Abstract

Type 2 diabetes (T2DM) is caused by the complex interaction of multiple genes and environmental factors. T2DM is characterized by hyperglycemia, insulin resistance in peripheral tissues and impaired insulin secretion by the pancreas. While the decline in insulin production and secretion was previously attributed to apoptosis of insulin-producing β-cells, recent studies indicate that β cell apoptosis rates are relatively low in diabetes. In this dissertation, I investigated β-cell failure in diabetes using KK and KKAy mouse models of polygenic T2DM, which spontaneously develop hyperglycemia, glucose intolerance, glucosuria, impaired insulin secretion and insulin resistance. I found that β-cell failure in KK and KKAy mouse models of polygenic T2DM is associated with loss of β-cell identity and function, along with a decrease in KATP channel density in the β-cell plasma membrane. Interestingly, intermittent fasting, a weight loss regimen, protected against loss of β-cell identity and function while also increasing β-cell plasma membrane KATP channel density. Furthermore, sulfonylurea (glibenclamide) therapy in KK mice led to secondary failure, with loss of β-cell identity and function along with increased α-cell turnover. The findings bolster the idea that loss of β-cell identity and function is the underlying cause in T2DM, and, importantly, a reversible process.

Committee Chair

Maria Remedi

Committee Members

Brian Finck; Colin Nichols; Fumihiko Urano; Michael Thompson

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

5-6-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0001-5256-0278

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