Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cellular and Molecular Physiology
First Advisor
Perry, Rachel
Abstract
As a highly utilized substrate in most cells of the body, glucose homeostasis is strictly regulated by a variety of mechanisms. Under physiological conditions, blood glucose is sophisticatedly maintained by temporal coordination of whole-body glucose uptake, absorption from the digestive system, and endogenous glucose production from the liver and kidney. However, the factors and mechanisms by which plasma glucose is regulated under pathological conditions are not clearly understood. In this Ph.D. thesis, we interrogated the role of two cytokines, Growth Differentiation Factor 15 (GDF15) and fibroblast growth factor-21 (FGF-21), in regulating glucose output under extreme metabolic stress. By employing two clinically relevant hypoglycemic models, the insulin tolerance test and hyperinsulinemic-hypoglycemic clamp, we found that GDF15 can be secreted from the S3 segment of the proximal tubules. For the first time, we identified the counterregulatory role of GDF15 during hypoglycemia by combining tracer infusion with a genetic knock-out mouse model, which shows the GDF15 can increase liver gluconeogenesis in an intrahepatic lipolysis-dependent manner. Regarding the diabetic condition, we found that recurrent hypoglycemia, which is frequently a concern in T1DM and advanced T2DM patients, can diminish the production of GDF15 in a rodent model. In accordance with this finding, T1DM patients showed attenuated GDF15 induction during the hypoglycemic clamp. To investigate the contribution of the liver and the kidney separately, REnal Gluconeogenesis Analytical Leads (REGAL) was developed based on the previous PINTA method1. This non-invasive and accurate method enables us to measure kidney gluconeogenesis flux, liver gluconeogenesis, and glycogenolysis by stable isotope infusion. We found that kidney glucose production is elevated in response to an unsatisfied systemic glucose demand during metabolic challenges. Furthermore, we identified that FGF21, which was previously considered as a catabolic cytokine, can increase renal glucose output via a liver-brain-kidney axis. Our genetic knock-out and pharmacological intervention model revealed that the critical function of FGF21 relies on the beta 2 adrenergic receptor (Adrb2) and intra-renal lipolysis. In addition, we showed that renal cell carcinoma can hijack this mechanism by inducing FGF21 production in the liver, possibly in a VGEF-dependent manner, to create a favorable microenvironment for itself. Taken together, we developed a method to understand the regulation of glucose output from the liver and kidney separately. Simply requiring jugular vein catheterization and stable isotope tracers, this method can be applied to a broad spectrum of rodent models, or even human subjects, with a high success rate. These studies give insight to how the two main sources of endogenous glucose production communicate with each other to maintain systemic glucose supply and how kidney tumor cells take advantage of this mechanism to support their own survival. Finally, the abnormal GDF15 production in T1DM patients, the anabolic role of FGF21 during metabolic stress, and the induction of FGF21 in RCC show the translational value of the study and inspire us to investigate the clinical application of GDF15 and FGF21 in insulin-related hypoglycemia, liver dysfunction, and renal cell carcinoma.
Recommended Citation
Li, Zongyu, "Identifying The Role And Mechanism By Which GDF15 And FGF21 Regulate Glucose Homeostasis" (2023). Yale Graduate School of Arts and Sciences Dissertations. 882.
https://elischolar.library.yale.edu/gsas_dissertations/882
