Category Archives: Sugar

Non-sequiter nutrition

Posted on April 16, 2012 | 3 comments

(or another over-caffeinated soapbox rant)

Taxing junk food?  If I thought the government had a clue what constituted “junk,” maybe I’d view this more favorably.  But my gut says no.

 

 

“Bad food? Tax it, and Subsidize Vegetables”  Mr. Bittman, we subsidize the hell out of corn; what good has that done?   I don’t think controlling diet via junk food taxes is the right way to healthify America, but if I had to choose I’d say shift subsidies away from corn and soybean, and toward things like organic spinach and grass fed beef.   This would impact a lot of foods containing ingredients that are [IMO] barely suitable for human consumption like high fructose corn syrup and trans fats (and corn & soybean oils).

 

 

Denmark and Romania taxing saturated fat?  Really?  we already went through this when we traded saturated fat-rich butter for diabesogenic trans fat-rich margarine-  (“saturated fat”).  A tax on saturated fat is non-specific; it hits many healthy foods and not enough junk food.  And it is, by definition, a tax NOT on the deceptively unsaturated trans fats.  Alternatively, subsidizing corn and soybeans is just making soda and junk food cheaper.

 

 

do NOT eat at KFC in Hungary, Peru, or Poland.  or anywhere.  that’s microwave popcorn levels of trans fat.

Better nutrition education and evidence-based recommendations are far better solutions, IMHO, but we aren’t a country of philosopher’s.  I’ve touched a bench on which the sign “wet paint” was taped, and I probably also touched a red hot stove despite my mother’s warning against it.  oh well.

 

 

calories proper

 

3 Comments

Posted in Advanced nutrition, Dietary fat, empty calories, Fructose, Sugar, Trans fat

Paleo vs. carbs (per se), Op. 68

Posted on April 6, 2012 | Leave a comment

The Paleo diet:

A)     the next big thing

B)      Atkins-lite

C)      Fail

D)     None of the above

While proponents of the Paleo diet take a page out of nutritionism‘s book and argue it’s about food choices, not macronutrients, my reductionism mandates inclusion of a comparative breakdown by protein, fat, and carbs.  In a recent publication, Lindeberg (a Paleo pioneer) compared Paleo to the Mediterranean diet in a cohort of CHD patients (Lindeberg et al., 2007 Diabetologia).  To make a long story short, Paleo came out on top in a variety of endpoint measures after 12 weeks.

Divide and conquer

The Paleo diet consisted of lean meat, fish, fruits, vegetables, potatoes, eggs, and nuts; grains and dairy were off-limits (Paleo is GFCF-friendly).  Paleo carbs include fruits, veggies, nuts, and beans… no starches, cereals, whole grains, added sugars, etc… FYI Atkins is very similar to Paleo but includes a lower absolute amount of Paleo carbs.  The Mediterranean dieters ate whole grains, low-fat dairy, vegetables, fruits, fish, oils, and margarines.  Both diets exclude processed junk food and both are relatively healthy diets.  

As such, both groups lost weight; slightly more on Paleo but this was probably due to reduced caloric intake (not uncommon for Paleo dieters; see below and also Osterdahl et al., 2008 EJCN):But the benefits of Paleo were much more robust WRT insulin sensitivity, which was markedly improved on Paleo but not Mediterranean.

Paleo: 1

Mediterranean: 0

With a 4% weight loss, why didn’t glucose tolerance improve in the Mediterranean dieters?  … weight loss is almost always accompanied by improved glycemic control…   The biggest difference in “foods” consumed by the two groups was cereals: 18 grams per day on Paleo vs. 268 on the Mediterranean diet… over 14 times more!  As I’ve discussed at length with gravitas, a high intake of cereals (aka grains aka fibre [in the figure below]) does not bode well for insulin sensitivity, inflammation, and outright all-cause mortality:

As such, Paleo does well to exclude grains.  Furthermore, Paleo is higher in protein and fat and lower in carbs- all good things.  A more interesting analysis showed that waist circumference (visceral fat) was associated with grain intake even when controlled for carbohydrates.  In other words, the detrimental impact of whole grains goes beyond their intrinsic carbohydrate content. (whole grains … insulin resistance … visceral fat)

Back to those calorie data for a moment, given that they were probably just as important as cereal exclusion in determining the results.  Why did Paleo dieters spontaneously eat so much less?  In a follow-up publication, Jonsson and colleagues assessed leptin and satiety in both groups (2010 Nutrition & Metabolism) and showed that despite eating less and losing more weight (things that should increase hunger and decrease satiety), Paleo actually did the opposite (hint: something to do with whole grains, perhaps?).

