Advertisement

Pancreatic Islet Pathology in Type 2 Diabetes

  • Anne Clark

Abstract

Inadequate insulin secretion is a major factor in type 2 diabetes. Islet dysfunction is evident at the onset of the disease but the causal factors are largely unknown; decreased beta-cell mass, as shown in rodent models of diabetes, has been proposed. Quantitative morphometry of post-mortem human pancreas has demonstrated 0–50% less beta-cell population in diabetic compared to nondiabetic subjects. The evidence for continuous turnover of beta cells in adult human pancreas by apoptosis and regeneration (as in rodents) has yet to be proven; low incidence of cell division in ducts or islets has been reported and no evidence for abnormal cell turnover contributing to decreased beta-cell mass in human diabetes has been seen. The functional capacity for increased insulin secretion is high in diabetic and nondiabetic subjects. It is likely that a deficit in function is a major contributor for type 2 diabetes in man. Islet amyloid deposition is heterogeneous in human diabetes and is unlikely to contribute to decreased beta-cell mass at onset of hyperglycemia in man as shown in rodent models, monkeys, and cats. The effects of elevated lipids on beta-cell function is mediated by modulation of metabolism but the cytotoxic effects of lipids on beta cells—lipotoxicity—is mediated largely by aberrant effects of saturated fatty acids on cells in vitro. Increased availability of human isolated islets will enable accurate determination of functional and morphological changes which contribute to impaired insulin secretion in type 2 diabetes.

Keywords

Insulin Secretion Beta Cell Islet Cell Nondiabetic Subject Islet Amyloid Polypeptide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Weir GC and Bonner-Weir S (2004) Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 53Suppl 3:S16–21PubMedGoogle Scholar
  2. 2.
    Kahn SE (2001) Beta cell failure: causes and consequences. Int J Clin Pract Suppl 13–18Google Scholar
  3. 3.
    Sempoux C, Guiot Y, Dubois D, Moulin P and Rahier J (2001) Morphological evidence for abnormal beta-cell function. Diabetes 50,supplement 1:S172–S177PubMedGoogle Scholar
  4. 4.
    Jones LC and Clark A (2001) beta-cell neogenesis in type 2 diabetes. Diabetes 50Suppl 1:S186–187PubMedGoogle Scholar
  5. 5.
    McCarthy MI (2004) Progress in defining the molecular basis of type 2 diabetes mellitus through susceptibility-gene identification. Hum Mol Genet 13 Spec No 1: R33–41PubMedGoogle Scholar
  6. 6.
    Gloyn AL (2003) The search for type 2 diabetes genes. Ageing Res Rev 2:111–127PubMedGoogle Scholar
  7. 7.
    Edlund H (2002) Pancreatic organogenesis-developmental mechanisms and implications for therapy. Nature Rev Genetics 3:524–532Google Scholar
  8. 8.
    Watada H, Scheel DW, Leung J and German MS (2003) Distinct gene expression programs function in progenitor and mature islet cells. J Biol Chem 278: 17130–17140PubMedGoogle Scholar
  9. 9.
    Madsen OD, Jensen J, Petersen HV, Pedersen EE, Oster A, Andersen FG, Jorgensen MC, Jensen PB, Lasson LI, Serup P. (1997) Transcription factors contributing to the pancreatic beta-cell phenotype. Hormone and Metabolic Research 29:265–270PubMedGoogle Scholar
  10. 10.
    Chakrabarti SK and Mirmira RG (2003) Transcription factors direct the development and function of pancreatic beta cells. Trends Endocrinol Metab 14:78–84PubMedGoogle Scholar
  11. 11.
    Prentki M and Nolan CJ (2006) Islet beta cell failure in type 2 diabetes. J Clin Invest 116:1802–1812PubMedGoogle Scholar
  12. 12.
