Diabetes pp 288-309 | Cite as

The Pancreatic β Cells in Human Type 2 Diabetes

  • Piero Marchetti
  • Marco Bugliani
  • Ugo Boggi
  • Matilde Masini
  • Lorella Marselli
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


β-cell (beta-cell) impairment is central to the development and progression of human diabetes, as a result of the combined effects of genetic and acquired factors. Reduced islet number and/or reduced β cells amount in the pancreas of individuals with Type 2 diabetes have been consistently reported. This is mainly due to increased β cell death, not adequately compensated for by regeneration. In addition, several quantitative and/or qualitative defects of insulin secretion have been observed in Type 2 diabetes, both in vivo and ex vivo with isolated islets. All this is associated with modifications of islet cell gene and protein expression. With the identification of several susceptible Type 2 diabetes loci, the role of genotype in affecting β-cell function and survival has been addressed in a few studies and the relationships between genotype and β-cell phenotype investigated. Among acquired factors, the importance of metabolic insults (in particular glucotoxicity and lipotoxicity) in the natural history of β-cell damage has been widely underlined. Continuous improvements in our knowledge of the β cells in human Type 2 diabetes will lead to more targeted and effective strategies for the prevention and treatment of the disease.


Insulin Secretion Beta Cell Chronic Pancreatitis Pancreatic Islet Human Islet 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2011; (Suppl 1)34: S62–S69.Google Scholar
  2. 2.
    Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 2005; 365: 1333–1346.PubMedCrossRefGoogle Scholar
  3. 3.
    Jensen CC, Cnop M, Hull RL et al. American Diabetes Association GENNID Study Group: Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes 2002; 51: 2170–2178.PubMedCrossRefGoogle Scholar
  4. 4.
    Cnop M, Vidal J, Hull RL 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: 677–682.PubMedCrossRefGoogle Scholar
  5. 5.
    Weyer C, Bogardus C, Mott DM et al. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999; 104: 787–794.PubMedCrossRefGoogle Scholar
  6. 6.
    Festa A, Williams K, D’Agostino R Jr. et al. The natural course of beta-cell function in nondiabetic and diabetic individuals: the insulin resistance atherosclerosis study. Diabetes 2006; 55: 1114–1120.Google Scholar
  7. 7.
    Levy J, Atkinson AB, Bell PM et al. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabet Med 1998; 15: 290–296.PubMedCrossRefGoogle Scholar
  8. 8.
    UK Prospective Diabetes Study 16.Overview of 6 years’ therapy of type II diabetes: a progressive disease. UK Prospective Diabetes Study Group. Diabetes 1995; 44: 1249–1258.CrossRefGoogle Scholar
  9. 9.
    Saito K, Takahashi T, Yaginuma N et al. Islet morphometry in the diabetic pancreas of man. Tohoku J ExpMed 1978; 125: 185–197.CrossRefGoogle Scholar
  10. 10.
    Westermark P, Wilander E. The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus. Diabetologia 1978; 15: 417–421.PubMedCrossRefGoogle Scholar
  11. 11.
    Saito K. Yaginuma N, Takahashi T. Differential volumetry of A, B and D-cells in the pancreatic islets of diabetic and non-diabetic subjects. Tohoku J Exp Med 1979; 129: 273–283.Google Scholar
  12. 12.
    Stefan Y, Orci L, Malaisse-Lagae F et al. Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans. Diabetes 1982; 31: 694–700.PubMedCrossRefGoogle Scholar
  13. 13.
    Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. Diabetologia 1983; 24: 366–371.PubMedCrossRefGoogle Scholar
  14. 14.
    Clark A, Wells CA, Buley ID et al. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res 1988; 9: 151–159.PubMedGoogle Scholar
  15. 15.
    Sakuraba H, Mizukami H, Yagihashi N et al. Reduced beta cell mass and expression of oxidative stress related DNA damage in the islets of Japanese type 2 diabetic patients. Diabetologia 2002; 45: 85–96.PubMedCrossRefGoogle Scholar
  16. 16.
    Yoon KH, Ko SH, Cho JH et al. Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes in Korea. J Clin Endocrinol Metab 2003; 88: 2300–2308.PubMedCrossRefGoogle Scholar
  17. 17.
    Butler AE, Janson J, Bonner-Weir S et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003; 52: 102–110.PubMedCrossRefGoogle Scholar
  18. 18.
