There are a couple of things I would just like to mention in passing. Jenny Ruhl has just posted a nice entry about ACCORD. This is very important. Lowering your blood glucose is significantly protective against CVD events. This is the exact opposite of the initial analysis of the results where a flawed interpretation of the data led to vociferous suggestions that lowering the HbA1c of diabetics might be actually dangerous. Hopefully this reanalysis will put an end to such stupid ideas which are still dangerously prevalent today.
Before Jenny posted the above I had been thinking about both metformin and insulin for the management of diabetes. I have posted on insulin, which is probably the ideal drug for diabetes management provided it is combined with low carbohydrate eating, in the past but it bears reiterating.
This is my opinion. If you can control your diabetes with metformin and wish to eat lots of carbohydrate, by all means get on with it, that's your choice. Not checking or not worrying about your blood glucose excursions might be a mistake. What you mean by good control might not involve HbA1c values in the 5% region or below.
If you need insulin to control your blood glucose, you have no choice. It's low carb. Live with it.
Some researchers (who write third rate papers using a rather inappropriate pancreatectomised dog model) are now starting to wake up to the fact that the pancreas secretes insulin in to the portal vein, not the subcutaneous tissues. In normal individuals insulin/glucose arrives at the liver via the portal vein and insulin facilitates transport of the glucose in to the liver, being metabolised in the process. Relatively little post pranial insulin or glucose penetrates to the peripheral circulation in a normal individual.
EDIT: Gretchen has kindly pointed out that the liver uptakes glucose through GLUT2, not GLUT4. The function of insulin, acting on its receptor (facilitating its degradation), is to suppress gluconeogenesis and hepatic glucose output. This is the correct function of the elevated portal insulin level. It makes no difference to the issues with peripheral vs portal insulin, but the correction is welcome. END EDIT
Once a person needs insulin to control their blood sugar levels they inject it subcutaneously. This will invariably elevate the systemic concentration of insulin. It will only modestly elevate the portal vein level. This is very important.
In the cited paper the dogs get a meal with 50% of calories from carbohydrate, 30% from fat and 20% from protein. In control dogs, instrumented but not pancreatectomised, the portal vein insulin after the meal is, at certain time points, ten times the peripheral systemic concentration. This is what is needed to allow the liver deal with the glucose load from the meal while simultaneously protecting the body from both hyperglycaemia and hyperinsulinaemia.
Subcutaneous insulin will make the rest of the body do the liver's job of clearing post prandial glucose, the liver can't manage because it never sees the requisite ten times the normal peripheral insulin concentration needed to deal effectively with the portal glucose load.
What happens when you use the rest of the body as a glucose sump? From the paper:
"Peripheral hyperinsulinemia is associated not only with increased risk of hypoglycemia, but also an increase in catechol and cortisol secretion and lipolysis , deleterious effects on vessel walls , ischemic heart disease, hypertension and hyperlipidemia , and abnormalities in hemostasis "
As always, I would add that it's the obese, blind, legless person in the queue for dialysis who pays the bill for eating the carbohydrate.
This is the situation for all type I diabetics and the more advanced type 2 diabetics. The only route round it is to use intra peritoneal insulin which is, in part, absorbed through the mesenteric veins so is partially portal vein selective. There are, needless to say, a stack of complications to intra peritoneal insulin infusion. Tight control of glucose using subcutaneous insulin from a blood glucose controlled pump is no solution. Though glycaemia is better controlled it is still at the cost of too little insulin in the portal vein and too much in the periphery, using the body as a glucose sump. Over the years I have never been quite able to decide whether hyperinsulinaemia or hyperglycaemia is the primary factor which kills nerves and kidneys. It's a difficult call. And a fascinating discussion in its own right.
What happens if you eat a diet very low in starch?
Very little insulin is ever secreted by the pancreas, especially as glucokinase down regulates. Very little glucose ever needs to be taken up by the liver. Very little insulin will be metabolised by the liver. The insulin gradient between the portal vein and the systemic circulation will be as low as you can practically get it. If someone still needs to inject insulin alongside a very low carbohydrate diet, and many might not, injecting a very small amount subcutaneously will deliver an arterial concentration to the gut, pancreas and eventually to the portal vein and liver which is still quite close to what the portal vein might have supplied. If the body is not using insulin the tissues will not extract it, so portal and systemic concentrations will converge. Everything pans out at some near basal level.
A very low carbohydrate diet is not perfect for insulin dependent diabetics but it is streets ahead of anything else. What people do or do not consider a "normal" human diet will not get around this. Need exogenous insulin? You are not in a position to eat ancestral starch. It's a simple matter of anatomy, physiology and biochemistry.
Thursday, December 04, 2014
ACCORD and musings on insulin
Posted by Peter at Thursday, December 04, 2014
Labels: ACCORD and musings on insulin
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Peter, what are your thoughts on the glucagonocentric view on the etiology of diabetes as long proposed by Unger?
Long before diabetes becomes manifest, the alfa cells lose some of their paracrine (listening to insulin) and autocrine (listening to their own glucagon and shut up). Without an inappropiate glucagon signal no diabetes, even absent insulin. Do you have any idea what might underlie the alfa cell dysfunction?
You have addressed (and dismissed) this study, if memory serves.
One thing strikes me now. Long term ketogenesis reduces alpha cell mass in proportion to beta cell mass. From a glucagonocentric point of view this would be a positive.
I meant paracrine/autocrine function, in my first reaction.
"Relatively little insulin or glucose penetrates to the peripheral circulation in a normal individual."
Just to be mildly pedantic, I have mentally added 'priandial' before insulin and glucose in this sentence, in order to explain it to myself.
