Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin

1995 ◽  
Vol 132 (4) ◽  
pp. 487-496 ◽  
Author(s):  
Kazuo Yagui ◽  
Takahide Yamaguchi ◽  
Azuma Kanatsuka ◽  
Fumio Shimada ◽  
Choug I Huang ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transgenic Mice ◽  
Beta Cells ◽  
Amyloid Fibrils ◽  
Secretory Granules ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Amyloid Deposits

Yagui K, Yamaguchi T, Kanatsuka A, Shimada F, Huang CI, Tokuyama Y, Ohsawa H, Yamamura K, Miyazaki J. Mikata A, Yoshida S, Makino H. Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin. Eur J Endocrinol 1995:132:487–96. ISSN 0804–4643 To investigate the relationship between human islet amyloid polypeptide (IAPP)/amylin expression and islet amyloid deposits in the pathogenesis of human non-insulin-dependent diabetes mellitus (NIDDM), we developed transgenic mice using a human IAPP cDNA connected to an insulin promoter. Ribonucleic acid blotting and immunohistochemistry revealed the expression of the transgene in the pancreatic beta cells. Immunogold electron microscopy showed that beta-secretory granules contained the human C-terminal flanking peptide of the IAPP precursor. Reverse-phase HPLC demonstrated human and mouse IAPP amide in the pancreas. Electron microscopy showed the accumulation of fibril-like material in a considerable number of beta-secretory granules. These results suggest that in transgenic mice, the human IAPP precursor is expressed in beta cells and becomes normally sorted into beta-secretory granules in which normal conversion to mature human IAPP takes place. The human IAPP molecules, because of their amyloidogenesis, aggregate into amyloid fibrils in secretory granules. Glucose tolerance was normal at 7 months old and islet amyloid was not observed. A longer time may be required for islet amyloid deposits and hyperglycemia to develop in mice. Our working hypothesis is that in human NIDDM, IAPP aggregates into amyloid fibrils in beta-secretory granules, and that the fibrils are released into the extracellular space and islet amyloid deposits become substantial with time. Azuma Kanatsuka, Second Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan

Human islet amyloid polypeptide accumulates at similar sites in islets of transgenic mice and humans

Diabetes ◽  
1994 ◽  
Vol 43 (5) ◽  
pp. 640-644 ◽  
Author(s):  
E. J. de Koning ◽  
J. W. Hoppener ◽  
J. S. Verbeek ◽  
C. Oosterwijk ◽  
K. L. van Hulst ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

scholarly journals Human Islet Amyloid Polypeptide Fibril Binding to Catalase: A Transmission Electron Microscopy and Microplate Study

2010 ◽  
Vol 10 ◽  
pp. 879-893 ◽  
Author(s):  
Nathaniel G. N. Milton ◽  
J. Robin Harris
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Islet Amyloid Polypeptide ◽  
Amyloid Β ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Transmission Electron

The diabetes-associated human islet amyloid polypeptide (IAPP) is a 37-amino-acid peptide that forms fibrilsin vitroandin vivo. Human IAPP fibrils are toxic in a similar manner to Alzheimer's amyloid-β (Aβ) and prion protein (PrP) fibrils. Previous studies have shown that catalase binds to Aβ fibrils and appears to recognize a region containing the Gly-Ala-Ile-Ile sequence that is similar to the Gly-Ala-Ile-Leu sequence found in human IAPP residues 24-27. This study presents a transmission electron microscopy (TEM)—based analysis of fibril formation and the binding of human erythrocyte catalase to IAPP fibrils. The results show that human IAPP 1-37, 8-37, and 20-29 peptides form fibrils with diverse and polymorphic structures. All three forms of IAPP bound catalase, and complexes of IAPP 1-37 or 8-37 with catalase were identified by immunoassay. The binding of biotinylated IAPP to catalase was high affinity with a KDof 0.77nM, and could be inhibited by either human or rat IAPP 1-37 and 8-37 forms. Fibrils formed by the PrP 118-135 peptide with a Gly-Ala-Val-Val sequence also bound catalase. These results suggest that catalase recognizes a Gly-Ala-Ile-Leu—like sequence in amyloid fibril-forming peptides. For IAPP 1-37 and 8-37, the catalase binding was primarily directed towards fibrillar rather than ribbon-like structures, suggesting differences in the accessibility of the human IAPP 24-27 Gly-Ala-Ile-Leu region. This suggests that catalase may be able to discriminate between different structural forms of IAPP fibrils. The ability of catalase to bind IAPP, Aβ, and PrP fibrils demonstrates the presence of similar accessible structural motifs that may be targets for antiamyloid therapeutic development.

