This post relates in some way to each of the three previous posts.
The definition of MCFA is a little unclear. Wikipedia lists lauric acid as a MCFA, making the range C:6-12, whereas commercial MCTs are almost completely made from C:8 and C:10, as C:6 is not available in any significant amount from coconut oil, and about 32% of lauric acid is not deposited into to the hepatic portal vein, whereas the totality of shorter chain MCFAs is. It is likely that both lauric and myristic (C:14) acids exist in a grey zone where they have partial MCFA properties. It is also relevant that triglycerides that contain longer chain fatty acids are hydrolysed more slowly and a rapid rate of hydrolysis in the gut is one of the properties desired of MCTs.
In a previous post I wrote about a case study where a ketogenic diet prevented symptomatic hypoglycaemia in a child with hyperinsulinism. I wrote at the time that this was as close as we would get to a proof that slightly elevated ketone levels due to carbohydrate restriction are protective against symptomatic hypoglycaemia in people with type 1 diabetes treated with insulin.
I was wrong - there has been a human trial of the concept, using MCT oil.[1]
In this study "A total of 11 intensively treated type 1 diabetic subjects participated in stepped hyperinsulinemic- (2 mU · kg−1 · min−1) euglycemic- (glucose ∼5.5 mmol/l) hypoglycemic (glucose ∼2.8 mmol/l) clamp studies. During two separate sessions, they randomly received either medium-chain triglycerides or placebo drinks and performed a battery of cognitive tests."
"During the medium-chain triglycerides session, a total of 40 g of medium-chain triglycerides (derived from coconut oil containing 67% octanoate, 27% decanaote, and 6% other fatty acids; Novartis) was ingested at 25-min intervals with front loading of 20 g then 10 g twice. During the control session, cherry-flavored water sweetened with sucralose was ingested at identical time intervals."
The beta-hydroxybutyrate level attained 40 minutes after the MCT drinks was about 3.4 mmol/l.
"We conclude that ingestion of medium-chain triglycerides improves cognitive function without affecting the adrenergic hormonal or symptomatic responses to acute hypoglycemia in intensively controlled type 1 diabetic patients. These findings suggest that medium-chain triglycerides could be used as prophylactic therapy for such patients with the goal of preserving brain function during hypoglycemic episodes, such as when driving or sleeping, without producing hyperglycemia."
There was another interesting aspect of this experiment.
"In vitro rat hippocampal slice preparations were used to assess the ability of β-hydroxybutyrate and octanoate to support neuronal activity when glucose levels are reduced."
The reason for this is, that the authors wanted to be sure whether the protective effects of MCT oil were due to the brain using ketone bodies or due to the brain's use of MCFAs. It turns out that the MCFAs used in MCTs can cross the blood-brain barrier and be used in brain metabolism. In another rat paper, "We found that oxidation of 13C-octanoate [C:8] in brain is avid and contributes approximately 20% to total brain oxidative energy production."[2]
The C:8 is mainly being oxidised by astrocytes. If this happens in a hypoglycaemic brain, it's possible that due to lack of oxaloacetate ketone bodies will be produced, which can be used by the neurons.
What I really want to know is how coconut oil compares to MCT oil as a means to elevate serum ketone bodies. I suspect that ketone elevation from coconut oil has a slower onset and is more protracted due to the slower rate of hydrolysis of MCFAs from triglycerides with some longer-chain fatty acids, and if so this "time release" effect could be beneficial during sleep.
There is only one study I can find online which shows ketone levels after feeding coconut oil, and this is Mary Newport's n=1 experiment.[powerpoint here]
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I don't know what to make of this, beyond the expected drop in glucose (due to insulin response to lauric acid - this wouldn't apply in type 1 diabetes); the levels, though elevated by both interventions, are still within the reference range (and very different from those in the diabetes paper), unless I'm reading the measurements wrong, and the time scale with coconut oil stops short. I'd like to see many more comparisons like this, with higher doses, in healthy volunteers. The coconut oil industry and coconut oil aficionados have been accused of extrapolating from MCT studies in the absence of evidence about coconut oil, for example by the Heart Foundation of New Zealand here. While I don't think it's justifiable to ignore animal studies of coconut oil, which tell us that coconut oil protects the liver and pancreas from chemical injury, totally consistent with the MCT research, I don't see why the coconut oil industry can't fund proper comparative studies of ketogenesis in humans, which would not be at all expensive.
