Summary
Islet amyloid polypeptide which is normally coexpressed with insulin in beta cells, forms amyloid deposits especially in islets of Type 2 (non-insulin-dependent) diabetic subjects. Occurrence of islet amyloid is paradoxically associated with loss of islet amyloid polypeptide immunoreactivity in beta cells. The present study was undertaken to examine whether the islet amyloid polypeptide gene is expressed in islets with decreased islet amyloid polypeptide immunoreactivity. Pancreatic tissue from 14 patients, 7 with Type 2 diabetes and 7 non-diabetic, were obtained at autopsy or surgery and studied for islet amyloid polypeptide expression by in situ hybridization and for presence of insulin and islet amyloid polypeptide by immunohistochemistry. Six of the specimens from the diabetic and three of those from the non-diabetic patients had varying degrees of islet amyloid polypeptide-derived islet amyloid. Amyloid deposits were associated with decreased numbers of beta cells with islet amyloid polypeptide immunoreactivity despite an apparent normal frequency of insulin-containing cells. This discrepancy might reflect an alteration in islet amyloid polypeptide production or processing at a transcriptional or post-transcriptional level. In contrast to the varying immunohistochemical patterns, islets of all categories showed strong labelling using an islet amyloid polypeptide probe for in situ hybridization. It is concluded that islet amyloid polypeptide production is not altered at the transcriptional level. The following possibilities remain: (1) islet amyloid polypeptide production may be altered at a post-transcriptional level or (2) that islet amyloid polypeptide production is normal but the reduced immunoreactivity of the cells reflects a reduced storage of IAPP in secretory granules. We favour the second possibility since islet amyloid deposition is incompatible with reduced islet amyloid polypeptide synthesis.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Westermark P, Wernstedt C, Wilander E, Sletten K (1986) A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas. Biochem Biophys Res Commun 140: 827–831
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: 3881–3885
Westermark P, Wernstedt C, O'Brien TD, Hayden DW, Johnson KH (1987) Islet amyloid in type 2 human diabetes mellitus and adult diabetic cats contains a novel putative polypeptide hormone. Am J Path 127: 414–417
Cooper GJ, Willis AC, Clark A, Turner AC, Sim RB, Reid KBM (1987) Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA 84: 8628–8632
Johnson KH, O'Brien TD, Hayden DW et al. (1988) Immunolocalization of islet amyloid polypeptide (IAPP) in pancreatic beta cells by means of peroxidase-antiperoxidase (PAP) and protein A-gold techniques. Am J Path 130: 1–8
Lukinius A, Wilander E, Westermark GT, Engström U, Westermark P (1989) Co-localization of islet amyloid polypeptide and insulin in the B cell secretory granules of the human pancreatic islets. Diabetologia 32: 240–244
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: 179–185
Rindi G, Terenghi G, Westermark G, Westermark P, Moscoso G, Polak JM (1991) Islet amyloid polypeptide in proliferating pancreatic B cells during development, hyperplasia, and neoplasia in humans and mice. Am J Path 138: 1321–1334
Hartter E, Svoboda T, Ludvik B et al. (1991) Basal and stimulated plasma levels of pancreatic amylin indicate its co-secretion with insulin in humans. Diabetologia 34: 52–54
Butler PC, Chou J, Carter WB et al. (1990) Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans. Diabetes 39: 752–756
Kahn SE, D'Alessio DA, Schwartz MW et al. (1990) Evidence of cosecretion of islet amyloid polypeptide and insulin by b-cells. Diabetes 39: 634–638
Nakazato M, Asai J, Kangawa K, Matsukura S, Matsuo H (1989) Establishment of radioimmunoassay for human islet amyloid polypeptide and its tissue content and plasma concentration. Biochem Biophys Res Commun 164: 394–399
Sanke T, Hanabusa T, Nakano Y et al. (1991) Plasma islet amyloid polypeptide (amylin) levels and their responses to oral glucose in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 34: 129–132
Madsen OD, Nielsen JH, Michelsen B et al. (1991) Islet amyloid polypeptide and insulin expression are controlled differently in primary and transformed islet cells. Mol Endocrinol 5: 143–148
Sanke T, Bell GI, Sample C, Rubenstein AH, Steiner DF (1988) An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing. J Biol Chem 263: 17243–17246
Betsholtz C, Svensson V, Rorsman F et al. (1989) Islet amyloid polypeptide (IAPP): cDNA cloning and identification of an amyloidogenic region associated with species-specific occurrence of age-related diabetes mellitus. Exp Cell Res 183: 484–493
Mosselman S, Höppener JWM, Lips CJM, Jansz HS (1989) The complete islet amyloid polypeptide precursor is encoded by two exons. FEBS Lett 247: 154–158
Leighton B, Cooper GJS (1988) Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 335: 632–635
Leighton B, Foot E (1990) The effects of amylin on carbohydrate metabolism in skeletal muscle in vitro and in vivo. Biochem J 269: 19–23
Zierath JR, Galuska D, Engström Å et al. (1992) Human islet amyloid polypeptide at pharmacological levels inhibits insulin and phorbol ester-stimulated glucose transport in in vitro incubated human muscle strips. Diabetologia 35: 26–31
Johnson KH, O'Brien TD, Jordan K, Betsholtz C, Westermark P (1990) The putative hormone islet amyloid polypeptide (IAPP) induces impaired glucose tolerance in cats. Biochem Biophys Res Commun 167: 507–513
Sowa R, Sanke T, Hirayama J et al. (1990) Islet amyloid polypeptide amide causes peripheral insulin resistance in vivo in dogs. Diabetologia 33: 118–120
Westermark P, Johnson KH, O'Brien TD, Betsholtz C (1992) Islet amyloid polypeptide — a novel controversy in diabetes research. Diabetologia 35: 297–303
Westermark P, Wilander E, Westermark GT, Johnson KH (1987) Islet amyloid polypeptide-like immunoreactivity in the islet B cells of type 2 (non-insulin-dependent) diabetic and non-diabetic individuals. Diabetologia 30: 887–892
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 Path 135: 245–250
Westermark P, Wilander E (1983) Islet amyloid in type 2 (non-insulin-dependent) diabetes is related to insulin. Diabetologia 24: 342–346
Hsu SM, Raine L, Fanger H (1981) Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29: 577–580
Sternberger LA (1979) Immunocytochemistry (2nd edn.). John Wiley, New York
Gibson SJ, Polak JM (1990) Principles and applications of complementary RNA probes. In: Polak JM, McGee JO (eds) In situ hybridization. Principles and practice. Oxford University Press, Oxford, pp 81–94
Cox KH, DeLeon DV, Angerer LM, Angerer RC (1984) Detection of mRNAs in sea urchin embryos by in situ hybridization using asymmetric RNA probes. Develop Biol 101: 485–502
Shorrock K, Roberts P, Pringle JH, Lauder I (1991) Demonstration of insulin and glucagon mRNA in routinely fixed and processed pancreatic tissue by in-situ hybridization. J Path 165: 105–110
Westermark P, Engström U, Johnson KH, Westermark GT, Betsholtz C (1990) Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci USA 87: 5036–5040
Westermark P, Grimelius L (1973) The pancreatic islet cells in insular amyloidosis in human diabetic and non-diabetic adults. Acta Path Microbiol Scand A 81: 291–300
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Westermark, G.T., Christmanson, L., Terenghi, G. et al. Islet amyloid polypeptide: demonstration of mRNA in human pancreatic islets by in situ hybridization in islets with and without amyloid deposits. Diabetologia 36, 323–328 (1993). https://doi.org/10.1007/BF00400235
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00400235