Islet amyloid polypeptide

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

Kayed R, Bernhagen J, Greenfield N, Sweimeh K, Brunner H, Voelter W, Kapurniotu A. Conformational transitions of islet amyloid polypeptide (IAPP) in amyloid formation in vitro. J Mol Biol 1999 287 781-796. 

Charge SB, de Koning EJ, Clark A. Effect of pH and insulin on fibrillogenesis of islet amyloid polypeptide in vitro. Biochemistry 1995 34 14588-14593. 

Human amylin, or islet amyloid polypeptide (hlAPP), is a 37-residue peptide hormone which forms both intracellular and extracellular (EC) amyloid deposits in the pancreas of most type II diabetic subjects. The core of the structure in the SDS micelle is an ot-helix that runs from about residues 5-28. Although the basic structural unit in the fibrils in... 

Jayasinghe, S. A., and Langen, R. (2004). Identifying structural features of fibrillar islet amyloid polypeptide using site-directed spin labeling. J. Biol. Chem. 279, 48420-48425. 

Reches, M., and Gazit, E. (2004). Amyloidogenic hexapeptide fragment of medin Homology to functional islet amyloid polypeptide fragments. Amyloid 11, 81-89. 

Tenidis, K., Waldner, M., Bemhagen.J., Fischle, W., Bergmann, M., Weber, M., Merkle, M. L., Voelter, W., Brunner, H., and Kapumiotu, A. (2000). Identification of a penta- and hexapeptide of islet amyloid polypeptide (IAPP) with amyloidogenic and cytotoxic properties. / Mol. Biol. 295, 1055-1071. 

Higham, C. E., Jaikaran, E. T., Fraser, P. E., Gross, M., and Clark, A. (2000). Preparation of synthetic human islet amyloid polypeptide (LAPP) in a stable conformation to enable study of conversion to amyloid-like fibrils. FEBS Lett. 470, 55-60. 

B cell (beta) 75 Insulin, C-peptide, proinsulin, islet amyloid polypeptide (IAPP)... 

Figure 10.4 Electron microscope image of negatively stained amyloid fibrils formed by islet amyloid polypeptide showing long, unbranching fibrils of 100 A in diameter (reproduced with permission from [4]).

Gill and Yen (1991) studied the effects on endogenous plasma islet amyloid polypeptide and insulin sensitivity in obese-diabetic viable yellow mice. 

There is also a strong inheritable genetic connection in type 2 diabetes. Having relatives (especially first degree) with this disorder substantially increases the risk of developing type 2 diabetes. Additionally there is a mutation to the islet amyloid polypeptide gene that results in an earlier-onset, more severe form of diabetes. 

Meng F. Abedini A, Song B, Raleigh DP. Amyloid formation by pro-islet amyloid polypeptide processing intermediates examination of the role of protein heparan sulfate interactions and impUcations for islet amyloid formation in type 2 diabetes. Biochemistry 2007 46 12091-12099. 

Recently, it has been ascertained that the pathologic self-assembly nature of inherent peptides or proteins is one major event that leads to the development of many diseases such as prion protein in prion disease, a-synuclein in Parkinson s disease, and islet amyloid polypeptide in type 2 diabetes, as well as Api-42 in AD (9). 

The amyloidoses are a class of conformational diseases that arise from the conversion of normally unfolded or globular proteins into fibrillar aggregates that are either pathogenic or non-functional. At present there are more than 20 proteins that are associated with human amyloid diseases. This review focuses on three natively unfolded proteins that form fibrillar aggregates amyloid-, islet amyloid polypeptide ( amylin ), and a-synuclein, the diseases they contribute to and chemical and biophysical approaches that are used to investigate these proteins aggregation. 

In this review, we will discuss the aggregation of three intrinsically unstructured peptides and proteins and the diseases to which they contribute. Specifically we wiU concentrate on amyloid-P (A ), islet amyloid polypeptide (LAPP), and a-synuclein. 

Islet amyloid polypeptide (lAPP) and type 2 diabetes... 

Jaikaran ETAS, et al. Identification of a novel human islet amyloid polypeptide (beta)-sheet domain and factors influencing fibrillogenesis. J. Molec. Biol. 2001. 308 515. 

Exogenous insulin or insulinotropic oral agents such as sulphonylureas are not suitable for improving insulin resistance. Non-insulinotropic hypoglycaemic medication such as biguanides and/or acarbose, however, is recommended if diet alone fails to achieve sufficient metabolic control. It is still controversial, however, whether the reduction of endogenous insulin also reduces the synthesis of islet amyloid polypeptide (IAPP) sufficiently to slow down the progression of NIDDM (Clark et al., 1987). 

Bretlierton-Watt D, Gilbey SG, Ghatei MA, Beacham J, Bloom SR. Failure to establish islet amyloid polypeptide (amylin) as a circulating beta cell inhibiting hormone in man. Diabetologia 1990 33 115-7. 

Porat Y, Mazor Y, Effat S, Gazit E (2004) Inhibition of islet amyloid polypeptide fibril formation a potential role for heteroaromatic interactions. Biochemistry 43 14454-14462... 

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