Gluconeogenesis Drives Ketogenesis - role of the Nutritional Prometheus.

In trying to explain the findings of Newburgh and Marsh*, and of Karl Petren, from 1923 that switching to a high fat, restricted protein, and very low carbohydrate diet - a ketogenic diet - suppresses diabetic ketoacidosis (DKA) in diabetics without access to insulin, I can't help noticing that gluconeogenesis is a driver of ketogenesis. DKA is a dehydrating syndrome characterized by hyperglycaemia, due in large part to runaway gluconeogenesis, plus levels of ketone bodies, much higher than those seen in starvation or nutritional ketosis, which result in a lethal acidosis. And excess glucose and excess ketones are linked metabolically.

Remember the old saw, that fat burns in a carbohydrate flame? Laugh all you like, but this is true. And it is even more true when the flame is taken away - when carbohydrate (glucose) is being stolen from mitochondrial metabolism. Gluconeogenesis involves a direct loss of oxaloacetate from the citric acid (Krebs, TCA) cycle. Without this oxaloacetate, the fat-burning flame sputters; the smoke that escapes from incomplete combustion is the ketone bodies. I'm not a chemist, but this seems to me a pretty certain way of interrupting the TCA cycle. And a very convenient one in evolutionary terms; at times when you need endogenous glucose, you can use a few extra ketones as well.

Pyruvate from glucose can supply acetyl-CoA or oxaloacetate, fatty acids can only supply acetyl-CoA, if there's no oxaloacetate acetyl-CoA can't be converted to citrate and is converted to ketone bodies instead (not shown).


[In Starvation] degradation of fatty acids in the liver proceeds more rapidly than usual, with augmented production of of acetoacetyl-CoA and acetyl-CoA and their products.
In addition there is a deficit of oxaloacetate and thus a decrease in formation of citrate.
The low level of oxaloacetate is further accentuated because it is being utilized for gluconeogenesis.
This further impairs operation of the citric acid cycle.

Ketosis incident to starvation is most frequently encountered clinically in gastrointestinal disturbances in infancy or pregnancy. Other circumstances in normal individuals in which excessive lipid and diminished carbohydrate are being metabolised may also lead to ketosis, e.g. renal glycosuria and abrupt replacement of a normal diet by one low in carbohydrate and very rich in lipid.

Clinically, the most important cause of ketosis is diabetes mellitus. In the diabetic individual, in contrast to the above situations, glucose is present in excessive amounts in the fluids of the body; however, the metabolic defect, viz., insulin deficiency, prevents glucose utilization from operating at a normal rate. From the point of view of the effect upon lipid metabolism, diabetes and starvation resemble one another.

In diabetic individuals with severe ketosis, urinary excretion of ketone bodies may be as high as 5,000mg/24 h and the blood concentration may reach 90mg/100ml, in contrast to normal values of less than 125mg and less than 3mg respectively.

Ketogenesis, from Principles of Biochemistry, 5th Edn, White A, Handler P, Smith EL. McGraw Hill, 1973, p577-578.


[NB: acetyl-CoA is also a precursor for cholesterol;
"The data suggest that, although acetyl-CoA is channeled towards ketone body formation in both diabetes and fasting, augmented cholesterol synthesis is evident only in diabetes." This suggests that the closer the diabetic diet gets to a ketogenic diet, the less cholesterol synthesis will be augmented - as does seem to be the case in practice.]



So what happens when a diabetic without insulin eats carbohydrate or excess protein?
As we saw in earlier posts, glucagon is released from pancreatic alpha cells in response to carbohydrate and protein. This elevates gluconeogenesis in the liver. Blood glucose is elevated by the meal and by GNG, and hyperglycaemia itself increases hepatic GNG further. Lipolysis is increased by the glucagon, so the liver has additional fatty acids to metabolize. Perfect conditions for ketogenesis to be enhanced above normal levels, because oxaloacetate is being extracted from the TCA in record amounts as this fat is being burned.

What happened when diabetics, in acidosis and without insulin, were switched to the Newburgh and Marsh ketogenic diet in 1923?
With no glucose and minimal protein to trigger glucagon, hepatic GNG is lower. With no glucose to add its load to hyperglycaemia, there is less portal hyperglycaemia to additionally drive GNG.
Less GNG = less ketogenesis.
And, as a bonus, it is likely that dietary fat has an inhibitory effect on lipolysis that is independent of hormonal controls. As long as it's saturated, or not polyunsaturated - in 1923, endocrinologists favoured butter as a source of fat.


Beef tallow diet decreases beta-adrenergic receptor binding and lipolytic activities in different adipose tissues of rat.
Matsuo T, Sumida H, Suzuki M. Metabolism. 1995 Oct;44(10):1271-7.