Extended life span is associated with insulin resistance in a transgenic mouse model of insulinoma secreting human islet amyloid polypeptide

2004 ◽  
Vol 286 (3) ◽  
pp. E418-E424 ◽  
Author(s):  
Sofianos Andrikopoulos ◽  
Rebecca L. Hull ◽  
C. Bruce Verchere ◽  
Feng Wang ◽  
Shani M. Wilbur ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Life Span ◽  
Amyloid Fibrils ◽  
Islet Amyloid Polypeptide ◽  
Transgenic Animals ◽  
Human Islet ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Glucose Levels ◽  
Human Islet Amyloid Polypeptide

Pancreatic amyloid is found in patients with insulinomas and type 2 diabetes. To study mechanisms of islet amyloidogenesis, we produced transgenic mice expressing the unique component of human islet amyloid, human islet amyloid polypeptide (hIAPP). These mice develop islet amyloid after 12 mo of high-fat feeding. To determine whether we could accelerate the rate of islet amyloid formation, we crossbred our hIAPP transgenic animals with RIP-Tag mice that develop islet tumors and die at 12 wk of age from hypoglycemia. At 12 wk of age, this new line of hIAPP×RIP-Tag mice was heavier (29.7 ± 1.0 vs. 25.0 ± 1.3 g, P < 0.05) and had increased plasma glucose levels (4.6 ± 0.4 vs. 2.9 ± 0.6 mmol/l, P < 0.05) compared with littermate RIP-Tag mice. However, the hIAPP×RIP-Tag mice did not display islet amyloid or amyloid fibrils despite high circulating hIAPP levels (24.6 ± 7.0 pmol/l). Interestingly, hIAPP×RIP-Tag mice had a longer life span than RIP-Tag mice (121 ± 8 vs. 102 ± 5 days, P < 0.05). This increase in life span in hIAPP×RIP-Tag was positively correlated with body weight ( r = 0.48, P < 0.05) and was associated with decreased insulin sensitivity compared with RIP-Tag mice. hIAPP×RIP-Tag mice did not develop amyloid during their 4-mo life span, suggesting that increased hIAPP secretion is insufficient for islet amyloid formation within such a short time. However, hIAPP×RIP-Tag mice did have an increase in life span that was associated with insulin resistance, suggesting that hIAPP has extrapancreatic effects, possibly on peripheral glucose metabolism.

Differences in amyloid deposition in islets of transgenic mice expressing human islet amyloid polypeptide versus human islets implanted into nude mice

Metabolism ◽  
1999 ◽  
Vol 48 (4) ◽  
pp. 448-454 ◽  
Author(s):  
Gunilla Westermark ◽  
Per Westermark ◽  
Decio L. Eizirik ◽  
Claes Hellerström ◽  
Niles Fox ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Nude Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islets ◽  
Amyloid Deposition ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Biologically active human islet amyloid polypeptide/amylin in transgenic mice

1997 ◽  
Vol 136 (1) ◽  
pp. 107-113 ◽  
Author(s):  
Karen L van Hulst ◽  
Walter Born ◽  
Roman Muff ◽  
Cor Oosterwijk ◽  
Marinus A Blankenstein ◽  
...  
Keyword(s):  
Biological Activity ◽  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Cell Protein ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Human And Mouse

