Bump: The Diabetes "Crash" Cure & Pancreatic Fat

Today's 8/15/13 bump was inspired by a comment by Tsimblist (thanks!) alerting me to this paper:  Type 2 Diabetes Etiology and reversibility

Reversal of type 2 diabetes to normal metabolic control by either bariatric surgery or hypocaloric diet allows for the time sequence of underlying pathophysiologic mechanisms to be observed. In reverse order, the same mechanisms are likely to determine the events leading to the onset of hyperglycemia and permit insight into the etiology of type 2 diabetes. Within 7 days of instituting a substantial negative calorie balance by either dietary intervention or bariatric surgery, fasting plasma glucose levels can normalize. This rapid change relates to a substantial fall in liver fat content and return of normal hepatic insulin sensitivity. Over 8 weeks, first phase and maximal rates of insulin secretion steadily return to normal, and this change is in step with steadily decreasing pancreatic fat content.

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Toxic!

There hasn't been much buzz about this year's LC Cruise, but a couple of days ago, a tweet from the presentation of one Dr. Dwight Lundell made a little splash on Twitter and FB.  

The most toxic chemical in the human diet is GLUCOSE. -Dr. @dwightlundell #sugarkills #LCCruise13
— Dietitian Cassie, RD (@dietitiancassie) May 7, 2013

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An American Justice System for Food ~ Part I Intro and Carbs in General

The cornerstone of the American justice system:  Innocent until proven guilty.  According to Wikipedia: sometimes referred to by the Latin expression Ei incumbit probatio qui dicit, non qui negat (the burden of proof lies with who declares, not who denies).  I like the first part of that Latin expression and suggest that what is truly needed in nutritional circles is to put the burden of proof on those making claims.  My point here is not a political one, it is not to argue the merits of my country's justice system or its implementation, or anything of the sort.  It is to put forth a suggestion -- that ALL who demonize foods be tasked with proving their charges.   I suggest this because it is darned near impossible to do the opposite especially in the face of baseless charges.  

It is a bit of a stretch, but keep in mind that many of the compounds, such as water, can be toxic at some level of ingestion.  Furthermore, some of the chemical and/or physical properties of many innocuous compounds found in foods can seem quite daunting when taken out of context.   This is an obvious spoof, but hopefully it makes a point.

Now, the vegans and vegetarians and raw and fruitarian crowds are all just as guilty of this, but since I've never been even remotely a part of any of those communities, I'll leave it to someone else to call out their hyperbole, scaremongering and outright disinformation.   I'm also not talking about new non-foods such as artificial sweeteners, chemically modified foods (e.g. hydrogenated fats), non-food chemicals such as preservatives and I'll even throw in GM in with substances that should be considered unsafe until proven otherwise.  

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Ketosis and Burning Body Fat

Alternate Title:  Picture Worth More Than 1000 Words.  In speeches and interviews lately, Jimmy Moore has become fond of mentioning a few things (well, in addition to name dropping Robb Wolf)

• Nutritional Ketosis as being somehow unique from run-of-the-mill, what, biochemical ketosis.  NK requires blood ketone testing as this is more accurate.  And,
• Ketosis is evidence of burning body fat which he wasn't doing prior to this experiment.
• Ketones and blood glucose being reciprocal

Tis true that measuring blood ketone levels is more accurate than urine ketones.  For one thing, urine levels vary widely with fluid intake, frequency of urination, etc.  Urine ketones are also "spill-over".  This is why nobody is ever busted for DUI on the basis of a urine test.  But just because urine levels are not necessarily representative of one's ketogenic production doesn't mean a person is, or is not, in NuttyK.  But let's presume that to be truly NuttyK one must also be a prick-er.  

