Diabetes is characterized by excess levels of glucose and lipid in the blood, which have been proposed to directly and negatively impact islet β cells, exacerbating symptoms and promoting disease progression. Our understanding of glucotoxicity and lipotoxicity in human type 2 diabetes is limited, because most investigation has used either rodent islets or human islets in vitro. Based on these studies, numerous mechanisms have been proposed, but not tested, in human islets in vivo. To investigate the molecular mechanisms of excess glucose or lipid, we developed and employed three complementary models of nutrient excess, hyperglycemia (excess glucose), insulin resistance (excess lipid), or both, and examined direct effects on human islets in vivo. In response to hyperglycemia or insulin resistance, stimulated insulin secretion, the main indicator of β cell function, is severely reduced from human islet grafts. Surprisingly, in contrast to rodent islets, neither excess of lipid or glucose stimulated β cell proliferation or caused β cell apoptosis. In human islets in vivo, insulin resistance (1) blunted the unfolded protein response (UPR), (2) increased reactive oxygen species production and oxidative stress, (3) increased lipid droplets and amyloid deposits, and (4) reduced the key β cell transcription factors MAFB and NKX6.1. In contrast, hyperglycemia only blunted the UPR and reduced expression MAFB. Importantly, we found fundamental differences between human and mouse islets in response to identical metabolic conditions, such as stimulated insulin secretion, proliferative response, UPR induction, and transcription factor expression. To complement these studies, we performed a comprehensive, systematic, post-hoc analysis of variation of attributes and function across human islet preparations. Based on our data, we propose a model of glucotoxic and liptoxic consequences for human islets in vivo in which insulin resistance induces significantly more detrimental effects for human β cells in vivo than does hyperglycemia alone, but both conditions mechanistically converge to impair stimulated insulin secretion from human β cells in vivo. This work is the first to demonstrate and mechanistically investigate glucotoxic and lipotoxic consequences for human β cells in vivo, and the models developed will be useful to better understand and test interventions for gluco- and lipotoxicity.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-10162015-113112 |
| Date | 20 October 2015 |
| Creators | Bryant, Nora Kayton |
| Contributors | Wenbiao Chen, Roger Colbran, Richard O'Brien, Brian Wadzinski, William Russell |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-10162015-113112/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.002 seconds