ATP and thyroid are closely related in that the thyroid hormone is essential for the rapid turnover of ATP, both inside and outside of cells. ATP, in turn, affects processes as diverse as pain, inflammation, blood clotting, bone formation, cognition, blood pressure, and insulin secretion – among many others.
Considering the intensive research currently underway to develop compounds with specificity for ATP receptors in various tissues, and the wide range of disorders these compounds could, when it is all said and done, treat, it is obvious that ATP, in particular its turnover, has a wide range of drug-like effects that are independent of its role in energy metabolism. All of the conditions that have been linked with hypothyroidism – most comprehensively by Broda Barnes – can, in my estimation, be traced back to the impact of thyroid hormone on ATP.
Well known now is that ATP is involved in repair and regeneration processes following injury or stress to tissues. Platelets, for instance, express certain ATP receptors (the discovery of which drug companies have capitalized on with the blockbuster drug Clopidogrel) that, upon binding ADP, an ATP metabolite, undergo conformational changes that ultimately lead to the formation of a blood clot. ATP also binds and activates the smooth muscle cells of blood vessels, powerfully causing them to constrict so as to limit the loss of blood following an injury. And, equally as important in terms of therapeutic potential, ATP acts on sensory nerves whose job is to sense harmful stimuli in the body and to transmit those messages to the brain – without which we would lack the wherewithal to quickly withdraw from harmful situations or to keep away from a damaged body part while it healed. In the presence of thyroid hormone, all of these processes function to full capacity.
ATP is released from neurons and non-neuronal cells in either a controlled way or in an erratic way, for instance, when there is tissue damage and the ATP stored in cells spill out into the extracellular space. In addition to acting on sites outside of the cell in which it is produced, ATP executes basic physiological processes as an intracellular mediator such as insulin secretion. In fact, ATP is present, albeit in tiny amounts, in the cytosol of all cells.
Diabetes is a topic I have written a post on in the past with a focus on the mechanisms that inhibit the complete combustion of glucose by cells. One point of neglect was in regard to the role of ATP. In essence, the oxidative metabolism of glucose and the subsequent generation of ATP is a major pathway for insulin secretion. But ATP also acts in a more general way, being released with acetylcholine or noradrenalin, as a co-transmitter, from nerve endings that extend from the brain to the pancreas. Indeed, specific ATP receptors, of the P2Y class, have been identified on insulin-secreting cells in the pancreas. Ultimately, ATP results in elevated calcium levels in these cells, which is the trigger to release insulin. Interestingly, biotin enhances the synthesis of ATP in the pancreas by increasing the rate of glucose oxidation.1
Following meals, the rapid rise in insulin and blood glucose levels is normal and desirable – contrary to uninformed opinion. As a general rule, what is abnormal is when a person’s blood glucose levels do not rise by at least 50 percent from baseline fasting levels. Almost all of the oral diabetes drugs that I can think of off-hand, including the most successful ones (such as Onglyza, Januvia, Byetta, and Symlin), work, in one way or another, by way of enhancing the secretion of insulin and suppressing the secretion of glucagon. Still and all, diet gurus know what researchers and doctors do not know, because high protein, low carbohydrate diets are posed as the best diet for diabetes owing, in part, to the ability of these diets to keep insulin down and glucagon up. An adequate amount of protein is essential, and should ideally be eaten at every meal. But in order to use that protein as constructively as possible, it should be offset with carbohydrate and minerals, such as from fruit.
And because fruit also contains fructose, which does not stimulate the release of insulin nearly as much as glucose, it helps to potentiate glucose-stimulated insulin secretion, presumably by intensifying the depolarization of insulin-secreting cells more than glucose could alone.2 In general, fruit also contains mineral salts of potassium, magnesium, and calcium that are highly absorbable; they also contain little to no starch.
Cardiovascular disease is considered a major (and highly fatal) complication of diabetes. But the thyroid and cardiovascular disease are highly connected, too. Broda Barnes described one case after another of the striking absence of cardiovascular disease in patients on thyroid replacement therapy.3 Barnes attributed this protective effect mainly to the fact that thyroid hormone prevented the accumulation of the water-loving jellylike material called mucopolysaccharide in the connective tissue of the heart and blood vessels, causing thickening, as well as to reduced circulation.
As it happens, the metabolism of ATP (and of other purines) goes off the rails in hypothyroidism as well. In platelets, for instance, the activity of the enzymes that degrade ATP increases, resulting in an excess of ADP in relation to ATP and therefore errant clot formation.4
In general, the complications seen in diabetes are the same complications seen in hypothyroidism, and the fact that the so-called “diabetic complications” sometimes precede the onset of diabetes suggests that those who are diagnosed as diabetic, by a standard glucose tolerance test, may actually be hypothyroid. A person who is hypothyroid has a slower rate of digestion, absorption, and assimilation of nutrients so that when blood samples are drawn during a glucose tolerance test, blood glucose levels will appear elevated not because of diabetes, but because of the sluggish extraction of glucose from the intestines. Hypothyroidism also slows the uptake and oxidative metabolism of glucose by cells.5
The rapid degradation of ATP from hypothyroidism not only affects the cardiovascular system, but also the brain. The impairment of cognition in hypothyroidism, in fact, could simply come down to the decline in ATP levels, caused by upregulation of the activity of an ATP degrading enzyme.6 Thyroid hormone ‘lights up’ the brain like caffeine does, in that they both lead to an increase in blood glucose levels and shift the balance away from ADP, an inhibitory neurotransmitter, to ATP, an excitatory neurotransmitter.
