Substrate cycling between gluconeogenesis and glycolysis in euthyroid, hypothyroid, and hyperthyroid man

Area of Science:

• Metabolic Regulation
• Endocrinology
• Biochemistry

Background:

• Substrate cycling, or futile cycles, are hypothesized to be under hormonal control and play a role in metabolic regulation and thermogenesis.
• Thyroid hormones are known regulators of metabolism, but their specific role in controlling substrate cycling rates in humans is not well-defined.

Purpose of the Study:

• To investigate the role of thyroid hormones in regulating substrate cycling rates within glycolysis and gluconeogenesis.
• To determine if substrate cycling rates in hypothyroid and hyperthyroid individuals differ from normal subjects.
• To assess the impact of thyroid hormone treatment on substrate cycling.

Main Methods:

• Employed a stable isotope turnover technique using deuterium-labeled glucose (2-D1-, 3-D1-, and 6,6-D2-glucose) infused into normal, hypothyroid, and hyperthyroid subjects.
• Measured rates of appearance (Ra) for isotopic tracers via gas-chromatography mass-spectrometry.
• Calculated substrate cycling rates (SCR) between glucose and glucose-6-phosphate, and between fructose-6-phosphate and fructose-1,6-diphosphate based on differences in Ra values.

Main Results:

• Hypothyroid subjects exhibited significantly decreased rates of appearance for all tracers and a significantly reduced combined substrate cycling rate (SCR) compared to normal subjects.
• Hyperthyroid subjects showed increased rates of appearance for specific tracers (Ra2 and Ra6) compared to normal subjects.
• Acute thyroid hormone treatment in hypothyroid subjects did not change the combined SCR, but chronic L-thyroxine therapy for 6 months normalized the combined SCR to levels observed in normal subjects.

Conclusions:

• Substrate cycling between glucose/glucose-6-phosphate and fructose-6-phosphate/fructose-1,6-diphosphate occurs in humans and is significantly influenced by thyroid hormone status.
• Thyroid hormones may modulate metabolic sensitivity by altering substrate cycling rates.
• Long-term thyroid hormone replacement therapy can restore normal substrate cycling rates in hypothyroid individuals.