At last, a study vindicating the Bernstein position.
PS prandial NOT priandial!!
Circadian mismatches destroy alpha cells by not allowing them to get to autophagy and facilitate the pathway to apoptosis as lipofuscin accumulates which is like remnants of poorly digested mitochondria.
"Some researchers (who write third rate papers using a rather inappropriate pancreatectomised dog model) are now starting to wake up to the fact that the pancreas secretes insulin in to the portal vein, not the subcutaneous tissues. In normal individuals insulin/glucose arrives at the liver via the portal vein and insulin facilitates transport of the glucose in to the liver, being metabolised in the process. Relatively little insulin or glucose penetrates to the peripheral circulation in a normal individual."
I LOVE learning something new every day. Less wrong than yesterday!
OK, so on the surface, before digging deeper, a pancreas is not the same as a brain, meter, hormone in a bottle and needle that's not long enough to inject into the portal vein. Or, a continuous glucose-monitoring insulin pump.
Of this, I have no doubt. However, I'll have to do my own Googling to determine how important the distinction is. Distinctions are so important that one must be on constant guard for those distinctions that make no essential difference.
My best anecdote is my mid-80's father in law.
Here's another with his daughters, plus a bonus pic with me an J Stanton (blow the fold).
T2 for over 50 years. Managed by meter and metformin/glucophage until the last few years where he has to shoot sometimes.
But he's never been overweight. This is probably important. But I'm not sure why.
But, he eats a pretty regularly balanced macro diet. On the other hand, his Mexican heritage is such that he prefers real, homemade food and his wife takes pride in such preparation (we were just down there for the week).
This sort of thing I doubt is unique, also, has to be integrated if one's goal is better understanding.
We'll never know, but sometimes I wonder if there were hundreds of millions of people throughout history who lived full lives into 70s and 80s, and never got a diagnosis of diabetes, but were nonetheless diabetic (T2) by today's standards. Speculative, and we can never know, so weight is what it is which isn't much. But, sugar for thought nonetheless.
I'm happy that someone is bringing this up. As a T1D on a pump my goal is to use as little insulin as possible. For me that's 20-25U per day, which is probably double what I'd guess I'd need if it wasn't administered peripherally.
The darned catch to the situation is that as my body has adapted to very low carb (usually <30g/day), my insulin to carb ratio has devolved from being very insulin sensitive at 40g:1U to now only 8g:1U. This pigeon holes me a bit into this strategy, but it's the best option I've got.
Melchior, I think glucagon is very important, especially following protein ingestion. With a lack of insulin unopposed glucagon will push glucose from the liver in to the systemic circulation. This became abundantly clear in my early days of treating diabetic dogs where a protein meal spikes glucose immediately and severely. Insulin/glucagon cross talk is clearly very important. There were papers supportive of Unger’s view on Dr B’s forum about 10 years ago. I guess they still apply.
I think I may have the full text of the mouse paper on the hard drive of my last Mac but I have to say I would be rather cautious about eating the sorts of levels of omega 6 PUFA some ketogenic mice routine eat. I think hepatic inflammation was the problem I’d noted in other ketogenic mouse studies.
Leon, agree. Added “post prandial”.
Richard, people can eat as much starch as they like. But not my choice.
Kory, that’s a bummer. It’s interesting to look at the glucose intolerance of starvation and tease it apart in to a a failure of insulin secretion due to glucokinase down regulation (a big effect, but irrelevant to a pump derived insulin system) and the much smaller effect on insulin responsiveness. Peak suppression of blood glucose by exogenous insulin is delayed by about half an hour but is of similar magnitude. From http://www.ncbi.nlm.nih.gov/pubmed/5056667. Bear in mind that the people pre-starvation may well have been insulin resistant secondary to elevated FFAs due to adipocyte FFA release due to insulin resistance and the deep starvation state due to even higher but more physiologically normal starvation FFAs. Comparing a lean individual pre and post fasting might show more difference, which might well be where you have moved from and to… You also do have to wonder about insulin induced insulin resistance and failure to suppress glucagon as possible contributors to the increased glucose requirement per gm of glucose.
"The darned catch to the situation is that as my body has adapted to very low carb (usually <30g/day), my insulin to carb ratio has devolved from being very insulin sensitive at 40g:1U to now only 8g:1U. This pigeon holes me a bit into this strategy, but it's the best option I've got."
Way back, when I was advocating for VLC Paleo, I began noting my own elevated BG, and getting emails, even from family, with sudden elevated fasting BG (115-125 pretty common). It was around that time Peter blogged about physiological insulting resistance.
Having an explanation is comforting. But, why? So, if not VLC, you're diabetic or near, but if VLC, and even otherwise perfectly healthy, it's A-OK?
Smells funny to me. And again, can't help thinking about the couch potato that can't exercise because it makes his heart race.
This may not apply to the special case of a diabetic, especially T1 (best option you got is a reasonable judgment), but for me, wife, and other family, beans have returned all of us to normal fasting BG. No weight gain and in fact, weight loss in most cases.
Fartage ameliorates over time, just like heat rates go down with exercise.
"Richard, people can eat as much starch as they like. But not my choice."
Mine either. I find 150ish carbs (in total, including a few ounces of OJ on a typical day) to be a pretty decent zone. I don't get comatose, have great energy, warm fingers and toes, fasting BG in the 90s instead of 105-115 for years, no weight gain, etc.
I additionally take comfort in the fact that I'm likely eating pretty non-obsessively again, with no downside noted.
