Publication Date
2021
Document Type
Thesis
Committee Members
Mauricio Di Fulvio, Ph.D. (Advisor); Khalid Elased, Pharm.D., Ph.D. (Committee Member); Courtney Sulentic, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Insulin secretion plays a crucial role in energy homeostasis. Accordingly, disrupted insulin secretion has been associated with metabolic disorders such as insulin resistance syndrome and diabetes mellitus. Insulin secretion from pancreatic β-cells is tightly regulated by complex ionic mechanisms usually included in a consensus mechanism involving ATP-sensitive K+ channels as the only key player. However, K+ channels solely do not reflect the whole mechanism. Anionic channels also contribute to the machinery of insulin secretion by initiating electrogenic Cl– fluxes in β-cells. The Na+K+2Cl– cotransporter 1 (Nkcc1) and other Cl– transporters participate in the non-equilibrium distribution of Cl– in β-cells. Recent studies from our laboratory and others have demonstrated a potential role of Nkccs in insulin secretion. However, virtually nothing is known regarding the role of Nkcc1 in energy homeostasis. In this study, we unravel part of the physio-pathological consequences that follow the disruption of insulin secretion upon elimination of Nkcc1 from β-cells in mice. Our results suggest that deficient insulin secretion due to altered β-cells Cl– homeostasis impairs satiation responses to feeding leading to nocturnal hyperphagia before the onset of overweight and metabolic complications including, hyperglycemia, hyperinsulinemia, glucose/insulin resistance, steatohepatitis, fat tissue inflammation and obesity. Everything considered, we conclude that loss of β-cell Nkcc1 impairs insulin secretion in vivo impinging long-term metabolic consequences triggered by an early impairment in the feeding behavior. Altogether, our results suggest that elimination of Nkcc1 from β-cells recapitulates, at least in part, the natural progression of metabolic syndrome, a major risk factor for the development of type-2 diabetes.
Page Count
70
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2021
Copyright
Copyright 2021, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0002-2430-3458