ΝΑΚΑΖΑΤΟ et al 5. New Type of Amyloidosis b) Islet Amyloid Polypeptide (IAPP/Amylin) in Non-Insulin-Dependent Diabetes Mellitus Masamitsu NAKAZATO and Shigeru MATSUKURA Key words: IAPP, amylin, Langerhans, diabetes mellitus, amyloid Introduction be co-localized with insulin in B cells and with somatostatin in some D cells (5). IAΡΡ was also observed in some G cells in the Amyloid deposition in the islets of Langerhans is a major pyloric antrum of the stomach and mucosal cells in the duode- pathological feature of non-insulin-dependent diabetes mellitus num, jejunum, ileum, and colon at 0.1-0.8% of the level of (NIDDM). The amyloid is often observed in insulinoma tissues pancreas. It was not detected in any other systemic organs and the islets of elderly non-diabetic subjects. Islet amyloid including the central nervous system. polypeptide (1), also designated amylin (2), is a 37-amino acid IΑPP messenger RNA whose size is 900 bases is also peptide that was isolated from islet amyloid in 1987. The predominantly expressed in the pancreas. IAPP is detected in peptide might be involved in the etiology of NIDDM by rat fetal pancreas, and its content gradually increases during opposing insulin action in peripheral tissues and by destroying development. IAPP in the antrum appears 3 days after birth. In islet construction through amyloid deposition. We studied the the human pancreas, IAPP is detected at 15 weeks of gestation. properties of ΙΑΡΡ, its synthesis and secretion in abnormal Although ΙΑΡΡ and insulin are co-localized in B cells, synthesis glucose tolerance, and amyloidogenesis of the islet in NIDDM. and secretion of the two peptides are not proportionally changed in dexamethasone- and streptozotocin-induced rat models of Property of IAPP diabetes. There might be different systems to regulate synthesis The molecular weight of human IAPP is 3,903 daltons and and secretion of the two peptides. its amino acid sequence has 46% homology with calcitonin Basal plasma immunoreactive IAPP level in normal indi- gene-related peptide (CGRP). Α sulfide bond, essential for the viduals was 2.4-5.8 fmol/ml, being increased in subjects with expression of its physiological function, is formed between obesity or impaired glucose tolerance, and decreased in diabetic position 2 and 7 in the molecule. Amino acids from the 25 to patients. Human plasma IAPP level was increased in response 29th position yield beta structure which is responsible for to glucose, arginine and glucagon, and decreased by somatostatin amyloid formation by ΙΑΡΡ. Mature IAPP is derived from injection (6). A similar response was also observed in the prepro-ΙAPP by proteolytic processing at the pairs of basic perfusion study with rat pancreas. ΙΑΡΡ was co-secreted with amino acids of Lys-Arg followed by C-terminal amidation. An insulin in these physiological experiments. The plasma ΙΑPΡ analysis of the IAPP gene suggested that ΙΑΡΡ is an ancestral response to glucose was decreased in NIDDM patients who gene product of CGRP. We developed three RIAs for IAPP: were treated with diet alone, oral hypoglycemic agents and human and rat common N-terminal region of ΙΑPΡ, and both insulin in that order, being correlated to the remaining B cell human and rat C-terminal ΙΑΡΡ (3). We also identified function. endogeneous molecular forms of ΙΑΡΡ in pancreata, gastro Recent physiological studies indicate that ΙΑΡP inhibits intestinal tracts and plasma of many mammals (4). Processing glycogen synthesis in skeletal muscle, stimulates hepatic glu- of IAPP differs by species, but does not differ by tissues in the cose production, and reduces glucose uptake in the liver and species. No amino acid substitution was detected in IAPP muscles. Furthermore, ΙΑPΡ is also present in osteoblasts and isolated from islet amyloid in diabetic cases and from normal serves as paracrine to inhibit osteoclast activity. ΙAPΡ de- human pancreas, indicating that the amyloid is not associated creases the serum calcium level and may be implicated in with molecular abnormality of the peptide. calcium metabolism. The richest specific binding site of