“Having an explanation is comforting. But, why? So, if not VLC, you're diabetic or near, but if VLC, and even otherwise perfectly healthy, it's A-OK?
Smells funny to me…”
Perhaps, it shouldn’t.
From what I’ve read it’s glucose levels over 140 mg/dl that cause damage. It’s not the fasting blood glucose (FBG) in the 100-120 range that does the damage. FBG is just a cheap and easy measurement.
For people eating normal amounts of carbs, a FBG in the 100-120 range indicates that glucose levels 1 hour after a meal are likely to be over 140, and causing damage. Maybe, at the lower levels of the FGB 100-120 range, it’s simply and indicator that someone eating a normal amount of carbs is heading toward trouble.
For someone on a VLC /ketogenic diet, it’s unlikely that their glucose levels 1 hour after a meal will be > 140, even if FBG is in the 100-120 range… Of course, the only way to really know is to do the measurements 1 hour after eating.
My husband of 23 years would develop painful foot ulcers mostly on the ankle every few years or so. We chalked it up to his poor circulation and family blood clotting problems. A teeny tiny ulcer the size of a pencil point is very painful.
I started to see a pattern eventually. Hmmm. Why is this always occurring after the holidays.
Flash forward vlc. 30 grams or less. No foot ulcers. My husband runs high FBG numbers. Between 103 and 115. We fretted over this
tested and tweaked his diet. We finally gave
up and let his feet be the guide. As long as he avoids the spikes in BG his feet are healthy and he can put in the long hours outside on our ranch like he loves.
I am the complete opposite of him. Extremely low FBG. Low 70s usually. Very good numbers. Failed a glucose tolerance test miserably. He actually did better than me. So tell me what that means. I don't know. We never test anymore. We just eat vlc and avoid the big spikes. Seems to be working well for us.
Oh and all our senior equines are on Safe Choice low starch low sugar feed.
I think a vet just trumped the doctors here.
You've really opened the portal.
Thought I would clarify our GTTs were done before VLC. I was eating a healthy well rounded diet:-) and spending hours at the gym. 75 gram bolus and 200 after 2 hours. With excellent FBG.
Will never take that test again. Have no desire to tolerate 75 grams of glucose straight into the blood.
You might enjoy this snippet I got via email from Kelly. There is an ongoing trial in Texas using exogenous leptin to supplement insulin for unstable type 1 diabetics. Central leptin is a suppressor of excess glucagon from alpha cells. Sigh. I really do need to do more reading on leptin.
From the trial blurb, see the bit about glucagon
“The adipocyte hormone, leptin, has been shown to restore the health and glucoregulation of near-death, insulin deficient diabetic rodents. This makes leptin the only hormone, since the discovery of insulin in 1922, with this capability. Leptin normalizes the hyperglucagonemia of diabetes and reduces lipogenesis and cholesterologenenesis. Treatment of diabetic rodents with a combination of leptin and insulin, leads to a stable pattern of glucose control with reduced insulin requirements, as opposed to the high glucose variability that characterizes the treatment of type 1 diabetes with supraphysiologic doses of insulin alone”
Of course they are not looking at ketogenic low dose insulin treated mice. But the information on central leptin signalling looks depressingly important!
Bea, I have a long thought train about what exactly we mean by hyperglycaemia, how important insulin is under conditions where glucose is "elevated", how this all fits in to the Crabtree effect which does look to be what kills nerve cells, especially non myelinated nerve cells. 140-150mg/dl as a spike does seem to be some sort of threshold...
@Melch - Talk of insulin without glucagon considered is hugely misleading, and I reckon there's at least one more biomarker we haven't discovered or nailed down yet which also needs to be taken into account for a proper aspect. Yet over and over again the arguments are about insulin alone.
It's about as useful as measuring the speed I'm travelling in a Lamborghini against the centre of the universe and ignoring the relative speed I'm *measurably* going on this spinning ball of dirt and thick air.
indeed very interesting this, and I do wonder how it fits in with the idea of obese/diabetic people having increased glucose transporters in the duodenum and this facilitating too rapid absorption of glucose into the portal vein?
hyperinsulinemia due to zerging of glucose from the intestine anyone?
rate of absorption of food products from the intestine is clearly a very under-appreciated variable.
"rate of absorption of food products from the intestine is clearly a very under-appreciated variable."
Likely the primary reason gastric bypass surgery cures T2D instantly.
...Also why beans are unlike all other carbs in terms of glycemic response and even blunt spikes hours after for other, fast digesting carbs consumed.
In my inbox this morning:
Furiously elegant, this makes me think fondly of a pal who died a few years ago of nasty T2D sequelae. Sure seemed as though sugar, insulin injections, and body as glucose sump duked it out to the painful end.
My friend would have appreciated this post.
Excellent as always Peter...
If I have not learned something new each day I always visit you blog to see what else I can learn...
As a research guy myself I am now wondering about abdominal injections vs. my usual subcutaneous in fat around the middle. The issue however is one of control.
One can always inject IM if you have an OMG! spike after eating out from the occult carbs in restaurant food. The issue is your BG will drop very very rapidly and perhaps unpredictably after eons of subcutaneous injecting. Perhaps into dangerous hypoglycemia levels.
Keep on posting!
Thanks yet again Peter for concise and comprehensible intperpretations of various evidence.
Peter: "This is my opinion. If you can control your diabetes with metformin and wish to eat lots of carbohydrate, by all means get on with it, that's your choice. Not checking or not worrying about your blood glucose excursions might be a mistake. What you mean by good control might not involve HbA1c values in the 5% region or below."
