Dynamics of insulin secretion and the clinical implications for obesity and diabetes

Journal of Clinical Investigation

Volumn 121, Issue 6, 2011, Pages 2118-2125

  Seino, Susumu ^a,b   Shibasaki, Tadao ^a   Minami, Kohtaro ^a  

^a KOBE UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b JAPAN SCIENCE AND TECHNOLOGY AGENCY   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIC AMP; CYCLIC AMP DEPENDENT PROTEIN KINASE 2; EXENDIN 4; HORMONE; LIRAGLUTIDE; RAP1 PROTEIN; SULFONYLUREA;

DIABETES MELLITUS; GLUCOSE INTOLERANCE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INSULIN RELEASE; INSULIN RESISTANCE; MOLECULAR PATHOLOGY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; NUTRIENT; OBESITY; PANCREAS; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; CIRCADIAN RHYTHM; CYCLIC AMP; CYTOPLASMIC GRANULES; DIABETES MELLITUS; EATING; GLUCOSE METABOLISM DISORDERS; GUANINE NUCLEOTIDE EXCHANGE FACTORS; HUMANS; HYPOGLYCEMIC AGENTS; INCRETINS; INSULIN; INSULIN RESISTANCE; ISLETS OF LANGERHANS; MODELS, BIOLOGICAL; OBESITY; POTASSIUM CHANNELS; SECRETORY RATE; SIGNAL TRANSDUCTION;

EID: 79957900616     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI45680     Document Type: Review

References (119)

1. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287(2):E199-E206. (Pubitemid 38943883)
2. Newsholme P, Bender K, Kiely A, Brennan L. Amino acid metabolism, insulin secretion and diabetes. Biochem Soc Trans. 2007;35(pt 5):1180-1186. (Pubitemid 350206456)
3. Keane D, Newsholme P. Saturated and unsaturated (including arachidonic acid) non-esterified fatty acid modulation of insulin secretion from pancreatic β-cells. Biochem Soc Trans. 2008; 36(pt 5):955-958.
4. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131-2157. (Pubitemid 46711096)
5. Winzell MS, Ahrén B. G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. Pharmacol Ther. 2007;116(3):437-448. (Pubitemid 350116941)
6. Prentki M, Matschinsky FM. Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol Rev. 1987; 67(4):1185-1248. (Pubitemid 18003171)
7. Wollheim CB, Sharp GW. Regulation of insulin release by calcium. Physiol Rev. 1981;61(4):914-973.
8. Ashcroft FM. ATP-sensitive potassium channelopathies: focus on insulin secretion. J Clin Invest. 2005;115(8):2047-2058. (Pubitemid 41134141)
9. Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes. 2000;49(11):1751-1760.
10. Weigle DS. Pulsatile secretion of fuel-regulatory hormones. Diabetes. 1987;36(6):764-775. (Pubitemid 17141116)
11. Lefèbvre PJ, Paolisso G, Scheen AJ, Henquin JC. Pulsatility of insulin and glucagon release: physiological significance and pharmacological implications. Diabetologia. 1987;30(7):443-452. (Pubitemid 17139070)
12. Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988;81(2):442-448. (Pubitemid 18075238)
13. Lang DA, Matthews DR, Peto J, Turner RC. Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl J Med. 1979; 301(19):1023-1027. (Pubitemid 10158038)
14. Matthews DR, Naylor BA, Jones RG, Ward GM, Turner RC. Pulsatile insulin has greater hypoglycemic effect than continuous delivery. Diabetes. 1983;32(7):617-621. (Pubitemid 13062843)
15. Stagner JI, Samols E, Weir GC. Sustained oscillations of insulin, glucagon, and somatostatin from the isolated canine pancreas during exposure to a constant glucose concentration. J Clin Invest. 1980; 65(4):939-942. (Pubitemid 10144072)
16. Matthews DR, et al. Greater in vivo than in vitro pulsatility of insulin secretion with synchronized insulin and somatostatin secretory pulses. Endocrinology. 1987;120(6):2272-2278. (Pubitemid 17084897)
17. Gilon P, Ravier MA, Jonas JC, Henquin JC. Control mechanisms of the oscillations of insulin secretion in vitro and in vivo. Diabetes. 2002; 51(suppl 1):S144-S151. (Pubitemid 34761510)
18. Cerasi E, Luft R. The plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus. Acta Endocrinol (Copenh). 1967;55(2):278-304.