On the right sidebar are Jimmy's NuttyK experiment results from Days 180-209.  Top to bottom we have AM glucose, AM ketones, PM ketones,  and body weight.  Do YOU notice any correlation?   Here's what I see:

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Ketone and Fat "Burning" are Not the Same Thing to Your Mitochondria

This notion of being a "sugar burner" vs. a "fat burner" -- with the latter being touted as preferable based on nothing I've seen in the scientific literature -- is getting really out of hand.  This is not a new idea, but it certainly seems to be being pushed more lately, particularly in the area of athletic performance.  There were a smattering of posts about the diets of Olympians about the net and I just have to shake my head at the one that goes something like "just imagine how much better fill in the blank would do if (s)he didn't eat grains" or "ate LCHF" or "went paleo".  C'mon already ... Michael Phelps is a prime offender of all laws and gods nutritional, but will someone please remind me how many medals he's earned and records he's held/broken in his career?  Gawd forbid any of these elite athletes set a bad example by having their face put on a box of Wheaties!  I dunno ... it all seems so silly when Phelps sports one of the leanest torsos on the planet burning sugar.  But I digress ...

But with ketomania in full-blown fad form, there's a new twist on the fat burning meme which is to confuse fat burning with ketone burning.  It is not.  Yes, ketones are produced mostly from the breakdown of fatty acids (they are also produced from some amino acids), so you "burn fat" in your liver to produce them.  If you are in caloric deficit, the source of the fatty acids will be body fat.  However, if you're fueling the other cells of your body with ketones, this is not the same as the mitochondria in those cells "burning fat".  

Below is a schematic of a brain cell mitochondria and the metabolic pathways showing where ketones feed into Krebs (aka the TCA), from:  D-β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease (thus it shows the points of issue for these two diseases) 

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Ketones Fuel Cancer?!

Ketones and lactate “fuel” tumor growth and metastasis

Previously, we proposed a new model for understanding the “Warburg effect” in tumor metabolism. In this scheme, cancer-associated fibroblasts undergo aerobic glycolysis and the resulting energy-rich metabolites are then transferred to epithelial cancer cells, where they enter the TCA cycle, resulting in high ATP production via oxidative phosphorylation. We have termed this new paradigm “the Reverse Warburg effect.” 

Here, we directly evaluate whether the end-products of aerobic glycolysis (3-hydroxy-butyrate and L-lactate) can stimulate tumor growth and metastasis, using MDA-MB-231 breast cancer xenografts as a model system. More specifically, we show that administration of 3-hydroxy-butyrate (a ketone body) increases tumor growth by ~2.5-fold, without any measurable increases in tumor vascularization/angiogenesis. Both 3-hydroxy-butyrate and L-lactate functioned as chemo-attractants, stimulating the migration of epithelial cancer cells.  Although L-lactate did not increase primary tumor growth, it stimulated the formation of lung metastases by ~10-fold.  thus, we conclude that ketones and lactate fuel tumor growth and metastasis, providing functional evidence to support the “reverse Warburg effect.” 

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Irresponsible Advice from Dr. Eades

Again, leaving aside the creepiness of this man's words, I've got to address how irresponsible his advice in a recent blog post was.  I may come back at some point and address the "Listen to your body?" stuff, but MM reminded me in the comments on another post of some more disturbing content in the post.

His advice boils down to "up the fat" to hasten the transition into ketosis so that your "induction flu" is as short as possible.  Now, I've never experienced any such symptoms so I can't really relate to this, but apparently newbies and restarters have done very well taking the advice in The New Atkins to increase salt intake by sipping a little bullion.  Anyway, Eades -- oddly enough author of a book subtitled "The High-Protein/Low-Carbohydrate ..." --  has now jumped full on into a tub of Mangalista lard.

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Before The New Atkins

Westman, Volek and Phinney were among the contributers (and Westman headlined) the following, partially Atkins Foundation funded, review:

Low-carbohydrate Nutrition and Metabolism

I can't recommend reading this highly enough.

I've listed the references in a separate post, numbered (the formatting farkled the last few but I'll let you count ;) )

For a non-gimmicky discussion of how low carb diets REALLY work for weight loss, this is where it's at!