While the Paleo meals were smaller (5th and 6th rows) and contained fewer calories (3rd and 4th rows), they were just as satiating as Mediterranean diet meals (7th through 9th rows), leading the authors to conclude Paleo is more satiating calorie-for-calorie and pound-for-pound.  And if that isn’t enough, Paleo dieters also experienced a significantly greater reduction in leptin! (probably caused by their reduced food intake and body weight loss)  While the general consensus is that such a change in leptin should enhance hunger, as discussed previously I think lower leptin in this context reflects enhanced leptin sensitivity, which also helps to explain the improved insulin sensitivity.  Last but not least, WRT the Mediterranean diet I suspect reduced calories explains the weight loss, but the abundance of whole grains explains the blunted glycemic improvements.  (hint: whole grains … leptin resistance … insulin resistance) … (whole grain exclusion … leptin sensitivity … insulin sensitivity)

Paleo, the next big thing?  I’m holding out for a one-on-one with low-carb proper to exclude the role of Paleo’s lower carb content.  The whole grains issue requires no further confirmation IMO (e.g., Burr et al., 1989 Lancet, Jenkins et al., 2008 JAMA, etc.).

The Paleo diet:

A)     the next big thing

B)      Atkins-lite

C)      Fail

D)     None of the above

might be considered “Atkins-lite,” probably not “the next big thing,” definitely not “fail.”

+1 for excluding grains

 

calories proper

Leave a comment

Posted in Advanced nutrition, empty calories, Energy balance, Grains, Leptin, Protein, Sugar

the other liquor, Op. 67

Posted on March 30, 2012 | 1 comment

First pizza became a vegetable, now chocolate cures obesity, what’s next, cigarettes are the fountain of youth?

The publication that spawned the recent news flurry:  Association between more frequent chocolate consumption and lower body mass index (Golomb et al., 2012 JAMA)

The humble title doesn’t come close to the media’s interpretation, which included such deluded phrases as “A chocolate a day to get slimmer?” and  “Is chocolate the secret to a skinny waistline?”

While a chocolate bar isn’t the most nutritionally offensive dessert, it is neither a panacea of health nor a cure for obesity.  Chocolate 101: milk chocolate is loaded with sugar; dark chocolate usually has a little less sugar, it’s “dark” because it has less milk and more chocolate liquor (no, not that kind of liquor); unsweetened chocolate has no added sugar and is usually reserved for baking.  If you think you’re having a genuine chocolate craving, you, like many others, may have been beguiled by the serpent sugar. want proof? next time you’re in the mood, try some high-cocoa unsweetened chocolate; it’s the purest chocolate that chocolate can be.   While it can be rich and delicious in its own unique way, even the fanciest stuff tastes little like “chocolate”

And this “high-cocoa unsweetened chocolate” (shown on the bottom of the figure below) is probably the only kind that can be remotely called “healthy.”  The chocolate mentioned in this study was probably a blend of this, milk, and a ton of sugar (aka “milk chocolate”).

High-cocoa unsweetened chocolate is less sweet, higher in fat, and has more health-promoting compounds than any other type.

Back to the groundbreaking study for a moment:The third line of the results says that people who ate more chocolate were more depressed and ate more calories, both of which were associated with higher body weight.  But two lines later, we are told increased frequency of chocolate consumption by itself was linked with lower body weight…  let me get this straight: the people who ate more chocolate were fatter because they were depressed and ate more calories, not because they were eating more chocolate …? sounds like statistical sorcery of the highest degree.

