People with a specific genetic variation called DIO2 Thr92Ala who follow a ketogenic diet experience reduced conversion of thyroid hormone to its active form, leading to lower levels of active...
Mechanism
Synthesis from 1 study
Eating a very low-carb diet lowers insulin, which turns down the enzyme that makes thyroid hormone active. People with a specific gene variation have a weaker version of this enzyme, so they make even less active hormone in their tissues. At the same time, the body makes more inactive hormone that...
Most probable mechanism
When someone eats a very low-carb, high-fat diet, insulin levels drop, which turns down the activity of an enzyme that converts thyroid hormone into its active form. This enzyme works poorly in people with a specific gene variation, so less active hormone reaches cells. At the same time, the body makes more inactive thyroid hormone, which blocks the active form from working. The result is that cells do not get enough active thyroid hormone, even if blood tests look normal.
Carbohydrate restriction reduces glucose availability and suppresses insulin secretion
Low insulin fails to relieve transcriptional repression of the DIO2 gene in skeletal muscle, brown adipose tissue, and glial cells
DIO2 enzyme expression and activity decline, reducing conversion of T4 to active T3 in peripheral tissues
The DIO2 Thr92Ala polymorphism further reduces enzyme stability and catalytic efficiency, impairing local T3 production
Reduced DIO2 activity increases the relative proportion of T4 converted to reverse T3 by DIO3
Elevated reverse T3 competes with T3 for nuclear receptor binding, reducing thyroid hormone signaling in target tissues
Tissue-level T3 deficiency occurs despite normal serum T4, resulting in functional hypothyroidism
Less supported by current evidence, but not ruled out
Weight loss from the diet reduces fat tissue, which lowers leptin levels. Low leptin signals the brain to reduce the command to produce thyroid-stimulating hormone, which in turn lowers thyroid hormone production.
Reduced adipose tissue mass decreases leptin secretion from fat cells
Low leptin reduces stimulation of TRH-producing neurons in the hypothalamus
Reduced TRH release decreases TSH secretion from the pituitary gland
Lower TSH reduces thyroid gland stimulation and decreases T4 and T3 synthesis
The diet removes fiber, which starves gut bacteria that produce short-chain fatty acids. These fatty acids normally help activate the enzyme that converts thyroid hormone into its active form. Without them, less active hormone is made in the gut and nearby tissues.
Elimination of dietary fiber reduces populations of butyrate-producing gut bacteria
Short-chain fatty acid production, especially butyrate, declines in the colon
Reduced butyrate decreases DIO2 expression in enterocytes and glial cells
Local T4-to-T3 conversion in gut-associated tissues is impaired
Systemic T3 availability declines, contributing to functional hypothyroidism
When the diet starts, the body responds to low carbs as a stress, releasing cortisol. Cortisol blocks the brain from signaling the thyroid and turns down the enzyme that makes active thyroid hormone, increasing inactive forms.
Carbohydrate restriction activates the hypothalamic-pituitary-adrenal axis
Cortisol secretion increases in the early phase of adaptation
Elevated cortisol inhibits TRH synthesis in the hypothalamus and TSH release from the pituitary
Cortisol suppresses DIO1 and DIO2 enzyme activity and promotes DIO3-mediated conversion of T4 to reverse T3
Evidence from Studies
Supporting (1)
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Ketogenic Diet and Thyroid Function: A Delicate Metabolic Balancing Act
Contradicting (0)
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