    Haataja L, Gurlo T, Huang CJ et al. Islet amyloid in type 2 diabetes and the toxic oligomer hypothesis. Eudocr Rev 2008; 29: 303–316.CrossRefGoogle Scholar
  19. 19.
    Rahier J. Guiot Y, Goebbels RM et al. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab 2008; 10(Suppl 4): 32–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Hanley SC, Austin E, Assouline-Thomas B et al. Beta-cell mass dynamics and islet cell plasticity in human type 2 diabetes. Endocrinology 2010; 151: 1462–1472.PubMedCrossRefGoogle Scholar
  21. 21.
    Marchetti P, Bugliani M, Lupi R et al. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 2007; 50: 2486–2494.PubMedCrossRefGoogle Scholar
  22. 22.
    Marchetti P, Del Guerra S, Marselli L et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 2004; 89: 5535–5541.PubMedCrossRefGoogle Scholar
  23. 23.
    Laybutt DR, Preston AM. Åkerfeldt MC et al. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 2007; 50: 752–763.PubMedCrossRefGoogle Scholar
  24. 24.
    Kroemer G, El-Deiry WS, Golstein P et al. Nomenclature committee on cell death: classification of cell death: recommendations of the nomenclature committee on cell death. Cell Death Differ 2005; 12(Suppl 2): 1463–1467.PubMedCrossRefGoogle Scholar
  25. 25.
    Bredesen DE, Rao RV, Mehlen P. Cell death in nervous system. Nature 2006; 443: 796–802.PubMedCrossRefGoogle Scholar
  26. 26.
    Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 2005; 12(Suppl 2): 1509–1518.PubMedCrossRefGoogle Scholar
  27. 27.
    Masini M, Bugliani M, Lupi R et al. Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 2009; 52: 1083–1086.PubMedCrossRefGoogle Scholar
  28. 28.
    Piper K, Brickwood S, Turnpenny LW et al. Beta cell differentiation during early human pancreas development. J Endocrinol 2004; l81: 11–23.CrossRefGoogle Scholar
  29. 29.
    Meier JJ, Kohler CU, Alkhatib B et al. Beta-cell development and turnover during prenatal life in humans. Eur J Eudocrinol 2010; 152:559–568.CrossRefGoogle Scholar
  30. 30.
    Kassem SA, Ariel L, Thornton PS et al. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 2000; 49: 1325–1333.PubMedCrossRefGoogle Scholar
  31. 31.
    Meier JJ, Butler AE, Saisho Y et al. Beta-cell replication is the primary mechanism subserving the postnatal expansion of beta-cell mass in humans. Diabetes 2008; 57: 1584–1594.PubMedCrossRefGoogle Scholar
  32. 32.
    Cnop M, Hughes SJ, Igoillo-Esteve M et al. The long lifespan and low turnover of human islet beta cells estimated by mathematical modelling of lipofuscin accumulation. Diabetologia 2010; 53: 321–330.PubMedCrossRefGoogle Scholar
  33. 33.
    Perl S, Kushner JA, Buchholz BA et al. Significant human beta-cell turnover is limited to the first three decades of life as determined by in vivo thymidine analog incorporation and radiocarbon dating. J Clin Endocrinol Metab 2010; 95: E234–E239.PubMedCrossRefGoogle Scholar
  34. 34.
    Butler AE, Cao-Minh L, Galasso R et al. Adaptive changes in pancreatic beta cell fractional area and beta cell turnover in human pregnancy. Diabetologia 2010; 53: 2167–2176.PubMedCrossRefGoogle Scholar
  35. 35.
    Tancredi M, Marselli L, Lencioni C et al. Histopathology and ex vivo insulin secretion of pancreatic islets in gestational diabetes. A case report. Islets 2011, in press.Google Scholar
  36. 36.
    Schrader H, Menge BA, Schneider S et al. Reduced pancreatic volume and beta-cell area in patients with chronic pancreatitis. Gastroenterology 2009; 136: 513–522.PubMedCrossRefGoogle Scholar
  37. 37.
    Menge BA, Schrader H, Breuer TG. Metabolic consequences of a 50% partial pancreatectomy in humans. Diabetologia 2009; 52: 306–317.PubMedCrossRefGoogle Scholar
  38. 38.
    Jalleh RP, Williamson RC. Pancreatic exocrine and endocrine function after operations for chronic pancreatitis. Ann Surg 1992; 216: 656–662PubMedCrossRefGoogle Scholar
  39. 39.