On the other hand, a much more convincing study specifically on dark chocolate:  Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons (Grassi et al., 2005 AJCN)

These lean (~140 lbs) healthy subjects were given, in a randomized crossover study, 100 grams (~3.5 ounces, 480 kcal) of dark or white chocolate for 2 weeks.  Dark chocolate contains all the health-promoting compounds (e.g., flavonoids, like those found in red wine and green tea); white chocolate has none.  The subjects were apparently prescribed a 1,400 kcal/d diet (semi-starvation) but didn’t lose any weight over the entire period.  So unless they were bedridden, this is probably not true.  But I’ll admit, the effect on insulin sensitivity was quite remarkable:White chocolate (open circles) was health neutral or even slightly modestly detrimental (all of the sugar, none of the flavonoids).  But dark chocolate profoundly enhanced insulin sensitivity-

Flavonoids: 1

Sugar: 0

(granted, this was probably the healthiest dark chocolate in the world…)Although this was a high quality study design (randomized crossover), I will [stubbornly] wait for independent confirmation before making any heretical paradigm shifts.

… uh-oh

High-cocoa polyphenol-rich chocolate improves HDL cholesterol in Type 2 diabetes patients (Mellor et al., 2010 Diabetes Medicine)

In contrast to the first study, this study didn’t use chocolate per se, but rather polyphenol-rich high-cocoa solids which is probably more similar in flavonoids to high-cocoa unsweetened chocolate.

Again, the results were fairly outstanding:Flavanoids: 2

Sugar: 0

Consumption of the regular (low-polyphenol) chocolate induced a pro-diabetic phenotype (increased glucose & insulin; decreased HDL), while the super-chocolate was potently anti-inflammatory (reduced CRP and increased HDL).  While these findings are indeed impressive, sorry, but the inconsistent effects on insulin sensitivity still give me pause (markedly effective in the Grassi study with dark chocolate vs. no effect at all in the Mellor study with polyphenol-rich cocoa solids).

In conclusion: milk chocolate candy bars are still on the list of “clearly unhealthy foods,” especially for anyone with metabolic syndrome or excess body fat; rare European dark chocolate is temporarily classified as “probably not harmful;” and high-cocoa unsweetened chocolate is upgraded to “possibly beneficial.”

unless it explodes(Weinzirl, 1922 Journal of Bacteriology)

calories proper

1 Comment

Posted in Advanced nutrition, Dietary fat, empty calories, Energy balance, Sugar

Yogurt black belt test, Op. 65

Posted on March 17, 2012 | 2 comments

Proper yogurt can serve as a delicious and healthy addition to any meal of the day.  It contains probiotics, whose role in promoting a healthy gut flora and overall well-being is widely appreciated.  As such, yogurt can be considered an acceptable source of a little bit of sugar in your diet.  (I don’t say that very often… actually, that was probably the first time.)

BUT (you had to know there was a “but”) there are a lot of caveats.  First and foremost is selecting the best yogurt product, since not many people are down with DIY fermentation (which is unfortunate given its tremendous ease).  The yogurt with the most gravitas on the market: FAGE.  It’s supposedly Greek, but I’d say given it’s macronutrient composition, it’s more Spartan.  There are considerable differences between the plain and fruity varieties worth considering.  For example, one serving of plain contains 190 kcal, 10g fat, 8g sugar, and 19g protein, whereas one serving of the blueberry-flavored variety contains 170 kcal, 6g fat, 16g sugar, and 11g protein.  twice the sugar! This is unacceptable, primarily because while I’m not really clear what’s in the “blueberry fruit preparation” that’s listed in the ingredients, I’m sure it’s not real blueberries.  Since real blueberries have negligible protein, we can assume the total protein content of the final product is entirely from the yogurt; therefore, their ambiguously named “blueberry fruit preparation” contributes about 27 grams to the entire 150 gram serving.  This adds 12 grams of sugar, whereas 27 grams of real blueberries would provide only 3 grams of sugar (and some fiber and phytonutrients).

And pass on the 0% fat version; one serving contains all of the sugar but none of  the healthy fats that slow down sugar absorption and contribute to satiation.

