D-Lactate: Groundbreaking Research No One Is Talking About
D-lactate has long been considered a product of microbial metabolism, with assumptions in the medical literature implying that it originates exclusively from gut bacteria. This narrative has persisted for decades despite evidence to the contrary. In this article, we aim to challenge this conventional understanding by exploring the human enzymatic production of D-lactate and its physiological relevance. We also discuss the underappreciated role of D-lactate in various metabolic processes, including gluconeogenesis, energy production, and its potential implications for neurological conditions.
Debunking the Myth of Microbial-Only D-Lactate Production
The microbial origin of D-lactate in humans was popularized by a 2018 study that suggested small intestinal bacterial overgrowth could lead to elevated D-lactate levels in the urine, allegedly contributing to brain fog. The study claimed that treatment with antibiotics and cutting out probiotics led to improvements in brain function. However, the findings were flawed in several respects, including the lack of follow-up data, absence of control groups, and failure to separate the effects of antibiotics and probiotics. Furthermore, the study did not establish clear evidence that D-lactate in these cases was of microbial origin, leading to premature conclusions about its relationship to brain fog and probiotics.
While it is undeniable that bacteria produce D-lactate, it is crucial to recognize that human enzymes also generate this compound. D-lactate is produced endogenously from methylglyoxal, which can be synthesized from glucose, threonine, or acetone. The enzyme D-lactate dehydrogenase, which is dependent on riboflavin and manganese, plays a critical role in converting D-lactate into L-pyruvate. This process occurs in the mitochondria, where D-lactate is oxidized and contributes to ATP production. When functioning normally, D-lactate does not present a problem. However, elevated plasma levels of D-lactate can lead to neurotoxicity, causing symptoms such as confusion, disorientation, slurred speech, and even hallucinations.
The D-Lactate Shuttle: A Critical but Overlooked Pathway
The metabolic importance of D-lactate in humans is often underestimated. In this article, I introduce the concept of the “D-lactate shuttle,” which I believe should be recognized alongside other established biochemical shuttles, such as the malate-aspartate and glycerol phosphate shuttles. The D-lactate shuttle is involved in balancing critical metabolic functions, including conserving cytosolic NAD+, reducing cellular acidity, bypassing complex I in the mitochondrial respiratory chain, and generating ATP.
One of the key advantages of the D-lactate shuttle is its ability to operate under conditions where there is an absolute deficit of NAD+ or NAD(H). Under normal circumstances, the body uses NAD+ to facilitate glycolysis, but in conditions where NAD+ levels are depleted, D-lactate can step in as a backup shuttle. This process helps alleviate the metabolic strain caused by limited NAD+ availability and prevents the backup of glycolytic intermediates.
While D-lactate concentrations in human plasma are generally low, its importance becomes apparent in cases where metabolic pathways involving D-lactate and L-lactate are disrupted. In certain genetic disorders, the concentrations of D-lactate in plasma become comparable to those of L-lactate, challenging the common claim that flux through the D-lactate pathway is “minuscule.” It is likely that D-lactate is produced in substantial quantities in organs such as the liver and kidney, but it is rarely secreted into the bloodstream due to the risk of neurotoxicity. Thus, D-lactate should not be dismissed as an insignificant metabolite but should instead be regarded as a crucial contributor to metabolic homeostasis.
D-Lactate and Gluconeogenesis: A Key Source of Glucose Production
D-lactate plays an important role in gluconeogenesis, the process by which the body generates glucose from non-carbohydrate sources. During fasting or periods of low carbohydrate availability, D-lactate can account for up to 11% of gluconeogenesis, which is comparable to the contribution of individual amino acids. This underscores the metabolic significance of D-lactate in maintaining energy balance, particularly during periods of nutrient scarcity. While methylglyoxal, a precursor to D-lactate, has been primarily associated with diabetes, the role of D-lactate in gluconeogenesis highlights its essential function in energy metabolism.
In conditions where glycolysis is impaired or inhibited, such as in genetic disorders that affect the metabolism of lactate, the concentrations of D-lactate and L-lactate in plasma can become similar. This provides further evidence that D-lactate is an important metabolic intermediate that should not be overlooked in discussions of energy production and gluconeogenesis. Additionally, the liver and kidney are likely the primary sites of D-lactate production, as these organs are known to handle large volumes of metabolic intermediates. Therefore, it is essential to consider the role of D-lactate in these organs when evaluating its contribution to overall metabolic health.
The Role of D-Lactate in Neurological Disorders and Diabetes
D-lactate has been implicated in a variety of neurological conditions, including Parkinson’s disease, and may also play a role in the pathogenesis of diabetes. Methylglyoxal, the precursor to D-lactate, is known to accumulate in diabetic patients due to impaired insulin signaling and increased oxidative stress. As methylglyoxal levels rise, D-lactate production increases, which may exacerbate the effects of the metabolic imbalance.
In neurological conditions such as Parkinson’s disease, D-lactate may contribute to neurotoxicity by bypassing the mitochondrial respiratory chain’s complex I, which is crucial for ATP production. This can lead to cellular dysfunction and exacerbation of disease symptoms. Additionally, research has shown that the clearance of D-lactate is impaired in conditions such as autism, which may be linked to oxalate buildup. Oxalate can inhibit D-lactate dehydrogenase, the enzyme responsible for metabolizing D-lactate, leading to higher plasma levels of this toxic metabolite.
The Gut and Microbial Contribution to D-Lactate Production
While the gut microbiome is often implicated in the production of D-lactate, especially in conditions like short-bowel syndrome, the evidence suggests that microbial contributions to D-lactate production in healthy individuals are negligible. Studies on germ-free rats and pigs have shown no significant difference in D-lactate concentrations between the portal vein and the general circulation, suggesting that the microbiome does not significantly contribute to D-lactate production under normal circumstances. Thus, the idea that gut bacteria are the primary source of D-lactate in humans is likely exaggerated.
D-Lactate and Diabetes: A Link to Methylglyoxal
In diabetes, the increased production of methylglyoxal is closely tied to elevated D-lactate levels. Methylglyoxal’s role in the development of advanced glycation end products (AGEs) contributes to the complications of diabetes, such as vascular damage and neuropathy. As the levels of methylglyoxal rise in diabetic individuals, so does the production of D-lactate, further exacerbating the metabolic imbalance. Given the role of D-lactate in gluconeogenesis and its impact on insulin resistance, it is critical to investigate D-lactate’s potential role in the pathophysiology of diabetes more thoroughly.
Conclusion: Rethinking D-Lactate’s Role in Human Physiology
D-lactate is a crucial but often overlooked metabolite with important roles in energy metabolism, gluconeogenesis, and the maintenance of redox balance. While microbial production of D-lactate may contribute to certain health conditions, it is clear that humans also produce D-lactate endogenously through the methylglyoxal pathway. This discovery has significant implications for understanding metabolic diseases like diabetes and neurological disorders such as Parkinson’s disease.
The concept of the “D-lactate shuttle” adds a new dimension to our understanding of cellular energy metabolism. By bypassing complex I in the mitochondrial respiratory chain, D-lactate helps conserve NAD+ and reduce cellular acidity, making it a valuable metabolic intermediate under specific conditions. However, excessive D-lactate production can lead to neurotoxicity and other health issues, especially when its clearance is impaired by factors such as oxalate buildup.
As we continue to explore the complexities of D-lactate’s role in human physiology, it is essential to reconsider its importance in metabolic health and disease. Further research into D-lactate’s involvement in diabetes, neurological disorders, and gluconeogenesis could unlock new therapeutic strategies for managing these conditions.
Update from Chris Masterjohn, on 2024-07-31Source