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Friday, 22 May 2015

How a high fat ketogenic diet prevents diabetic ketoacidosis – somatostatin

Karl Petren 1868-1927
How a high fat ketogenic diet prevents diabetic ketoacidosis – somatostatin

It is pretty well-accepted now that nutritional ketosis and diabetic ketoacidosis are quite different things, but it is not yet understood how nutritional ketosis prevents diabetic ketoacidosis. That it does so was clear in 1923; both Newbugh and Marsh[1] and Karl Petren[2] reported in that year from their respective diabetes clinics that a diet high in fat, restricted in protein, and very low in carbohydrate, fed to diabetic patients, including (certainly in the case of Newburgh and Marsh) those with juvenile-onset, or type 1 diabetes, prior to the introduction of insulin, resulted in no cases of DKA developing. Newburgh and Marsh also reported DKA developing in a fasting case, so the inhibition of DKA was not a result of carbohydrate restriction alone.
DKA is the result of the unrestrained action of glucagon, which stimulates lipolysis and proteolysis, flooding the liver with substrates for ketogenesis (fat and ketogenic amino acids) and gluconeogenesis (glycerol and glucogenic amino acids), in the absence of insulin. Glucose, in the absence of insulin, is also a glucogenic substrate and increases both glucagon release and hepatic gluconeogenesis. The combination of hyperglycaemia and hyperketonaemia that ensues produces a loss of fluid volume and a life-threatening acidosis.
How might feeding fat prevent this?

Raphi Sirt, in response to my restatement of this question recently, tweeted a paper that cited another paper referring to a 1970’s experiment in which people with insulin-dependent diabetes were withdrawn off insulin and given a peptide called somatostatin by researchers happily free from modern ethics committee constraints.[3] This hormone prevented DKA by inhibiting glucagon release from the pancreatic alpha-cells. Somatostatin exists in two main forms in human metabolism, as 14 and 28 length peptides, and somatostatin 28 is released from the delta cells of the gut and pancreas proportionately in response to the ingestion of fat; there is a partial response to protein and no response to carbohydrate, making the somatostatin 28 ratio of macronutrients the inverse of the insulin ratio.[4]
In normal metabolism somatostatin inhibits both insulin and glucagon release. It is probably responsible for mediating the slower digestive response needed when fat is consumed in a meal. But if you have no insulin to begin with, somatostatin is just a glucagon inhibitor. If you have too much insulin and low insulin sensitivity (and hence too much hepatic glucagon activity) it’s probably helpful too, as long as you aren’t also eating carbohydrate.

Unusually I could not find full-text version of references 3 and 4, so there are still some very unanswered questions. Did Gerich et al. know of the findings of Newburgh and Marsh in designing their experiment? What was the form of somatostatin they used? And, did the serum concentrations of somatostatin approximate those that might be attained with high fat feeding? If not, does the paracrine release of somatostatin 28 that inhibits glucagon necessarily result in such high serum levels?
All your help, as always, is appreciated.

[Update 23-05-15] The somatostatin that prevents DKA in the Gerich study is somatostatin 14, whereas that which is elevated by dietary fat is somatostatin 28. How might this work? Somatostatin 14 has a higher affinity for the distribution of receptors on alpha cells, somatostatin 28 for that in beta cells. So in normal physiology somatostatin 28 is mainly inhibiting insulin, more so than glucagon. However, in physiology without functioning beta cells, the weaker effect on alpha cells is all that there is, and somatostatin 28 is inhibiting glucagon.

[1] Further observations on the use of a high fat diet in diabetes mellitus. Newburgh LH and Marsh PL. Archives of Internal Medicine April 1923 Vol. 31 No. 4.

[2] Über Eiweissbeschränkung in der Behandlung des Diabetes gravis, Petren K, 1923 - On protein restriction in the treatment of diabetes gravis. Cited in: A Substance in Animal Tissues which stimulates Ketone-Body Excretion, Stewart FB and Young HG, Nature 1952; 170, 976 - 977 doi:10.1038/170976b0

[3] Prevention of Human Diabetic Ketoacidosis by Somatostatin — Evidence for an Essential Role of Glucagon. Gerich JE, Lorenzi M, Bier DM et al. N Engl J Med 1975; 292:985-989. DOI: 10.1056/NEJM197505082921901

[4] Effect of ingested carbohydrate, fat, and protein on the release of somatostatin-28 in humans. Ensinck JW, Vogel RE, Laschansky EC, Francis BH. Gastroenterology 1990 Mar;98(3):633-8


Passthecream said...

Dear George,

you continue to educate us amazingly!

This sentence above caught my eye:

"Glucose, in the absence of insulin, is also a glucogenic substrate and increases both glucagon release and hepatic gluconeogenesis."

Could you expand on that a little?


George Henderson said...

The references to this are in the posts labelled "diabetes question 1-5" in the right bar. The idea that hyperglycaemia increases hepatic GNG is in #3, that glucose elevates glucagon in the absence of insulin is in #2.