    Beger HG, Büchler M. Duodenum-preserving resection of the head of the pancreas in chronic pancreatitis with inflammatory mass in the head. World J Surg 1990; 14: 83–87.PubMedCrossRefGoogle Scholar
  40. 40.
    Boggi U, Amorese G. Marchetti P et al. Segmental live donor pancreas transplantation: review and critique of rationale, outcomes and current recommendations. Clin Transplant 2011; 25: 4–12.PubMedCrossRefGoogle Scholar
  41. 41.
    Kendall DM, Sutherland DE, Najarian JS et al. Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. N Engl J Med 1990; 322: 898–903.PubMedCrossRefGoogle Scholar
  42. 42.
    Kumar AF, Gruessner RW, Seaquist ER. Risk of glucose intolerance and diabetes in hemipancreatectomized donors selected for normal preoperative glucose metabolism. Diabetes Care 2008; 31: 1639–1643.PubMedCrossRefGoogle Scholar
  43. 43.
    Fernandez-Alvarez J, Conget I, Rasschaert J et al. Enzymatic, metabolic and secretory patterns in human islets of type 2 (noninsulin-dependent) diabetic patients. Diabetologia 1994; 37:177–181.PubMedCrossRefGoogle Scholar
  44. 44.
    Deng S, Vatamaniuk M, Huang X et al. Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes 2004; 53: 624–632.PubMedCrossRefGoogle Scholar
  45. 45.
    Del Guerra S, Lupi R, Marselli L et al. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 2005; 54: 727–735.PubMedCrossRefGoogle Scholar
  46. 46.
    Marchetti P, Dotta F, Lauro D et al. An overview of pancreatic beta-cell delects in human type 2 diabetes: implications for treatment. Regul Pept 2008; 146: 4–11.PubMedCrossRefGoogle Scholar
  47. 47.
    Anello M, Lupi R, Spampinato D et al. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 2005; 48: 282–289.PubMedCrossRefGoogle Scholar
  48. 48.
    Gunton JE. Kulkarni RN, Yim S et al. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell 2005; 122: 337–349.PubMedCrossRefGoogle Scholar
  49. 49.
    Ostenson CG, Gaisano H, Sheu L et al. Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients. Diabetes 2006; 55: 435–440.PubMedCrossRefGoogle Scholar
  50. 50.
    Brun T, Hu He KH, Lupi R et al. The diabetes-linked transcription factor Pax-4 is expressed in human pancreatic islets and is activated by mitogens and GLP-1. Hum Mol Genet 2008; 17:478–489.PubMedCrossRefGoogle Scholar
  51. 51.
    Lyssenko V, Lupi R, Marchetti P et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 2007; 117: 2155–2163.PubMedCrossRefGoogle Scholar
  52. 52.
    Marselli L, Thorne J, Ahn YB et al. Gene expression of purified beta cell tissue obtained from human pancreas with laser capture microdissection. J Clin Endocrinol Metab 2008; 93: 1045–1053.Google Scholar
  53. 53.
    Marselli L, Thorne J, Dahiya S et al. Gene expression profiles of Beta-cell enriched tissue obtained by laser capture microdissection from subjects with type 2 diabetes. PLoS One 2010; 5(7): e11499.PubMedCrossRefGoogle Scholar
  54. 54.
    Shu L, Matveyenko AY, Kerr-Conte J et al. Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP-and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet 2009; 18: 2388–2299.PubMedCrossRefGoogle Scholar
  55. 55.
    Nyblom HK, Bugliani M, Fung E et al. Apoptotic, regenerative and immune-related signaling in human islets from type 2 diabetes individuals. J Proteome Res 2009; 8: 5650–5656.PubMedCrossRefGoogle Scholar
  56. 56.
    McCarthy MI. Genomics, type 2 diabetes and obesity. N Engl J Med 2010; 363: 2339–2350.PubMedCrossRefGoogle Scholar
  57. 57.
    Groop L, Lyssenko V. Genes and type 2 diabetes mellitus. Curr Diab Rep 2008; 8: 192–197.PubMedCrossRefGoogle Scholar
  58. 58.
    Trajkovski M, Mziaut H, Solimena M. Genes of type 2 diabetes in beta cells. Endocrinol Metab Clin North Am 2006; 35: 357–369.PubMedCrossRefGoogle Scholar
  59. 59.
    Marchetti P, Lupi R, Federici M et al. Insulin secretory function is impaired in isolated human islets carrying the Gly(972)→Arg IRS-1 polymorphism. Diabetes 2002; 51: 1419–1424.PubMedCrossRefGoogle Scholar
  60. 60.
