Abstract
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 β-cell mass as a result of misfolded human islet amyloid polypeptide (h-IAPP) which forms toxic aggregates that destroy pancreatic β-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 β-cells. Moreover, Hsp72 (HSPA1A) overexpression in pancreatic β-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 β-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 β-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.
Highlights
The number of people with diabetes worldwide reached 382 million and by 2035 this number will increase to 592 million (International Diabetes Federation); 90% of whom have type 2 diabetes
Cell viability was not affected after 30 min of heat shock; this treatment was selected to evaluate the role of Hsp72 (HSPA1A) in preventing human islet amyloid polypeptide (h-IAPP) toxicity
Having demonstrated that heat stress increased the levels of Hsp72 (HSPA1A), we established whether this induction protects β-cells against exogenously added h-IAPP
Summary
The number of people with diabetes worldwide reached 382 million and by 2035 this number will increase to 592 million (International Diabetes Federation); 90% of whom have type 2 diabetes. An important characteristic of type 2 diabetes is a deficit in β-cell mass as a result of misfolded human islet amyloid polypeptide hormone (h-IAPP, called amylin), which forms toxic aggregates that destroy pancreatic β-cells [1]. HIAPP is a 37-amino acid hormone co-secreted with insulin by pancreatic β-cells, and is initially synthesized as a 89-amino acid pre-prohormone containing a 22 amino-acid signal peptide and two short flanking peptides that are later cleaved [3]. The signal peptide is cleaved in the endoplasmic reticulum (ER), where pre-proIAPP is converted into proIAPP and converted into IAPP in secretory granules [3]. In vitro studies demonstrated that proIAPP aggregates are toxic to pancreatic beta cells [6]. Feline and non-human primate forms of IAPP are the only forms with the capacity to oligomerize and form aggregates
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