Islet amyloid and type 2 diabetes: from molecular misfolding to islet pathophysiology

Abstract

Islet amyloid polypeptide (IAPP, amylin) is secreted from pancreatic islet beta-cells and converted to amyloid deposits in type 2 diabetes. Conversion from soluble monomer, IAPP 1-37, to beta-sheet fibrils involves changes in the molecular conformation, cellular biochemistry and diabetes-related factors. In addition to the recognised amyloidogenic region, human IAPP (hIAPP) 20-29, the peptides human or rat IAPP 30-37 and 8-20, assume beta-conformation and form fibrils. These three amyloidogenic regions of hIAPP can be modelled as a folding intermediate with an intramolecular beta-sheet. A hypothesis is proposed for co-secretion of proIAPP with proinsulin in diabetes and formation of a 'nidus' adjacent to islet capillaries for subsequent accumulation of secreted IAPP to form the deposit. Although intracellular fibrils have been identified in experimental systems, extracellular deposition predominates in animal models and man. Extensive fibril accumulations replace islet cells. The molecular species of IAPP that is cytotoxic remains controversial. However, since fibrils form invaginations in cell membranes, small non-toxic IAPP fibrillar or amorphous accumulations could affect beta-cell stimulus-secretion coupling. The level of production of hIAPP is important but not a primary factor in islet amyloidosis; there is little evidence for inappropriate IAPP hypersecretion in type 2 diabetes and amyloid formation is generated in transgenic mice overexpressing the gene for human IAPP only against a background of obesity. Animal models of islet amyloidosis suggest that diabetes is induced by the deposits whereas in man, fibril formation appears to result from diabetes-associated islet dysfunction. Islet secretory failure results from progressive amyloidosis which provides a target for new therapeutic interventions.

Fiber-dependent amyloid formation as catalysis of an existing reaction pathway

“…Previous work has shown that full-length IAPP forms amyloid by both fiber-independent and fiber-dependent pathways (9). Here, we show that the 2°mechanism of nucleation also plays a prominent role in the fibrous assembly of IAPP [20][21][22][23][24][25][26][27][28][29] . We then determine the origins of this pathway and relate it to 1°n ucleation.…”

“…Then, for each pathway, we characterize the reaction order and enthalpy of the transition state barrier of the rate-limiting step. Nucleation of IAPP [20][21][22][23][24][25][26][27][28][29] fibers occurs on surfaces. This is evident by comparing the kinetics of fiber formation reactions that differ only in the extent of filtration used to prepare reaction buffer.…”

“…This is evident by comparing the kinetics of fiber formation reactions that differ only in the extent of filtration used to prepare reaction buffer. Fiber formation reactions are initiated by diluting a DMSO stock solution of IAPP [20][21][22][23][24][25][26][27][28][29] (10 mM) into aqueous buffer. The buffer is prepared by using a filtered (0.2 m) 10ϫ stock diluted with water that is either nominally free of particulates (Milli-Q; Millipore, Billerica, MA) or has had an additional 0.2-m filtration step applied immediately before use.…”

“…Recent transgenic models, e.g., the HIP rat, strongly support a role for IAPP in diabetic pathology (17). Residues 20-29 of IAPP, SNNFGAILSS, referred to here as IAPP [20][21][22][23][24][25][26][27][28][29] , have previously been shown to form amyloid independently of the rest of the sequence (18)(19)(20). Here, we study the kinetics of assembly of the cationic form of the peptide (amidated C terminus).…”

α-helix to β-hairpin transition of human amylin monomer

“…Subsequent CD studies demonstrated that the hIAPP monomer adopts primarily a random coil structure. 16,[33][34][35][36][37] Recent NMR studies on human amylin, 38 rat amylin and pramlintide peptides, which have sequences similar to that of amylin, suggest that an α-helical structure is adopted near the N-terminus. 39,40 By interpreting the results of ion mobility mass spectroscopy experiments with a molecular implicit-solvent model, Dupuis et al 29 showed that the hIAPP monomer adopts an α-helical conformation between residues 9-17 on the terminus end, and a short β-hairpin between residues 24-28 and 31-35 on the C-terminus.…”