At the age of 60 I have been 'officially' T2d for about 10 years now, and at first the combination of metformin and low GI eating seemed to be keeping it under control. The amount of metformin required crept up over time tho', to 4x the original dose. However in the last 14 months eliminating pufa, lowering carbs to Lutz type levels and restoring saturated fats to their rightful position in my diet has taken my hbA1c down to ~5% from 7.5 a year ago and dropped my TAG to 50% of its long term stable value. Cholesterol is now ticking along nicely at 5.5, I thought it too low before. Sometimes my FBG is 6mmol or so in the mornings but it doesn't get much higher during the day and sometimes is lower. I can't list all of the other physical changes that LC eating led to but some of them were quite surprising, 'features' which I had taken for granted since I was a teenager such as thin fingernails---surprising until I read some of your posts on starch vs. immune system. Now I am trying to work out whether to phase out the Metf. or not ???
The dynamics of metformin vs diet is hard to get a grip on, as are those of all of these hormones and their interactions. I recall a paper in the area of system dynamics which concluded that humans are very poor at making accurate predictions about complex interactive systems
whereas even simple software models can be quite informative. Here are a few links to typical
but I'm not too sure about some of the assumptions. It would be interesting to do some of that modelling with a more Hyperlipid-oriented outlook.
@Kory did you progress from 40 to 8 grams CHO per IU while on 30g of carbs, or does the 40 relate to former higher CHO intakes ?
How about lowering your glycogen stores to always not full by excercise?
While ancestral starches are the more acceptable compromise for a general population, or at least not a fattening food, than most modern versions, they don't prevent members of the population from modern deceases, especially as people age. Also, it looks like a not-diabetic person has to make a pick, what to eat liberally without damaging own health, fats or starches. When people are not young any longer , they rarely can do both.
I suggest that how much, and what kinds, of fiber one can safely eat is a matter between you and your blood sugar meter. One can theorize as one will, but the meter says what the meter says. Inulin and fructo-oligosaccharides are not metabolized in the upper gut, but by your gut bacteria. They are not turned into sugar, but into butyrate.
Peter, I'm not sure your EDIT takes care of everything.
'EDIT: Gretchen has kindly pointed out that the liver uptakes glucose through GLUT2, not GLUT4. The function of insulin, acting on its receptor (facilitating its degradation), is to suppress gluconeogenesis and hepatic glucose output. This is the correct function of the elevated portal insulin level. It makes no difference to the issues with peripheral vs portal insulin, but the correction is welcome. END EDIT'
Here's what you say later on.
'Subcutaneous insulin will make the rest of the body do the liver's job of clearing post prandial glucose, the liver can't manage because it never sees the requisite ten times the normal peripheral insulin concentration needed to deal effectively with the portal glucose load.'
This seems to contradict your EDIT. Continuing:
'What happens when you use the rest of the body as a glucose sump? From the paper:
"Peripheral hyperinsulinemia is associated not only with increased risk of hypoglycemia, but also an increase in catechol and cortisol secretion and lipolysis , deleterious effects on vessel walls , ischemic heart disease, hypertension and hyperlipidemia , and abnormalities in hemostasis "'
Since the liver does not have the insulin/GLUT4 glucose disposal mechanism, 'using the rest of the body as a glucose sump' would seem to be normal physiology.
Hyperinsulinemia is of course associated with a lot of bad stuff, but it's also associated with magnesium deficiency. Perhaps the magnesium deficiency is to blame? Perhaps it's refined carbs that are the problem?
I know i'm super late to the party but this was a fantastic post peter, as have all your posts lately.
Your post conjures up images of my late grandmother injecting insulin on her stomach and legs. I was already furious with her doctors for the standard shitty advice given and now I have yet another reason. Sad.
HbA1c has been criticized for failing to show the peaks and valleys, while providing a potentially misleading average. According to some, the average is less useful than the roller coaster ride - what say you?
[to my mind, HbA1c has its limitations but isn't a 'bad' measure as some have called it]
"...people can eat as much starch as they like."
Well I hope they are FREE to do that - but if the result is elevated BG over time I think you these people will have more health problems and higher cancer rates.
It has only been in the last 5000 years that man has started eating lots of monocotyledons - and today’s monocots have been selected for large carbohydrate content.
Some of the starch is already converted to sugar by the time it get to the stomach.
Cancer cells rely on glycosis and an environment of high BG improves the odds of the cancer out growing ones immune system.
There is observation data -
Nutrition and Health – The Association between Eating Behavior and Various Health Parameters: A Matched Sample Study
That makes me question that eating starches is risk free. ( quality of life appears to be an issue as well. )
I'm not a paleo nut myself (I want to eat better than early man) - but there are a few points I find interesting - a lot of primitive tribes eat a lot of bugs - high in protein - low in starch. As we have moved away from eating bugs and towards eating monocots I don't think evolution has had time to re-tweak the balance.
An interesting ted talk: "What Veterinarians know that Physicians Don't"
Thank you, that was very helpful to understand that FBG is just a short hand that only works for people on high carbs and not an end goal to get as low to 84 as possible for longevity as an article at lef.org suggests.
As a matter of fact, the glucagon paper that Melchoir linked at the start of this thread says that insulin does increase liver uptake of glucose; there would presumably be upstream effects of increased glygogenolysis and DNL that would account for this, for example by upregulating Glut2 production.
Hi Peter, I'm the classic regular reader first time poster generally looking to expand my knowledge to inform my own diet but a very recent trip to the vet has revealed pancreatitis in my dog.
