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

ORCID ID

0000-0002-2430-3458


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