Ketones - AntiDiabeticMeds

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Ketones are water-soluble acids produced mainly in the liver in a process called ketogenesis. Ketones are produced when there is substrate from the lipolysis, mainly oxidation of fatty acids. Lipolysis may involve dietary lipids in the digestive tract, circulating lipids in the blood and stored lipids in the apidose tissue or the liver (1). Production of ketones occur to create energy for the body, i.e. in starvation, in intense training when glycogen storage is depleted and with autoimmune diabetes, when there is insufficient insulin.

Ketones is an important energy source, which some of the body´s cells can use as energy. The brain and central nervous system (CNS) are the parts where tight glucose regulation is critical. An adult human brain and CNS needs ~120 gram glucose per day. If as an adult eating less than ~100 gram carbs a day the body will produce ketones for particular the brain and CNS (2). It´s a myth that the brain is dependent of glucose and can´t use ketones as energy, but eventual long-term consequences of being in ketosis, consistently eating low carb and use ketones as the main source of energy, is unknown. As I write in the chapter “glucose” above (3), glucose is still seen as the main source for energy in science, particular if having autoimmune diabetes.

What are Ketones

There are three ketone bodies: beta-hydroxybutyrate (3HB), acetoacetate and acetone (Lori Laffel at one of the oldest and largest diabetes centers, Joslin, has an old but great and comprehensive paper 4). The latter is what might give the specific breath if being in ketosis or ketoacidosis. Please note that there is a common misunderstanding there is a specific “starvation ketone”, it´s not as seen above. That name arises from the condition or situation when ketones has occurred. There is no harmless ketone, but ketones don´t automatically lead to a life-threatening condition. Not contradictory. Ketones can be measured in urine, where acetoacetate is detected, and in blood, where you measure 3HB. 3HB is more reliable to measure since it shows the current ketone level, in the urine there is a delay naturally. For non-diabetic subjects there is not much to bother about ketones.

Ketones with Diabetes

High levels of ketones can be produced when having diabetes of several reasons, commonly endos refer to absolute or relative insulin deficiency. Absolute insulin deficiency naturally means having a high blood sugar (as I wrote about hyperglycemia above don´t necessary lead to ketones) and relative insulin deficiency when for example having a normal blood sugar but due to a starvation (knowingly or unknowingly), intensive training, a virus or insufficient amount of carbs. Relative insulin deficiency in fact means that the insulin is perfect enough for keeping blood sugar in target, but since insulin have many tasks (see chapter insulin 5), it´s not enough to ensure production of ketones is out of control. Exact reason why this may happen we don´t know but there are some great hypothesis, more below.

DKA

Diabetes ketoacidosis, DKA, is a life-threatening condition treated at a hospital. Elevated ketones out of control can lead to a DKA due to a number of reasons (6, 7, 8). Main reason is though lack of insulin. DKA develop over several hours but can happen faster. Under normal conditions the different ketones are produced 1:1 but please note, regarding measuring in urine or blood, that If having elevated ketones the ratio can rise to 10:1 in favour of 3HB (4), the ketone which can only be detected in blood. Pump users are more prone to DKA since they are more vulnerable due to using only one kind of insulin and distribution, the pump uses the same insulin as both basal and bolus. That doesn´t mean pump users get a DKA every week of course, but the risk is higher.

DKA can happen to people with type 2 diabetes as well but the prevalence is not as high as for autoimmune diabetes. Mortality for DKA differ between countries/regions. Characteristic symptoms for a DKA are similar to those at diagnose:

Excessive thirst
Frequent urination
Extreme fatigue
Dizziness
Blurry vision
Nausea and vomiting
Stomach pain
Headache
Kussmaul respiration, hyperventilation
Acetone breath

Recommendations are slightly different in countries. In Sweden, we are recommended to contact our health care provider or the ER if ketones measured in blood are above 3 mmol, no matter what glucose is. ADA says (9); “Ketoacidosis (DKA) is dangerous and serious. If you have any of the above symptoms, contact your health care provider IMMEDIATELY, or go to the nearest emergency room of your local hospital.” NHS says (7); “Go to your nearest accident and emergency (A&E) department straight away if you think you have DKA, especially if you have a high level of ketones in your blood or urine. DKA is an emergency and needs to be treated in hospital immediately. Call your diabetes team or GP as soon as possible if you’re not sure if you need emergency help – for example:

your blood sugar or ketone levels are high or getting higher over time but you don’t feel unwell
you feel unwell but your blood sugar or ketone levels are normal or are only a little bit higher than usual”

Euglycemic ketoacidosis

A ketoacidosis with normal, or close to normal, blood sugar is called euglycemic ketoacidosis (euDKA), or normoglycemic. It was first described 1973 in patients with autoimmune diabetes by Munro et al (10), and the definition has changed slightly since then. It´s a rare condition and the vast majority of the DKA´s are with absolute insulin deficiency and high glucose. An euDKA can for example be caused by starvation, calici virus, vomiting due to gastroparesis, pregnancy, several diseases (i.e. cirrhosis), SGLT2 inhibitors (type 2 diabetes medication 11) as well as with autoimmune diabetes, insufficient amount of carbs.