So there are two sides to this - carbohydrate elevates glucagon release and also elevates GNG non-hormonally in the absence of insulin, decreasing GNG also puts the brakes on ketogenesis, and fat decreases glucagon release.

That's how it looks at present, and it's consistent with both the pre-insulin clinical research, and also the animal experiments of the 30s and 40s where feeding fat normalised the metabolism of animals without a pancreas.

George Henderson said...

The synthetic somatostatin used in the experiment was "un tetradecapeptide" hence the 14-residue version, not the 28-residue peptide released in response to fat. Are they interchangeable when it comes to paracrine glucagon regulation? This is the explanation consistent with the clinical facts, but case not closed yet obviously!

Ash Simmonds said...

I can't find a full-text for #4 either, but #3 is here (PDF). They don't reference the others you mention.

George Henderson said...

Thanks Ash!

1 and 2 are, of course, referenced in the Principia Ketogenica, but they are also referenced, with a lot of other interesting stuff, here

Passthecream said...

Thanks, George, Ash,

it is difficult to get your head aorund the way the various hormones and substrates interact and I am struggling with it. In paper #3 there are two things worth commenting. One is that obviously since the subjects were lacking endogenous insulin then the typical insulin + glucose response to meat or dairy would be faulty and it almost seems like a perfect adpatation that fat should also stimulate somatostatin in turn suppressing glucagon. But maybe it is harder to unravel this when the normal responses obtain, or when insulin+glucagon+somatostatin are stimulated by intake but insulin resistance prevails. Which leads to my second comment - fig6 in paper #3 is the sort of operational diagram which, together with some real reaction constants, time delays and further elaboration, is likely to lead to a better understanding of these processes. I don't think you can do it by mental arithmetic!


George Henderson said...

You might appreciate this detailed overview of diabetes and glyceamic control systems by Raphi Sirt.

Passthecream said...

Another interesting writer!

Seemingly the endogenous somatostatin is not very strongly generated in the GI system, well, not compared to receiving it in the doses that these subjects did. Plus it has many other effects. As always, the situation is more complicated by


which may explain the gastric slowing you mention above,


On the subject of modelling, this next link is the simplest possible insulin/glucose simulation, trivial but nonetheless clearly showing some dynamical effects that you wouldn't understand from thinking about how the individual components behave:

add in a few more hormonal/substrate/locus interactions and this really starts to get somewhere:

and this one very complex:


George Henderson said...

Thanks for those links - I hope I get time to read them soon!

My understanding of how somatostatin and other glucagon-inhibiting hormones work is that they are released from endocrine cells (delta pancreatic cells as well as gut cells in the case of somatostatin 28) and act on nearby alpha cells at a much higher concentration, and on hepatocytes at higher concentrations, than those seen in serum - this first is the paracrine action, similar to that of insulin, which is present in pancreas at high concentrations, in liver at medium concentrations, and in serum at a low concentration, the insulin sensitivity of each target (alpha cells, hepatocytes, muscle) being relative to the usual concentration of insulin.

George Henderson said...

Here's an interesting footnote to this post - a 1978 paper by Philip Raskin and Roger Unger where somatostatin is used to suppress glucagon in diabetics on a ketogenic diet plus insulin.

Michal said...

Just a note to congratulate you on your excellent remarks regarding historical background of the role of glucagon in ketogenic diet. Recent evidence suggest that FGF21 may also play important role (see more in my presentation on the mechanisms of nutritional ketosis, unfortunately in Slovak language)

Michal said...

Here is another intersting study. The authors conclude that the their data are not in keeping with a significant role for intraislet S-14 in B cell regulation. By contrast, they believe that they provide compelling evidence that during the postprandial period, S-28 released from the gut into the circulation in response to luminal nutrients inhibits the islet B cell and, as a participant in the enteroinsular axis, provides a regulated attenuation of insulin release.

Excerpted from:

George Henderson said...

Thanks Michal.

I found this Roger Unger study which distinguishes effects of somatostatin between non-diabetic (suppresses insulin and glucagon) and diabetic (suppresses glucagon and glucose) dogs.

'Linear somatostatin, a gift of Dr. Roger Guillemin, Salk
Institute, La Jolla, Calif., was employed in all experiments
in nondiabetic dogs. Cyclic somatostatin, a gift of Dr.
Romano DeGenghi, Ayerst Company, Montreal, Canada,
was used in all experiments in diabetic dogs.

Linear is reduced, cyclic is oxidised somatostatin. Exact sort I'm not sure.

George Henderson said...

Hey Michal, I hope you're following this comment thread - it looks like you're on the money with the FGF21.
This does present another insulin-independent pathway for limiting lipolysis and thus ketogenesis on a keto diet.
When you don't eat carbs and limit protein, the regulation of metabolism seems to move away from the insulin dependent model, to some (unknown) extent.