T3, which is ‘stored’ inside cells (as opposed to T4, which is mainly ‘stored’ in the bloodstream), guards against the depletion of ATP, whose turnover is needed continuously in the brain to promote the growth and development of the axons of certain brain cells.7 However, in hypothyroidism, the energy charge decreases, and all cellular processes, in effect, slow down so as to decrease metabolic requirements.8 The presynaptic inhibition of neurons in the brain, for instance, accounts for the neuroprotective effects of intravenous injections of adenosine.9
The fact that adenosine worsens many of the symptoms of asthma by – causing bronchoconstriction, stimulating the release of histamine from mast cells, and promoting hyper-reactivity of airway neurons – further speaks to its relationship with hypothyroidism, as merely raising blood glucose levels softens, and sometimes momentarily completely eradicates, these symptoms of asthma. It has been said that asthmatics, compared to non-asthmatics, do not release the counterregulatory hormones, especially adrenalin, when the blood glucose levels dip below normal. But, asthmatics have many of the features of hypothyroidism, such as the tendency to concentrate potassium and sodium in the blood. What is more, adenosine, which accumulates in hypothyroidism, stimulates the production of mucopolysaccharide in the airway of asthmatics, as well as inflammation.10 It would be interesting and informative to compare the presence of asthma in hypothyroid versus euthyroid individuals.
The effects of thyroid hormone replacement have historically been both immediate and delayed, further reinforcing the idea that the benefits of such therapy is executed by ATP. The P2X receptor is an ion-channel linked receptor whose activation takes milliseconds. On the other hand, the activation of the P2Y receptor initiates an intracellular cascade ending in an increase in intracellular calcium levels and changes in gene expression, which can take from hours to days.
Anything but merely a molecule involved in energy metabolism, ATP also assumes the role of neurotransmitter, hormone, and intracellular mediator. Free ATP molecules are found, in tiny amounts, in every cell in the body, and they are released either constitutively or in response to stress or tissue injury, by way of exocytosis or simultaneously with other neurotransmitters from neurons. Receptors for these ATP molecules, as well as their metabolites, have been identified in virtually every site in the body that has been checked so far, and pharmaceutical companies are chomping at the bit to get their drugs that target various ATP receptors approved for a myriad of indications including pain, inflammation, rheumatoid arthritis, and cystic fibrosis. But simply optimizing thyroid functioning, by signs and symptoms and not lab tests, including the basal body temperature, shifts the ratio of ATP to its metabolites, and therefore the pattern of receptors and targets that are occupied and activated. If hypothyroidism is suspected, foremost, the basal body temperature should be checked and corrected with dietary changes (mainly avoiding carbohydrate restriction and under-eating) and thyroid replacement therapy, if needed, before moving onto more invasive and riskier interventions.
1. Sone, H. et al. Biotin enhances ATP synthesis in pancreatic islets of the rat, resulting in reinforcement of glucose-induced insulin secretion. Biochem. Biophys. Res. Commun. 314, 824–9 (2004).
2. Kyriazis, G. A., Soundarapandian, M. M. & Tyrberg, B. Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proc. Natl. Acad. Sci. U. S. A. 109, E524–32 (2012).
3. Barnes, B. Hypothyroidism: The Unsuspected Illness. (Whiteside Limited, 1976).
4. Bruno, A. N. et al. 5’-nucleotidase activity is altered by hypo- and hyperthyroidism in platelets from adult rats. Platelets 16, 25–30 (2005).
5. Solini, A. et al. Defective P2Y purinergic receptor function: A possible novel mechanism for impaired glucose transport. J. Cell. Physiol. 197, 435–44 (2003).
6. Bruno, A. N. et al. Hypo-and hyperthyroidism affect the ATP, ADP and AMP hydrolysis in rat hippocampal and cortical slices. Neurosci. Res. 52, 61–8 (2005).
7. Rathbone, M. P. et al. Trophic effects of purines in neurons and glial cells. Prog. Neurobiol. 59, 663–90 (1999).
8. Brundege, J. M. & Dunwiddie, T. V. Role of adenosine as a modulator of synaptic activity in the central nervous system. Adv. Pharmacol. 39, 353–91 (1997).
9. Cunha, R. A. Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem. Int. 38, 107–25 (2001).
10. Wilson, C. N. Adenosine receptors and asthma in humans. Br. J. Pharmacol. 155, 475–86 (2008).