Ketones, Anaplerosis & Insulin

Acetoacetate and β-hydroxybutyrate in combination with other metabolites release insulin from INS-1 cells and provide clues about pathways in insulin secretion

Putting this here for my own orgnization

Conclusions:

The synergistic insulin release by compounds that can be metabolized to mitochondrial acetyl-CoA, such as KIC, β-hydroxybutyrate, or acetoacetate, in combination with methyl succinate that can be metabolized to mitochondrial oxaloacetate, suggests that acetyl-CoA and oxaloacetate condense in the citrate synthase reaction to form citrate. Numerous compounds can be formed from citrate, and citrate can carry acetyl-CoA and oxaloacetate out of the mitochondria to the cytosol. Many compounds, including most short-chain acyl-CoAs, can be formed from acetyl-CoA in the cytosol. KIC and β-hydroxybutyrate can also be directly converted to acetoacetate and acetyl-CoA in the mitochondria. Acetoacetate can be exported to the cytosol and converted to acetoacetyl-CoA to form several other short-chain acyl-CoAs. The results support the idea that anaplerosis is important for insulin secretion and suggest that multiple short-chain acyl-CoAs may be some of the products of anaplerosis in the β-cell.

Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans

Long term exposure to fatty acids and ketones inhibits B-cell functions in human pancreatic islets of Langerhans

We previously demonstrated in the rat that long term exposure to fatty acids inhibits B-cell function in vivo and in vitro. To further assess the clinical significance of these findings, we tested in human islets the effects of fatty acids on glucose-induced insulin release and biosynthesis and on pyruvate dehydrogenase (PDH) activity.

PDH is the enzyme thought to control the entry of acetyl CoA from glycolysis into the Kreb's / TCA /Citric Acid Cycle.

These authors did an in vitro study with human cells to see if the results compared with those seen both in vitro and in vivo in rats.  While in vitro observations don't always correlate with what we see in whole organisms, this did correlate for the rat.  Therefore it is reasonable to believe that the results of this experiment are applicable to human metabolism.

Human islets were obtained from the β-Cell Transplant Unit (Brussels, Belgium). Exposure to 0.125 mmol/l palmitate or oleate for 48 h during tissue culture (RPMI-1640 and 5.5 mmol/l glucose) inhibited the postculture insulin response to 27 mmol/l glucose by 40% and 42% (P<0.01 for difference). Inhibition was partly prevented by coculture with 1 μmol/l etomoxir, a carnitine-palmitoyl-transferase-I inhibitor (P<0.05 for effect of etomoxir).

Etomoxir inhibits fatty acid oxidation.  Recent developments employ this to treat chronic heart failure associated with Type II Diabetes.   

Inhibitory effects on glucose-induced insulin secretion by previous palmitate were additive to the inhibitory effects exerted by previous high glucose (11 and 27 mmol/l). Palmitate-induced inhibition of insulin secretion was evident after exposure to 25 μmol/l added fatty acid. The insulin content of islets exposed to fatty acids was significantly reduced, and glucose-induced proinsulin biosynthesis was inhibited by 59% after palmitate addition and by 51% after oleate exposure (P<0.01). These effects were partly prevented by etomoxir (P<0.05). The activity of PDH in mitochondrial extracts of islets preexposed for 48 h to palmitate was decreased by 35% (P<0.05) υs. that in control islets, whereas the activity of PDH kinase (which inactivates PDH) was significantly increased in the same preparations (P<0.05).

This underlines that high levels of both -- glucose/carbs and fatty acids -- wreak havoc on the body.

The effects of ketones were tested by 48-h exposure to β-hydroxybutyrate (β-D-OHB). Ten millimoles of D-β-OHB per L inbibited the subsequently tested insulin response to 27 mmol/L glucose by 56% (P<0.001). Half-maximal inhibitory effects of D-β-OHB on insulin secretion and insulin content were seen at concentrations between 0.5-2.5 mmol/l. Inhibition by D-β-OHB was partially reversed by etomoxir, whereas exposure to D-β-OHB failed to affect PDH and PDH kinase activities. 

