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Cited by 364Pancreatic function and diabetesDiabetes and associated disordersDiabetes Treatment and Management

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

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Seino, Susumu, Shibasaki, Tadao, Minami, Kohtaro·2011·Journal of Clinical Investigation
DOI 10.1172/jci45680PMC PMC3104758
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Abstract

Insulin secretion is a highly dynamic process regulated by various factors including nutrients, hormones, and neuronal inputs. The dynamics of insulin secretion can be studied at different levels: the single β cell, pancreatic islet, whole pancreas, and the intact organism. Studies have begun to analyze cellular and molecular mechanisms underlying dynamics of insulin secretion. This review focuses on our current understanding of the dynamics of insulin secretion in vitro and in vivo and discusses their clinical relevance.

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  • There is also agreement that 2nd phase GIIS largely reflects the release of 'newcomer' granules rather than granules that are initially docked below the plasma membrane.

    “There is also agreement that 2nd phase GIIS largely reflects the release of ‘newcomer’ granules (Figure 23A) rather than granules that are initially docked below the plasma membrane (610).”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [610]

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  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.
  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.
  3. Keane D, Newsholme P. Saturated and unsatu- rated (including arachidonic acid) non-esteri- fied fatty acid modulation of insulin secretion from pancreatic β-cells. Biochem Soc Trans. 2008; 36(pt 5):955-958.
  4. 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.
  5. Prentki M, Matschinsky FM. Ca 2+ , cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol Rev. 1987; 67(4):1185-1248.
  6. Wollheim CB, Sharp GW. Regulation of insulin release by calcium. Physiol Rev. 1981;61(4):914-973.
  7. Ashcroft FM. ATP-sensitive potassium channelo- pathies: focus on insulin secretion. J Clin Invest. 2005;115(8):2047-2058.
  8. Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes. 2000;49(11):1751-1760.
  9. Weigle DS. Pulsatile secretion of fuel-regulatory hormones. Diabetes. 1987;36(6):764-775.
  10. Lefèbvre PJ, Paolisso G, Scheen AJ, Henquin JC. Pul- satility of insulin and glucagon release: physiologi- cal significance and pharmacological implications. Diabetologia. 1987;30(7):443-452.
  11. 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.
  12. 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.
  13. Matthews DR, Naylor BA, Jones RG, Ward GM, Turner RC. Pulsatile insulin has greater hypogly- cemic effect than continuous delivery. Diabetes. 1983;32(7):617-621.
  14. Stagner JI, Samols E, Weir GC. Sustained oscilla- tions 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.
  15. Matthews DR, et al. Greater in vivo than in vitro pulsatility of insulin secretion with synchronized insulin and somatostatin secretory pulses. Endocri- nology. 1987;120(6):2272-2278.
  16. Davis SN, et al. Proinsulin and insulin concentra- tions following intravenous glucose challenges in normal, obese, and non-insulin-dependent diabetic subjects. Metabolism. 1993;42(1):30-35.
  17. Rorsman P, Renström E. Insulin granule dynamics in pancreatic beta cells. Diabetologia. 2003;46(8):1029-1045.
  18. Axelrod D. Selective imaging of surface fluorescence with very high aperture microscope objectives. J Biomed Opt. 2001;6(1):6-13.
  19. Tsuboi T, Zhao C, Terakawa S, Rutter GA. Simul- taneous evanescent wave imaging of insulin vesicle membrane and cargo during a single exocytotic event. Curr Biol. 2000;10(20):1307-1310.
  20. Shibasaki T, et al. Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynam- ics by cAMP. Proc Natl Acad Sci U S A. 2007; 104(49):19333-19338.
  21. 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.
  22. Yasuda T, et al. Rim2α determines docking and priming States in insulin granule exocytosis. Cell Metab. 2010;12(2):117-129.
  23. Wilson JR, Ludowyke RI, Biden TJ. A redistribution of actin and myosin IIA accompanies Ca 2+ -dependent insulin secretion. FEBS Lett. 2001;492(1-2):101-106.
  24. 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.
  25. Jewell JL, Oh E, Thurmond DC. Exocytosis mechanisms underlying insulin release and glu- cose uptake: conserved roles for Munc18c and syntaxin 4. Am J Physiol Regul Integr Comp Physiol. 2010;298(3):R517-R531.
  26. Wang Z, Thurmond DC. Differential phosphory- lation of RhoGDI mediates the distinct cycling of Cdc42 and Rac1 to regulate second-phase insulin secretion. J Biol Chem. 2010;285(9):6186-6197.
  27. Malacombe M, Bader MF, Gasman S. Exocytosis in neuroendocrine cells: new tasks for actin. Biochim Biophys Acta. 2006;1763(11):1175-1183.
  28. Tsuboi T, Rutter GA. Insulin secretion by 'kiss-and- run' exocytosis in clonal pancreatic islet beta-cells. Biochem Soc Trans. 2003;31(pt 4):833-836.
  29. Eliasson L, Abdulkader F, Braun M, Galvanovskis J, Hoppa MB, Rorsman P. Novel aspects of the molec- ular mechanisms controlling insulin secretion. J Physiol. 2008;586(14):3313-3324.
  30. Ma L, et al. Direct imaging shows that insulin gran- ule exocytosis occurs by complete vesicle fusion. Proc Natl Acad Sci U S A. 2004;101(25):9266-9271.
  31. 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 inges- tion in man: acute post-prandial and 24-h secretion patterns. J Endocrinol. 1993;138(1):159-166.
  32. Dupre J, Ross SA, Watson D, Brown JC. Stimu- lation of insulin secretion by gastric inhibitory polypeptide in man. J Clin Endocrinol Metab. 1973; 37(5):826-828.