On to more pressing, or ‘popular,’ matters.  Dannon is the most widely purchased yogurt on the market.  One serving of plain Dannon yogurt contains 160 kcal, 8g fat, 12g sugar, and 9 grams of protein (less protein and healthy fats, and more sugar than its Spartan counterpart).  Their vanilla-flavored variety has a whopping 25 grams of sugar (and it’s certainly not natural dairy sugar…).  One serving of blueberry-flavored Fruit-on-the-Bottom contains 140 kcal, 1.5g fat, 26g sugar, and 6g protein.  If you added real blueberries to the plain variety this would only yield 15 grams of sugar (still more than FAGE, FTR).  Again, this additional sugar is not coming from real blueberries; unlike FAGE, who disguises their mystery flavor as “blueberry fruit preparation,” Dannon doesn’t even try to hide it.  Right in the ingredients list you’ll find strike 1: sugar, strike 2: fructose syrup, and strike 3: high fructose corn syrup (I honestly don’t know why that’s listed as three separate ingredients.  It’s like they’re trying to boast about it).  I feel pre-diabetic just reading it.  Yoplait is just as bad (high sugar and low protein); come on, Trix -flavored yogurt?  Really?

With regard to promoting a healthy gut flora:  Dannon contains only 1 probiotic strain: L. acidophilus; Yoplait has 2: L. bulgaricus and S. thermophiles; FAGE has 5, L. acidophilus, L. bulgaricus, S. thermophiles, Bifidus, and L. casei.

FAGE: winner.

 

calories proper

2 Comments

Posted in Advanced nutrition, Dietary fat, empty calories, Protein, Sugar, Uncategorized

Volumetrics II

Posted on March 12, 2012 | 1 comment

Volumetrics, take II, Op. 64

Greatest dietary predictors of 2-year weight loss success: increased intake of vegetables and meat and reduced intake of empty calories   (sugars and starchy carbs).

Proponents of the low-fat diet cite the high energy density of fat (9 kcal/g) relative to carbohydrate (4 kcal/g) and claim you can eat more carbs than fat without exceeding your daily calorie budget: 100 grams of carbs = 400 kcal; 100 grams of fat = 900 kcal.  And by extension, you will: 1) feel fuller after a high carb meal; 2) eat fewer calories; and 3) lose weight.  Bollocks, bollocks, and bollocks.  Diet studies that compare low-fat to low-carb impose strict calorie restrictions on the former and unlimited consumption of the latter.

The “energy density of food” theory is about as valuable for weight loss as “eat less, move more,” and “a calorie is a calorie.”  

Fiber  and water, the great filler-uppers, have done nothing in the battle of the bulge.

The figure above is from the now famous (or infamous, in certain crowds) Shai study.  A manuscript was recently published that tried to figure out which foods were most (or least) associated with successful body weight management at two distinct time points: 1) weight loss at 6 months; and 2) weight maintenance after 2 years.

Effects of changes in the intake of weight of specific food groups on successful body weight loss during a multi-dietary strategy intervention trial (Canfi et al., 2011 JACN)

The reduction in food consumed was ~24% on the low fat diet and ~33% on the low carb diet, despite a similar reduction in calories (~22%) in both groups.  The low fat diet was not “more satiating;” both groups were eating the same amount of calories.  Yet the low carb dieters lost more weight.  But the point of the new study was about which foods were the best predictors of success in all of the groups.  Ample information about the dietary intervention, cute food pyramids (see below), and sample meal plans are available in the online supplement.

By and large, the results were similar for weight loss (at 6 months) and weight maintenance (24 months); IOW, whatever helps you lose weight also helps keep it off.  But there some interesting differences. For example, increasing vegetable intake assisted weight loss but was less important in the long-term.  Conversely, reducing starchy carbs (bread, pasta, cereals and potatoes) was moderately important for weight loss but universally important for maintenance of a reduced body weight.  Increased meat intake was one of the best predictors of successful long-term weight loss independent from background diet (it was equally true for low carb and low fat dieters).  In other words, increasing vegetable intake can help jumpstart a weight loss diet, but reducing starchy carbs increasing meat intake need to be permanent lifestyle changes.