    Westermark P (1972) Quantitiative studies on amyloid in the islets of Langerhans. Upps. J. Med. Sci. 77:91–94Google Scholar
  13. 13.
    Röcken C, Linke RP and Saeger W (1992) Immunohistology of islet amyloid polypeptide in diabetes mellitus: semi-quantitative studies in a post-mortem series. Virchows Arch A Pathol Anat Histopathol 421:339–344PubMedGoogle Scholar
  14. 14.
    Clark A, Matthews DR, Naylor BA, Wells CA, Hosker JP and Turner RC (1987) Pancreatic islet amyloid and elevated proinsulin secretion in familial maturity-onset diabetes. Diabetes Res 4:51–55PubMedGoogle Scholar
  15. 15.
    Foulis AK, Liddle CN, Farquharson MA, Richmond JA and Wier RS (1986) The histopathology of the pancreas in Type 1 (insulin dependent) diabetes mellitus: a 25-year review of deaths in patients under 20years of age in the United Kingdom. Diabetologia 29:267–274PubMedGoogle Scholar
  16. 16.
    Porte D, Jr. and Kahn SE (2001) beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes 50 Suppl 1:S160–163PubMedGoogle Scholar
  17. 17.
    MacLean N and Ogilvie RF (1955) Quantitative estimation of pancreatic islet tissue in diabetic subjects. Diabetes 4:367–376PubMedGoogle Scholar
  18. 18.
    Saito K, Yaginuma N and Takahashi T (1979) Differential volumetry of A, B and D cells in the pancreatic islets of diabetic and non-diabetic subjects. Tohoku J Exp Med 129:273–283PubMedGoogle Scholar
  19. 19.
    Stephan Y, Grasso S, Perrelet A and Orci L (1983) A quantitative immunofluorescent study of the endocrine cells in the developing human pancreas. Diabetes 32:293–301Google Scholar
  20. 20.
    Rahier J, Goebbels RM and Henquin JC (1983) Cellular composition of the human diabetic pancreas. Diabetologia 24:355–371Google Scholar
  21. 21.
    Clark A, Wells CA, Buley ID, Cruickshank JK, Vanhegan RI, Matthews DR, Cooper GJS, Holman RR, Turner RC (1988) Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 9:151–159PubMedGoogle Scholar
  22. 22.
    Guiot Y, Sempoux C, Moulin P and Rahier J (2001) No decrease of the b-cell mass in Type 2 diabetic patients. Diabetes 50,Suppl 1:S188PubMedGoogle Scholar
  23. 23.
    Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S (2002) Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients. Diabetologia 45:85–96PubMedGoogle Scholar
  24. 24.
    Yoon KH, Ko SH, Cho JH, Lee JM, Ahn, YB, Song KH, Yoo SJ, Kang MI, Cha, BY, Lee KW, Son HY, Kang SK, Kim HS, Lee IK, Bonner-Weir S (2003) Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88:2300–2308PubMedGoogle Scholar
  25. 25.
    Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110PubMedGoogle Scholar
  26. 26.
    Ectors N, Maillet B, Aerts R, Geboes K, Donner A, Borchard F, Lankisch P, Stolte H, Luttges J, Kremer B, Kloppel G (1997) Non-alcoholic duct destructive chronic pancreatitis. Gut 41:263–268PubMedGoogle Scholar
  27. 27.
    Olsen TS (1978) Lipomatosis of the pancreas in autopsy material and its relation to age and overweight. Acta Path microbiol Scand. Sect A 86:367–373Google Scholar
  28. 28.
    Kloppel G, Lohr M, Habich K, Oberholzer M and Heitz PU (1985) Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res 4:110–125PubMedGoogle Scholar
  29. 29.
    Ritzel RA, Butler AE, Rizza RA, Veldhuis JD and Butler PC (2006) Relationship between beta-cell mass and fasting blood glucose concentration in humans. Diabetes Care 29:717–718PubMedGoogle Scholar
  30. 30.
