Low-grade metabolic acidosis as a driver of insulin resistance

Abstract

Metabolic acidosis occurs when there is retention of acid in the body which leads to a drop in the acid buffering capacity of the body. However, acid retention can occur even when serum bicarbonate is normal.1 There are four mechanisms through which the body can develop metabolic acidosis: (1) increased ingestion of dietary acid, (2) increased production of fixed acid such as in diabetic ketoacidosis, alcoholic ketoacidosis or prolonged fasting, (3) increased loss of base (ie, diarrhoea) and (4) reduced kidney excretion of acid. Additionally, specific medications can cause or contribute to metabolic acidosis. There are two major types of acid in the body, carbonic acid and non-carbonic acid. Carbonic acid is formed when a bicarbonate molecule combines with a hydrogen ion. Eventually carbonic acid is turned into water and carbon dioxide. Thus, if we create bicarbonate in the body from alkalinity supplied by the diet then we can breathe out the acid without depleting our own bicarbonate levels. Non-carbonic acids are fixed acids and cannot be exhaled via the lungs. They include lactic acid, phosphoric acid, sulfuric acid, uric acid and the ketoacids acetoacetic acid and beta-hydroxybutyric acid. Some of these fixed acids can be excreted in the urine in their free form, however, the urine pH can only drop to around 4.4 and hence only negligible quantities of strong acids, like sulfuric acid, can be eliminated in its free titratable form.2 So, 99% of the time sulfuric acid must be turned into hydrogen ions and sulfate and then it can be eliminated by the body. When we eat animal protein high in sulfur-containing amino acids such as methionine, cysteine and taurine, we form sulfuric acid, which gets broken down into two hydrogen ions and one sulfate molecule. If we consume a large amount of animal protein, this leads to large amounts of hydrogen ions being produced which gets neutralised by citrate or bicarbonate. Thus, consuming large amounts of animal protein depletes our bicarbonate and citrate buffering capacity. This especially can become problematic once we start producing more than 40–70 mEq of acid per day, which typically occurs at a urinary pH of 6.25–6.5. Thus, if the urinary pH is 6.5 or less this suggests acid retention and risk for developing low-grade metabolic acidosis. When sulfuric acid is formed in the body the hydrogen ions must be neutralised via bicarbonate. Additionally, the negatively charged sulfate must be eliminated, which requires a positively charged molecule to be excreted out the body. Typically, this means that positively charged minerals like magnesium, calcium, sodium or potassium are eliminated out the urine with the negatively charged sulfate, which tends to deplete the body of minerals. Sulfuric acid has a molecular structure of H2SO4. The two hydrogen ions are neutralised by two bicarbonate molecules (or three hydrogen ions can get neutralised by one citrate molecule), which leaves sulfate remaining. Since we cannot breathe out sulfate it must be excreted out the kidneys. However, to maintain electroneutrality, the negatively charged sulfate (SO42−) must be combined with a positively charged substance. If the diet contains enough alkaline minerals, such as magnesium, calcium, sodium or potassium, then the sulfate can be excreted with the dietary cations. However, if the diet is lacking these minerals, then the body will lose minerals until the kidneys can increase the production of ammonia to eliminate the sulfate. For example, two positively charged hydrogen ions (2H+) are produced in the kidneys to combine with two ammonia molecules (2 NH3) forming 2 NH4+. This provides the 2+ charge to offset the 2− charge of sulfate to form neutral ammonium sulfate (NH4SO4) for excretion. However, muscle and connective tissue are broken down to form the ammonia in order to eliminate the sulfate. Furthermore, once the kidneys’ capacity for acid excretion is reached, then eliminating sulfate by using hydrogen ions and ammonia goes down, necessitating a greater reliance on alkaline minerals. It also takes time for the kidneys to synthesise ammonia to excrete sulfate, thus, alkaline minerals will also be excreted until the kidneys can ramp up the production of ammonia. Thus, acid-base status in the body is a balancing act determined by the overall acid load of the diet, the kidneys’ capacity to eliminate acid, the dietary intake of alkaline minerals and bicarbonate-forming substances. In other words, eating a high animal protein diet can eventually lead to problems if the diet does not contain adequate amounts of bicarbonate-forming substances and alkaline minerals. Consuming a diet high in high animal protein, but insufficient in alkaline minerals and bicarbonate-forming substances can deplete the mineral status of the body, predispose to bone, muscle and connective tissue breakdown and eventually lead to kidney damage. This is why consuming bicarbonate mineral water and/or plant foods and alkaline minerals, in the context of an animal based or omnivorous diet is an important step to maintaining acid-base status of the body. Thus, there is a cost to eating a diet rich in animal protein related to producing more ammonia (which induces muscle, connective tissue and kidney damage), and/or losing more alkaline minerals (via bone breakdown). In the modern diet, the slow acidification of the body mainly occurs from the proportionately high consumption of animal protein and grains compared with the base-supplying fruits and vegetables. Additionally, phosphoric acid-containing beverages (carbonated soft drinks) also contribute to the dietary acid load. When we consume organic anions found in fruits and vegetables, like citrate, malate and gluconate, they can convert to bicarbonate in the body and accept hydrogen ions for excretion. This is how we preserve our buffering capacity. The more protein we eat, or the more muscle we have, the more acid we can excrete out the urine as ammonium.2 Consuming adequate protein and building/maintaining robust muscle is important for health because it helps reduce the risk of sarcopenia, falls and frailty, and creates more muscle and bone reserves to eliminate extra acid. However, there is still a negative impact on the kidneys from the increased production of ammonia to eliminate the hydrogen ions and sulfate coming from animal protein. Balance studies from 1966 have shown that healthy humans consuming diets that produce >0.4 to 1 mEq of acid/kg of body weight leads to the retention of acid in the body.3 For an average healthy adult, consuming a diet that leads to 40–70 mEq or more of net endogenous acid production will lead to acid retention.3 This means that most Americans are consuming diets that will likely result in some acid retention—triggering the production of large amounts of ammonia and other adverse health consequences such as kidney stones, muscle, connective tissue and bone breakdown, high blood pressure, insulin resistance, chronic pain and other health issues.4–6 Metabolic acidosis also increases renal plasma flow and glomerular filtration rate in order to increase the excretion of the acid load.7–9 Similar effects have been observed eating high meat meals or carnivore diets.10 11 The kidneys can even hypertrophy due to the increased production of ammonia.12 Thus, eating a high dietary acid load can be damaging to the kidneys.

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