Given your background, my first inclination was to see if you had written anything related to this as my basic understanding of a keto based diet would suggest it may be useful with pancreas based afflictions but that would seem contrary to the advice I'm receiving (not dissimilar to human nutrition, but I'm willing to experiment on myself more than I am to do the same with my beloved pet).
Are you aware of any issues with attempting to put my dog on a keto diet in this situation?
Thanks for any information you can provide in addition to the already amazing blog!
For example, insulin stimulates TG synthesis, DNL, and glycogenolysis.
If the liver sans insulin is taking up the exact same amount of glucose as it does with insulin, what the heck is happening to it all?
A Randomized Cross-Over Trial of the Postprandial
Effects of Three Different Diets in Patients with Type 2
See Figure 2. Effects of three different diets on glucose, insulin, triglycerides and glucose-dependent insulinotropic-polypeptide (GIP)
Regarding the primary factors from hyperinsulinaemia and hyperglycaemia.
Area under the curve levels - versus- peak value levels per 24h cycle?
"Acute nutritional ketosis: implications for exercise performance and metabolism"
Also these glucose-sensitive enterocytes are good at DNL and making TGs. TG spikes after high-carb feeding relate to enterocytes as much as hepatocytes.
Glucagon is released from gastric cells first, this might account for T2D benefits of gastric surgery.
Sorry everyone, no time for the blog recently! Matt, this is complex and would make a good post if I thought I had any answers. The problem is that no one would even consider a ketogenic or near ketogenic diet for pancreatitis, though intrinsically this may be therapeutic in the same way it is for fatty liver and its progression to NASH. As part of a multi vet practice I have used protein fat diets for diabetes and all that happens is that when they have a problem when I'm not on call, they get a positive pancreatic lipase (many dogs get diabetes as a late stage of undiagnosed chronic pancreatitis) and get referred to a specialist as an unstable diabetic with pancreatitis and always come back on a low fat diet and permanent unstable control of their diabetes. It's very frustrating and potentially legally dangerous. Sadly there are limits to what you can do in practice.
Out of interest, humans chronic pancreatitis is related to recreational fructose and alcohol use, much as cirrhosis of the liver is. Dogs don't do this and my main suspect is omega 6 PUFA. Dog food labels rarely give a fatty acid breakdown and liver problems are very, very common from middle age onwards in dogs, as are pancreatic problems. Biopsy is usually very non specific inflammatory disease in both organs...
@ Kory Seder
I am in the same boat as you. In fact I used LCHF to treat myself while misdiagnosed as type 2 :(
You might want to look at adding in some carb eating windows ... separate from fatty foods ... IM injections or inhalable insulin to match fast carbs. ( I can use IM with quick carbs to have a more predictable application of the carb feeding) Short window of carb/insulin spike, frequency and carb levels would need to be determined.
I see it as a targeted cyclical keto approach... try to keep the glucose sparing from going into full effect but be in keto as much as possible. For me doing carbs in the morning when I have nothing to do works best.
It could be an experiment to see if you can regain your insulin sensitivity with minimal glucose surges. It is also assuming high circulating insulin levels for a few hours at a time a few days a week are not going to cause much issue (a question in itself).
As a side note I tend to match those days with heavier kettle bells sessions and try to derive some secondary benefit from it.
All that said I find being full on Keto or on the border of to be the easiest and most free of stress approach, which I keep going back to :)
Many well wishes!
I'm not young. Robert Unger wrote this, with Leonard Madison in the year I was born.
THE PHYSIOLOGIC SIGNIFICANCE OF THE SECRETION OF ENDOGENOUS INSULIN INTO THE PORTAL CIRCULATION. I. COMPARISON OF THE EFFECTS OF GLUCAGON-FREE INSULIN ADMINISTERED VIA THE PORTAL VEIN AND VIA A PERIPHERAL VEIN ON THE MAGNITUDE OF HYPOGLYCEMIA AND PERIPHERAL GLUCOSE UTILIZATION
He has published a new paper this year.
Peter and Melchior, thanks for opening my eyes to this great scientist. Everything in his work quietly screams low carb, there's even a metabolic ward diabetes diet study from 1988.
George and others, please, please watch this recent Rolf Luft lecture (May 2014) by this great man of science. I have listened to it three times now. Mind blowing stuff and really frightening that Unger has been more or less ignored. The current mainstream (insulinocentric) view on diabetes is an absolute joke.
Melchio, Unger's video is compelling. Now I have to look more into glucagon (alongside mTor).
Melchio, Unger's video is compelling. Now I have to look more into glucagon (alongside mTor).
Thanks for paying attention, Matt! And also thanks for reminding me of Godwin's law. I walked into the trap with my eyes wide open :-).
I have been following Unger for quite some time, but only recently (especially after reading Watve's Doves, Diplomats and Diabetes) the implications of his findings have really sunken in.
Periferal insulin resistance becomes a total non item. All that's needed for glucose homeostasis is the tiny, local, paracrine insulin signal and listening alpha cells.
Type 1 diabetics are really stuck between a rock and a hard place with the current treatment. Exogenous insulin therapy provides extremely supraphysiological periferal insulin concentrations, but still insufficient concentrations at the level of the alpha cells. You can never win that game. It is known that leptin shots shut down over secreting alpha cells very nicely, effecting excellent glucose control in type 1 (even without any insulin). Why don't we use this superior intervention? Must be a money question.
We also have to pay close attention to the delta cells. Somatostatin puts a brake on both beta and alpha cells, but it's effect on alpha cells seems to be bigger. Is somatostatin output impaired in type 2 diabetes?
There are many more burning questions. Type 1 diabetic mice do perfectly fine if you take away all their functioning glucagon receptors. No insulin needed at all. What would happen if we aborted glucagon in humans? Doesn't sound like a safe idea.