We conclude that fatty acids as well as ketone bodies diminish B-cell responsiveness to glucose in human islets by way of a glucose-fatty acid cycle. Increased plasma concentrations of fatty acids and ketones are likely to be important factors behind the negative influences on B-cell function exerted by a diabetic state in botb type 1 and type 2 diabetes.

I don't have access to the full-text.  Seems "long term exposure" consisted of 48 hours.  I am curious what long term exposure of a ketogenic VHF diet  does to someone in the long haul.  At least early on, Type II's make insulin just fine -- just that they make too much of it b/c their cells are insulin resistant.  In researching to determine for myself if my low carb diet is healthy for the long haul, I've come across a lot of disturbing information on free fatty acids.  If by lowering BG we send FFA levels skyrocketing through the roof, do we mask a problem that still exists?  

I see no reason why IR cannot be reversed.  Indeed I believe the "lose 10% of weight cure" for T2 basically demonstrates this for persons whose pancreas has not yet been compromised (e.g. still able to produce insulin).  Indeed even the T2's with insufficient insulin responses may well have that inhibited by high NEFA/FFA -- restore fuel balance and there's no reason to believe this too can be reversed.

The relationship between high NEFA and sudden cardiac death continues to haunt me, and VLC/VHF diets have been shown to dramatically increase these!  So I remain skeptical of LC for weight maintenance and/or especially if one is gaining weight on such a diet.

Carbohydrate restriction regulates the adaptive response to fasting

Carbohydrate restriction regulates the adaptive response to fasting

The importance of either carbohydrate or energy restriction in initiating the metabolic response to fasting was studied in five normal volunteers. The subjects participated in two study protocols in a randomized crossover fashion. In one study the subjects fasted for 84 h (control study), and in the other a lipid emulsion was infused daily to meet resting energy requirements during the 84-h oral fast (lipid study). Glycerol and palmitic acid rates of appearance in plasma were determined by infusing [2H5]glycerol and [1-13C]palmitic acid, respectively, after 12 and 84 h of oral fasting. Changes in plasma glucose, free fatty acids, ketone bodies, insulin, and epinephrine concentrations during fasting were the same in both the control and lipid studies. Glycerol and palmitic acid rates of appearance increased by 1.63 +/- 0.42 and 1.41 +/- 0.46 mumol.kg-1.min-1, respectively, during fasting in the control study and by 1.35 +/- 0.41 and 1.43 +/- 0.44 mumol.kg-1.min-1, respectively, in the lipid study. These results demonstrate that restriction of dietary carbohydrate, not the general absence of energy intake itself, is responsible for initiating the metabolic response to short-term fasting.

I've felt for a long time that LC is equivalent to "starvation mode".  It is interesting that NEFA/FFA were the same in both the fasted group and that getting the lipid infusion.  This would indicate to me that "dietary" fat in and of itself does not stimulate further lipolysis.  It would be interesting to see if the result would differ if the fats were ingested.

The New Atkins ~ Ketosis & The "Atkins Edge"

One of my "bad" issues with TNA is the whole issue of some magic carbohydrate level for weight loss. 

I had a big problem with this point which led me to go off Atkins "big time" the prior two times I tried it (for extended periods and with much success at the time, I might add).

I'm a firm believer that for a goodly portion of adults, it is dieting and a diet mentality that has contributed to becoming overweight/obese.  If you're not following all the rules, then why bother ... right?  Or you've been good so what's one restaurant or take-out meal going to do -- forget that many of those meals, especially if you add a cocktail, can tally up to 3000 cals in one pop!

At least with CRD's, if you eat maintenance level calories one day, you just put off one or two sevenths of a lb weight loss for a day or so.   Of course plenty of folks on CRD's will continue to eat the entire pkg of cookies or whatever the forbidden goodie is, but the successful ones aren't always purists -- rather they accept the occasional indulgence and move on.