19. Curry DL, Bennett LL, Grodsky GM. Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology. 1968;83(3):572-584.
20. Luzi L, DeFronzo RA. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol. 1989;257(2 pt 1):E241-E246.
21. Davis SN, et al. Proinsulin and insulin concentrations following intravenous glucose challenges in normal, obese, and non-insulin-dependent diabetic subjects. Metabolism. 1993;42(1):30-35. (Pubitemid 23019929)
22. Rorsman P, Renström E. Insulin granule dynamics in pancreatic beta cells. Diabetologia. 2003;46(8):1029-1045. (Pubitemid 37041234)
23. Axelrod D. Selective imaging of surface fluorescence with very high aperture microscope objectives. J Biomed Opt. 2001;6(1):6-13. (Pubitemid 32254908)
24. Tsuboi T, Zhao C, Terakawa S, Rutter GA. Simultaneous evanescent wave imaging of insulin vesicle membrane and cargo during a single exocytotic event. Curr Biol. 2000;10(20):1307-1310.
25. Shibasaki T, et al. Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP. Proc Natl Acad Sci U S A. 2007; 104(49):19333-19338.
26. Kasai K, Fujita T, Gomi H, Izumi T. Docking is not a prerequisite but a temporal constraint for fusion of secretory granules. Traffic. 2008;9(7):1191-1203. (Pubitemid 351916892)
27. Ohara-Imaizumi M, et al. Imaging analysis reveals mechanistic differences between first- and second-phase insulin exocytosis. J Cell Biol. 2007; 177(4):695-705. (Pubitemid 46799840)
28. Seino S, Takahashi H, Fujimoto W, Shibasaki T. Roles of cAMP signalling in insulin granule exocytosis. Diabetes Obes Metab. 2009;11 suppl 4:180-188.
29. Yasuda T, et al. Rim2α determines docking and priming States in insulin granule exocytosis. Cell Metab. 2010;12(2):117-129.
30. Maechler P, Wollheim CB. Mitochondrial signals in glucose-stimulated insulin secretion in the beta cell. J Physiol. 2000;529 pt 1:49-56.
31. Wilson JR, Ludowyke RI, Biden TJ. A redistribution of actin and myosin IIA accompanies Ca2+-dependent insulin secretion. FEBS Lett. 2001;492(1-2):101-106. (Pubitemid 32206728)
32. Thurmond DC, Gonelle-Gispert C, Furukawa M, Halban PA, Pessin JE. Glucose-stimulated insulin secretion is coupled to the interaction of actin with the t-SNARE (target membrane soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein) complex. Mol Endocrinol. 2003;17(4):732-742. (Pubitemid 36403583)
33. Wang Z, Thurmond DC. Mechanisms of biphasic insulin-granule exocytosis - roles of the cytoskeleton, small GTPases and SNARE proteins. J Cell Sci. 2009;122(pt 7):893-903.
34. Jewell JL, Oh E, Thurmond DC. Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4. Am J Physiol Regul Integr Comp Physiol. 2010;298(3):R517-R531.
35. Wang Z, Thurmond DC. Differential phosphorylation of RhoGDI mediates the distinct cycling of Cdc42 and Rac1 to regulate second-phase insulin secretion. J Biol Chem. 2010;285(9):6186-6197.
36. Malacombe M, Bader MF, Gasman S. Exocytosis in neuroendocrine cells: new tasks for actin. Biochim Biophys Acta. 2006;1763(11):1175-1183. (Pubitemid 44779865)
37. Tsuboi T, Rutter GA. Insulin secretion by 'kiss-andrun' exocytosis in clonal pancreatic islet beta-cells. Biochem Soc Trans. 2003;31(pt 4):833-836.
38. Eliasson L, Abdulkader F, Braun M, Galvanovskis J, Hoppa MB, Rorsman P. Novel aspects of the molecular mechanisms controlling insulin secretion. J Physiol. 2008;586(14):3313-3324. (Pubitemid 352003868)
39. Ma L, et al. Direct imaging shows that insulin granule exocytosis occurs by complete vesicle fusion. Proc Natl Acad Sci U S A. 2004;101(25):9266-9271. (Pubitemid 38812864)
40. Nauck MA. Unraveling the science of incretin biology. Am J Med. 2009;122(6 suppl):S3-S10.
41. Elliott RM, Morgan LM, Tredger JA, Deacon S, Wright J, Marks V. Glucagon-like peptide-1 (7-36)amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol. 1993;138(1):159-166.