A 1982 review of medium chain triglycerides stated that "MCTs are ketogenic in the normal subject
and even more in the patient with hyperosmolar diabetic syndrome (117). Hence, MCTs should not be given to patients with diabetes. They should also not be given to patients with ketosis or acidosis."[3]
Whilst no-one would treat diabetic ketoacidosis with MCTs, the statement "MCTs should not be given to patients with diabetes" is unfounded. People with type 2 diabetes, due to hyperinsulinaemia, are not at an increased risk of diabetic ketoacidosis*, and the experiment I posted above shows that those with intensively controlled type 1 diabetes may benefit from their use. The reference (117) which is the only reference in this section is a rat experiment; the hyperosmolar diabetic syndrome described is high glucose with normal ketones, not DKA.
A 2010 review cites several reports that "suggest that MCFAs/MCTs offer the therapeutic advantage of preserving insulin sensitivity in animal models and patients with type 2 diabetes".[4]
This is consistent with the Malmö Diet and Cancer study epidemiology I posted here. Which implies that even the small amounts of MCFAs in foods such as coconut and dairy are beneficial for maintaining metabolic homeostasis at a population level.
*Edit: thanks to Carol Loffelman for reminding me of this - type 2 diabetes is a risk factor for ketoacidosis if it's being treated with a SLGT2 inhibitor. See this link, but there are many cases of ketoacidosis on SLGT2 inhibitors where a low carb diet is not involved. I have looked for case studies of ketoacidosis in diabetic patients that were triggered by carbohydrate restriction or MCTs without SLGT2 administration and have not yet found one.
This is a case study of DKA in a woman with decompensated T2D [link] where there is not enough insulin to prevent it. There's no low carb diet or SGLT2i involvement, and my expectation is that a normal calorie very low carbohydrate diet would most likely have prevented the syndrome in this patient as it did in the patients of Newburgh and Marsh back in the day.
[1] Page KA, Williamson A, Yu N et al. Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia. Diabetes. 2009 May; 58(5): 1237–1244
[2] Ebert D, Haller RG, Walton ME. Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J Neurosci. 2003 Jul 2;23(13):5928-35.
[3] Bach AC, Babayan VK. Medium-chain triglycerides: an update. Am J Clin Nutr. 1982 Nov;36(5):950-62.
[4] Nagao K, Yanagita T. Medium-chain fatty acids: functional lipids for the prevention and treatment of the metabolic syndrome. Pharmacol Res. 2010 Mar;61(3):208-12. doi: 10.1016/j.phrs.2009.11.007. Epub 2009 Nov 30.
The definition of MCFA is a little unclear. Wikipedia lists lauric acid as a MCFA, making the range C:6-12, whereas commercial MCTs are almost completely made from C:8 and C:10, as C:6 is not available in any significant amount from coconut oil, and about 32% of lauric acid is not deposited into to the hepatic portal vein, whereas the totality of shorter chain MCFAs is. It is likely that both lauric and myristic (C:14) acids exist in a grey zone where they have partial MCFA properties. It is also relevant that triglycerides that contain longer chain fatty acids are hydrolysed more slowly and a rapid rate of hydrolysis in the gut is one of the properties desired of MCTs.
In a previous post I wrote about a case study where a ketogenic diet prevented symptomatic hypoglycaemia in a child with hyperinsulinism. I wrote at the time that this was as close as we would get to a proof that slightly elevated ketone levels due to carbohydrate restriction are protective against symptomatic hypoglycaemia in people with type 1 diabetes treated with insulin.
I was wrong - there has been a human trial of the concept, using MCT oil.[1]
In this study "A total of 11 intensively treated type 1 diabetic subjects participated in stepped hyperinsulinemic- (2 mU · kg−1 · min−1) euglycemic- (glucose ∼5.5 mmol/l) hypoglycemic (glucose ∼2.8 mmol/l) clamp studies. During two separate sessions, they randomly received either medium-chain triglycerides or placebo drinks and performed a battery of cognitive tests."
"During the medium-chain triglycerides session, a total of 40 g of medium-chain triglycerides (derived from coconut oil containing 67% octanoate, 27% decanaote, and 6% other fatty acids; Novartis) was ingested at 25-min intervals with front loading of 20 g then 10 g twice. During the control session, cherry-flavored water sweetened with sucralose was ingested at identical time intervals."
The beta-hydroxybutyrate level attained 40 minutes after the MCT drinks was about 3.4 mmol/l.
"We conclude that ingestion of medium-chain triglycerides improves cognitive function without affecting the adrenergic hormonal or symptomatic responses to acute hypoglycemia in intensively controlled type 1 diabetic patients. These findings suggest that medium-chain triglycerides could be used as prophylactic therapy for such patients with the goal of preserving brain function during hypoglycemic episodes, such as when driving or sleeping, without producing hyperglycemia."
 |
| BOHB levels for MCT vs Placebo in insulin-induced hypoglycaemia after overnight fast, down arrows = 20g, 10g, 10g MCT or placebo drinks. 100 umol/l = 0.96 mmol/l. |
"In vitro rat hippocampal slice preparations were used to assess the ability of β-hydroxybutyrate and octanoate to support neuronal activity when glucose levels are reduced."
