Abstract
β-cell dysfunction is central to the onset and progression of type 2 diabetes. Reduced islet number and/or diminished β-cell mass/volume in the pancreas of type 2 diabetic subjects have been reported by many authors, mainly due to increased apoptosis not compensated for by adequate regeneration. In addition, ultrastructural analysis has shown reduced insulin granules and morphological changes in several β-cell organelles, including mitochondria and endoplasmic reticulum. Several quantitative and qualitative defects of β-cell function have been described in human type 2 diabetes using isolated islets, including alterations in early phase, glucose-stimulated insulin release. These survival and functional changes are accompanied by modifications of islet gene and protein expression. The impact of genotype in affecting β-cell function and survival has been addressed in a few studies, and a number of gene variants have been associated with β-cell dysfunction. Among acquired factors, the role of glucotoxicity and lipotoxicity could be of particular importance, due to the potential deleterious impact of elevated levels of glucose and/or free fatty acids in the natural history of β-cell damage. More recently, it has been proposed that inflammation might also play a role in the dysfunction of the β-cell in type 2 diabetes. Encouraging, although preliminary, data show that some of these defects might be directly counteracted, at least in part, by appropriate in vitro pharmacological intervention.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008;31 (Suppl 1):S55–60.
Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365:1333–13.
Kahn SE. The relative contribution of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 2003;46:3–19.
Marchetti P, Dotta F, Lauro D, Purrello F. An overview of pancreatic beta-cell defects in human type 2 diabetes: Implications for treatment. Regul Pept 2008;146:4–11.
Wajchenberg BL. beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007;28:187–218.
Meier JJ. Beta cell mass in diabetes: a realistic therapeutic target? Diabetologia. 2008;51: 703–13.
Kumar AF, Gruessner RW, Seaquist ER. Risk of glucose intolerance and diabetes in hemipancreatectomized donors selected for normal preoperative glucose metabolism. Diabetes Care 2008;31:1639–43.
Porte D Jr. Banting lecture 1990. Beta-cells in type II diabetes mellitus. Diabetes 1991;40:166–80.
Ferrannini E, Mari A. Beta-cell function and its relation to insulin action in humans: a critical appraisal. Diabetologia 2004;47:943–56.
Kahn SE, Carr DB, Faulenbach MV, Utzschneider KM. An examination of beta-cell function measures and their potential use for estimating beta-cell mass. Diabetes Obes Metab 2008; 10 Suppl 4:63–76.
Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev 2008;29:254–64.
Saito K, Takahashi T, Yaginuma N, Iwama N. Islet morphometry in the diabetic pancreas of man. Tohoku J Exp Med 1978;125:185–97.
Westermark P, Wilander E. The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus. Diabetologia 1978;15:417–21.
Saito K, Yaginuma N, Takahashi T. Differential volumetry of A, B and D cells in the pancreatic islets of diabetic and non diabetic subject. Tohoku J Exp Med 1979;129:273–83.
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.
Rahier J, Goebbels RM, Henquin JC. Cellular composition of the human diabetic pancreas. Diabetologia 1983;24:366–71.
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;9:151–59.
Sakuraba H, Mizukami H, Yagihashi N, Wada R, Hanyu C, Yagihashi S. 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.
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;88:2300–8.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–10.
Rahier J, Guiot Y, Goebbels RM, Sempoux C, Henquin JC. Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab 2008;10 Suppl 4:32–42.
Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab 2004;89:5535–41.
Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, Filipponi F, Weir GC, Eizirik DL, Cnop M. The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia 2007;50:2486–94.
Fernandez-Alvarez J, Conget I, Rasschaert J, Sener A, Gomis R, Malaisse WJ. Enzymatic, metabolic and secretory patterns in human islets of type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1994;37:177–81.
Deng S, Vatamaniuk M, Huang X, Doliba N, Lian MM, Frank A et al. Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes 2004;53:624–32.
Del Guerra S, Lupi R, Marselli L, Masini M, Bugliani M, Sbrana S, Torri S, Pollera M, Boggi U, Mosca F, Del Prato S, Marchetti P. Functional and molecular defects of pancreatic islets in human type 2 diabetes. Diabetes 2005;54:727–35.
Anello M, Lupi R, Spampinato D, Piro S, Masini M, Boggi U, Del Prato S, Rabuazzo AM, Purrello F, Marchetti P. Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients. Diabetologia 2005;48:282–89.
Gunton JE, Kulkarni RN, Yim S, Okada T, Hawthorne WJ, Tseng YH, Roberson RS, Ricordi C, O’Connell PJ, Gonzalez FJ, Kahn CR. Loss of ARNT/HIF1beta mediates altered gene expression and pancreatic-islet dysfunction in human type 2 diabetes. Cell. 2005;122:337–49.
Ostenson CG, Gaisano H, Sheu L, Tibell A, Bartfai T. 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;55:435–40.
Brun T, Hu He KH, Lupi R, Boehm B, Wojtusciszyn A, Sauter N, Donath M, Marchetti P, Maedler K, Gauthier BR. The Diabetes-Linked Transcription Factor Pax4 is Expressed in Human Pancreatic Islets and is Activated by Mitogens and GLP-1. Hum Mol Genet 2008;17:478–89.
Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjogren M, Ling C, Eriksson KF, Lethagen UL, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 2007;117:2155–63.
Marselli L, Sgroi DC, Thorne J, Dahiya S, Torri S, Omer A, Del Prato S, Towia L, Out HH, Sharma A, Bonner-Weir S, Marchetti P, Weir GC. Evidence of inflammatory markers in beta-cells of type 2 diabetic subjects. Diabetologia 2007;50 (Suppl 1):S178.
Nyblom HK, Bugliani M, Marchetti P, Bergsten P. Islet protein expression from type 2 diabetic donors correlating with impaired secretory response. Diabetologia 2007;50 (Suppl 1):S178.
Jafar-Mohammadi B, McCarthy MI. Genetics of type 2 diabetes mellitus and obesity-a review. Ann Med 2008;40:2–10.
Owen KR, McCarthy MI. Genetics of type 2 diabetes. Curr Opin Genet Dev 2007;17:239–44.
Groop L, Lyssenko V. Genes and type 2 diabetes mellitus. Curr Diab Rep 2008;8:192–97.
Parikh H, Groop L. Candidate genes for type 2 diabetes. Rev Endocr Metab Disord 2004;5:151–76.
Vaxillaire M, Froguel P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr Rev 2008;29:254–64.
Hattersley AT, Pearson ER. Minireview: pharmacogenetics and beyond: the interaction of therapeutic response, beta-cell physiology, and genetics in diabetes. Endocrinology 2006;147:2657–63.
Marchetti P, Lupi R, Federici M, Marselli L, Masini M, Boggi U, Del Guerra S, Patane G, Piro S, Anello M, Bergamini E, Purrello F, Lauro R, Mosca F, Sesti G, Del Prato S. Insulin secretory function is impaired in isolated human islets carrying the Gly(972) → Arg IRS-1 polymorphism. Diabetes 2002;51:1419–24.
Federici M, Hribal ML, Ranalli M, Marselli L, Porzio O, Lauro D, Borboni P, Lauro R, Marchetti P, Melino G, Sesti G. The common Arg972 polymorphism in insulin receptor substrate-1 causes apoptosis of human pancreatic islets. FASEB J 2001;15:22–24.
Sesti G, Laratta E, Cardellini M, Andreozzi F, Del Guerra S, Irace C, Gnasso A, Grupillo M, Lauro R, Hribal ML, Perticone F, Marchetti P. The E23K variant of KCNJ11 encoding the pancreatic {beta}-cell KATP channel subunits Kir6.2 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes. J Clin Endocrinol Metab 2006;91:2334–39.
Cauchi S, Froguel P. TCF7L2 genetic defect and type 2 diabetes. Curr Diab Rep 2008;8: 149–55.
Shu L, Sauter NS, Schulthess FT, Matveyenko AV, Oberholzer J, Maedler K. Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes 2008;57:645–53.
Poitout V, Robertson RP. Minireview: Secondary beta-cell failure in type 2 diabetes – a convergence of glucotoxicity and lipotoxicity. Endocrinology 2002;143:339–42.
Böni-Schnetzler M, Thorne J, Parnaud G, Marselli L, Ehses JA, Kerr-Conte J, Pattou F, Halban PA, Weir GC, Donath MY. 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;93:4065–74.
Ehses JA, Böni-Schnetzler M, Faulenbach M, Donath MY. Macrophages, cytokines and beta-cell death in Type 2 diabetes. Biochem Soc Trans 2008;36:340–2 .
Welsh N, Cnop M, Kharroubi I, Bugliani M, Lupi R, Marchetti P, Eizirik DL. 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;54:3238–44.
Lupi R, Del Guerra S, Mancarella R, Novelli M, Valgimigli L, Pedulli GF, Paolini M, Soleti A, Filipponi F, Mosca F, Boggi U, Del Prato S, Masiello P, Marchetti P. Insulin secretion defects of human type 2 diabetic islets are corrected in vitro by a new reactive oxygen species scavenger. Diabetes Metab 2007;33:340–5 .
Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696–705.
Lupi R, Mancarella R, Del Guerra S, Effects of exendin-4 on islets Bugliani M, Del Prato S, Boggi U, Mosca F, Filipponi F, Marchetti P. from type 2 diabetes patients. Diabetes Obes Metab 2008;10:515–9.
Acknowledgments
Supported in part by the Italian Ministry of University and Research (PRIN 2007–2008).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2010 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Marchetti, P., Lupi, R., Del Guerra, S., Bugliani, M., Marselli, L., Boggi, U. (2010). The β-Cell in Human Type 2 Diabetes. In: Islam, M. (eds) The Islets of Langerhans. Advances in Experimental Medicine and Biology, vol 654. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3271-3_22
Download citation
DOI: https://doi.org/10.1007/978-90-481-3271-3_22
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-90-481-3270-6
Online ISBN: 978-90-481-3271-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)