Recall broadly, how glucose moves into the cytosol and gets converted to pyruvate. This process leads to a crossroad of either bringing the pyruvate into the mitochondrion to eventually make adenosine triphosphate (ATP) through the TCA cycle or the development of lactate through lactate dehydrogenase (LDH). In the mitochondrion, a key enzyme, pyruvate dehydrogenase (PDH), is what is needed for pyruvate to turn into the acetyl Co-A utilized in the TCA cycle.
Breaking the process down even further, a thiamine product is needed as a co-factor for PDH to convert pyruvate to acetyl Co-A. However, thiamine needs additional help to allow this process to occur. It is not thiamine itself that is required for the conversion to acetyl Co-A but thiamine diphosphate (TDP). As we look at magnesium in relation to TDP, its importance becomes clear. To achieve TDP, thiamine needs ATP and magnesium to work with the enzyme thiamine pyrophosphokinase. This gives the TDP required to work as a cofactor to PDH and other enzymes in the TCA cycle.
Application to the Human Condition
The average American man and woman consume 1.87 mg and 1.39 mg of thiamine daily, respectively, according to the United States Department of Agriculture.
This is more than the recommended daily allowance (RDA) of 1.3 mg/day, which was based on studies in the 1930s when diets consumed much less glucose. In the case of magnesium, many diets do not even achieve the RDA of 420 mg for men and 320 mg for women. If the body is not getting enough thiamine and/or magnesium to compensate for the increased glucose intake of modern diets, where does the excess glucose go?
Recall the alternative mechanism if pyruvate does not go into the mitochondrion and becomes part of the TCA cycle. Increased LDH is used to process this excess pyruvate to lactate. When we take a look at the lab work of a patient, LDH can be used as a general indicator with many inflammatory responses and disease states.
Where Does Obesity Come into Play?
Obesity is a defined risk factor for conditions such as cancer, cardiovascular disease, and type 2 diabetes (T2D). Adipocytes have been demonstrated to produce LDH, leading to insulin resistance. A possible reason behind this has been observed with in-vitro studies with astrocytes from obese individuals. As PDH is responsive to insulin in healthy cells, it loses this responsiveness in obese cells. If TDP promotes PDH production/efficacy, a deficiency in thiamine or magnesium may lead to this loss of responsiveness to insulin.
Multiple disease states and even lifestyles can lead to deficiencies in either or both thiamine and magnesium. Inverse relationships have been observed with circulating magnesium levels in hypertension and T2D, and thiamine depletion can be attributed to chronic alcohol use. However, it should be noted that because of stores inside of cells and variability in inflammatory conditions, blood levels of either thiamine or magnesium are not the ideal ways to measure a true reading in the body, and there are more accurate ways. These data require a prospective intention and intervention to draw a more reliable correlation.
A Direction of Research: Thiamine, Magnesium, and LDH
There is little doubt that all 3 of these are related on a mechanistic level. Questions involving supplementation, treatment strategies, as well as another look at recommended daily allowances reflective of modern diets are yet to be addressed. Do we start testing overweight patients for thiamine and magnesium or even LDH levels during an office visit? After all, increased chronic lactic acid could possibly lead to increased systemic oxidative stress, driving disease progression or occurrence, such as cancer. There stands a correlation of constant increased caloric intake and a progressive depletion of thiamine, magnesium, or both in cells.
We can also look at genetic profiles, which include patients who already have deficiencies because of a genetic mutation, such as deficiencies in thiamine transporters that have been shown to lead to an increased renal loss of thiamine. Using this group of individuals along with those who are overweight or have a history of chronic alcohol use may provide a better clinical model to see a possible true deficiency in our population.
Does this mean start recommending thiamine and magnesium supplements to patients? More data based on accurate levels of these substrates need to be used and looked at with appropriate prospective forethought. Adding a supplement to a disease state is a very important decision to broadly recommend and should never be taken lightly off 1 review or even 1 trial, but it is more than worth considering.
Maguire D, Talwar D, Shiels PG, McMillan D. The role of thiamine dependent enzymes in obesity and obesity related chronic disease states: a systematic review. Clin Nutr ESPEN, 2018;25:8-17. doi: 10.1016/j.clnesp.2018.02.007.