Abstract Objective: Human islet amyloid polypeptide (hIAPP), also named amylin, is a pancreatic β cell protein implicated in the pathogenesis of pancreatic islet amyloid formation and type 2 diabetes mellitus. To study the (patho)physiological roles of hIAPP, we have generated transgenic mice that overexpress hIAPP mRNA, in relation to endogenous mouse IAPP (mIAPP) mRNA, in pancreatic β cells. The biological activity of human and mouse IAPP derived from pancreatic extracts was determined. Methods: Pancreatic and plasma extracts of transgenic and control mice were analyzed by reversedphase high-performance liquid chromatography (HPLC) and radioimmunoassay, yielding a separation of hIAPP from mIAPP. Biological activity of immunoreactive human and mouse IAPP components derived from pancreatic extracts was assessed by calcitonin receptor-mediated stimulation of cyclic AMP accumulation in T47D human breast carcinoma cells. Results: The predominant immunoreactive human and mouse IAPP gene products had the retention times on HPLC analysis of the corresponding synthetic peptides. The ratio of bioactive over immunoreactive hIAPP and mIAPP was 0·93 ±0·18 and 1·19 ±0·56 respectively. In extracts of two plasma pools from 4 transgenic animals, hIAPP was 4·6- to 7-fold more abundant than mIAPP. Conclusion; This study has shown that correctly processed hIAPP produced in transgenic mouse pancreatic β cells exhibits full biological activity. The results validate these transgenic mice for the study of (patho)physiological roles of hIAPP in vivo. European Journal of Endocrinology 136 107–113

Oophorectomy promotes islet amyloid formation in human islet amyloid polypeptide transgenic mice

Diabetes ◽  
2001 ◽  
Vol 50 (Supplement 1) ◽  
pp. S184-S185 ◽  
Author(s):  
R. L. Hull ◽  
B. Verchere ◽  
S. Andrikopoulos ◽  
F. Wang ◽  
J. Vidal ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

Human Islet Amyloid Polypeptide Accumulates at Similar Sites in Islets of Transgenic Mice and Humans

Diabetes ◽  
1994 ◽  
Vol 43 (5) ◽  
pp. 640-644 ◽  
Author(s):  
E. J. P. de Koning ◽  
J. W. M. Hoppener ◽  
J. S. Verbeek ◽  
C. Oosterwijk ◽  
K. L. van Hulst ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Islet Amyloid Polypeptide ◽  
Human Islet ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide

scholarly journals Extracellular vesicles from human pancreatic islets suppress human islet amyloid polypeptide amyloid formation

2017 ◽  
Vol 114 (42) ◽  
pp. 11127-11132 ◽  
Author(s):  
Diana Ribeiro ◽  
Istvan Horvath ◽  
Nikki Heath ◽  
Ryan Hicks ◽  
Anna Forslöw ◽  
...  
Keyword(s):  
Pancreatic Islets ◽  
Extracellular Vesicles ◽  
Islet Amyloid Polypeptide ◽  
Cell Communication ◽  
Human Islet ◽  
Amyloid Formation ◽  
Islet Amyloid ◽  
Human Islet Amyloid Polypeptide ◽  
Amyloid Deposits

Extracellular vesicles (EVs) are small vesicles released by cells to aid cell–cell communication and tissue homeostasis. Human islet amyloid polypeptide (IAPP) is the major component of amyloid deposits found in pancreatic islets of patients with type 2 diabetes (T2D). IAPP is secreted in conjunction with insulin from pancreatic β cells to regulate glucose metabolism. Here, using a combination of analytical and biophysical methods in vitro, we tested whether EVs isolated from pancreatic islets of healthy patients and patients with T2D modulate IAPP amyloid formation. We discovered that pancreatic EVs from healthy patients reduce IAPP amyloid formation by peptide scavenging, but T2D pancreatic and human serum EVs have no effect. In accordance with these differential effects, the insulin:C-peptide ratio and lipid composition differ between EVs from healthy pancreas and EVs from T2D pancreas and serum. It appears that healthy pancreatic EVs limit IAPP amyloid formation via direct binding as a tissue-specific control mechanism.

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