    Federici M, Hribal ML, Ranalli M et al. The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. FASEB J 2001; 15: 22–24.PubMedGoogle Scholar
  61. 61.
    DiPaola R, Caporarello N, Marucci A et al. ENPP1 affects insulin action and secretion: evidences from in vitro studies. PLoS One 2011; 6: e19462.PubMedCrossRefGoogle Scholar
  62. 62.
    Prudente S, Searpelli D, Chandalia M et al. The TRIB3 Q84R polymorphism and risk of early-onset type 2 diabetes. J Clin Endocrinol Metab 2009; 94: 190–196.PubMedCrossRefGoogle Scholar
  63. 63.
    Tong Y, Lin Y, Zhang Y et al. Association between TCF7L2 gene polymorphisms and susceptibility to type 2 diabetes mellitus: a large Human Genome Epidemiology (HuGE) review and meta-analysis. BMC Med Genet 2009; 10:15.PubMedCrossRefGoogle Scholar
  64. 64.
    Shu L, Sauter NS, Schulthess FT et al. Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes 2008; 57: 645–653.PubMedCrossRefGoogle Scholar
  65. 65.
    Lyssenko V, Nagorny CL, Erdos MR et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 2009; 4: 82–88.CrossRefGoogle Scholar
  66. 66.
    Ling C, Groop L, Guerra SD et al. Calpain-10 expression is elevated in pancreatic islets from patients with type 2 diabetes. PLoS One 2009; 18;4(8): e6558.PubMedCrossRefGoogle Scholar
  67. 67.
    Sesti G, Cardellini M, Marini MA et al. A common polymorphism in the promoter of UCP2 contributes to the variation in insulin secretion in glucose-tolerant subjects. Diabetes 2003; 52: 1280–1283.PubMedCrossRefGoogle Scholar
  68. 68.
    Sesti G, Laratta E. Cardellini M et al. The E23K variant of KCNJ11 encoding the pancreatic beta-cell adenosine 5′-tripliosphate-sensitive potassium channel subunit Kir6.2 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. J Clin Endocrinol Metab 2006; 91: 2334–2339.PubMedCrossRefGoogle Scholar
  69. 69.
    Cauchi S, Del Guerra S. Choquet H et al. Meta-analysis and functional effects of the SLC30A8 rs 13266634 polymorphism on isolated human pancreatic islets. Mol Genet Metab 2010; 100: 77–82.PubMedCrossRefGoogle Scholar
  70. 70.
    Federici M, Hribal M, Perego L et al. High glucose causes apoptosis in cultured human pancreatic islets of Laugerhans: a potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. Diabetes 2001; 50: 1290–2301.PubMedCrossRefGoogle Scholar
  71. 71.
    D’Alessandris C, Andreozzi F, Federici M et al. Increased O-glycosylation of insulin signaling proteins results in their impaired activation and enhanced susceptibility to apoptosis in pancreatic beta-cells. FASEB J 2004; 18: 959–961.Google Scholar
  72. 72.
    Robertson RP. Oxidative stress and impaired insulin secretion in type 2 diabetes. Curr Opin Pharmacol 2006; 6: 615–619.PubMedCrossRefGoogle Scholar
  73. 73.
    Del Guerra S, D’Aleo V, Lupi R et al. Effects of exposure of human islet beta-cells to normal and high glucose levels with or without gliclazide or glibenclamide. Diabetes Metab 2009; 35: 293–298.PubMedCrossRefGoogle Scholar
  74. 74.
    Davalli AM. Ricordi C. Socci C et al. Abnormal sensitivity to glucose of human islets cultured in a high glucose medium: partial reversibility after an additional culture in a normal glucose medium. J Clin Endocrinol Mctab 1991; 72: 202–208.CrossRefGoogle Scholar
  75. 75.
    Weir GC, Marselli L, Marchetti P et al. Towards better understanding of the contributions of overwork and glucotoxicity to the betacell inadequacy oftype 2 diabetes. Diabetes Obes Metab 2009; 11(Suppl 4): 82–90.PubMedCrossRefGoogle Scholar
  76. 76.
    Lupi R, Del Guerra S, Tellini C et al. The biguanide compound metformin prevents desensitization of human pancreatic islets induced by high glucose. Eur J Pharmacol 1999; 364: 205–209.PubMedCrossRefGoogle Scholar
  77. 77.
    Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 2004; 279: 42351–42354PubMedCrossRefGoogle Scholar
  78. 78.
