How a high fat ketogenic diet prevents diabetic ketoacidosis – somatostatin
|Karl Petren 1868-1927|
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 and Karl Petren 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with insulin-dependent diabetes were withdrawn off insulin and given a peptide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.
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.
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.
 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.
 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 -
 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:
 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
In 1977, when I was 19, and shortly before I cut my hair and joined a punk group, I worked as an apple picker in Upper Moutere, near Mapua, in the Tasman district of New Zealand.
The orchard was an eerie pace - no insects, no weeds, it even seemed that birds didn't fly over it, they certainly never ate the fruit. The fruit we picked had a white film on it. One of the guys I worked with drove the spray tractor, and he complained that he was loosing his vision due to the effects of the spray. None of us had protective gear. Our fires at night, fueled with cut-down apple trees, smelled like burning tyres. The factory that made some chemicals, including DDT, DDD, and which processed others, including 2,4,5-T and 2,4-D, was only 8 kilometres away, as the crow flies. Crows were probably the only thing that flew there.
There is a short report on this factory here. You can see that environmental standards were non-existent in New Zealand during the heyday of the persistent organochlorine pesticides and herbicides, which were used on the food everyone ate. Those who lived near or worked on farms were exposed to the highest levels, and urban workers were not exempt because PCBs were used in multiple industries and very similar organochlorine chemicals were added to petrol as "anti-knock" agents (they were, and probably still are, used in proprietary formulations such as STP).
My boss was a fit and hard-working guy, a non-smoker, who looked to be about 50. He was completely positive about the pesticides; it was as if he had a death-wish, or even an addiction. If Apocalypse Now had been released back then, I can imagine him saying "I love the smell of Dieldrin in the morning!" on a daily basis. I always assumed he sprayed Dieldrin for insects, because DDT was becoming less popular by 1977, even in New Zealand. He used to stand in the orchard while we worked and sneeze, loudly and often. He'd tell us how good sneezing made him feel - "like an orgasm!" - as he stood there in his shorts and plaid shirt, braced with his hands to his sides, like a jolly scoutmaster.
I only worked there for a month or so, but shortly after I left I had problems with recurrent flus, chronic fatigue, and headaches that lasted a long time. After a year or two I got word that my employer had died of a heart attack.
It never occurred to me for a moment that the butter in his diet had killed him. Obviously his blithe disregard for the dangers inherent in pesticide use had done him in.
Here is the NZ graph for mortality trends in CHD among people in their 50s. This is the historical ecological data cited by epidemiologists like Rod Jackson to make the case against saturated fat.
Saturated fat consumption in NZ increased between 1950 and 1970, but saturated fat consumption was always high - the increase did not represent a huge spike, and besides atherosclerosis is supposed to take 20 years or more. And women also ate more saturated fat - we are talking about the end of rationing and a new prosperity - yet the spike in CHD for women is minute - and this was the period when women started smoking in greater numbers. Sugar consumption skyrocketed at the end of rationing in 1950, polyunsaturated fats (and vitamin E) began to increase during the 1970's, selenium began to increase during the 1980's. I remember that women in the 1960's and 1970's often avoided sugar - saccharine and other artificial sweeteners were popular products specifically marketed to women in those days.
Meanwhile there was a growing awareness of the dangers of persistent pesticide use, the dangers of smoking, and the dangers of air pollution. New Zealand, despite its socialist politics, was completely dependent on primary industry - agriculture and manufacturing. The tourism and film industries, which benefit from pristine natural reputation, were insignificant. Not to put too fine a point on it, the situation was a messy scandal which few people want to go near even today. Proper records were not kept, guidelines were not followed, laws were ignored. It was only cleaned up slowly by a combination of a groundswell of increasing "green" criticism, the exposure of the Agent Orange scandal in South East Asia (involving the same chemicals we used for agricultural weed control in New Zealand) and, perhaps more important than any other factor, the rise of Monsanto, who had new and less persistent toxins to sell, and were actually in a position to convince the die-hards that the old poisons needed replacing.
All this would be moot if there was no evidence that organochlorines cause atherosclerosis. However, it is quite clear that they do.
This lovely document came out last year:
Chemical Atherogenesis: Role of Endogenous and Exogenous Poisons in Disease Development. Ross MK, Matthews AT, Mangum LC. Toxics 2014, 2(1), 17-34; doi:10.3390/toxics2010017
Chemical atherogenesis is an emerging field that describes how environmental pollutants and endogenous toxins perturb critical pathways that regulate lipid metabolism and inflammation, thus injuring cells found within the vessel wall. Despite growing awareness of the role of environmental pollutants in the development of cardiovascular disease, the field of chemical atherogenesis can broadly include both exogenous and endogenous poisons and the study of molecular, biochemical, and cellular pathways that become dysregulated during atherosclerosis. This integrated approach is logical because exogenous and endogenous toxins often share the same mechanism of toxicity. Chemical atherogenesis is a truly integrative discipline because it incorporates concepts from several different fields, including biochemistry, chemical biology, pharmacology, and toxicology. This review will provide an overview of this emerging research area, focusing on cellular and animal models of disease.
[N.B. the authors mention saturated fat as an endogenous atherogenic factor - not a dietary one. However their reference 18, cited to support this claim, a tasty review of ApoE knockout mouse research, doesn't really back it up - maybe because the experiments it cites rely on dietary fat, not endogenoous SFA].
So here we have the alternative hypothesis to explain the late 20th century rise and fall in CHD mortality. As cities and the countryside became more polluted, with particulate pollution, smoking, and organochlorines in agriculture and industry, which seeped into the food supply and home furnishings, heart disease rose. It rose significantly more in men because men - almost exclusively - worked in the industries, and at the automotive and electronic hobbies, that increased exposure to these pollutants the most. A few years after the publication of Silent Spring, as use of the most egregious pesticides lessened, it began to fall. As the rate of use, and the persistence of these chemicals fell further, CHD rates steadily dropped. The Clean Air Acts and improving Vehicle Emissions Standards of the 1970's-2000's, and the invention of the catalytic converter gradually reduced exposure to particulates and anti-knock additives, and lead was eliminated from petrol and paint. Better antioxidant and other micronutrition and the war against smoking also played an important role in its decline, and we can only hope that medicine was improving too, because some of the atherogenic chemicals were likely to have been drugs in common use - this is still a problem with SSRIs and antipsychotics today.
What is the role of sugar? Still not likely to be good. Not everyone had heart attacks from pollutant exposure; the dietary and hormonal drivers still operate. What about saturated fat?
This is likely to be bidirectional. Hence there is no association in prospective population studies. Saturated fat, when it increases LDL-cholesterol, is giving more hostages to fortune; but it is also less prone to oxidation than other lipids (though MUFA is no slouch in this regard), and it decreases gut permeability, reducing uptake of some swallowed atherogenic factors, and makes the liver less sensitive to toxins. Thus it can help some and harm others, so that the net effect is a wash-out at a population level. Maybe. A further factor is, that the atherogenic organochlorines were all lipid-soluble, and perhaps accumulated in animal fat (though the amount left on bought fruits and vegetables was sometimes visible to the naked eye), and at least one of the atherogenic factors, acrolein, is formed from the glycerol in burning fat - possibly helping to account for the differential CHD associations of meat SFA (always cooked, often burnt) vs. dairy SFA (usually eaten uncooked, and rarely burnt).
And this is my picture.