And surprise surprise, reducing “sweets and cakes” was also a major factor across all diets.  With regard to weight loss, reducing sweets and cakes was statistically more important than increasing vegetables.  In fact, it was the most important change of all.

In sum, long-term weight loss success includes a diet with more meat and vegetables and fewer empty calories (starchy carbs, sweets and cakes, etc.).

 

calories proper

 

Become a Patron!

 

 

1 Comment

Posted in Advanced nutrition, Dietary fat, empty calories, Energy balance, Protein, Sugar

LPL, insulin, and diet, Op. 62

Posted on February 29, 2012 | Leave a comment

There are many ways to address the etiology of obesity and insulin resistance (or insulin resistance and obesity).  For example, you can follow a group of healthy people for a long time and compare those who become insulin resistant with those who don’t; alternatively, you can study a population who is predisposed to insulin resistance (e.g., offspring of type II diabetics)… regarding the latter, although it’s kind of grim, apparently healthy children of obese or diabetic parents are often in an intermediate state of insulin resistance.  It’s impossible to exclude a genetic component, but I believe environmental influences are dominant: the poor diet and lifestyle of obese parents is just as likely as obesogenic DNA to be passed on to their children.

The main reason to be concerned with these questions is that there is considerable disagreement about the specific cause of obesity and insulin resistance; i.e., which came first and does one cause the other?  Or do they simply share a common cause (e.g., hyperinsulinemia)?   I currently lean toward the “common cause” hypothesis.  Alternatively, I’d say “it’s complicated”  … insulin resistance is not one isolated phenomenon, but the end result of many interconnected biological processes.  This has important implications for treatment and prevention- if, for example, hyperinsulinemia causes obesity and/or insulin resistance, then reducing insulin levels or preventing insulin spikes should be prioritized.  And mitochondria also seem to be important.

Regulation of mitochondrial biogenesis by lipoprotein lipase in muscle of insulin-resistant offspring of parents with type 2 diabetes (Morino et al., 2012 Diabetes)

The subjects in this study were body weight and age-matched; the only major difference was impaired glucose tolerance and the presence of at least one diabetic parent in the “insulin-resistant offspring” group.  They took muscle biopsies and found, somewhat surprisingly, one of the biggest differences was the content of lipoprotein lipase (LPL).LPL is responsible for hydrolyzing circulating triacylglycerols (from chylomicrons and VLDL) to free fatty acids for tissue uptake.  Thus, this finding suggests muscle from insulin-resistant offspring is not as good at sequestering fatty acids (despite these subjects oftentimes having paradoxically higher intramuscular fat levels).  This corresponded with lower PPAR activity, mitochondria volume, and fatty acid oxidation.  And interestingly, in a set of follow-up cell culture experiments, they found that the fish oil fatty acid EPA (but not DHA) could correct this deficiency.

Ideally, we would like LPL activated in muscle (to take up and oxidize fatty acids) and inhibited in adipose (to prevent fat cells from getting fatter).  Fortunately, there are some relatively easy ways this can be accomplished… exercise selectively activates LPL in muscle and inhibits it in adipose, while insulin does the exact opposite.  So eat salmon, exercise, and avoid insulinogenic sugars and carb-rich foods!

Tissue-specific responses of lipoprotein lipase to dietary macronutrient composition as a predictor of weight gain over 4 years (Ferland et al., 2012 Obesity)

This study was a little more complicated than inferred by the title.  First, they took healthy adults, measured body composition and then assessed adipose vs. skeletal muscle LPL activity in the fasted and fed states after 2 weeks of a high fat or high carb diet.  To make a long story short:In lean subjects (table above), a high carb meal (after 2 weeks of high carb dieting) markedly increased adipose LPL by 153% (top row) (this is bad), and modestly increased it in skeletal muscle (80%, second row).  The high fat meal (after 2 weeks of high fat dieting) caused a smaller increase in adipose LPL (92% vs. 153%) and bigger increase in skeletal muscle LPL (80% vs. 100%) (this is good).  Thus, a high carb diet caused the most detrimental changes in adipose LPL while a high fat diet caused the most beneficial changes in skeletal muscle LPL.