42. Dupre J, Ross SA, Watson D, Brown JC. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973; 37(5):826-828.
43. Schmidt WE, Siegel EG, Creutzfeldt W. Glucagonlike peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancreatic islets. Diabetologia. 1985;28(9):704-707. (Pubitemid 16226411)
44. Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon- like peptide 1. Proc Natl Acad Sci U S A. 1992; 89(18):8641-8645.
45. Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI. Gastric inhibitory polypeptide receptor, a member of the secretin-vasoactive intestinal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology. 1993;133(6):2861-2870. (Pubitemid 24000747)
46. Yasuda K, Inagaki N, Yamada Y, Kubota A, Seino S, Seino Y. Hamster gastric inhibitory polypeptide receptor expressed in pancreatic islets and clonal insulin-secreting cells: its structure and functional properties. Biochem Biophys Res Commun. 1994; 205(3):1556-1562.
47. Miki T, et al. Distinct effects of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 on insulin secretion and gut motility. Diabetes. 2005;54(4):1056-1063. (Pubitemid 40446319)
48. Fujimoto W, et al. Niflumic acid-sensitive ion channels play an important role in the induction of glucose-stimulated insulin secretion by cyclic AMP in mice. Diabetologia. 2009;52(5):863-872.
49. Gembal M, Detimary P, Gilon P, Gao ZY, Henquin JC. Mechanisms by which glucose can control insulin release independently from its action on adenosine triphosphate-sensitive K+ channels in mouse B cells. J Clin Invest. 1993;91(3):871-880. (Pubitemid 23095261)
50. Shima K, Hirota M, Ohboshi C. Effect of glucagon- like peptide-1 on insulin secretion. Regul Pept. 1988;22(3):245-252.
51. Holz GG 4th, Kühtreiber WM, Habener JF. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide- 1(7-37). Nature. 1993;361(6410):362-365.
52. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest. 1993;91(1):301-307. (Pubitemid 23037285)
53. Seino S, Shibasaki T. PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev. 2005;85(4):1303-1342. (Pubitemid 41362272)
54. Iwasaki M, Minami K, Shibasaki T, Miki T, Miyazaki J-I, Seino S. Establishment of new clonal pancreatic β-cell lines (MIN6-K) useful for study of incretin/ cAMP signaling. J Diabetes Invest. 2010;1(4):137-142.
55. 2+ and cAMP signaling in the insulin-secreting MIN6 beta-cell line. J Biol Chem. 2005;280(35):31294- 31302.
56. Dyachok O, Isakov Y, SÅgetorp J, Tengholm A. Oscillations of cyclic AMP in hormone-stimulated insulin-secreting β-cells. Nature. 2006; 439(7074):349-352. (Pubitemid 43128861)
57. Dyachok O, et al. Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion. Cell Metab. 2008;8(1):26-37. (Pubitemid 351859229)
58. Malaisse WJ, Malaisse-Lagae F. The role of cyclic AMP in insulin release. Experientia. 1984; 40(10):1068-1074.
59. Jones PM, Persaud SJ. Protein kinases, protein phosphorylation, and the regulation of insulin secretion from pancreatic beta-cells. Endocr Rev. 1998; 19(4):429-461. (Pubitemid 29116376)
60. Eliasson L, et al. SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B-cells. J Gen Physiol. 2003;121(3):181-197. (Pubitemid 36292989)
61. Ozaki N, et al. cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nat Cell Biol. 2000; 2(11):805-811.
62. Bos JL. Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci. 2006;31(12):680-686. (Pubitemid 44791945)
63. Niimura M, Miki T, Shibasaki T, Fujimoto W, Iwanaga T, Seino S. Critical role of the N-terminal cyclic AMP-binding domain of Epac2 in its subcellular localization and function. J Cell Physiol. 2009;219(3):652-658.
