, Volume 36, Issue 5, pp 378–384 | Cite as

Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population

  • E. J. P. de Koning
  • N. L. Bodkin
  • B. C. Hansen
  • A. Clark


Diabetes mellitus in Macaca mulatta rhesus monkeys is preceded by phases of obesity and hyperinsulinaemia and is similar to Type 2 (non-insulin-dependent) diabetes mellitus in man. To relate the progression of the disease to quantitative changes in islet morphology, post-mortem pancreatic tissue from 26 monkeys was examined. Four groups of animals were studied: group I — young, lean and normal (n=3); group II — older (>10 years), lean and obese, normoglycaemic (n=9); group III — normoglycaemic and hyperinsulinaemic (n=6); group IV — diabetic (n=8). Areas of islet amyloid, beta cells and islets were measured on stained histological sections. Islet size was larger in animals from groups III (p<0.01) and IV (p<0.0001) compared to groups I and II. The mean beta-cell area per islet in Μm2 was increased in group III (p<0.05) and reduced in group IV (p<0.001) compared to groups I and II. Mean beta-cell area per islet correlated with fasting plasma insulin (r=0.76, p<0.001) suggesting that hyper- and hypoinsulinaemia are related to the beta-cell population. Amyloid was absent in group I but small deposits were present in three of nine (group II) and in four of six (group III) animals, occupying between 0.03–45% of the islet space. Amyloid was present in eight of eight diabetic animals (group IV) occupying between 37–81% of the islet area. Every islet was affected in seven of eight diabetic monkeys. There was no correlation of degree of amyloidosis with age, body weight, body fat proportion or fasting insulin. Islet amyloid appears to precede the development of overt diabetes in Macaca mulatta and is likely to be a factor in the destruction of islet cells and onset of hyperglycaemia.

Key words

Type 2 (non-insulin-dependent) diabetes mellitus Macaca mulatta islet of Langerhans — pathology amyloid islet amyloid polypeptide beta cells obesity 


