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Dissertation
Mitochondrial regulation of hepatic glucose production in type 2 diabetes
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007854
Abstract
Insulin resistance and resultant hyperglycemia during type 2 diabetes (T2D) contribute to vascular disease, driving T2D morbidity and mortality. In T2D patients, fasting blood glucose levels directly correlate with rates of hepatic gluconeogenesis (GNG), the de novo synthesis of glucose. GNG requires carbon substrate and reducing equivalents. Major gluconeogenic substrates include lactate and the amino acids glutamine and alanine. In T2D, hepatic uptake of these precursors increases. For GNG, they must first be imported into mitochondria and incorporated into the TCA cycle. However, mitochondria must export carbon substrate and reducing equivalents to the cytosol. Previous studies in ex vivo models suggest the mitochondrial dicarboxylate carrier (DIC) exports mitochondrial malate to contribute both carbon substrate and reducing equivalents for GNG. However, the role of DIC has not been tested in vivo. Given this, we hypothesized that hepatic DIC disruption would limit GNG to attenuate hyperglycemia and insulin resistance in a mouse model of T2D. To test our hypothesis, we generated liver-specific DIC knockout (DIC-LivKO) mice. We found that hepatic DIC disruption decreased, but did not eliminate, glucose production from lactate/pyruvate and glutamine. In addition, we found that hepatic aspartate is increased in DIC-LivKO mice, suggesting it is an alternative export substrate. The mitochondrial aspartate-glutamate carrier 2 (AGC2) exports aspartate in the liver. Hepatic AGC2 deletion suppressed glucose production from lactate/pyruvate. Finally, we found that hepatic DIC disruption in western diet fed mice ameliorated hyperglycemia and insulin resistance by decreasing hepatic glucose production from lactate/pyruvate. Overall, these studies show DIC supports hepatic GNG. Thus, DIC may be an attractive therapeutic target for suppressing excessive GNG in T2D.
Details
- Title: Subtitle
- Mitochondrial regulation of hepatic glucose production in type 2 diabetes
- Creators
- Daniel J Pape
- Contributors
- Eric B Taylor (Advisor)Adam Dupuy (Committee Member)Lilliana Radoshevich (Committee Member)Tom Rutkowski (Committee Member)Ling Yang (Committee Member)Leonid Zingman (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Molecular Medicine)
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007854
- Publisher
- University of Iowa
- Number of pages
- ix, 133 pages
- Copyright
- Copyright 2025 Daniel J Pape
- Language
- English
- Date submitted
- 04/16/2025
- Description illustrations
- illustrations, graphs
- Description bibliographic
- Includes bibliographical references (pages 114-133).
- Public Abstract (ETD)
- In type 2 diabetes (T2D), chronically high blood sugar damages blood vessels, decreasing blood flow to tissues and leading to health problems such as vision loss, recurrent infections, stroke, and heart failure. Given this, lowering blood sugar is a primary goal of therapy. To accomplish this, patients eat healthy foods and exercise. Oftentimes, these interventions do not lower blood sugar enough to prevent complications. Therefore, a critical challenge for treating T2D is decreasing blood sugar. Previous studies found that the liver makes too much sugar in T2D patients using gluconeogenesis (GNG), the de novo synthesis of glucose. The liver uses different fuels for GNG, which must be first metabolized and then exported by mitochondria. However, the specific substrates and export mechanisms remain unknown. Previous studies suggest the mitochondrial dicarboxylate carrier (DIC) exports malate for GNG. In addition, DIC protein abundance increases in T2D. Given this, our work asked the major question: Does deleting the DIC decrease high blood sugar in T2D? We found that deleting DIC in the liver of diabetic mice decreased blood sugar by suppressing sugar production by the liver. Overall, this suggests that the DIC may be a good therapeutic target for treating T2D.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9984831231102771
Metrics
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