    Lenzen S. Oxidative stress: the vulnerable beta-cell. Biochem Soc Trans 2008; 36:343–347.PubMedCrossRefGoogle Scholar
  79. 79.
    Robertson RP, Harmon JS. Pancreatic islet beta-cell and oxidative stress: the importance of glutathione peroxidase. FEBS Lett 2007; 581: 3743–3748PubMedCrossRefGoogle Scholar
  80. 80.
    Grankvist K, Marklund SL, Taljedal IB. CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J 1981; 199: 393–398.PubMedGoogle Scholar
  81. 81.
    Robertson RP, Harmon J, Tran PO et al. Glucose toxicity in beta-cells: type 2 diabetes, good radicals gone bad and the glutathione connection. Diabetes 2003; 52: 581–587.PubMedCrossRefGoogle Scholar
  82. 82.
    Tonooka N, Oseid E, Zhou H et al. Glutathione peroxidase protein expression and activity in human islets isolated for transplantation. Clin Transplant 2007; 21: 767–772.PubMedGoogle Scholar
  83. 83.
    Welsh N, Margulis B, Borg LA et al. Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus. Mol Med 1995; 1: 806–820.PubMedGoogle Scholar
  84. 84.
    Kashyap S, Belfort R, Gastaldelli A et al. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 2003; 52: 2461–2474.PubMedCrossRefGoogle Scholar
  85. 85.
    Giacca A, Xiao C, Oprescu AI et al. Lipid-induced pancreatic β-cell dysfunction: focus on in vivo studies. Am J Physiol Endocrinol Metab 2011; 300: E255–E262.PubMedCrossRefGoogle Scholar
  86. 86.
    Lupi R, Dotta F, Marselli L et al. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway and Bcl-2 regulated. Diabetes 2002; 51: 1437–1442PubMedCrossRefGoogle Scholar
  87. 87.
    Maedler K, Oberholzer J, Bucher P et al. Mouounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose onhuman pancreatic beta-cell turnover and function. Diabetes 2003; 52: 726–733.PubMedCrossRefGoogle Scholar
  88. 88.
    Eitel K. Staiger H, Brendel MD et al. Different role of saturated and unsaturated fatty acids in beta-cell apoptosis. Biochem Biophys Res Commun 2002; 299: 853–856.PubMedCrossRefGoogle Scholar
  89. 89.
    El-Assaad W, Buteau J, Peyot ML et al. Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death. Endocrinology 2003; 144: 4154–4163.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhou YP, Grill V. Long-term exposure to fatty acids and ketones inhibits beta-cell function in human pancreatic islets of Langerhans. J Clin Endocrinol Metab 1995; 80: 1584–1590.PubMedCrossRefGoogle Scholar
  91. 91.
    Randle PJ, Garland PB, Hales CN et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963; 13: 785–789.Google Scholar
  92. 92.
    Bouckenooghe T, Muharram G, D’Herbomez M et al. Non-esterified fatty acids are deleterious for human pancreatic islet function at physiological glucose concentration. Diabetologia 2004; 47: 463–469PubMedCrossRefGoogle Scholar
  93. 93.
    Lupi R, Del Guerra S, Fierabracci V et al. Lipotoxicity in human pancreatic islets and the protective effect of metformin. Diabetes 2002; 51(Suppl 1): 134–137.CrossRefGoogle Scholar
  94. 94.
    Cunha DA, Hekerman P, Ladrière L et al. Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci 2008; 121: 2308–2318.PubMedCrossRefGoogle Scholar
  95. 95.
    Lupi R, Del Guerra S, Marselli L et al. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR gamma2 in the modulation of insulin secretion. Am J Physiol Endocrinol Metab 2004; 286: E560–E567.PubMedCrossRefGoogle Scholar
  96. 96.
    Cunha DA, Ladrière L, Ortis F et al. Glucagon-like peptide-1 agonists protect pancreatic beta-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB. Diabetes 2009; 58: 2851–2862.PubMedCrossRefGoogle Scholar
  97. 97.
    Hoppener JWM, Lips CJM. Role of amyloid in type 2 diabetes mellitus. Intern J Biochem Cell Biol 2006; 38: 726–736.CrossRefGoogle Scholar
  98. 98.
    Ritzel RA, Meier JJ, Lin CY et al. Human islet amyloid polypeptide oligormers disrupt cell coupling, induce apoptosis and impair insulin secretion in isolated human islets. Diabetes 2007; 56: 65–71.PubMedCrossRefGoogle Scholar
  99. 99.