ΙAPΡ is noted in the lung, where ΙΑΡΡ is, however, not present. ΙΑΡΡ Synthesis, secretion and physiological function of IAPP may function in the lung other than regulating glucose and Pancreatic IAPP content was 221.6±78.2 pmol/g wet weight calcium metabolism. in man and 328.5±25.0 pmol/g wet weight in rat, being approxi- mately 1 –2% of insulin content. Fasting decreased the pancre- Amyloidogenesis of IAPP atic ΙAΡP content. ΙAΡΡ was immunohistochemically shown to We studied 300 islets per one individual pancreas in 36 The Third Department of Internal Medicine, Miyazaki Medical College, Kihara, Kiyotake, Miyazaki 889-16 928 Internal Medicine Vol. 32, No. 12 (December 1993) ΙΑΡΡ in NIDDM NIDDM patients and 25 non-diabetic subjects. Amyloid depos- physiological function and amyloidogenesis of IAPP, which its were found in 91% of the diabetic cases. The incidence of may provide new insights into islet physiology and the islets with amyloid varied from 1 to 97% among the cases, and pathogenesis of NIDDM. it correlated with the severity of DM. Islet amyloid was ob- served in 20% of elderly non-diabetic subjects. In comparison Acknowledgements: This research was supported in part by Grant-in-Aids to subjects having no islet amyloid, IAPP-immunoreactivity in for Scientific Research from the Ministry of Education, Science and Culture, Japan, (M.N. and S.M.) and from the Intractable Disease Division, Ministry of B cells was markedly reduced even in islets with small amyloid Health and Welfare, Primary Amyloidosis Research Committee, Japan (M.N.). deposits in these diabetic and elderly subjects. Islet amyloid deposition generally occurred after IAPP-immunoreactivity in References B cells decreased, suggesting the possibility that amyloid deposition may be simply a secondary manifestation of disor- 1) Westermark P, Wernstedt C, Wilander E, et al. Amyloid fibrils in human dered islet function. In NIDDM- and aging-associated islet insulinoma and islets of Langerhans of the diabetic cats are derived from amyloid, IAPP could form amyloid due to disturbed catabolism a neuropeptide-like protein also present in normal islet cells. Proc Nat! Acad Sci USA 84: 3881, 1987. of the peptide and/or due to impaired secretion of IAPP causing 2) Cooper GJS, Leighton B, Dimitriadis GD, et a!. Amylin found in amyloid intracellular accumulation in disordered B cells. Normal B cells deposits in human type 2 diabetes mellitus may be a hormone that completely disappeared in the islets with massive amyloid regulates glycogen metabolism in skeletal muscle. Proc Natl Acad Sci deposits in advanced diabetic patients. Amyloid was observed USA 85: 7763, 1988. in 3 out of 13 insulinomas where overproduction of IAPP could 3) Shiomi K, Nakazato M, Miyazato M, et al. Establishment of hyper- sensitive radioimmunoassay for islet amyloid polypeptide using anti- result in amyloid formation. serum specific for its N-terminal region. Biochem Biophys Res Commun It has been suggested that IAPP potentially participates in 186: 1065, 1992. the pathogenesis of NIDDM. IAPP was shown to inhibit insulin 4) Miyazato M, Nakazato M, Shiomi K, et al. Molecular forms of islet release and to oppose insulin action in peripheral tissues. These amyloid polypeptide (ΙΑPΡ/amylin) in four mammals. Diabetes Res Clin functions were derived by pharmacological concentrations of Pract 15: 31, 1992. ΙΑΡΡ, ΙΑ Ρ 5) Toshimori H, Narita R, Nakazato M, et al. Islet amyloid polypeptide and it remains to be clarified whether P at physiologi- (ΙΑΡΡ) in the gastrointestinal tract and pancreas in man and rat. Cell cal concentrations acts as a counter-regulatory hormone to Tissue Res 262: 401, 1990. insulin. Islet amyloid deposition is not responsible for the 6) Mitsukawa T, Takemura J, Asai J, et al. Islet amyloid polypeptide primary etiology of NIDDM, however, the amyloid deposits response to glucose, insulin and somatostatin analogue administration. may intensify islet dysfunction and contribute to the progres- Diabetes 39: 639, 1990. sion of NIDDM. Much remains to be resolved for evaluating Internal Medicine Vol. 32, No. 12 (December 1993) 929.