    Westermark P (1994) Amyloid and polypeptide hormones: what is their interrelationship? Amyloid: International Journal of Experimental and Clinical Investigation 1:47–57Google Scholar
  31. 31.
    Edlund H (2002) Pancreatic organogenesis—developmental mechanisms and implications for therapy. Nat Rev Genet 3:524–532PubMedGoogle Scholar
  32. 32.
    Edlund H (2001) Factors controlling pancreatic cell differentiation and function. Diabetologia 44:1071–1079PubMedGoogle Scholar
  33. 33.
    Bernard-Kargar C and Ktorza A (2001) Endocrine pancreas plasticity under physiological and pathological conditions. Diabetes 50Suppl 1:S30–35PubMedGoogle Scholar
  34. 34.
    Bouwens L and Rooman I (2005) Regulation of pancreatic beta-cell mass. Physiol Rev 85:1255–1270PubMedGoogle Scholar
  35. 35.
    Kahn SE (2004) Engineering a new beta-cell: a critical venture requiring special attention to constantly changing physiological needs. Semin Cell Dev Biol 15:359–370PubMedGoogle Scholar
  36. 36.
    Matsumoto S, Okitsu T, Iwanaga Y, Noguchi H, Nagata H, Yonekawa Y, Yamada Y, Nakai Y, Ueda M, Ishii A, Yabunaka E, Shapiro JA, Tanaka Kl. (2005) Insulin independence of unstable diabetic patient after single living donor islet transplantation. Transplant Proc 37:3427–3429PubMedGoogle Scholar
  37. 37.
    Ward WK, LaCava EC, Paquette TL, Beard JC, Wallum BJ, Porte D Jr. (1987) Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulindependent) diabetes mellitus and in experimental insulin resistance. Diabetologia 30:698–702PubMedGoogle Scholar
  38. 38.
    Matveyenko AV, Veldhuis JD and Butler PC (2006) Mechanisms of impaired fasting glucose and glucose intolerance induced by an approximate 50% pancreatectomy. Diabetes 55:2347–2356PubMedGoogle Scholar
  39. 39.
    Rorsman P and Renstrom E (2003) Insulin granule dynamics in pancreatic beta cells. Diabetologia 46:1029–1045PubMedGoogle Scholar
  40. 40.
    Van Assche FA, Gepts W and Aerts L (1980) Immunocytochemical study of the endocrine pancreas in the rat during normal pregnancy and during experimental diabetic pregnancy. Diabetologia 18:487–491PubMedGoogle Scholar
  41. 41.
    Van Assche FA, Aerts L and De Prins F (1978) A morphological study of the endocrine pancreas in human pregnancy. Br J Obstet Gynaecol 85:818–820PubMedGoogle Scholar
  42. 42.
    Agren G, Narbro K, Naslund I, Sjostrom L and Peltonen M (2002) Long-term effects of weight loss on pharmaceutical costs in obese subjects. A report from the SOS intervention study. Int J Obes Relat Metab Disord 26:184–192PubMedGoogle Scholar
  43. 43.
    Rachman J, Barrow BA, Levy JC and Turner RC (1997) Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 40:205–211PubMedGoogle Scholar
  44. 44.
    Hosker JP, Rudenski AS, Burnett MA, Matthews DR and Turner RC (1989) Similar reduction of first-and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy. Metabolism 38:767–772PubMedGoogle Scholar
  45. 45.
    Bonner-Weir S (2000) Islet growth and development in the adult. J Mol Endocrinol 24:297–302PubMedGoogle Scholar
  46. 46.
    Dor Y, Brown J, Martinez OI and Melton DA (2004) Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature 429:41–46PubMedGoogle Scholar
  47. 47.
    Bonner-Weir S and Sharma A (2002) Pancreatic stem cells. J Pathol 197:519–526PubMedGoogle Scholar
  48. 48.