Next, they compared these acute effects with changes in body composition over the course of 4 years and found that the biggest predictor of increased fat mass was the response of adipose LPL to a high carb diet.

The Morino study showed that increased skeletal muscle LPL was positively associated with insulin sensitivity, while the Ferland study showed that a high carb diet increased adipose LPL and this was positively associated with fat mass gain over 4 years.  Skeletal muscle LPL is good, adipose LPL is bad (Rx: EPA [salmon], exercise, and keep insulin levels low).

Dare I say “nutrient partitioning?”  this might be one way to reduce body fat without drastically cutting calories.  Adopt an LPL-modulating diet and lifestyle!  The effect on fat mass not huge, about a pound per year, but that adds up to 10 pounds over the course of a decade… obesity doesn’t happen overnight.

 

calories proper

Leave a comment

Posted in Advanced nutrition, Dietary fat, Energy balance, Fish, Sugar

Insulin per se

Posted on February 23, 2012 | 1 comment

This recent manuscript nearly slid beneath the radar… almost stopped reading at the abstract until the word “nifedipine” appeared (among its widely pleiotropic effects, nifedipine also lowers insulin).

The series of experiments described below demonstrate one aspect of the scientific method reasonably well.  None of the individual experiments, when viewed in isolation, really prove the hypothesis.  But the researchers tested it with a variety of widely different methods and all of the results went in the same direction.  The hypothesis in question: insulin causes fat gain, and hyperinsulinemia per se, not macronutrients or calories, is the root cause.

This group has previously shown that sucrose is more detrimental than fish oil is beneficial toward obesity and glycemic control.

High glycemic index carbohydrates abrogate the anti-obesity effect of fish oil in mice (Hao et al., 2012 AJP)

Divide and conquer
Mouse study.  Lots of diets, in brief:
Pair fed: high fish oil (180 g/kg) plus 13%, 23%, 33%, and 43% sucrose (by weight, switched out for casein [a poor choice IMO])
High fish oil (180 g/kg) plus sucrose, fructose, glucose, low GI carbs, and high GI carbs.
That’s a lot of diets.  Kudos.

As expected, higher sugar and lower protein intakes enhance weight gain (yes, even when pair-fed similar calories [i.e., a calorie is not a calorie]) and this is at least partly due to reduced metabolic rate (as per the poor man’s energy expenditure test- measuring body weight before and after 24 hours starvation [higher weight loss = higher metabolic rate]):High sucrose-fed mice also had more inflamed adipose tissue and less thermogenic brown fat, which likely contributed to their glycemic dysregulation and elevated adiposity.

Sucrose is comprised of glucose and fructose, so to determine which component was causing obesity, they fed mice high fish oil diets plus either sucrose, glucose, or fructose.  Interestingly, the glucose group gained as much weight as the sucrose group.  Since the fructose group gained the least amount of weight, the researchers attributed the sucrose-induced obesity to insulin! (fructose doesn’t elicit an insulin response; and insulin levels were lowest in the fructose group).

Body weight, plasma insulin, and glucose tolerance:

I. Thus far: glucose and sucrose cause obesity by stimulating insulin secretion.  Glycemic deterioration is worst in the glucose-fed group because they were consuming most of the most insulinogenic sugar: glucose.  It was lower in the sucrose and fructose groups because sucrose contains only half as much glucose as pure glucose, and fructose contains no glucose.  IOW, these data suggest hyperinsulinemia per se causes obesity and insulin resistance.  Gravitas.

They further tested this by comparing high and low GI diets which cause higher and lower insulin levels, respectively.  As expected, the low GI diet led to less weight gain, and significantly lower insulin levels and adipose tissue accumulation compared to the high GI diet:

II. Thus far: high insulin levels, whether induced by glucose, sucrose, or high GI starch, lead to obesity.

They next took a non-dietary approach by artificially increasing insulin levels with glybenclamide in fish oil-fed mice to see if hyperinsulinemia could still cause obesity.  The results weren’t robust, but the higher insulin levels tended to increase adiposity even in mice fed the anti-obesogenic fish oil diet. 

