Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes Treatment
Type 2 diabetes is a growing public health concern and accounts for approximately 90% of all the cases of diabetes. Besides insulin resistance, type 2 diabetes is characterized by a deficit in b cell mass as a result of misfolded human islet amyloid polypeptide (h IAPP) which forms toxic aggregates that destroy pancreatic b cells. Heat shock proteins (HSP) play an important role in combating the unwanted self association of unfolded proteins. We hypothesized that Hsp72 (HSPA1A) prevents h IAPP aggregation and toxicity. In this study, we demonstrated that thermal stress significantly up regulates the intracellular expression of Hsp72, and prevents h IAPP toxicity against pancreatic b cells. Moreover, Hsp72 (HSPA1A) overexpression in pancreatic b cells ameliorates h IAPP toxicity. To test the hypothesis that Hsp72 (HSPA1A) prevents aggregation and fibril formation, we established a novel C. elegans model that expresses the highly amyloidogenic human pro IAPP (h proIAPP) that is implicated in amyloid formation and b cell toxicity. We demonstrated that h proIAPP expression in body wall muscles, pharynx and neurons adversely affects C. elegans development. In addition, we demonstrated that h proIAPP forms insoluble aggregates and that the co expression of h Hsp72 in our h proIAPP C. elegans model, increases h proIAPP solubility. Furthermore, treatment of transgenic h proIAPP C. elegans with ADAPT 232, known to induce the expression and release of Hsp72 (HSPA1A) significantly improved the growth retardation phenotype of transgenic worms. Taken together, this study identifies Hsp72 (HSPA1A) as a potential treatment to prevent b cell mass decline in type 2 diabetic patients and establishes for the first time a novel in vivo model that can be used to select compounds that attenuate h proIAPP aggregation and toxicity.
PloS one