, K., Ichisaka, T. and Yamanaka, S. (2007) Generation of germline-competent induced pluripotent stem cells. Nature 448, 313-317 CrossRef PubMed
220. D'Amour, K.A., Bang, A.G., Eliazer, S., Kelly, O.G., Agulnick, A.D., Smart, N.G., Moorman, M.A., Kroon, E., Carpenter, M.K. and Baetge, E.E. (2006) Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells. Nat. Biotechnol. 24, 1392-1401 CrossRef PubMed
221. Pagliuca, F.W., Millman, J.R., Gurtler, M., Segel, M., Van, D.A., Ryu, J.H., Peterson, Q.P., Greiner, D. and Melton, D.A. (2014) Generation of functional human pancreatic beta cells in vitro. Cell 159, 428-439 CrossRef PubMed
222. Rezania, A., Bruin, J.E., Arora, P., Rubin, A., Batushansky, I., Asadi, A., O'Dwyer, S., Quiskamp, N., Mojibian, M., Albrecht, T. et al. (2014) Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol. 32, 1121-1133 CrossRef PubMed
223. Nicolson, T.J., Bellomo, E.A., Wijesekara, N., Loder, M.K., Baldwin, J.M., Gyulkhandanyan, A.V., Koshkin, V., Tarasov, A.I., Carzaniga, R., Kronenberger, K. et al. (2009) Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58, 2070-2083 CrossRef PubMed