64. Inagaki N, et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995;270(5239):1166-1170.
65. Aguilar-Bryan L, et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science. 1995;268(5209):423-426.
66. Seino S. ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu Rev Physiol. 1999;61:337-362. (Pubitemid 29143174)
67. Zhang CL, et al. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science. 2009;325(5940):607-610.
68. Seino S, Zhang CL, Shibasaki T. Sulfonylurea action re-revisited. J Diabetes Invest. 2010;1:37-39.
69. Groop LC, et al. Effect of sulphonylurea on glucose- stimulated insulin secretion in healthy and non-insulin dependent diabetic subjects: a dose-response study. Acta Diabetol. 1991;28(2):162-168.
70. Kramer W, Muller G, Geisen K. Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at beta-cells. Horm Metab Res. 1996; 28(9):464-468. (Pubitemid 26343739)
71. 2+-dependent exocytosis in pancreatic beta cells is mediated by a 65-kDa mdr-like P-glycoprotein. Proc Natl Acad Sci U S A. 1999;96(10):5539-5544.
72. + channel-independent action. Diabetes. 2002;51(suppl 1):S33-S36.
73. Deriy LV, et al. The granular chloride channel ClC-3 is permissive for insulin secretion. Cell Metab. 2009; 10(4):316-323.
74. Barg S, et al. Priming of insulin granules for exocytosis by granular Cl- uptake and acidification. J Cell Sci. 2001;114(pt 11):2145-2154.
75. Li DQ, et al. Suppression of sulfonylurea- and glucose- induced insulin secretion in vitro and in vivo in mice lacking the chloride transport protein ClC-3. Cell Metab. 2009;10(4):309-315.
76. Faber OK, Christensen K, Kehlet H, Madsbad S, Binder C. Decreased insulin removal contributes to hyperinsulinemia in obesity. J Clin Endocrinol Metab. 1981;53(3):618-621. (Pubitemid 12005809)
77. Meistas MT, Rendell M, Margolis S, Kowarski AA. Estimation of the secretion rate of insulin from the urinary excretion rate of C-peptide. Study in obese and diabetic subjects. Diabetes. 1982; 31(5 pt 1):449-453.
78. Polonsky KS, et al. Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest. 1988;81(2):435-441. (Pubitemid 18075237)
79. Jones CN, Abbasi F, Carantoni M, Polonsky KS, Reaven GM. Roles of insulin resistance and obesity in regulation of plasma insulin concentrations. Am J Physiol Endocrinol Metab. 2000;278(3):E501-E508. (Pubitemid 30149395)
80. Bergman RN, Phillips LS, Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and betacell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981;68(6):1456-1467. (Pubitemid 12194400)
81. Kahn SE, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes. 1993;42(11):1663-1672.
82. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999;104(6):787-794. (Pubitemid 29536364)
83. Elbein SC, Wegner K, Kahn SE. Reduced beta-cell compensation to the insulin resistance associated with obesity in members of caucasian familial type 2 diabetic kindreds. Diabetes Care. 2000;23(2):221-227. (Pubitemid 30071028)
84. Bacha F, Gungor N, Lee S, Arslanian SA. In vivo insulin sensitivity and secretion in obese youth: what are the differences between normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes? Diabetes Care. 2009;32(1):100-105.
85. Taniguchi A, et al. Insulin sensitivity, insulin secretion, and glucose effectiveness in obese subjects: a minimal model analysis. Metabolism. 1995; 44(11):1397-1400. (Pubitemid 26082528)
86. Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell. 1999;96(3):329-339. (Pubitemid 29077587)
87. Kahn CR, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man. N Engl J Med. 1976;294(14):739- 745.
88. Schoenle EJ, Zenobi PD, Torresani T, Werder EA, Zachmann M, Froesch ER. Recombinant human insulin-like growth factor I (rhIGF I) reduces hyperglycaemia in patients with extreme insulin resistance. Diabetologia. 1991;34(9):675-679.
89. Mandavilli A, Cyranoski D. Asia's big problem. Nat Med. 2004;10(4):325-327. (Pubitemid 38508499)
90. Welch S, Gebhart SS, Bergman RN, Phillips LS. Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab. 1990;71(6):1508-1518. (Pubitemid 120032768)
91. Taniguchi A, et al. Glucose effectiveness in two subtypes within impaired glucose tolerance. A minimal model analysis. Diabetes. 1994;43(10):1211-1217.
92. Kendall DM, Sutherland DE, Najarian JS, Goetz FC, Robertson RP. Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. N Engl J Med. 1990;322(13):898-903. (Pubitemid 20108379)
93. McCulloch DK, et al. Defects in beta-cell function and insulin sensitivity in normoglycemic streptozocin- treated baboons: a model of preclinical insulin-dependent diabetes. J Clin Endocrinol Metab. 1988;67(4):785-792.