    Westermark P, Wernstedt C, Wilander E et al. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuopeptide-like protein also present in normal islet cells. Proc Natl Acad Sci U S A 1987; 84: 3881–3885PubMedCrossRefGoogle Scholar
  100. 100.
    Cooper GJ, Willis AC, Clark A et al. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci U S A 1987; 84: 8628–8632PubMedCrossRefGoogle Scholar
  101. 101.
    Ritzel RA, Butler PC. Replication increases beta cell vulnerability to human is let amyloid polypeptide-induced apoptosis. Diabetes 2003; 52: 1701–1708.PubMedCrossRefGoogle Scholar
  102. 102.
    Meier JJ, Kayed R, Lin CY et al. Inhibition of human IAPP fibril formation does not prevent beta cell death: evidence for distinct actions of oligomers and fibrils of human IAPP. Am J Physiol Endocrinol Metab 2006; 291: E1317–E1324.PubMedCrossRefGoogle Scholar
  103. 103.
    Gurlo T, Ryazantsev S, Huang CJ et al. Evidence for proteotoxicity in beta cells in type 2 diabetes: toxic islet amyloid polypeptide oligomers form intracellularly in the secretory pathway. Am J Pathol 2010; 176: 861–869.PubMedCrossRefGoogle Scholar
  104. 104.
    Lin CY, Gurlo T, Haataja L et al. Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3′-kinase-dependent pathway. J Clin Endocrinol Metab 2005; 90: 6678–6686.PubMedCrossRefGoogle Scholar
  105. 105.
    Böni-Schnetzler M, Thorne J, Parnaud G et al. Increased interleukin (IL)-1beta messenger ribonucleic acid expression in beta-cells of individuals with type 2 diabetes and regulation of IL-1beta in human islets by glucose and autostimulation. J Clin Endocrinol Metab 2008; 93: 4065–4074.PubMedCrossRefGoogle Scholar
  106. 106.
    Ehses JA, Böni-Schnetzler M, Faulenbach M et al. Macrophages, cytokines and beta-cell death in Type 2 diabetes. Biochem Soc Trans 2008; 36: 340–342PubMedCrossRefGoogle Scholar
  107. 107.
    Richardson SJ, Willcox A, Bone AJ et al. Islet-associatcd macrophages in type 2 diabetes. Diabetologia 2009; 52: 1686–1688.PubMedCrossRefGoogle Scholar
  108. 108.
    Welsh N, Cnop M, Kharroubi I et al. Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes 2005; 54: 3238–3244.PubMedCrossRefGoogle Scholar
  109. 109.
    Igoillo-Esteve M, Marselli L, Cunha DA et al. Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes. Diabetologia 2010; 53: 1395–1405.PubMedCrossRefGoogle Scholar
  110. 110.
    Larsen CM, Faulenbach M, Vaag A et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007; 356: 1517–1526PubMedCrossRefGoogle Scholar
  111. 111.
    Marchetti P, Lupi R, Del Guerra S et al. Goals of treatment for type 2 diabetes: beta-cell preservation for glycemic control. Diabetes Care 2009; 32 (Suppl 2): S178–S183.PubMedCrossRefGoogle Scholar
  112. 112.
    Lupi R, Del Guerra S, Mancarella R et al. Insulin secretion defects of human type 2 diabetic islets are corrected in vitro by a new reactive oxygen species scavenger. Diabetes Metab 2007; 33: 340–345.PubMedCrossRefGoogle Scholar
  113. 113.
    Drucker DJ. Nauck MA. The incretin system: glucagonlike peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696–1705.PubMedCrossRefGoogle Scholar
  114. 114.
    Knop FK, Vilsbøll T, Holst JJ. Incretin-based therapy of type 2 diabetes mellitus. Curr Protein Pept Sci 2009; 10: 46–55.PubMedCrossRefGoogle Scholar
  115. 115.
    Lupi R, Mancarella R, Del Guerra S et al. Effects of exendin-4 on islets from type 2 diabetes patients. Diabetes Obes Metab 2008; 10: 515–519.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2013

Authors and Affiliations

  • Piero Marchetti
    • 1
  • Marco Bugliani
    • 1
  • Ugo Boggi
    • 1
  • Matilde Masini
    • 1
  • Lorella Marselli
    • 1
  1. 1.Department of Endocrinology and MetabolismUniversity of PisaPisaItaly

Personalised recommendations