The reason for this is, that the authors wanted to be sure whether the protective effects of MCT oil were due to the brain using ketone bodies or due to the brain's use of MCFAs. It turns out that the MCFAs used in MCTs can cross the blood-brain barrier and be used in brain metabolism. In another rat paper, "We found that oxidation of 13C-octanoate [C:8] in brain is avid and contributes approximately 20% to total brain oxidative energy production."[2]
The C:8 is mainly being oxidised by astrocytes. If this happens in a hypoglycaemic brain, it's possible that due to lack of oxaloacetate ketone bodies will be produced, which can be used by the neurons.
What I really want to know is how coconut oil compares to MCT oil as a means to elevate serum ketone bodies. I suspect that ketone elevation from coconut oil has a slower onset and is more protracted due to the slower rate of hydrolysis of MCFAs from triglycerides with some longer-chain fatty acids, and if so this "time release" effect could be beneficial during sleep.
There is only one study I can find online which shows ketone levels after feeding coconut oil, and this is Mary Newport's n=1 experiment.[powerpoint here]
I don't know what to make of this, beyond the expected drop in glucose (due to insulin response to lauric acid - this wouldn't apply in type 1 diabetes); the levels, though elevated by both interventions, are still within the reference range (and very different from those in the diabetes paper), unless I'm reading the measurements wrong, and the time scale with coconut oil stops short. I'd like to see many more comparisons like this, with higher doses, in healthy volunteers. The coconut oil industry and coconut oil aficionados have been accused of extrapolating from MCT studies in the absence of evidence about coconut oil, for example by the Heart Foundation of New Zealand here. While I don't think it's justifiable to ignore animal studies of coconut oil, which tell us that coconut oil protects the liver and pancreas from chemical injury, totally consistent with the MCT research, I don't see why the coconut oil industry can't fund proper comparative studies of ketogenesis in humans, which would not be at all expensive.
A 1982 review of medium chain triglycerides stated that "MCTs are ketogenic in the normal subject
and even more in the patient with hyperosmolar diabetic syndrome (117). Hence, MCTs should not be given to patients with diabetes. They should also not be given to patients with ketosis or acidosis."[3]
Whilst no-one would treat diabetic ketoacidosis with MCTs, the statement "MCTs should not be given to patients with diabetes" is unfounded. People with type 2 diabetes, due to hyperinsulinaemia, are not at an increased risk of diabetic ketoacidosis*, and the experiment I posted above shows that those with intensively controlled type 1 diabetes may benefit from their use. The reference (117) which is the only reference in this section is a rat experiment; the hyperosmolar diabetic syndrome described is high glucose with normal ketones, not DKA.
A 2010 review cites several reports that "suggest that MCFAs/MCTs offer the therapeutic advantage of preserving insulin sensitivity in animal models and patients with type 2 diabetes".[4]
This is consistent with the Malmö Diet and Cancer study epidemiology I posted here. Which implies that even the small amounts of MCFAs in foods such as coconut and dairy are beneficial for maintaining metabolic homeostasis at a population level.
*Edit: thanks to Carol Loffelman for reminding me of this - type 2 diabetes is a risk factor for ketoacidosis if it's being treated with a SLGT2 inhibitor. See this link, but there are many cases of ketoacidosis on SLGT2 inhibitors where a low carb diet is not involved. I have looked for case studies of ketoacidosis in diabetic patients that were triggered by carbohydrate restriction or MCTs without SLGT2 administration and have not yet found one.
This is a case study of DKA in a woman with decompensated T2D [link] where there is not enough insulin to prevent it. There's no low carb diet or SGLT2i involvement, and my expectation is that a normal calorie very low carbohydrate diet would most likely have prevented the syndrome in this patient as it did in the patients of Newburgh and Marsh back in the day.
[1] Page KA, Williamson A, Yu N et al. Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia. Diabetes. 2009 May; 58(5): 1237–1244
[2] Ebert D, Haller RG, Walton ME. Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J Neurosci. 2003 Jul 2;23(13):5928-35.
[3] Bach AC, Babayan VK. Medium-chain triglycerides: an update. Am J Clin Nutr. 1982 Nov;36(5):950-62.
[4] Nagao K, Yanagita T. Medium-chain fatty acids: functional lipids for the prevention and treatment of the metabolic syndrome. Pharmacol Res. 2010 Mar;61(3):208-12. doi: 10.1016/j.phrs.2009.11.007. Epub 2009 Nov 30.