Abstract
Human islet amyloid polypeptide or amylin (hA) is a 37-amino acid peptide hormone produced and co-secreted with insulin by pancreatic β-cells. Under physiological conditions, hA regulates a broad range of biological processes including insulin release and slowing of gastric emptying, thereby maintaining glucose homeostasis. However, under the pathological conditions associated with type 2 diabetes mellitus (T2DM), hA undergoes a conformational transition from soluble random coil monomers to alpha-helical oligomers and insoluble β-sheet amyloid fibrils or amyloid plaques. There is a positive correlation between hA oligomerization/aggregation, hA toxicity, and diabetes progression. Because the homeostatic balance between hA synthesis, release, and uptake is lost in diabetics and hA aggregation is a hallmark of T2DM, this chapter focuses on the biophysical and cell biology studies investigating molecular mechanisms of hA uptake, trafficking, and degradation in pancreatic cells and its relevance to h’s toxicity. We will also discuss the regulatory role of endocytosis and proteolytic pathways in clearance of toxic hA species. Finally, we will discuss potential pharmacological approaches for specific targeting of hA trafficking pathways and toxicity in islet β-cells as potential new avenues toward treatments of T2DM patients.
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Abbreviations
- AFM:
-
Atomic force microscopy
- CD:
-
Circular dichroism
- CTX:
-
Cholera toxin
- EM:
-
Electron microscopy
- hA:
-
Human amylin
- HFIP:
-
Hexafluoride isopropanol
- HSP:
-
Heat shock protein
- Lac:
-
Lactacystin
- MB:
-
Methylene blue
- MT:
-
MitoTracker
- MTT:
-
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- PepA:
-
Pepstatin A
- PM:
-
Plasma membrane
- rA:
-
Rodent amylin
- T2DM:
-
Type 2 diabetes mellitus
- ThT:
-
Thioflavin-T
- Trf:
-
Transferrin
- Ub:
-
Ubiquitin
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Acknowledgment
This work was supported by the NIH grant RO1DK091845 and the ICR Basic Science Islet Distribution Program (to A.J.).
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Bhowmick, D.C., Singh, S., Trikha, S., Jeremic, A.M. (2017). The Molecular Physiopathogenesis of Islet Amyloidosis. In: Ulloa-Aguirre, A., Tao, YX. (eds) Targeting Trafficking in Drug Development. Handbook of Experimental Pharmacology, vol 245. Springer, Cham. https://doi.org/10.1007/164_2017_62
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