Maelan Fontes (ADILAN study, Lanzarote), has been hooked on Ungers work and the glucagonocentric view. His co worker Tommy Jönsson showed that wheat leads to an enhanced and prolonged postprandial glucagon response. In other words: bread and pasta are directly diabetogenic :-).
Quite right Melchior,
And Tommy Jönsson just published "Digested wheat gluten inhibits binding between leptin & its receptor" [in vitro] http://www.biomedcentral.com/content/pdf/s12858-015-0032-y.pdf
Riddle me this -
A high fat diet prevents ketoacidosis in type 1 diabetes sans insulin.
What is the mechanism? Insulin regulates ketones normally by suppressing glucagon (and norepinephrine?) and lipolysis.
Even starvation suppresses insulin enough to cause ketoacidosis.
Yet fat without insulin prevents it.
It's a mystery. Answers on a postcard please.
overall, running cells with energy from our own fat stores is a different process than doing so from dietary fat & protein. catabolic and repair processes as well as tissue-energy partitioning and behavioral adaptations are a snapshot of that.
Cells T1D "sans" insulin still incorporate & metabolize FAs, aminos, sugars in a non-insulin dependent manner (analogous to the different strategies for cellular endocytosis)...but this kinda sucks. I love me some insulin function. On one level, a LCHF diet is skewed towards the fundamentals (essential aminos & FAs) which in the context of no insulin function is less of a burden than handling non-essential sugars would be.
As for the exact transporters of FAs and aminos, I'm not too sure. But glucagon will play its role as a component of the liver responding to, for e.g., either a shortage of exogenous calories or just to an absence of sugars. Ketoacidosis isn't a normal 'response' to starvation but more of a predictable metabolic breakdown. For a dying cell their is no way but forward so uncontrolled ketone production is a last gasp of sorts.
George, I came across information that ketones are potent glucagon suppressors or antagonists. I will look up the link.
Excuse me George, I realize how stupid my answer was.
Ketones suppress glucagon, but apparently this doesn't happen in diabetic ketoacidosis. So there you have a situation in which ketones are sky high, but the alpha cells keep pouring out glucagon.
Fat prevents it. What a conundrum. Peter to the rescue :-).
Bite your tongue, Raphi.
Peter has discovered that there is absolutely no Yang to Insulin Yin.
Lots of people think he's brilliant about that.
I don't think that's true in the slightest.
Peter has attacked his own ideas, showing where they're incomplete. He dove into the specific mechanisms, giving others the opportunity to evaluate his claims fairly (if so inclined). He also distinguishes, clearly, between plausible conjecture and established (falsifiable) biochemistry. The majority of keyboard warriors do not.
Insulin also has its fingers in many pots, so context specific reductionism is appropriate and necessary to accurately characterize its actions. There are many things I don't understand about insulin and this blog has been great for deepening my understanding of it, by bouncing ideas off other genuinely curious people.
However, he is not Jesus. No saviours here.
Well, I used to think Peter was far more Poperian than I do now. I think I used to be far less.
Now, my sense is that Peter operates from a certain degree of certitude, seeking to be more and more right all the time, where I've gone 180 and seek only to be a little less wrong every day.
Or, more simply, there are too many megatons of high starches consumed by high longevity people over millennia worldwide than Peter can even begin to account for.
Falsification is falsification, and the cool thing about it is that it's the only time you can be absolutely certain.
Well Raphi, Anna comes close, but She has left us mere mortals in despair :-).
Richard, I don't exactly know what you mean, but in normal people there will always be some insulin signal. The lower the better, but unless you have no functioning beta cells it will be there. The largely ignored Charles Mobbs has proven beyond doubt that it is glycolysis itself which drives aging and underlies virtually all degenerative disease. We need a little of it, but the less the better. To run your metabolism predominantly on glycolysis - which is entirely substrate driven - is very unnatural. I can hardly dream up an eco niche in which it is possible to ingest the massive amounts of carbohydrates that most people today see as normal. Even orangutans in the rainforest spend 6 months of the year in ketosis (in deep ketosis if they happen to be female and pregnant). Ketones are important signaling molecules.
Please study Mobbs. Both (predominant) betaoxidation and (intermittent) ketosis seem to be required for health and longevity. He has some very good evidence for it.
On a side note, announcing the demise of the Ancestral Health Symposium is nothing more than wishful thinking. I am involved in organizing AHS Netherlands 2015 and I know how easy small things can ruin a plan. The evolutionary perspective on health and disease is not fading, it's getting more and more popular. It is not going away, as you predict. Why? Because it is logical and because it works. That is, if you stick to the basic principles :-).
"Or, more simply, there are too many megatons of high starches consumed by high longevity people over millennia worldwide than Peter can even begin to account for."
Peasants workings like slaves on an energy restricted regimen. Probably running predominantly on fat. And still suffering from neolithic diseases that are more or less absent in hunter gatherers.
“...there are too many megatons of high starches consumed by high longevity people over millennia worldwide…”
You are oversimplifying (somewhat understandably) but the gist of that comment has merit. I do think that the data from Papa New Guinea (the Tukisenta & Kitava) and New Zealand (Tokelau) should not be ignored. However, the ‘weight’ of that data has to be contrasted with other anthropological and epidemiological observations as well as the testable, replicable and falsifiable biochemistry. There are several important limitations to this data (or this kind of data) and the 5 I’ve listed aren’t exhaustive.