    Finegood DT, Scaglia L and Bonner-Weir S (1995) Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 44:249–256PubMedGoogle Scholar
  49. 49.
    Bouwens L and Pipeleers DG (1998) Extra-insular beta cells associated with ductules are frequent in adult human pancreas. Diabetologia 41:629–633PubMedGoogle Scholar
  50. 50.
    Ohike N, Jurgensen A, Pipeleers-Marichal M and Kloppel G (2003) Mixed ductal-endocrine carcinomas of the pancreas and ductal adenocarcinomas with scattered endocrine cells: characterization of the endocrine cells. Virchows Arch 442:258–265PubMedGoogle Scholar
  51. 51.
    Brubaker PL and Drucker DJ (2004) Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 145:2653–2659PubMedGoogle Scholar
  52. 52.
    Xu G, Stoffers DA, Habener JF and Bonner-Weir S (1999) Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 48:2270–2276PubMedGoogle Scholar
  53. 53.
    Bock T, Pakkenberg B and Buschard K (2003) Increased islet volume but unchanged islet number in ob/ob mice. Diabetes 52:1716–1722PubMedGoogle Scholar
  54. 54.
    Lipsett M and Finegood DT (2002) beta-cell neogenesis during prolonged hyperglycemia in rats. Diabetes 51:1834–1841PubMedGoogle Scholar
  55. 55.
    Montanya E, Nacher V, Biarnes M and Soler J (2000) Linear correlation between beta-cell mass and body weight throughout the lifespan in Lewis rats: role of beta-cell hyperplasia and hypertrophy. Diabetes 49:1341–1346PubMedGoogle Scholar
  56. 56.
    Teta M, Long SY, Wartschow LM, Rankin MM and Kushner JA (2005) Very slow turnover of beta-cells in aged adult mice. Diabetes 54:2557–2567PubMedGoogle Scholar
  57. 57.
    Wright A (1927) Hyaline degeneration of the islets of Langerhans in non-diabetics. American Journal of Pathology 3Google Scholar
  58. 58.
    Schneider HM, Storkel S and Will W (1980) Das Amyloid der Langerhansschen Inseln und seine Beziehung zum Diabetes mellitus. Dtsch Med Wochenschr 105: 1143–1147PubMedGoogle Scholar
  59. 59.
    Clark A, Saad MF, Nezzer T, Uren C, Knowler WC, Bennett PH and Turner RC (1990) Islet amyloid polypeptide in diabetic and non-diabetic Pima Indians. Diabetologia 33:285–289PubMedGoogle Scholar
  60. 60.
    Vishwanathan KA, Bazaz-Malik G, Dandekar J and Vaishnava O (1972) A qualitative and quantitative histological study of the islets of Langerhans in diabetes mellitus. Indian J Med Sci 26:807–812PubMedGoogle Scholar
  61. 61.
    Lee SC, Hashim Y, Li JK, Ko, GTC, Critchley JAJH Cockram CS, Chan JCNl. (2001) The islet amyloid polypeptide (amylin) gene S20G mutation in Chinese subjects: evidence for associations with type 2 diabetes and cholesterol levels. Clin Endocrinol (Oxf) 54:541–546Google Scholar
  62. 62.
    Clark A, Holman R, Matthews D, Hockaday T and Turner R (1984) Non-uniform distribution of islet amyloid in the pancreas of ‘maturity-onset’ diabetic patients. Diabetologia 27:527–528PubMedGoogle Scholar
  63. 63.
    Maloy AL, Longnecker DS and Greenberg ER (1981) The relation of islet amyloid to the clinical type of diabetes. Hum Pathol 12:917–922PubMedGoogle Scholar
  64. 64.
    Esapa C, Moffitt J, McNamara C, MacNamara CM, Levy JC, Laakso M, Gomis R, Clark A (2001) Prevalence of islet amyloid polypeptide promoter mutation (−132 G to A) in type 2 diabetes. Diabetologia 44:A89, 339Google Scholar
  65. 65.