  33. Schmidt WE, Siegel EG, Creutzfeldt W. Glucagon- like peptide-1 but not glucagon-like peptide-2 stimulates insulin release from isolated rat pancre- atic islets. Diabetologia. 1985;28(9):704-707.
  34. Thorens B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone gluca- gon-like peptide 1. Proc Natl Acad Sci U S A. 1992; 89(18):8641-8645.
  35. Usdin TB, Mezey E, Button DC, Brownstein MJ, Bonner TI. Gastric inhibitory polypeptide recep- tor, a member of the secretin-vasoactive intesti- nal peptide receptor family, is widely distributed in peripheral organs and the brain. Endocrinology. 1993;133(6):2861-2870.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. Shima K, Hirota M, Ohboshi C. Effect of gluca- gon-like peptide-1 on insulin secretion. Regul Pept. 1988;22(3):245-252.
  41. Holz GG 4th, Kühtreiber WM, Habener JF. Pancre- atic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide- 1(7-37). Nature. 1993;361(6410):362-365.
  42. Seino S, Shibasaki T. PKA-dependent and PKA-inde- pendent pathways for cAMP-regulated exocytosis. Physiol Rev. 2005;85(4):1303-1342.
  43. 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.
  44. Landa LR Jr, et al. Interplay of Ca 2+ and cAMP sig- naling in the insulin-secreting MIN6 beta-cell line. J Biol Chem. 2005;280(35):31294-31302.
  45. Dyachok O, Isakov Y, SÅgetorp J, Tengholm A. Oscillations of cyclic AMP in hormone-stimu- lated insulin-secreting β-cells. Nature. 2006; 439(7074):349-352.
  46. Dyachok O, et al. Glucose-induced cyclic AMP oscillations regulate pulsatile insulin secretion. Cell Metab. 2008;8(1):26-37.
  47. Malaisse WJ, Malaisse-Lagae F. The role of cyclic AMP in insulin release. Experientia. 1984; 40(10):1068-1074.
  48. Jones PM, Persaud SJ. Protein kinases, protein phos- phorylation, and the regulation of insulin secre- tion from pancreatic beta-cells. Endocr Rev. 1998; 19(4):429-461.
  49. Eliasson L, et al. SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancre- atic B-cells. J Gen Physiol. 2003;121(3):181-197.
  50. Ozaki N, et al. cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nat Cell Biol. 2000; 2(11):805-811.
  51. Bos JL. Epac proteins: multi-purpose cAMP targets. Trends Biochem Sci. 2006;31(12):680-686.
  52. Niimura M, Miki T, Shibasaki T, Fujimoto W, Iwanaga T, Seino S. Critical role of the N-termi- nal cyclic AMP-binding domain of Epac2 in its subcellular localization and function. J Cell Physiol. 2009;219(3):652-658.
  53. Inagaki N, et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science. 1995;270(5239):1166-1170.
  54. Aguilar-Bryan L, et al. Cloning of the beta cell high- affinity sulfonylurea receptor: a regulator of insu- lin secretion. Science. 1995;268(5209):423-426.
  55. Seino S. ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu Rev Physiol. 1999;61:337-362.
  56. Zhang CL, et al. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science. 2009;325(5940):607-610.
  57. Seino S, Zhang CL, Shibasaki T. Sulfonylurea action re-revisited. J Diabetes Invest. 2010;1:37-39.
  58. Groop LC, et al. Effect of sulphonylurea on glu- cose-stimulated insulin secretion in healthy and non-insulin dependent diabetic subjects: a dose- response study. Acta Diabetol. 1991;28(2):162-168.
  59. 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.
  60. Barg S, et al. The stimulatory action of tolbutamide on Ca 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.
  61. Deriy LV, et al. The granular chloride channel ClC-3 is permissive for insulin secretion. Cell Metab. 2009; 10(4):316-323.
  62. 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.
  63. 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.
  64. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 dia- betes mellitus. J Clin Invest. 1999;104(6):787-794.
  65. 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.
  66. Taniguchi A, et al. Insulin sensitivity, insulin secretion, and glucose effectiveness in obese sub- jects: a minimal model analysis. Metabolism. 1995; 44(11):1397-1400.
  67. Kulkarni RN, Brüning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knock- out 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.
  68. Kahn CR, et al. The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disor- ders in man. N Engl J Med. 1976;294(14):739-745.
  69. 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.
  70. Mandavilli A, Cyranoski D. Asia's big problem. Nat Med. 2004;10(4):325-327.
  71. Welch S, Gebhart SS, Bergman RN, Phillips LS. Min- imal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects. J Clin Endocrinol Metab. 1990;71(6):1508-1518.
  72. Taniguchi A, et al. Glucose effectiveness in two sub- types within impaired glucose tolerance. A minimal model analysis. Diabetes. 1994;43(10):1211-1217.
  73. 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.
  74. McCulloch DK, et al. Defects in beta-cell function and insulin sensitivity in normoglycemic strep- tozocin-treated baboons: a model of preclinical insulin-dependent diabetes. J Clin Endocrinol Metab. 1988;67(4):785-792.
  75. Rachman J, Gribble FM, Barrow BA, Levy JC, Buchanan KD, Turner RC. Normalization of insu- lin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM. Diabetes. 1996;45(11):1524-1530.
  76. Fritsche A, Stefan N, Hardt E, Häring H, Stumvoll M. Characterisation of beta-cell dysfunction of impaired glucose tolerance: evidence for impair- ment of incretin-induced insulin secretion. Diabe- tologia. 2000;43(7):852-858.
  77. 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.
  78. Utzschneider KM, et al. Impact of differences in fast- ing glucose and glucose tolerance on the hyperbolic relationship between insulin sensitivity and insulin responses. Diabetes Care. 2006;29(2):356-362.

