Tag Archives: hypoglycemia

40 years ago a group of researchers turned ketosis into poetry.

But first, a brief primer.  In red.

“The glucose muscle-sparing effect of fat-derived fuels” 

or, the Randle Cycle 2.0.  it’s like a course in life enhancement.

Part I.  Intermediary metabolism

The glucose-fatty acid cycle
The Randle Cycle, as originally proposed, states that fatty acid oxidation inhibits glucose oxidation.  This is good because during starvation, every tissue than can survive on fatty acids instead of glucose should do so, sparing as much precious glucose as possible for the brain.

The glucose-sparing effect of fat-derived fuels
A critical vital horcrux to this is in the oh-so-humbly-disguised phrase “fat-derived fuels.”  The fat-derived fuels are ketones, and they are rescuing the brain from starvation (ie, neuroglycopenia); they do so by supplementing glucose as a fuel source.  Ketones are good at this; many tissues are happy to oxidize ketones when they are available.

The glucose muscle-sparing effect of fat-derived fuels
Ketones are derived from fat.  During prolonged starvation, glucose comes from skeletal muscle amino acids (eg, alanine).  Ketones spare glucose.  Thus, ketones spare muscle.  QED.

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what is our proper “natural” diet?

Figuring out how best to eat, physiological insulin resistance, and an homage to pioneering nutrition research.

Insulin resistance, as we know it today, is associated with poor nutrition, obesity, and the metabolic syndrome.  But it’s FAR more interesting than that.  Indeed, it could even save your life.  At the time when the pioneering studies discussed below were occurring, the researchers had no idea insulin resistance was going to become one of the most important health maladies over the course of the following century.  Furthermore, these somewhat-primitive studies also shed some light, possibly, on how we should be eating.  hint: it might all come down to physiological insulin resistance.

The reduced sensitivity to insulin of rats and mice fed on a carbohydrate-free, excess fat diet (Bainbridge 1925, Journal of Physiology)

Rats were fed either a normal starch-based diet (low fat), or a high butter diet (low carb) for one month, then fasted overnight and injected with a whopping dose of insulin (4 U/kg).  First, take a guess, what do you think happened and why.  Then, click on the table below.

To make a long story short, all the starch-fed rats died while all the butter-fed rats lived.

On a high-fat zero-carb diet, plasma insulin levels are low.  Insulin is low because there no carbs (i.e., it’s supposed to be low).  Under conditions of low insulin, unrestrained adipose tissue lipolysis leads to a mass exodus of fatty acids from adipose tissue.  These fatty acids accumulate in skeletal muscle and liver rendering these tissues insulin resistant.  But this doesn’t matter, because insulin sensitivity is unnecessary when there aren’t any carbs around.  So if that rogue research scientist who’s always trying to jab you with a syringe filled with insulin actually succeeds, you won’t die.  The high-fat diet prevents insulin-induced hypoglycemic death.  This is physiological and absolutely critical insulin resistance.

To determine if this was specific to dairy (butter) or a general effect of a high fat zero carb diet, Bainbridge repeated the experiments with lard.  Lo-and-behold, lard-fed rats were just as fine as those dining on butter.  

To be sure, these studies exhibited a high degree of animal cruelty… but their simplicity is laudable.  And Bainbridge’s findings are not an isolated case.

Studies on the metabolism of animals on a carbohydrate-free diet.  Variations in the sensitivity towards insulin of different species of animals on carbohydrate-free diets (Hynd and Rotter, 1931)

Instead of starch, lard, and butter, Hynd and Rotter used milk and bread, cheese, and casein.  And their findings were essentially identical to Bainbridge’s: mice, rats, or rabbits fed carbohydrate-free diets were insulin resistant and protected against insulin-induced tragedies.

The interesting finding was in kittens, who sadly maintained insulin sensitivity when fed fish (high protein) or cream (high fat).

You’re probably thinking: why would I say any state of heightened insulin sensitivity is “sad?”  WELL, I say “sad” because we’re talking about physiological insulin resistance; a condition when resistance to the hypoglycemic effect of insulin is essential, and lack thereof is incompatible with survival.  To be clear: 1) kittens remain insulin sensitive on high fat and protein diets; and 2) this is OK because there aren’t any rogue research scientists running around trying to jab them with insulin.  While I can’t say for sure, this might have something to do with what kittens are supposed to eat, i.e., their natural diet.  High protein and fat diets won’t make them insulin resistant because unlike rodents, that is their normal diet.  (real mice eat fruits and seeds; laboratory mice eat pelleted rodent chow; cartoon mice eat cheese.)   Lard causes ectopic lipid deposition in insulin sensitive tissues in rodents because they aren’t accustomed to it.  Mice are optimized to eat a high carb diet.  Kittens eat protein and fat, usually in the form of mice.  But when given bread, kittens develop insulin resistance.  There is no bread in mice.

While we shouldn’t base our diet around the possibility of turning a corner and being jabbed with a syringe filled with insulin, perhaps we are simply more similar to kittens.  Hypercaloric diets loaded with sugar, excess carbohydrates, and empty calories cause [pathological] insulin resistance (which could theoretically save your life if a rogue research scientist jabbed you with insulin), whereas the opposite is true for diets high in fat and protein.  This is repeatedly demonstrated in diet intervention studies, most recently in the notorious Ebbeling study (Missing: 300 kilocalories).  When people were assigned to the very low carbohydrate diet, insulin sensitivity was significantly higher than when they were on low fat diets:Soapbox rant: I’m not saying low carb is what we are supposed to eat.  Nor am I saying it is the optimal diet.  IMHO any diet which excludes processed junk food and empty calories is “healthy.”  The Paleo diet isn’t healthy because some nutritionista says it’s what we are supposed to eat; Paleo is healthy for the same reason as Atkins, Zone, South Beach, and a million others: no junk food.