Since low carb diet has gained some interest in Sweden for some years, a few case reports have been circulating between endos, which shows patients where a euDKA is incuded by low carb. This had lead that the Swedish Diabetology Association has officially warned patients to reduce carb to much (not below 100 gram per day for an adult), especially children. Since it´s a rare complication and many of the patients feel quite well until escalated ketone production and reduced pH value late in the process, it´s quite easy to miss the diagnose. At the ER particular ketones and base-excess are measured.

Science and physiology eudka – deeper explanation

There is a number of possible explanations that a euDKA can happen, but we don´t know exactly why. Studies are unfortunately few. First a theory that means insulin is insufficient to inhibit lipolysis and ketogenesis:

”Insulin and the counterregulatory hormones are critical regulators of the rate of lipolysis, and declining insulin levels probably influenced some of the changes that we observed. While it is evident that the insulin levels sufficient to maintain euglycemia during a fast were inadequate to suppress lipolysis and ketogenesis (as suggested by the elevated ketone levels in the fasting state at baseline), insulin levels did not differ significantly between the two experimental conditions.”

“While some have suggested a role for glucagon in the stimulation of lipolysis, the rise in serum glucagon in our study was relatively small. Although the time course of serum glucagon elevation in the fasting state corresponded with peak lipolysis, the lack of a similar correlation in the postprandial state makes it unlikely that the observed decompensations in lipid metabolism were due primarily to glucagon.” (12)

Another theory comes from the old thesis “glucose is needed to efficiently burn fat”. In fact, I believe this is partly what we see in the above study as well. The TCA cycle (Tricarboxylic acid cycle, or Krebs cycle or citric acid cycle) is an eight steps metabolic process that occurs in most plants, animals, fungi and bacteria. It´s where living cells break down molecules in the presence of oxygen to get needed energy to grow and divide. It´s well defined since many years. Lori Laffels paper:

“To enter the citric acid cycle, acetyl CoA first condenses with oxaloacetate. Oxaloacetate is derived from pyruvate during glycolysis. Therefore, it is essential to have a level of glycolysis that provides sufficient oxaloacetate to condense with acetyl CoA. If glucose levels become too low (e.g. during fasting or low insulin levels in diabetes), then oxaloacetate is preferentially utilized in the process of gluconeogenesis, instead of condensing with acetyl CoA. Acetyl CoA is then diverted to ketone body formation.”

“In the liver of patients with active DKA, the effective lack of insulin and the high levels of counterregulatory hormones combine to impair the reesterication of FFA (that is, to impair hepatic lipid synthesis) and to catalyze the processes by which FFA are transported into mitochondria and subsequently converted into ketone bodies. FFA transport into hepatic mitochondria is enhanced by glucagon-mediated reductions in the cytosolic malonyl-CoA, which removes inhibition of carnitine palmitoyltransferase 1 (CPT1). Malonyl-CoA competitively inhibits CPT1, the enzyme that transports fatty acyl CoA across hepatic mitochondrial membranes. Within the mitochondria, fatty acyl CoA normally undergoes b-oxidation to acetyl CoA, and acetyl CoA is in turn shunted into the tricarboxylic acid cycle. In DKA, however, the enormous supply of fatty acyl CoA and deciency in oxaloacetate overwhelm these normal biochemical pathways. When this occurs, excessive amounts of fatty acyl CoA derivatives are oxidized to form ketone bodies, and large quantities of 3HB and AcAc are released into the blood.” (4)

In the presence of ample carbohydrate fuel, there is plenty of oxaloacetate to react with acetyl-CoA, which means acetyl-CoA can easily enter the TCA cycle and generate ATP by oxidative phosphorylation. However, in a glucose-poor environment, too much oxaloacetate is diverted away into gluconeogenesis and Acetyl CoA is converted into ketone bodies. So where is the precise individual limit when the TCA cycle works in autoimmune diabetes, insulin inhibits ketogenesis and lipolysis without escalated ketones? We don´t know.

The third and most convincing and logical theory is the way we administer insulin. In a healthy individual, the impact of the hormones produced in the pancreas on the liver is huge thanks to portal vein, one of the body´s largest veins. The logic here is that the main difference between us with autoimmune diabetes and healthy individuals, is absolute insulin deficiency and subcutaneous administration of exogenous insulin. Insulin produced in a healthy individual have a highway to the liver. We have known for many years that insulin have a lot of tasks, mainly on the liver, and a ground breaking and frequent cited study from 2005 showed that up to as much as 80% of the insulin´s effect might be on the liver, 13. Subcutaneous administered insulin doesn´t reach the liver as endogenous insulin, this study says 30-40% does, 14. Even though difficult to study this make sense considering the physiology of the hepatic portal system vs systemic circulation and our way of administering insulin. This means that endogenous insulin affect primarily the liver and the portal system, exogenous insulin affect primarily the circulatory system.

