자료유형  

 학위논문

Control Number  

0017160391

International Standard Book Number  

9798383566619

Dewey Decimal Classification Number  

612

Main Entry-Personal Name  

LaMoia, Traci Ellen.

Publication, Distribution, etc. (Imprint  

[S.l.] : Yale University., 2024

Publication, Distribution, etc. (Imprint  

Ann Arbor : ProQuest Dissertations & Theses, 2024

Physical Description  

87 p.

General Note  

Source: Dissertations Abstracts International, Volume: 86-01, Section: B.

General Note  

Advisor: Shulman, Gerald I.

Dissertation Note  

Thesis (Ph.D.)--Yale University, 2024.

Summary, Etc.  

요약Type 2 diabetes (T2D) is one of the most common metabolic disorders worldwide and is characterized by defective insulin secretion, peripheral insulin resistance, and dysregulated whole-body glucose homeostasis. In Chapter 1 I review the etiology of T2D and describe the well-established link between T2D and metabolic dysfunction associated steatotic liver disease (MASLD). I also describe several pharmaceutical interventions for the treatment of T2D, including metformin, the first-line treatment for T2D, and glucagon-like peptide-1 receptor (GLP-1R)/glucagon receptor (gcgR) dual agonists, a class of recently developed and highly effective treatments for T2D. This sets up the major goal of the work presented in this dissertation, which is to build upon our understanding of the mechanism(s) regulating hepatic mitochondrial oxidation and gluconeogenesis, and to use these insights to inform the development of novel treatments for T2D. The first-line treatment for T2D is metformin, which exerts its glucose-lowering therapeutic effect primarily through inhibition of hepatic gluconeogenesis. Yet the precise mechanism by which metformin inhibits hepatic gluconeogenesis remains unclear. In Chapter 2 I show that the leading proposed mechanism of metformin action, complex I inhibition, is inconsistent with metformin's effect to reduce hepatic gluconeogenesis in a substrate selective manner. I go on to propose a novel mechanism of metformin action in which metformin interacts with complex IV to reduce its enzymatic activity, leading to indirect inhibition of glycerol-3-phosphate (GPD2), increased cytosolic redox, and reduced glycerol-derived gluconeogenesis. In Chapter 3 I investigate the role of intracellular calcium in modulating hepatic gluconeogenesis and mitochondrial oxidation. The emergence of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (gcgR) agonists as strikingly effective treatments for T2D and its comorbidities has renewed interest in understanding the mechanism(s) of hepatic glucagon action. Glucagon induced ER calcium release promotes CAMKII and ATGL phosphorylation, leading to the classical effect of glucagon to increase hepatic gluconeogenesis as well as increase mitochondrial oxidation and intrahepatic lipolysis. This increase in mitochondrial oxidation has been primarily attributed to mitochondrial calcium influx via the mitochondrial calcium uniporter (MCU), due to previous reports showing that mitochondrial calcium activates several mitochondrial dehydrogenases and increases oxidative activity. However, a role for MCU in mediating hepatic mitochondrial oxidation in vivo has not been thoroughly investigated. Here I investigate the role of cytosolic and mitochondrial calcium alterations in mediating hepatic intrahepatic lipolysis, gluconeogenesis, and mitochondrial oxidation. Using a liver-specific MCU KO mouse model, I show that deletion of hepatic MCU leads to paradoxically increased rates of mitochondrial oxidation as well as intrahepatic lipolysis and fatty acid oxidation (FAO). Taken together, I demonstrate that mitochondrial oxidative rates can be dissociated from mitochondrial calcium influx, and I establish a link between CAMKII activity, pyruvate anaplerosis, and mitochondrial oxidation such that cytosolic calcium potently modulates mitochondrial activity.

Subject Added Entry-Topical Term  

Physiology.

Subject Added Entry-Topical Term  

Pharmacology.

Index Term-Uncontrolled  

Calcium

Index Term-Uncontrolled  

Gluconeogenesis

Index Term-Uncontrolled  

Metformin

Index Term-Uncontrolled  

Mitochondrial Oxidation

Index Term-Uncontrolled  

Type 2 Diabetes

Added Entry-Corporate Name  

Yale University Cellular and Molecular Physiology

Host Item Entry  

Dissertations Abstracts International. 86-01B.

Electronic Location and Access  

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Control Number  

joongbu:657386