Abstract

In mammals, ATP-sensitive K+ (KATP) channels are essential regulators of insulin secretion from pancreatic islet [beta]-cells, illustrated by the finding that gain-of-function mutations in KATP channels (KATP-GOF) cause neonatal diabetes mellitus (NDM). However, variability in symptom severity and effectiveness of treatment is seen in NDM, even for those with the same mutation and in the same family. Short-term treatment of mice expressing KATP-GOF mutations in [beta]-cells (KATP-GOF mice) with the KATP blocker glibenclamide during disease onset results in two outcomes: one subset becomes severely diabetic (non-remitters), whereas the other subset remains below the glucose levels at which significant side effects occur (remitters). Remitters and non-remitters do not differ in insulin sensitivity early in the induction process, but remitter mice have lower levels of the inflammatory cytokines TNF-[alpha] and IL-6, as well as liver glucose production, suggesting roles for gluconeogenesis and inflammation in the pathogenesis of NDM.Whether KATP Фependent excitability is relevant to insulin secretory control in non-mammalian vertebrates is unclear. I have shown that zebrafish islet [beta]-cells express functional KATP channels, that these channels have similar properties to their mammalian orthologues, and that they regulate intracellular calcium and glucose homeostasis in zebrafish. Further, I have shown that zebrafish with inducible, [beta]-cell specific KATP-GOF mutations recapitulate loss of glucose-induced calcium response, severe hyperglycemia, and growth defects. These findings will inform studies of metabolism in zebrafish and enable the use of zebrafish for larger-scale studies of NDM to identify unknown modifiers regulating responses to [beta]-cell membrane inexcitability.

Committee Chair

Colin Maria G. Nichols Remedi

Committee Members

James Huettner, Charles Kaufman, Jean Schaffer,

Comments

Permanent URL: 2019-02-22

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Molecular Cell Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

Summer 8-15-2018

Language

English (en)

Author's ORCID

https://orcid.org/0000-0002-9130-4194

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