Increases in Thyroid Hormone‐Mediated Plasma Glucose Does Not Stimulate Insulin Secretion in Prolonged‐Fasting Northern Elephant Seal Pups
Authors: Horin Lillian Jessica , Martinez Bridget , Crocker Daniel E , Ortiz Rudy 
Published: November 2023

Prolonged‐food deprivation in mammals is associated with the suppression of metabolism via the down‐regulation of cellular thyroid hormone (TH)‐mediated components, insulin, and glucose concentrations. However, during a 2–3 month prolonged‐fast, northern elephant seal (NES) pups experience an up‐regulation of cellular TH‐mediated components and adipose‐specific insulin resistance with fasting duration. Additionally, to meet their energetic demands during the fast, NES pups rely primarily on the oxidation of fat stores. The functional relevance of these atypical responses, and the effect of TH‐mediated signaling on insulin signaling and lipid metabolism in a mammal adapted to prolonged food deprivation, is not well‐defined. To elucidate the potential for TH to promote gluconeogenesis and subsequent insulin signaling, we infused early (n=6) and late (n=6)‐fasted pups with thyroid‐stimulating hormone (TSH) and measured plasma glucose, and insulin concentrations. To better understand the associations between TH and lipid metabolism in NES pups, we also measured relative expressions of CD36, an integral membrane protein that aids entry of fatty acids into the cell to begin beta‐oxidation. We hypothesized that during the state of insulin resistance, or the late fast, the increase in cellular TH‐mediated components drives gluconeogenesis, but does not necessarily lead to an insulin response. We also hypothesized that protein expression of CD36 increases with a TSH‐induced increase in TH, and that the increase will be more rapid and pronounced during the late fast. Here we show that in late‐fasted pups, plasma glucose concentration increased by 14.9% ± 0.5, 15.5% ± 0.5, and 21% ± 0.7 at 30 min, 60, and 120 min post‐infusion, respectively. However, there was no significant change in plasma insulin concentration, suggesting that the elevation in THs is up‐regulating hepatic gluconeogenesis in late‐fasted NES pups but is not sufficient to trigger insulin secretion. Furthermore, plasma glucose concentration remained stable during the early fast, suggesting that TH‐mediated gluconeogenesis is more sensitive during the late fast when compared to early fasting. Meanwhile, CD36 expression increased 68% ± 16 after 60 min and remained elevated, suggesting that sensitivity to TSH increases with prolonged fasting, and that THs are contributing the regulation of lipid metabolism during fasting in NES pups. The data suggests that these animals have adapted to very unique endocrine responses that are triggered by specific metabolic substrates, where insulin signaling pathways have adapted to preferentially become more sensitive to substrates such as amino acids or lipids rather than carbohydrates.Support or Funding InformationThis project was supported by NIH NHLBI (R01HL09176) and the Integrative Organismal Systems Physiology (IOSP) Undergraduate Summer Research Fellowship funded by NSF IOSP Award (IOS‐1238831) and the American Physiological Society.