First and foremost, these high-starch populations are exceptions, not the norm, and the observations have rarely been checked multiple times (replicated). Secondly, the Kitavan diet (for e.g.) is based on self-reports and observations made by outsiders. This well known amongst anthropologists to only be marginally representative of what ‘normal’ might look like. Extrapolations are necessary but very risky, so we tend to not let too much ride on them.
Third, what you or I may call a tuber in a typical Western shop (e.g. plain old baked potato) has a strikingly different composition than a typical Hadza tuber which has little sugar and so much fiber it is often spat out after vigorous chewing. We’ve filled in a lot of data-gaps in these studies (yes I’ve read them). Again, the data requires a lot of re-assessing which dilutes its informative power ultimately.
Fourth, there are possible drawbacks to high starch diets such as limited protein availability exacerbating growth/development issues leading to, for e.g., smaller stature; the latter has been associated with such populations and has considerable biochemical rationale too.
Fifth, these data are observational. From them, I take: it is possible to be healthy on a high CHO diet (even if not as high as some report) but the number of factors it takes to make this happen appear quasi-impossible to control for in modern times. My grandmother smoked for +50 years and died at 90+..so this observation doesn’t undo the replicable and falsifiable experimental data about the harm of cigarettes. Lets avoid double-standards when it comes SWOT analyses of data.
Currently, my guess is these populations remained healthy despite their high CHO diet, not because of it. I’d LOVE to know how. If I were to look only at observational data, I might come to the same conclusion as you have. But I haven’t because I have a hierarchy of evidence.
These observations will never override experimental results. They cannot and should not. But…we do have to get our experiments right and therein lies the challenge.
AHS Netherlands 2015?? Cool! I'm in the South of France and I miss Holland. Leiden & Amsterdam have a place in my heart :)
Please let me know what's going on with that! :D
There is a case to be made for phosphoenolpyruvate as the core signalling molecule or metabolic fuel for aggressive phenotype of breast cancer cells. Of course, all of the normal caveats apply; it’s in a cell culture model, the cells have no accompanying fibroblasts, the cell culture is a novel 3D system etc etc. And, of course, you cannot say that glycolysis triggered the cancer, just that, in this model, it promotes a malignant phenotype.
As always, people are completely free to use as much glycolysis as they like. Doing it with their eyes open might be a good idea. Or not doing it, as the case may be.
"Peasants workings like slaves on an energy restricted regimen. Probably..."
In spite of evidence. Looked into to the research explosion into sedge tubers that 'Occam' were easier to get 80%+ nutrition for a big hominoid in a few hours of harvesting than hunting butter and cream? Many of the African sedge tubers have similar macro to mammalian milk, and micros that beat read meat (but not organ meat). But go on about your ways. You clearly know it all.
I'm tired of all "biochemistry" that doesn't integrate the bioCHEMICALS manufactured by gut bacteria and I'm even more tired of poseurs hedging on their ignorance in the matter.
You're ignorant of massive African sedge tubers that even baboons eat en mass to this day, so I really can't help you. Sorry. Very nearly everything I ever see from you is now an attempt to explain away. My perspective.
Thanks for your indulgence.
Richard, I know nothing. The only thing I know quite sure is that all the evidence suggests that if an organism is forced to rely predominantly on glycolysis, things tend to go to hell rather quickly.
The microbiome and RS are massively important, but I think overfeeding the critters is a bigger problem for most people than the microbiome starvation allegedly caused by low carb paleo diets.
I applaud you for giving the world raw potato starch. Many people see remarkable health improvements from it. A reader of my blog (long standing type 2 diabetic Mariet Hoen, whom you probably know) improved glucoregulation considerably by just adding some RS to her very low carb diet (higher is still no option for her).. Thanks for that.
But at the same time I think it is a non item if you are still healthy and eating an ancestral diet. My perspective is Mosselbaai. This is where we became fully human. Yes, we did eat the sedges that grow there in abundance. But even if you cook them (which they most probably did) the starch content is pretty low by all standards and more important, the glucose load is delivered in a cellular form (Ian Spreadbury). The carb density of the chyme will never be higher than 23%. The upper intestine (or the critters living in it) will never see a truly high carb load. I think this is crucial. Those sedges gave plenty of RS, I presume. As for nutrient density, only a marine environment could provide sufficient brain specific nutrients (iodine, choline, selenium, DHA, iron) to facilitate the exaptation that was necessary to unleash the explosive encephalisation that eventually made us human. That and an outstanding capability to make and utilize ketones. Human babies are born fat because their exploding brains have an absolute need for a steady ketone supply during the first years. I don't think it is such a stretch to assume that (intermittent) ketosis is what our system expects also later in life.
We ate also lots of bone marrow (fat) in this crucial period. Where do potatoes, beans, maize and grains (I suspect you are on the brink of embracing them again, correct me if I'm wrong) come in here?
Peter, very fascinating, thanks!
Raphi, I'll shoot you a mail.
What do you mean I ignore the biochemistry of bacteria? That couldn't be further from the truth - I am FASCINATED by them and liken them to studying little aliens in spaceships!
What's their role in the gut-brain axis? What happens when you decimate or overgrow some but not others? Can they serve as intermediary factors to increase or decrease the nutritional qualities of different foods? Where does scale tip if they're either along for the ride or carting us around? Quorum sensing appears quasi-magical - wtf is going on there?
I abhor the hype around the microbiome but also think it'll become (is becoming) a fundamental aspect of modern medicine.
You can see how, in my interview with Gary Taubes, (https://raphaels7.wordpress.com/2014/08/10/gary_taubes_obesity__calories_interview/) I was dismissive of 'probiotics' back then and happily changed my mind as I started to study them in my free time and as part of my degree. I tend to do that (be wrong and change my mind).