Cited by

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Authors
Seino, S., Shibasaki, T., & Minami, K.
Affiliations
Kobe University (JP)
Corresponding author
Seino, Susumu
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2011-06-01
Volume
121
Issue
6
Pages
2118-2125
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci45680
PMC
PMC3104758
OpenAlex
W2011267160
Cited by
364
References
18
Citations by year
2026: 7 · 2025: 19 · 2024: 13 · 2023: 20 · 2022: 19 · 2021: 35 · 2020: 20 · 2019: 19 · 2018: 20 · 2017: 17 · 2016: 28 · 2015: 40 · 2014: 34 · 2013: 36 · 2012: 30
FWCI
6.04
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of Chicago
  • Ministry of Education, Culture, Sports, Science and Technology
  • Japan Society for the Promotion of Science (21591137, 21249057, 21590308)
  • Japan Science and Technology Agency
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
insulin secretion, pancreatic beta cells, pancreatic islets, obesity, diabetes mellitus, glucose-stimulated insulin secretion
MeSH terms
Insulin Secretion, Cyclic AMP, Animals, Circadian Rhythm, Cytoplasmic Granules, Diabetes Mellitus, Eating, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Islets of Langerhans, Models, Biological, Obesity, Secretory Rate, Potassium Channels, Signal Transduction, Guanine Nucleotide Exchange Factors, Glucose Metabolism Disorders, Incretins

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