Abstract
The effects of dietary fats consisting of different fatty acids on lipolytic activity and body fat accumulation were studied in rats. Sprague-Dawley male rats were meal-fed an isoenergetic diet based on either beef tallow or safflower oil for 8 weeks. Lipolytic activities in epididymal and subcutaneous adipose tissues were lower in the beef tallow diet group than in the safflower oil diet group. Body fat accumulation was greater in rats fed the beef tallow diet versus the safflower oil diet. Norepinephrine (NE) turnover rates used as an index of sympathetic activities in adipose tissues were lower in the beef tallow diet group. beta-Adrenergic receptor binding was determined with [3H]dihydroalprenolol. Binding affinities of beta-receptors in adipose tissues were significantly lower in the beef tallow diet group. Membrane fluidities of adipose tissues were also lower in the beef tallow diet group. Membrane fluidities were correlated with the affinities of the beta-receptor. We believe from these correlations that the decreases in beta-receptor binding affinities are due to the changes in membrane fluidities. The results of the present study suggest that intake of the beef tallow diet promotes body fat accumulation by reducing lipolytic activities resulting from lower beta-receptor binding and sympathetic activity in adipose tissues.

Dr Bernstein describes the mechanism of DKA differently; he doesn't consider that the liver is the main source of ketones, or that gluconeogenesis drives ketogenesis. His description addresses the pathology of DKA well, but not I think the early links in the chain of causality. Perhaps the difference is that he is describing the failure of insulin to work, and I am describing the long-term absence of insulin. But we are both agreed; dietary carbohydrate is the cause of DKA in diabetics.

"Furthermore, the higher your blood sugars go, the more insulin resistance you will experience. The more insulin-resistant you are, the higher your blood sugars are going to be.

A vicious circle. To make the circle even more vicious, when you have high blood sugars, you urinate—and of course what happens then is that you get even more dehydrated and more insulin-resistant and your blood sugar goes even higher. Now your peripheral cells have a choice—either die from lack of glucose and insulin or metabolize fat. They’ll choose the latter. But ketones are created by fat metabolism, causing you to urinate even more to rid yourself of the ketones, taking you to a whole new level of dehydration."
See also http://www.diabetes-book.com/ketoacidosis-hyperosmolar-coma/
and http://www.diabetes-book.com/diabetes-dehydration/

Edit: here's a bit more on starvation, from this book
After about 3 days of starvation, the liver forms large amounts of acetoacetate and d-3-hydroxybutyrate (ketone bodies; Figure 30.17). Their synthesis from acetyl CoA increases markedly because the citric acid cycle is unable to oxidize all the acetyl units generated by the degradation of fatty acids. Gluconeogenesis depletes the supply of oxaloacetate, which is essential for the entry of acetyl CoA into the citric acid cycle. Consequently, the liver produces large quantities of ketone bodies, which are released into the blood. At this time, the brain begins to consume appreciable amounts of acetoacetate in place of glucose. After 3 days of starvation, about a third of the energy needs of the brain are met by ketone bodies (Table 30.2). The heart also uses ketone bodies as fuel.

And diabetes:
Because carbohydrate utilization is impaired, a lack of insulin leads to the uncontrolled breakdown of lipids and proteins. Large amounts of acetyl CoA are then produced by β-oxidation. However, much of the acetyl CoA cannot enter the citric acid cycle, because there is insufficient oxaloacetate for the condensation step. Recall that mammals can synthesize oxaloacetate from pyruvate, a product of glycolysis, but not from acetyl CoA; instead, they generate ketone bodies. A striking feature of diabetes is the shift in fuel usage from carbohydrates to fats; glucose, more abundant than ever, is spurned. In high concentrations, ketone bodies overwhelm the kidney's capacity to maintain acid-base balance. The untreated diabetic can go into a coma because of a lowered blood pH level and dehydration.

Note for future research: Mammals can synthesise oxaloacetate from pyruvate, but what if this step depends on insulin (which suppresses ketogenesis) and the conversion of pyruvate to acetyl-CoA doesn't?
The diabetic hepatocyte is swamped with glucose, it can't resist metabolising it, and 65-85% of the carbon from this glucose is recycled as GNG glucose.
What if this glucose, without the guiding hand of insulin, is, like fatty acids, a poor source of oxaloacetate and a good source of acetyl-CoA? After all, its metabolism is not suppressing ketogenesis - the opposite seems to be true.
Ketone bodies for use by heart muscle in normal hepatic metabolism are produced from glycogen, according to the first text I quoted.
So - is glucose itself a ketogenic substrate under certain conditions?
The quest continues...