You mention the baboon eating tuber example as if this, in and of itself, falsifies ANYTHING we've been talking about. It doesn't. I'm not surprised a baboon would eat that, honestly. You need a hierarchy of evidence otherwise, everything goes.
I am also 'that guy' who sees no evidence so far that vegetables are essential for humans. Yet, there are many strong arguments to be made for incorporating them in considerable quantities (bulk-wise...& predominantly the colourful, non-toxic fibrous types...a la Wahls Protocol).
You've painted me with excessively broad brush strokes.
OK, thanks for the distinctions and demonstration you're not afraid of knowing even more nothing. Only falsification is certainty, and being less wrong as a process is far more rewarding than forever trying to show you're right.
I think you're not accounting for how very long RAW African sedge tubers have played profoundly into human evolution, given we're going back 2 million years, and where baboons seem to have picked up the habit, still can't shake it, which led to this science:
Also, cooking destroys all RS, just like heating popcorn kernels changes them from something that will pass right through, to something our enzymes can attack (RS is in the middle, but heating it pops the granules into rapidly digesting starch). What's very cool about TGs is that they have both RS and rapid starch, and the best nutrition profile for a foraging human is to feed the body rapid fuel, and the gut fuel too.
You should spend more time on this. This is what ultimately showed me that the prevailing hypothesis that kill scavenging is what created big brains. I've no doubt it eventually played as role, as did seafood and releasing more and different nutrition than cooking. But tiger nuts are a serious Occam's monkey wrench in all of this, and most especially consumed raw, right out of the ground, along with the soil-based gut microorganisms in tow.
"Quorum sensing appears quasi-magical - wtf is going on there?"
Now, toss horizontal gene transfer into the mix and contemplate how we know even more than Melchior's noting.
In terms of vegetables, I kinda look at this as my dogs eat grass sometimes. The CW always hold that they have a tummy ache and do this to throw up. I know different. Sometimes they just want to eat grass and leaves (probiotics), or knaw at the dirt (probiotics).
So, perhaps we're on the same page, but only half of it because I think that the real thing is raw and cooked starches in various forms, not various forms of leaves (though they make a great substrate for my awesome classic French dijon vinaigrette that the stewards on the FNS DUQESNE taught me to make).
Thanks for more indulgence.
This from Newburgh and Marsh 1923
Not only does acidosis not develop in patients who are living on
this diet, but it is a fact that all our patients showing at admission an
acidosis short of coma rather promptly lost their acidosis while taking the high fat diet.
their diet is a ketogenic one - 35g carb, 0.65g protein per Kg, 30-40 calories Kg/day.
possibilities - (in the absence of insulin)
1) Dietary fat is less ketogenic than stored fat
2) Dietary fat is less ketogenic than protein, and spares protein (in the absence of insulin)
3) Diabetic ketoacidosis is driven by hyperglycaemia - not only in regard to reduced fluid volume (a sine qua non of DKA I think) but also in regard to ketogenesis itself.
i.e. - Hyperglycaemic glucose flux into hepatocytes impairs FAO and increases ketogenesis
- glucose is itself a ketogenic substrate at such high concentrations
The last being a heretical possibility I was reluctant to express, but there it is, ruat caelum.
Here's my current best shot.
Dietary carbohydrate spikes hyperglycaemia and glucagon (in the absence of insulin).
At very high concentrations glucose is driven into hepatocytes. Most of it is recycled to glucose via Krebs cycle.
Gluconeogenesis is increased by both glucagon spike from carbs and hyperglycaemia.
High glucose production during metabolism of FFAs (also high) is drawing oxaloacetate from Kerbs cycle, increasing glucose and ketones simultaneously.
Also, possibly dietary fat reduces norepinephrine-mediated lipolysis.
This gives dietary fat a mechanismm for suppressing lipolysis that is independent of insulin - as it should be - such redundancy is the norm in living systems.
Here we go - tallow FTW
Metabolism. 1995 Oct;44(10):1271-7.
Beef tallow diet decreases beta-adrenergic receptor binding and lipolytic activities in different adipose tissues of rat.
Matsuo T1, Sumida H, Suzuki M.
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.
George, you make sense. I like it.
Here is Dr Bernstein's explanation of DKA:
"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."
True enough, but surely not relevant to Newburgh and Marsh's patients, who had no insulin to speak of?
Nor to someone who is on a ketogenic diet and minimal insulin already?
I summed up this argument here:
I would love to know, too, if the insulin or sugar causes calcium dysregulation in diabetes.
"Soft tissue calcifications in the lower extremities of severely diabetic patients simulating venous stasis or collagen vascular disease.
Bone and soft tissue abnormalities of the upper extremity in diabetes mellitus.
Campbell WL, Feldman F.
Roentgenographic evidence of bone and soft tissue abnormalities may be noted in the upper extremities of diabetics. Major shoulder changes, typically associated with peripheral neuropathy, include humeral head deformity due to bone resorption, joint space narrowing, subchondral cysts and sclerosis, subluxation, and juxtra-articular soft tissue bone fragments. Charcot-type joints, characterized by severe joint destruction, sclerosis, multiple bone fragments, and soft tissue swelling may occur. Diabetic neuropathy can produce flexion contractures of the hand. Abnormalities not necessarily associated with clinical neuropathy include cystic bone changes, cortical bone erosions, soft tissue calcification (calcific tendinitis), and vascular calcification."
Please forgive the hyperquestioning, but just suppose it's copper radicals causing the calcium misplacement, what about diabetes could cause copper issues?
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