94. Rachman J, Gribble FM, Barrow BA, Levy JC, Buchanan KD, Turner RC. Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM. Diabetes. 1996;45(11):1524-1530.
95. Fritsche A, Stefan N, Hardt E, Häring H, Stumvoll M. Characterisation of beta-cell dysfunction of impaired glucose tolerance: evidence for impairment of incretin-induced insulin secretion. Diabetologia. 2000;43(7):852-858. (Pubitemid 30463164)
96. Brunzell JD, et al. Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests. J Clin Endocrinol Metab. 1976;42(2):222-229.
97. Utzschneider KM, et al. Impact of differences in fasting glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses. Diabetes Care. 2006;29(2):356-362. (Pubitemid 44106518)
98. Cnop M, et al. Progressive loss of beta-cell function leads to worsening glucose tolerance in first-degree relatives of subjects with type 2 diabetes. Diabetes Care. 2007;30(3):677-682. (Pubitemid 46354352)
99. Doi K, et al. Decreased glucose effectiveness but not insulin resistance in glucose-tolerant offspring of Japanese non-insulin-dependent diabetic patients: a minimal-model analysis. Metabolism. 1997;46(8):880-883. (Pubitemid 27339910)
100. Cavaghan MK, Ehrmann DA, Polonsky KS. Interactions between insulin resistance and insulin secretion in the development of glucose intolerance. J Clin Invest. 2000;106(3):329-333. (Pubitemid 30655631)
101. Emerson P, et al. Different pathophysiology of impaired glucose tolerance in first-degree relatives of individuals with type 2 diabetes mellitus. Metabolism. 2009;58(5):602-607.
102. Godsland IF, Jeffs JA, Johnston DG. Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia. 2004;47(7):1157- 1166. (Pubitemid 39093312)
103. Polonsky KS, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988;318(19):1231-1239.
104. Lang DA, Matthews DR, Burnett M, Turner RC. Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes. 1981;30(5):435-439. (Pubitemid 11022835)
105. O'Rahilly S, Turner RC, Matthews DR. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med. 1988;318(19):1225-1230.
106. Schmitz O, et al. Disorderly and nonstationary insulin secretion in relatives of patients with NIDDM. Am J Physiol. 1997;272(2 pt 1):E218-E226.
107. Byrne MM, Sturis J, Sobel RJ, Polonsky KS. Elevated plasma glucose 2 h postchallenge predicts defects in beta-cell function. Am J Physiol. 1996; 270(4 pt 1):E572-E579.
108. Marcheva B, et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466(7306):627-631.
109. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409-1439. (Pubitemid 350041474)
110. Quddusi S, Vahl TP, Hanson K, Prigeon RL, D'Alessio DA. Differential effects of acute and extended infusions of glucagon-like peptide-1 on first- and second-phase insulin secretion in diabetic and nondiabetic humans. Diabetes Care. 2003; 26(3):791-798. (Pubitemid 36929345)
111. Meier S, Hücking K, Ritzel R, Holst JJ, Schmiegel WH, Nauck MA. Absence of a memory effect for the insulinotropic action of glucagon-like peptide 1 (GLP-1) in healthy volunteers. Horm Metab Res. 2003;35(9):551-556. (Pubitemid 37260421)
112. Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003;114(2-3):115-121. (Pubitemid 36773875)
113. Elahi D, et al. The insulinotropic actions of glucose- dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects. Regul Pept. 1994;51(1):63-74.
114. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36(8):741-744. (Pubitemid 23218642)
115. Meier JJ, Nauck MA. Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired beta-cell function? Diabetes. 2010;59(5):1117-1125.
116. Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J Diabetes Invest. 2010;1(1-2):8-23.
117. Chang AM, et al. The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose. Diabetes. 2003; 52(7):1786-1791. (Pubitemid 36792471)
118. Fehse F, et al. Exenatide augments first- and second- phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2005;90(11):5991-5997. (Pubitemid 41606516)
119. Vilsbøll T, Krarup T, Madsbad S, Holst JJ. Defective amplification of the late phase insulin response to glucose by GIP in obese Type II diabetic patients. Diabetologia. 2002;45(8):1111-1119. (Pubitemid 34985287)