With LC plans, somehow 10g extra carbs is going to set you back days, weeks even?  It sounds so cool, almost, that we have some magical CCL for losing and an ACE for maintining.  All I have to do is find that number, stay at or under it, and voila!  But woe is me if I have a bite of mashed potatoes and exceed it.  

C'mon.  Does that REALLY make any sense?  It defies all earthly laws to gain a pound of body mass without consuming at least a pound of food -- and that would have to be a pound in excess of basic needs.  So any temporary setback on an LC diet is likely mostly water.  Now folks with water balance issues, and especially the rather overweight, can fluctuate by as many as 10 or more lbs just from water.  In my experience, I fluctuate ±3lbs about what I consider to be my true weight ... sometimes even when VLC'ing.  If I've gone from totally glycogen depleted to filling the stores, I can easily gain 5 lbs overnight (as I did on a recent vacation), but since that water weight is w/in my muscle cells distributed about my body, my clothing fits just about the same.  Bottom line, I don't sweat these pounds.  It may take some people longer to reverse the water weight pendulum, but they haven't gained energy-storage weight (outside the glycogen).

So anyway, in the original Atkins, Dr. A was clearly referring to a threshold to stay in ketosis with his CCL for weight loss.  On pg. 94 (paperback version, Sept. 1973 printing, ©1972 Bantam), The Diet Revolution Calorie Theory is stated:  Calories in equals calories used plus calories excreted unused.

Now Westman et.al. know full well that excess ketones don't add up to a whole lot of wasted calories.  These three are among the authors of a Review article entitled Low Carbohydrate Nutrition and Metabolism ... rather ironically funded by the Atkins Center but not referenced in TNA.  (Whassup wid dat??)

Two longer-term studies, in persons without diabetes, that measured fasting blood -hydroxybutyrate concentrations over 10 wk found that, whereas the concentrations increased over the first 2–4 wk, they then decreased and, after 10–12 wk, remained only slightly higher than those of dieters following other diets (21, 23).

In the article, they basically identify ~50g as the carb threshold for an LCKD.  In the book they refer to ketogenic diets several times (for treatment of epilepsy mostly and diabetes in one instance).  And yet mysteriously missing is any mention in determining CCL (only seeing if you lose weight).  I find this quite odd.

In the article the "low carb metabolism" is described for LCKD:  70% fatty acids (dietary and lipolysis of adipose tissue), 20% ketones ( dietary fat & protein and lipolysis and ketogenesis of adipose tissue), 10% glucose (gluconeogenesis, glycogenolysis).  If this isn't the "Atkins Edge", then they acknowledge that above 50g there's no significant switch to this alternate metabolism. 

As early as 1980, LaRosa found that subjects following an LCD do not necessarily replace the carbohydrate with either protein or fat, but that they, rather, reduce starch and sugar intake (9). Under such conditions, even though the absolute amounts of fat and protein do not increase, the percentage of fat and protein will increase. Recent research reviewed below has determined that the reduction in calorie intake is a result of appetite and hunger reduction. In this way, LCDs are also low-calorie diets that include an increase in the percentage of calories from fat and protein but not necessarily an increase in absolute amounts of fat and protein.

It seems to me that a more honest presentation and justification for CCL and ACE would be the above.  There does appear to be a spontaneous decrease in caloric intake associated with minimizing carbs.  I think that at least in part is due to the number of calorie dense carby/fatty foods (all those pastries, pizza, french fries and the like) one has to limit.  But given that adaptation to ketosis on LC is well-known (and Atkins isn't even close to the ketogenic diet used to treat epilepsy!), their description of the "Atkins Edge" seems disingenuous at best.  

These authors ignore their own (Atkins funded) writings to re-invent the same old wheel.  I would have loved for them to acknowledge that -- gasp!! -- Atkins was right on the health and weight loss aspects of his diet, but wrong on the calorie theory.

I don't see what's NOT exciting about spontaneously reducing intake without going hungry and possibly with a whole lot less discipline (it can be far easier to count carbs once you get the hang of it).  Wish they had done this.  It would have been a far more fitting tribute to Dr. Atkins.