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Tuesday, 6 October 2015

Do moderate ketone levels from low carb protect against symptomatic hypoglycemia in type 1 diabetes? A relevant case study.

Before many can know something, one must know it. 
- Dr Stockmann, in Ibsen's An Enemy of the People.



One of the benefits of a very low carbohydrate diet for type 1 diabetes is a much lower rate of hypoglycemic episodes, because of the need for less insulin, lower insulin doses and longer acting insulin overall (a greater proportion of the insulin used is basal dose). This is predicted by the laws of small numbers.
It is also reported anecdotally that hypoglycemia, when it does occur by the meter, is often non-symptomatic. The milder symptoms aren't easily ignored, and severe hypoglycaemia can lead to seizures, unconsciousness, and death. This is because the brain requires glucose at a steady rate. The brain can also use ketone bodies, which are generated by the liver from the incomplete combustion of fatty acids and some amino acids on a low carb diet. On the Bernstein diet carbohydrate intake is around 30g/day and this would provide deep ketosis if the protein intake were not high. As it is, the ketone level in someone on the Bernstein diet has been reported as 2 mmol/L.

Is this enough to protect against symptoms in insulin-induced hypoglycaemia? Does an oversupply of insulin suppress ketogenesis in the absence of carbohydrate?



These questions are impossible to test in someone with Type 1 Diabetes, no ethics committee would approve the experiment.

Luckily a case study has just been published that seems to answer them. Thanks to Bill Lagakos @caloriesproper for tweeting this.

Ketogenic diet in a patient with congenital hyperinsulinism: a novel approach to prevent brain damage. 
Maiorana, A, Manganozzi, L, Barbetti, F, Bernabei, S, Gallo, G, Cusmai, R, Caviglia, S, Dionisi-Vici, C. Orphanet Journal of Rare Diseases 2015, 10:120  doi:10.1186/s13023-015-0342-6

The subject is a child with congenital hyperinsulinism, that is, she has chronic high insulin levels (without apparent insulin resistance) and eating carbohydrate to relieve hypoglycaemia causes a further increase in insulin.

In addition to increased peripheral glucose utilization, dysregulated insulin secretion induces profound hypoglycemia and neuroglycopenia by inhibiting glycogenolysis, gluconeogenesis and lipolysis. This results in the shortage of all cerebral energy substrates (glucose, lactate and ketones), and can lead to severe neurological sequelae.
A child with drug-resistant, long-standing CHI caused by a spontaneous GCK activating mutation (p.Val455Met) suffered from epilepsy and showed neurodevelopmental abnormalities. After attempting various therapeutic regimes without success, near-total pancreatectomy was suggested to parents, who asked for other options. Therefore, we proposed KD in combination with insulin-suppressing drugs.We administered KD for 2 years. Soon after the first six months, the patient was free of epileptic crises, presented normalization of EEG, and showed a marked recover in psychological development and quality of life.


Note the points that a) insulin suppresses ketogenesis by suppressing lipolysis, b) neurologists know that lactate is a cerebral energy substrate.

At the age of 3 years laboratory tests were performed and showed hypoglycemia with hyperinsulinemia (blood glucose 1.95–2.3 mmol/L; plasma insulin 5.5–10.2 μUI/ml).

 A further association with slow-release carbohydrate to drugs did not elicit any clinical improvement, and the patient continued to present hypoglycemic episodes (0.5–1.6 mmol/L), seizures and absence epilepsy regardless of glycemic values, that required frequent hospitalizations.

Furthermore, at the age of 10 years the patient quickly gained 11.5 kg within 12 months, becoming mildly obese (BMI z-score: >97 th centile). Overall, her quality of life was very poor. The lack of response to drug therapy with risk of permanent and severe brain sequelae made us to consider a near-total pancreatectomy, that was discussed with parents with the warning of no guarantee to achieve normoglycemia and of the increased hazard of secondary diabetes. At parents’ request to avoid surgery, we then proposed a trial with KD, explaining that it was aimed to prevent neuroglycopenic epilepsy and to improve neurological status by providing ketone bodies as an alternative energy source for neurons, as seen in GLUT1 deficiency.