In the experiment, the opposite approach was taken: nifedipine was used to lower insulin.  The use of octreotide and diazoxide has been used in a similar context with similar results in humans, discussed HERE and HERE.Again, the results were not robust, but when viewed collectively a picture begins to emerge: raising insulin levels, whether it is with a high glucose or sucrose diet, a high GI diet, or glybenclamide increases adipose tissue growth; and conversely, lowering insulin levels, whether it is with a less insulinogenic sugar diet (fructose), a low GI diet, or nifedipine decreases adipose tissue growth.  Oh yeah, and low carb works too.

 

calories proper

 

 

1 Comment

Posted in Advanced nutrition, Energy balance, Fish, Fructose, pair-feeding, Protein, Sugar

Gluc-a-gone wild, Op. 60

Posted on February 17, 2012 | 1 comment

optional pre-reading

Q. What happens to a type I diabetic when you 1) withhold insulin, 2) provide insulin, or 3) withhold insulin and suppress glucagon?  (Charlton and Nair, 1998 Diabetes)…

…

A. You learn glucagon is the bad guy.

Divide and conquer

Zero insulin makes you hyperglucagonemic, hyperglycemic, and ketoacidotic (see first column).  Insulin cures all of these things (second column), but they aren’t caused by insulin deficiency, per se… they’re caused by high glucagon, which itself is cured by insulin (second column) and SRIH (somatostatin, third column).  Cure the hyperglycemia by inhibiting glucagon and pathological diabetic ketoacidosis suddenly becomes physiological ketosis.

Uncontrolled diabetes also wastes muscle:Zero insulin makes you hypermetabolic and increases amino acid oxidation.  Insulin cures this, but again, it appears to be driven by hyperglucagonemia, not insulin deficiency.

Glucagon directly correlates with energy expenditure, and this isn’t the good metabolic rate boost sought by dieters, it’s the type that indiscriminately burns everything including muscle.  High protein diets also increase energy expenditure, but in pathological hyperglucagonemia, the amino acids come from muscle, not food.

The above mentioned study is most relevant to type I diabetes.  The following study is about glucagon and the far more common type II diabetes (Petersen and Sullivan, 2001 Diabetologia).

The effects of hyperglucagonemia can be blunted by glucagon receptor antagonists (GRAs).  In the figure below, a GRA (Bay-27-9955), was administered immediately prior to a glucagon infusion.  The GRA significantly reduced blood glucose levels, an effect largely attributed to the reduction in endogenous glucose production:One of the ways GRA’s accomplish this is by keeping glucose tied up in hepatic glycogen instead of flooding into the plasma (Qureshi et al., 2004 Diabetes; “CPD” is the GRA used in this study).  The figure on the left is primary human hepatocytes; on the left is in mice.Another way of looking at this is in mice chronically treated with glucagon or glucagon plus a GRA.  Glucose tolerance is obviously deteriorated by glucagon treatment, but is completely restored by a GRA (Li et al., 2008 Clinical Science):

One of the most severe side effects of diabetic hyperglycemia is nephropathy, which is similarly cured by GRA treatment:

The physiological role of glucagon is to prevent hypOglycemia; but hypERglycemia is the problem most of the time.  Don’t get me wrong, hypOglycemia can be deadly, but 1) it’s not nearly as prevalent as hypERglycemia, and 2) inhibiting glucagon doesn’t cause hypoglycemia, there are a battery of counterregulatory hormones that prevent hypoglycemia.

Furthermore, reducing glucagon action isn’t limited to glucagon receptor antagonists (GRAs), leptin and amylin can do it too!

And while gastric bypass surgery is easily more extreme than GRA’s and leptin or amylin therapy, it’s magical effect on diabetes remission might also be partly attributed to glucagon suppression (Umeda et al., 2011 Obesity Surgery):

Convinced yet?