    Wang F, Hull RL, Vidal J, Cnop M and Kahn SE (2001) Islet amyloid develops diffusely throughout the pancreas before becoming severe and replacing endocrine cells. Diabetes 50:2514–2520PubMedGoogle Scholar
  66. 66.
    Jaikaran ET and Clark A (2001) Islet amyloid and type 2 diabetes: from molecular misfolding to islet pathophysiology. Biochim Biophys Acta 1537:179–203PubMedGoogle Scholar
  67. 67.
    Clark A and Nilsson MR (2004) Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes? Diabetologia 47:157–169PubMedGoogle Scholar
  68. 68.
    Westermark P, Wernstedt C, Wilander E, Hayden DW, O’Brien TD, Johnson KH (1987) Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci U S A 84:3881–3885PubMedGoogle Scholar
  69. 69.
    Clark A, Cooper GJ, Lewis CE, Morris JF, Willis AC, Reid KBM and Turner RC (1987) Islet amyloid formed from diabetes-associated peptide may be pathogenic in type-2 diabetes. Lancet 2:231–234PubMedGoogle Scholar
  70. 70.
    Cooper GJ, Willis AC, Clark A, Reid KBM, Clark A, Baker CA, Turner RC, Lewis CE, Morris JF, Howland K, Rothbard JB (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci U S A 84:8628–8632PubMedGoogle Scholar
  71. 71.
    Clark A, Edwards CA, Ostle LR, Sutton R, Rothbard JB, Morris JF, Turner RC (1989) Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects. Cell Tissue Res 257:179–185PubMedGoogle Scholar
  72. 72.
    Sanke T, Bell GI, Sample C, Rubenstein AH and Steiner DF (1988) An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing. J Biol Chem 263:17243–17246PubMedGoogle Scholar
  73. 73.
    Sakagashira S, Sanke T, Hanabusa T, Shimomura H, Ohagi S, Kumagaye KY, Nakajima K, Nanjo K (1996) Missense mutation of amylin gene (S20G) in Japanese NIDDM patients. Diabetes 45:1279–1281PubMedGoogle Scholar
  74. 74.
    Novials A, Rojas I, Casamitjana R, Usac EF and Gomis R (2001) A novel mutation in islet amyloid polypeptide (IAPP) gene promoter is associated with Type II diabetes mellitus. Diabetologia 44:1064–1065PubMedGoogle Scholar
  75. 75.
    Poa NR, Cooper GJ and Edgar PF (2003) Amylin gene promoter mutations predispose to Type 2 diabetes in New Zealand Maori. Diabetologia 46:574–578PubMedGoogle Scholar
  76. 76.
    Nishi M, Bell GI and Steiner DF (1990) Islet amyloid polypeptide (amylin): no evidence of an abnormal precursor sequence in 25 type 2 (non-insulin-dependent) diabetic patients. Diabetologia 33:628–630PubMedGoogle Scholar
  77. 77.
    Cook JT, Patel PP, Clark A, Höppener JWM, Lips CJM, Mosselman S, O’Rahilly SP, Page RC, Wainscoat JS and Turner RC (1991) Non-linkage of the islet amyloid polypeptide gene with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 34:103–108PubMedGoogle Scholar
  78. 78.
    Birch CL, Fagan LJ, Armstrong MJ, Turnbull DM and Walker M (1997) The S20G islet-associated polypeptide gene mutation in familial NIDDM. Diabetologia 40:1113PubMedGoogle Scholar
  79. 79.
    Paulsson JF, Andersson A, Westermark P and Westermark GT (2006) Intracellular amyloid-like deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressing the gene for human IAPP and transplanted human islets. Diabetologia 49:1237–1246PubMedGoogle Scholar
  80. 80.