Maybe the diet we’re supposed to eat has nothing to do with the healthiest diet.  Maybe not.  But it probably isn’t bad for you.  just sayin’

calories proper


ORIGIN vs. pre-diabetes, Op. 83

Sanofi, one of the world’s largest pharmaceutical companies, just released results from its ORIGIN trial.

Basal insulin and cardiovascular and other outcomes in dysglycemia (2012 NEJM)

The goal was to see if nightly insulin injections could prevent pre-diabetics  from becoming real diabetics.  ORIGIN was monstrous: >12000 participants, 40 countries, 6 years, etc.  FYI the subjects included in this study, mostly pre-diabetics, are not usually candidates for insulin injections (diet and lifestyle modification seem to work OK for this group).  If ORIGIN showed a positive result, then the number of patients to receive this treatment, and therefore the number of prescriptions written for Sanofi’s Insulin Glargine, would increase dramatically =  $anofi :)

IMHO, Sanofi is hunting for a new bunch of people to whom they can market their same old drug.  (Not a good practice.)  To stay alive in the fiercely competitive pharmaceutical industry, companies have to either invent new drugs to treat old diseases or invent new diseases that use old drugs.  In this case, they are saying that pre-diabetes, or “dysglycemia,” should be a new indication for insulin.  Pre-diabetes is not a new disease, but insulin was never warranted (Rx = diet and lifestyle modification).

I have no financial disclosures to report (but I’m open to offers).  Of moral disclosures, on the other hand, I’ve got but one.  Insulin injections are fraught with side effects and should be reserved for people who need them.  I don’t believe these people need them.

divide and conquer

After 6 long years of insulin injections (or standard care in the control group), the researchers tested for diabetes.  Lo and behold, diabetes was present in 35% of controls and 30% of the insulin-treated group; i.e., insulin-treated patients had a 20% lower chance of developing diabetes (odds ratio [OR] of 0.80, p = 0.05).  Apparently, insulin prevents diabetes.

Or not.

Exhibit A.  There’s a caveat to these diabetes rates.  The subjects were tested for diabetes at the end of the study.  Anyone who didn’t have it was re-tested a few weeks later; only those who didn’t have it were re-tested a few weeks later (during which time they received no treatment).  The researchers claim they were trying to assess the “durability of diabetes prevention.”  Here’s the rub:  25% of the patients on insulin tested positive for diabetes at the end of the study.  A few weeks later (during which time they weren’t being treated) some of the people who initially tested negative for diabetes (insulin obviously must have been protecting them), now tested positive, increasing the total to 30%.  This must have happened because they were no longer protected by insulin!  Err, no.  Diabetes in the control group, the group who was deprived of insulin from the start, went from 31% to 35% during the same exact time period.  It’s not “durability of diabetes prevention,” it’s experimental bias: by only RE-testing people who were initially negative, the total could only stay the same (if there were no false negatives) or go up (if there were false negatives).  The fact that it went up in both groups could simply mean that the re-test either: 1) detected diabetes in some people who falsely tested negative the first time around; and/or 2) generated some new false positives.  To correct for this, they should have also re-tested anyone who tested positive for diabetes.  *The importance of this difference is described below.

Exhibit B.  Disclaimer: statistics are the bane of my existence.  

The rate of disease was rather high in both groups (>>10%); if you calculated the  “relative risk (RR)” instead of “odds ratio (OR),” you’d get 0.857. An RR of 0.857 is not as pretty as an OR of 0.80 (lower is better).  Their “OR of 0.80” was barely statistically significant (p = 0.05); I’d be willing to bet that an “RR of 0.857” would not have been so lucky… so why did they choose to publish the OR?  OK, no suspense necessary:  I think if this measurement turned out non-significant, then the entire study would’ve been a waste of time and a LOT of money.  And they would have no shot at an entirely new market for their same old drug.  *This is precisely why proper diabetes diagnoses and statistical analyses were so critical in this study.  To be clear: this is going to come down to a numbers game, and the numbers don’t support a new indication for insulin in pre-diabetics.  But fuzzy math and biased testing makes this appear as though it is a debatable conclusion.

Moving on.

HbA1c, a marker of long-term glucose control was 6.4% at baseline in both groups.  Insulin therapy lowered this to 6.3% (not exactly something to write home about) while it drifted to 6.5% in controls.  This insignificant effect of insulin on HbA1c didn’t come cheap, however.  The insulin treated group experienced a huge number of severe hypoglycemic episodes:

Not surprisingly, the severity of hypoglycemia was totally downplayed in Sanofi’s press release despite it being the most robust and statistically significant finding in the entire study.

People in the insulin-treated group got a little heavier (by about 5 pounds), and surprisingly, the control group lost a little weight (about a pound).  I say “surprisingly” because this population is expected to be weight stable or gaining weight.

Lastly, fortunately, there was no difference in mortality.  This is not unexpected because the intervention was mild and the patients were relatively healthy (i.e., not people who need nightly insulin injections).  When a more intensive insulin intervention was tested on frank diabetics, the study was halted because too many people died.  Enter: The ACCORD study.

Effects of intensive glucose lowering in type 2 diabetes (circa 2008)

Intensive insulin therapy lowered HbA1c waay more in ACCORD than mild insulin therapy did in ORIGIN: 

but it also lowered lifespan: 

In conclusion:  YES, high blood glucose is the culprit, and YES, it needs to be lowered.  But NO, insulin injections are not the answer.  If you have lactose intolerance, you stop eating lactose.  These people have glucose intolerance; they need to stop eating glucose.

calories proper