UBC Theses and Dissertations
The activity and biosynthesis of beta-cell peptide hormones : implications in diabetes, obesity, and pancreatic cancer Taylor, Austin James
Type 1 and type 2 diabetes are characterized by hyperglycemia and loss of beta-cell mass, function, and peptide hormones. Beyond hyperglycemia, diabetes is also associated with obesity and increased risk of cancer, particularly pancreatic cancer. Islet amyloid polypeptide (IAPP) is the second most abundant beta-cell hormone, co-secreted with insulin, and reduced in diabetes. Paracrine actions of endogenous IAPP have been proposed in glycemic regulation and tumour growth suppression, but remain incompletely understood. To further characterize the effects of IAPP loss, we used an IAPP-knockout mouse fed a high-fat or control diet and assessed glycemia and adiposity. We also generated a genetic mouse model of pancreatic ductal adenocarcinoma in IAPP-knockout mice to investigate IAPP loss as a potential mechanism for the association of diabetes and pancreatic cancer. Trends in IAPP-knockout mice suggest elevated adiposity and glycemia in the absence of IAPP. We observed no effect of IAPP on pancreatic ductal adenocarcinoma survival in mice, or cancer cell proliferation, death, or glycolysis. A reduction in the processing efficiency of beta-cell peptide prohormones is also observed in diabetes. Pcsk1 and Pcsk2 are the two major prohormone endoproteases within insulin granules, and are responsible for multiple steps in the proIAPP and proinsulin processing pathways. To determine whether impaired processing functions as a biomarker or driver of beta-cell dysfunction, we generated mouse models of beta-cell specific (Ins1cre-driven) Pcsk1 and Pcsk2 deficiency using Cre-lox recombination. Loss of Pcsk1 in beta cells caused severe proinsulin processing impairments and increased diabetes susceptibility in male mice, while female mice remained euglycemic. In contrast, male and female beta-cell Pcsk2-deficient mice were euglycemic with minimally impaired proinsulin processing, but severely impaired proIAPP processing. Deletion of both Pcsk1 and Pcsk2 in beta cells blocked proinsulin processing, drove hyperglycemia, increased beta-cell glucose responsiveness and mass, and reduced beta-cell maturity and proliferative capacity. In a mouse model expressing amyloidogenic human IAPP in beta cells, Pcsk1 deficiency significantly increased amyloid deposition. Collectively, these findings show that loss of beta-cell prohormone processing alters beta-cell function and drives hyperglycemia, and that endogenous IAPP does not act as a pancreatic tumour suppressor but may alter glycemia and adiposity.
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