Akter, R; Abedini, A; Ridgway, Z; Zhang, X; Kleinberg, J; Schmidt, AM; Raleigh, DP; (2017) Evolutionary Adaptation and Amyloid Formation: Does the Reduced Amyloidogenicity and Cytotoxicity of Ursine Amylin Contribute to the Metabolic Adaption of Bears and Polar Bears? Israel Journal of Chemistry , 57 (7-8) pp. 750-761. 10.1002/ijch.201600081.

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Abstract

Much of our knowledge of diabetes is derived from studies of rodent models. An alternative approach explores evolutionary solutions to physiological stress by studying organisms that face challenging metabolic environments. Polar bears eat an enormously lipid‐rich diet without deleterious metabolic consequences. In contrast, transgenic rodents expressing the human neuropancreatic polypeptide hormone amylin develop hyperglycemia and extensive pancreatic islet amyloid when fed a high‐fat diet. The process of islet amyloid formation by human amylin contributes to β‐cell dysfunction and loss of β‐cell mass in type 2 diabetes. We show that ursine amylin is considerably less amyloidogenic and less toxic to β‐cells than human amylin, consistent with the hypothesis that part of the adaptation of bears to metabolic challenges might include protection from islet amyloidosis‐induced β‐cell toxicity. Ursine and human amylin differ at four locations: H18R, S20G, F23L, and S29P. These are interesting from a biophysical perspective, since the S20G mutation accelerates amyloid formation, but the H18R slows it. An H18RS20G double mutant of human amylin behaves similarly to the H18R mutant, indicating that the substitution at position 18 dominates the S20G replacement. These data suggest one possible mechanism underpinning the protection of bears against metabolic challenges and provide insight into the design of soluble analogs of human amylin.

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