There are some case reports of euDKA as well, here one by Thawabi and Studyvin; “Euglycemic Diabetic Ketoacidosis, a Misleading Presentation of Diabetic Ketoacidosis”. Conclusion: “Euglycemic DKA is usually seen in otherwise healthy patients with type 1 diabetes mellitus who have decreased carbohydrate intake in the presence of adequate hydration and a degree of insulin intake. Recognition of this entity by the emergency provider is crucial when patients with DM1 present with a picture of DKA, regardless of their blood sugar.” (15)

Another case, “Starvation-induced True Diabetic Euglycemic Ketoacidosis in Severe Depression”: 16.

In type 2 diabetes, high glucagon levels are seen in some subjects. This might contribute a DKA in type 2 diabetes: “The role of glucagon in the development of diabetic ketoacidosis is through suppression of malonyl coenzyme A (CoA) levels. Malonyl CoA is an inhibitor of carnitine palmityltransferase (CPT-I), an enzyme that catalyses the rate-limiting step in the transfer of fatty acids across the mitochondrial membrane for beta oxidation; malonyl CoA is therefore an inhibitor of ketogenesis.” (17)

Spring 2018 we had two case reports with euDKA in Sweden, in type 2 diabetes patients. One treated with SGLT2 inhibitors and one with metformin, both on low carb diet. Even though SGLT2 in one case, the HCP´s state the diet induced the euDKA. Presented in a Swedish Medical journal, only a very short summary in English, 18.

Diet

People who eat some kind of low carb diet tend to tell other that it´s a different between ketosis and ketoacidosis. It´s a straw man argument. The problem for us with the condition autoimmune diabetes, and a few with type 2 diabetes, is that the margin between ketosis and ketoacidosis can be minimal. I usually call it “Russian roulette”. Despite a rare condition it´s still life-threatening.

We don´t know exactly why this very rare condition can happen, and we can´t tell who will eventually develop a euDKA or not. But with autoimmune diabetes it´s easy to avoid and if not eating enough carbs, we must monitor ketones, preferable in blood. It might be a combination of the above mentioned theories as well.

The most popular spokesmen of low carb in Sweden are very open that the diet may cause a depleted glycogen storage, which with insulin dependent diabetes can be life-saving in counterregulation of a hypoglycaemia. There are evidence that glucagon injection may have less effect if adapting to a low carb diet, small but interesting study from Denmark 19. Last but not least, we don´t know eventual long-term consequences of ketogenic diet and particular the impact of LDL-C. Cardiovascular diseases are the most common cause of death for all kind of diabetes. There are no shortcuts 20, 21, 22.

euDKA has happened in people without diabetes but that is extremely rare. There seems to be seven case reports in lactating women as well, with different push factors into euDKA. This one got some attention in Sweden since it´s a lactating and healthy individual, where low carb was the stressor 23.

Listen to a registered dietician if having the opportunity, and individualize meal planning. We are not robots, and comorbidity is common among people with diabetes which can make it harder to find a method that works in the long-term. Nutritional recommendations for people with diabetes are, at least in Sweden, based on the same as for people in general. It´s also important to remember that depression and other psychiatric disorders are much more common in people with diabetes than healthy individuals.

There are no high quality studies with low carb in autoimmune diabetes, which would have been interesting in the past. We are on the verge of a change in paradigms with technology, not that all automatically will have access. But if getting access there is even less reason trying, “haste makes waste”.

Children and low carb diets

It´s well known that children have a relative smaller glycogen storage in the liver. Lori Laffel write in the article above (4):

“Children of this age are thus more susceptible to physiological ketosis because of their diminished hepatic stores of glycogen and their proportionately larger central nervous system than adults….”.

Ketosis is not DKA, but the margin gets non-existent if having constantly ketones at a few mmol. We also know carbs is a must in growing children. 2017 a study from Australia and New Zealand by Carmel et al gained a lot of attention; “Endocrine and metabolic consequences due to restrictive carbohydrate diets in children with type 1 diabetes: An illustrative case series”, 24. Adoption of a low carbohydrate diet in children impacted growth and cardiovascular risk factors with potential long-term sequelae. Cardiovascular diseases are the most common cause of death for all forms of diabetes.

As said above, HCP´s warns to reduce carb intake to much with diabetes, particular autoimmune diabetes. For children with autoimmune diabetes there is even higher risk. Try to find a better way to manage the disease together with your diabetes health care team.

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