Six months after KD was started, maintenance of blood ketones between 2–5 mmol/L (Fig. 1, panel a) fully resolved neuroglycopenic signs with parallel disappearance of both epileptic crisis and absence epilepsy, despite blood glucose levels permanently below 5.5 mmol/L even after meal, and close to 2.2–2.7 mmol/L most of time (Fig. 1, panel b). EEG improved and became normal within the first year on KD, showing no alteration even during episodes of hypoglycemia (Fig. 2). During the first 6 months of KD the patient lost 9 kg and her BMI normalized. Psychological evaluation revealed a strengthening of social, cognitive and verbal capacities (Fig. 3). The child and her family reported an improvement of physical and psychosocial well-being, reduction of fear of hypoglycemic symptoms and awareness of a lower risk of neurological injury, with an overall amelioration of the quality of life related to the management of disease. Diazoxide was discontinued, and currently the patient is given octreotide, reduced to 25 μg/kg/day, without any neuroglycopenic symptoms. KD was well tolerated over a period of 24 months, with no side-effects and no changes in laboratory tests.




Thus we see some relevant findings - excessive levels of insulin doesn't suppress ketogenesis completely on a ketogenic diet (but I would really like to know what the insulin levels were on the KD). Ketones rise steadily proportionate to the ketogenic ratio, there is no cut-off. Ketones can replace glucose in insulin-induced hypoglycaemia, as expected - and were still present in sufficient amounts to do so. Insulin doesn't cause weight gain in the absence of carbohydrate.
An interesting question is whether the insulin resistance that is supposed to be caused by a high-fat diet played a role in this child's recovery by increasing lipolysis, as shown by the weight loss.

This is a neat study that confirms the anecdotal accounts that hypoglycemic episodes in type 1 diabetes are less symptomatic on a very low carb diet (that they are much fewer is already confirmed). Of course we would like more information about this, but this young girl's ordeal, and her convincing recovery, is compelling evidence that we haven't been barking up the wrong tree, given the difficultly of gathering any evidence at all about what happens in this situation.



For support and information about the Bernstein Diet for type 1 diabetes, join the TypeOneGrit group on Facebook. For Dr Bernstein's book, look here. For more information, see Dr Bernstein's YouTube Channel "Dr Bernstein's Diabetes University".




Before many can know something, one must know it. 




5 comments:

John Velden said...

Resistance to Symptomatic Insulin Reactions after Fasting
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC332976/?tool=pmcentrez

George Henderson said...

Thank you John, that's brilliant.
I expect insulin's ability to suppress ketogenesis depends on how much glucose is available to supply oxaloacetate.
And that insulin's ability to store fat depends on how much glucose is available to supply glycogen. DGAT2 in adipocytes and liver, a rate-limiting step for triglyceride synthesis, is controlled by glucose, not insulin.

http://www.ncbi.nlm.nih.gov/pubmed/12413942

John Velden said...

Yes a very interesting paper, I doubt it would be possible to get permission to do it these days!

In prolonged fasting subjects have very high growth hormone levels which is lipolytic.

Even though the drop in FFA was high in fasting + insulin the level of FFA was still reasonable.
Beta oxidation derived Acetyl-CoA exceeding the capacity of the citric acid cycle especially with depletion of oxaloacetate due to up regulation of gluconeogenic pathway possible.

Even under relatively high glucose/insulin condition consuming ethanol/MCT/SCFA will promote excess acetyl-CoA that can spill over to ketone production.

George Henderson said...

They didn't say whether the KD included MCTs. It's safe to assume it did and that this accounts for the ketones showing at low ketogenic ratios.
Substrate availability can over-ride hormonal controls on metabolism, this is the case with hyperglycaemia which produces insulin-independent effects.

George Henderson said...

Medium-Chain Fatty Acids Improve Cognitive Function in Intensively Treated Type 1 Diabetic Patients and Support In Vitro Synaptic Transmission During Acute Hypoglycemia

Hypoglycemia impaired cognitive performance in tests of verbal memory, digit symbol coding, digit span backwards, and map searching. Ingestion of medium-chain triglycerides reversed these effects. Medium-chain triglycerides also produced higher free fatty acids and β-hydroxybutyrate levels compared with placebo. However, the increase in catecholamines and symptoms during hypoglycemia was not altered. In hippocampal slices β-hydroxybutyrate supported synaptic transmission under low-glucose conditions, whereas octanoate could not. Nevertheless, octanoate improved the rate of recovery of synaptic function upon restoration of control glucose concentrations.

CONCLUSIONS

Medium-chain triglyceride ingestion improves cognition without adversely affecting adrenergic or symptomatic responses to hypoglycemia in intensively treated type 1 diabetic subjects. Medium-chain triglycerides offer the therapeutic advantage of preserving brain function under hypoglycemic conditions without causing deleterious hyperglycemia.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671041/