  1. 1.
    Bell ET (1952) Hybridization of the islets of Langerhans in diabetes mellitus. Diabetes 1: 341–344Google Scholar
  2. 2.
    Clark A, Wells CA, Buley ID et al. (1988) Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in Type 2 diabetes. Diabetes Res 9: 151–160Google Scholar
  3. 3.
    Maclean N, Oglivie RF (1955) Quantitative estimation of the pancreas islet tissue in diabetic subjects. Diabetes 4: 367–376Google Scholar
  4. 4.
    Clark A, Lewis CE, Willis AC, Cooper GJS, Morris JF, Reid KBM (1987) Islet amyloid formed from diabetes-associated peptide may be pathogenic in type 2 diabetes. Lancet II:231–234Google Scholar
  5. 5.
    Schneider HM, Storkel S, Will W (1980) Das amyloid der Langerhansschen inseln und seine beziehung zum diabetes mellitus. Dtsch Med Wschr 105: 1143–1147Google Scholar
  6. 6.
    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 USA 84: 3881–3885Google Scholar
  7. 7.
    Cooper GJS, Leighton B, Dimitriadis GD et al. (1988) Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle. Proc Natl Acad Sci USA 85: 7763–7766Google Scholar
  8. 8.
    Lukinius A, Wilander E, Westermark GT, Engström U, Westermark P (1989) Co-localisation of islet amyloid polypeptide and insulin in the B-cell secretory granules of the human pancreatic islets. Diabetologia 32: 240–244Google Scholar
  9. 9.
    Clark A, Edwards CA, Ostle LR et al. (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: 179–185Google Scholar
  10. 10.
    Kanatsuka A, Makino H, Ohsawa H et al. (1989) Secretion of islet amyloid polypeptide in response to glucose. FEBS Lett 259: 199–201Google Scholar
  11. 11.
    Kahn SE, D'Alessio DA, Schwartz MW et al. (1990) Evidence of cosecretion of islet amyloid polypeptide and insulin by Β cells. Diabetes 40: 305–309Google Scholar
  12. 12.
    Inoue K, Hisatomi A, Umeda F, Nawata H (1990) Amylin release from perfused rat pancreas in response to glucose and arginine. Diabetes Res Clin Pract 10: 189–192Google Scholar
  13. 13.
    Steiner DF, Ohagi S, Nagamatou S, Bell GI, Nishi M (1991) Is islet amyloid polypeptide a significant factor in pathogenesis or pathophysiology of diabetes? Diabetes 40: 305–309Google Scholar
  14. 14.
    Johnson KH, O'Brien TD, Betsholtz C, Westermark P (1989) Islet amyloid, islet amyloid polypeptide and diabetes mellitus. N Engl J Med 321: 513–518Google Scholar
  15. 15.
    Jordan K, Murtaugh MP, O'Brien TD, Westermark P, Betzholtz C, Johnson KH (1990) Canine IAPP cDNA sequence provides important clues regarding diabetogenesis and amyloidogenesis in type 2 diabetes. Biochem Biophys Res Comm 169: 502–508Google Scholar
  16. 16.
    Ohagi S, Nishi M, Bell GI, Ensinck JW, Steiner DF (1991) Sequences of islet amyloid polypeptide precursors of an old world monkey, the pig-tailed macaque (Macaca nemestrina) and the dog (Canis familiaris). Diabetologia 34: 555–558Google Scholar
  17. 17.
    Hansen BC (1987) Prospective study of the development of diabetes in spontaneously obese monkeys. In: Berry EM, Blondheim SH, Eliahou HE, Shafrir E (eds) Recent advances in obesity research, John Libbey, London, pp 33–41Google Scholar
  18. 18.
    Hansen BC, Bodkin NL (1986) Heterogeneity of insulin responses: phases leading to type 2 (non-insulin-dependent) diabetes mellitus in the rhesus monkey. Diabetologia 29: 713–719Google Scholar
  19. 19.
    Howard CF (1974) Diabetes in Macaca nigra: metabolic and histologic changes. Diabetologia 10: 671–677Google Scholar
  20. 20.
    Howard CF (1986) Longitudinal studies on the development of diabetes in individual Macaca nigra. Diabetologia 29: 301–306Google Scholar
  21. 21.
    Howard CF (1986) Changes in islet cell composition during development of diabetes in Macaca nigra. Diabetes 35: 165–171Google Scholar
  22. 22.
    Orci L (1982) Macro and micro domains in the endocrine pancreas. Diabetes 31: 538–565Google Scholar
  23. 23.
    Rahier J, Goebbels RM, Henquin JC (1983) Cellular composition of the human diabetic pancreas. Diabetologia 24: 366–371Google Scholar
  24. 24.
    Clark A, Holman RR, Matthews DR, Hockaday TDR, Turner RC (1984) Non-uniform distribution of islet amyloid in the pancreas of ‘maturity-onset’ diabetic patients. Diabetologia 27: 527–528Google Scholar
  25. 25.
    McCulloch DK, Koerker DJ, Kahn SE, Bonner-Weir S, Palmer JP (1991) Correlations of in vivo Β-cell function tests with Β-cell mass and pancreatic insulin content in streptozocin-administered baboons. Diabetes 40: 673–679Google Scholar
  26. 26.
    Saito K, Yaginuma N, 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: 273–283Google Scholar
  27. 27.
    Johnson KH, O'Brien TD, Jordan K, Westermark P (1989) Impaired glucose tolerance is associated with increased islet amyloid polypeptide (IAPP) immunoreactivity in pancreatic beta-cells. Am J Pathol 135: 245–250Google Scholar
  28. 28.
    Pepys MB (1988) Amyloidosis: some recent developments. Quart J Med 252: 283–298Google Scholar
  29. 29.
    Bonner-Weir S, Deery D, Leahy JL, Weir GC (1989) Compensatory growth of pancreatic Β-cells in adult rats after short-term glucose infusions. Diabetes 38: 49–53Google Scholar
  30. 30.
    Petkov P, Marquie G, Donev S, Dahmani Y, Duhault J (1985) Morphology of the endocrine pancreas in the diabetic sand rat (Psammomys obesus). Cell Molec Biol 316: 61–74Google Scholar
  31. 31.
    Starich GH, Zafirora M, Jablenska R, Petkov P, Lardinois CL (1991) A morphological and immunohistochemical investigation of endocrine pancreata from obese ob+/ob+ mice. Acta Histochem 90: 93–101Google Scholar
  32. 32.
    Westermark P, Wilander E (1970) The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus. Diabetologia 15: 417–421Google Scholar
  33. 33.
    Weibel ER (1963) Principles and methods for the morphometric studies of the lung and other organs. Lab Invest 12: 131–155Google Scholar
  34. 34.
    Jones CW, Reynolds WA, Hogansen GE (1980) Streptozotocin diabetes in the monkey. Plasma levels of glucose, insulin, glucagon and somatostatin with corresponding morphometric analysis of islet endocrine cells. Diabetes 29: 536–546Google Scholar
  35. 35.
    Kloppel G (1984) Islet histopathology in diabetes mellitus In: Kloppel G, Heitz PU (eds) Pancreatic pathology. Churchill Livingstone, Edinburgh London Melbourne New York, pp 154–185Google Scholar
  36. 36.
    Fonseca V, Berger LA, Beckett AG, Dandona P (1985) Size of the pancreas in diabetes mellitus: a study based on ultrasound. Br Med J 291: 1240–1241Google Scholar
  37. 37.
    Dandona P, Freedman DB, Foo Y et al. (1984) Exocrine pancreatic function in diabetes mellitus. J Clin Pathol 37: 302–306Google Scholar
  38. 38.
    Korc M, Owerbach D, Quinto C, Ruttter WJ (1981) Pancreatic islet acinar cell interaction: amylase messenger RNA levels are determined by insulin. Science 213: 351–353Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • E. J. P. de Koning
    • 1
  • N. L. Bodkin
    • 2
  • B. C. Hansen
    • 2
  • A. Clark
    • 1
  1. 1.Diabetes Research LaboratoriesRadcliffe InfirmaryOxfordUK
  2. 2.Department of Physiology, Obesity and Diabetes Research CenterUniversity of Maryland Medical SchoolBaltimoreUSA

Personalised recommendations