    Park K and Verchere CB (2001) Identification of a heparin binding domain in the N-terminal cleavage site of pro-islet amyloid polypeptide. Implications for islet amyloid formation. J Biol Chem 276:16611–16616PubMedGoogle Scholar
  81. 81.
    Paulsson JF and Westermark GT (2005) Aberrant processing of human proislet amyloid polypeptide results in increased amyloid formation. Diabetes 54:2117–2125PubMedGoogle Scholar
  82. 82.
    Marzban L, Rhodes CJ, Steiner DF, Haataja L, Halban PA, Verchere CB (2006) Impaired NH2-terminal processing of human proislet amyloid polypeptide by the prohormone convertase PC2 leads to amyloid formation and cell death. Diabetes 55:2192–2201PubMedGoogle Scholar
  83. 83.
    Porte D and Kahn SE (1989) Hyperproinsulinaemia and amyloid in NIDDM: clues to etiology of islet b-cell dysfunction. Diabetes 38:1333–1336PubMedGoogle Scholar
  84. 84.
    de Koning EJ, Bodkin NL, Hansen BC and Clark A (1993) Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population. Diabetologia 36:378–384PubMedGoogle Scholar
  85. 85.
    Janson J, Soeller WC, Roche PC, Nelson RT, Torchia AJ, Kreutter DK, Butler PC (1996) Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci U S A 93:7283–7288PubMedGoogle Scholar
  86. 86.
    O’Brien T, Hayden D, Johnson K and Fletcher T (1986) Immuno-histochemical morphometry of pancreatic endocrine cells in diabetic normoglycaemic glucoseintolerant and normal cats. J. Comp. Pathol. 96:357–369PubMedGoogle Scholar
  87. 87.
    Hull RL, Shen ZP, Watts MR, Kodama K, Carr DB, Utschneider KH, Zraika S, Wang F, Kahn SE (2005) Long-term treatment with rosiglitazone and metformin reduces the extent of, but does not prevent, islet amyloid deposition in mice expressing the gene for human islet amyloid polypeptide. Diabetes 54:2235–2244PubMedGoogle Scholar
  88. 88.
    Hoenig M, Hall G, Ferguson F, Jordan K, Henderson M, Johnson K, O’Brien T (2000) A feline model of experimentally induced amyloidosis. American Journal of Pathology. 157:2143–2150PubMedGoogle Scholar
  89. 89.
    Meier JJ, Kayed R, Lin CY, Gurlo T, Haataja L, Jayasinghe, S, Langen P, Glabe CC, Butler PC (2006) Inhibition of human IAPP fibril formation does not prevent betacell death: evidence for distinct actions of oligomers and fibrils of human IAPP. Am J Physiol Endocrinol Metab 291:E1317–1324PubMedGoogle Scholar
  90. 90.
    Dobbins RL, Chester MW, Stevenson BE, Daniels MB, Stein DT, McGarry JDl (1998) A fatty acid-dependent step is critically important for both glucose-and nonglucose-stimulated insulin secretion. J Clin Invest 101:2370–2376PubMedGoogle Scholar
  91. 91.
    Stein DT, Esser V, Stevenson BE, Lane KE, Whiteside JM, Daniels MB Chen S, McGarry JD (1996) Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J Clin Invest 97:2728–2735PubMedGoogle Scholar
  92. 92.
    Prentki M and Corkey BE (1996) Are the beta-cell signaling molecules malonyl-CoA and cystolic long-chain acyl-CoA implicated in multiple tissue defects of obesity and NIDDM? Diabetes 45:273–283PubMedGoogle Scholar
  93. 93.
    Corkey BE, Deeney JT, Yaney GC, Tornheim K and Prentki M (2000) The role of long-chain fatty acyl-CoA esters in beta-cell signal transduction. J Nutr 130: 299S–304SPubMedGoogle Scholar
  94. 94.
    Beysen C, Karpe F, Fielding BA, Clark A, Levy JC, Frayn KN (2002) Interaction between specific fatty acids, GLP-1 and insulin secretion in humans. Diabetologia 45:1533–1541PubMedGoogle Scholar
  95. 95.
    Gravena C, Mathias PC and Ashcroft SJ (2002) Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans. J Endocrinol 173:73–80PubMedGoogle Scholar
  96. 96.
    Branstrom R, Leibiger IB, Leibiger B, Corkey BE, Berggren PO, Larsson O (1998) Long chain coenzyme A esters activate the pore-forming subunit (Kir6. 2) of the ATPregulated potassium channel. J Biol Chem 273:31395–31400PubMedGoogle Scholar
  97. 97.
    Larsson O, Deeney JT, Branstrom R, Berggren PO and Corkey BE (1996) Activation of the ATP-sensitive K+ channel by long chain acyl-CoA. A role in modulation of pancreatic beta-cell glucose sensitivity. J Biol Chem 271:10623–10626PubMedGoogle Scholar
  98. 98.
    Roduit R, Nolan C, Alarcon C, Moore P, Barbeau A, Delghingaro-Augusto V, Przybykowski E, Morin J, Masse F, Massie B, Rudenramn N, Phodes C, Pouitout V, Prentki M (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 53:1007–1019PubMedGoogle Scholar
  99. 99.
    Unger RH and Orci L (2002) Lipoapoptosis: its mechanism and its diseases. Biochim Biophys Acta 1585:202–212PubMedGoogle Scholar
  100. 100.
    Cnop M, Hannaert JC, Hoorens A, Eizirik DL and Pipeleers DG (2001) Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation. Diabetes 50:1771–1777PubMedGoogle Scholar
  101. 101.
    Briaud I, Rouault C, Reach G and Poitout V (1999) Long-term exposure of isolated rat islets of Langerhans to supraphysiologic glucose concentrations decreases insulin mRNA levels. Metabolism 48:319–323PubMedGoogle Scholar
  102. 102.
    Unger RH and Zhou YT (2001) Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50Suppl 1:S118–121PubMedGoogle Scholar
  103. 103.
    Ford ES, Giles WH and Dietz WH (2002) Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. Jama 287:356–359PubMedGoogle Scholar
  104. 104.
    Maedler K, Oberholzer J, Bucher P, Spinas GA and Donath MY (2003) Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes 52:726–733PubMedGoogle Scholar
  105. 105.
    Robertson RP, Harmon J, Tran PO, Tanaka Y and Takahashi H (2003) Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52:581–587PubMedGoogle Scholar
  106. 106.
    Kharroubi I, Ladriere L, Cardozo AK, Doguso Z, Cnop M, Eisirik DL (2004) Free fatty acids and cytokines induce pancreatic ta-cell apoptosis by different mechanisms: role of NF-{kappa}B and endoplasmic reticulum stress. EndocrinologyGoogle Scholar
  107. 107.
    Moffitt JH, Fielding BA, Evershed R, Berstan R, Currie JM, Clark A (2005) Adverse physicochemical properties of tripalmitin in beta cells lead to morphological changes and lipotoxicity in vitro. Diabetologia 48:1819–1829PubMedGoogle Scholar
  108. 108.
    Deng S, Vatamaniuk M, Huang X, Doliba N, Lian MM, Frank A, Velidideoglu E, Desai NM, Koberlein B, Wolf B, Braker CF, Naji A, Matchinsky FM, Markmann JF (2004) Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes 53:624–632PubMedGoogle Scholar
  109. 109.
    Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M, Bughani H, Boggi U, Vistoli F, Mosca F, Del Prato S (2004) Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 89:5535–5541PubMedGoogle Scholar
  110. 110.
    Stephan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y, Unger RH (1982) Quantitation of endocrine cell content in the pancreas of non-diabetic and diabetic humans. Diabetes 31:694–700Google Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Anne Clark
    • 1
  1. 1.Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and MetabolismChurchill HospitalOxfordUK

Personalised recommendations