 

calories proper

1 Comment

Posted in Advanced nutrition, Dietary fat, Energy balance, gastric bypass, Leptin, Sugar, Uncategorized

Leptin and insulin: resistance is futile, Op. 59

Posted on February 11, 2012 | Leave a comment

The biochemical similarities between resistance to the metabolic effects of leptin and insulin are ultra-complicated.  The studies discussed below suggest leptin sensitization is a pre-requisite for glycemic improvement and weight loss.  Similarly, low leptin levels (independent of fat mass) appear to be linked with high insulin sensitivity and the ability to lose weight.  “Low leptin” in this context (i.e., independent of fat mass) does not refer to the starvation-induced rapid decline of leptin or the complete absence of leptin, but rather to a high degree of leptin sensitivity (analogous to insulin sensitivity?).  The level at which this signal is mediated, however, remains to be determined (adipocyte? sympathetic nervous system? brain? in the Electric Kool-Aid?).

Is the resistance to high levels of endogenous leptin in established obesity similar to the effects (or lack thereof) of exogenously administered metreleptin?

Divide and conquer

My current hypothesis: 1) leptin sensitivity needs to be high and 2) leptin levels need to be adequate (too low and leptin sensitivity is meaningless; too high and you become leptin resistant).  This is summarized nicely in this clever little experiment (Knight et al., 2010 PLoS ONE).  Ob/ob mice genetically lack leptin.  Zero leptin, and monstrously obese (the mouse on the right).  If you add back the amount of leptin found in a lean insulin sensitive mouse (~5 ng/mL), they gain just as much weight on any diet as normal mice (and much less than untreated ob/ob mice [the mouse on the right]).  But here’s the catch: on a high fat diet, treated ob/ob mice gain as much weight (top row, left figure) despite much lower leptin levels (top row, right figure).

Ob-norm mice are phenomenally leptin sensitive (bottom right), but do not have enough leptin to support insulin sensitivity (bottom left) or physical activity (bottom middle figure).  If leptin levels are too high (wild-type mice on high-fat diet), on comes leptin resistance (bottom right) and glucose intolerance (bottom left).  This picture is incomplete but good enough to support the claim that leptin sensitivity needs to be high and leptin levels need to be adequate.

Insulin-resistant patients with type 2 diabetes mellitus have higher serum leptin levels independently of body fat mass (Fischer et al., 2002 Acta Diabetologia)

Higher insulin sensitivity in those with the lowest leptin levels (this group is probably the most leptin sensitive):The most insulin sensitive group (Tertile 3) has the lowest leptin levels but also the lowest body fat (i.e., it could be confounded by fat mass)

But the middle group is more insulin sensitive than the lowest group (by definition), and has lower leptin levels despite being fatter.  So it’s definitely not confounded by fat mass, and I think this is because they are more leptin sensitive.

Differential effects of gastric bypass and banding on circulating gut hormones and leptin levels (Korner et al., 2006 Obesity)  

Still not confounded by weight loss because the banded group weighed more but had lower leptin and higher insulin sensitivity than the overweight group.  In support of enhanced leptin sensitivity in the gastric bypass group, they experienced a significantly greater increase in post-meal satiety than the other groups.  Similarly, the overweight group (who have much higher leptin levels) actually experienced a decline in satiety after eating!

Now we’re getting somewhere!

Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice (Kusakabe et al., 2012 AJP)

Injection with leptin (squares) or amylin (triangles) alone does not reduce food intake or body weight in leptin-resistant diet-induced obese mice (open circles), but a combination of leptin and amylin does both (closed circles).Importantly, as seen in the figure below, neither leptin nor amylin alone improves glycemia.  Theoretically, this is because leptin sensitization is required to improve insulin sensitivity.  And amylin improves leptin but not insulin sensitivity.  The far right column in the right graph shows that the leptin-amylin co-treated group were more insulin sensitive.

Leptin sensitization is required to improve insulin sensitivity.  So why didn’t amylin alone improve the sensitivity to endogenous leptin? … perhaps because leptin sensitivity was high but leptin levels were inadequate.  Amylin-alone also lowered endogenous leptin levels, which may have counterbalanced the improved leptin sensitivity (top row, compare the first and third columns):In other words, the leptin-resistant mice could be artificially made more sensitive to their own endogenous 28.5 ng/mL of leptin with 100 ug/kg/d amylin, but not to their lower 19.7 ng/mL of leptin (in this study).

In rats, however, 100 ug/kg/d amylin is capable of endogenous leptin sensitization despite similar reductions in endogenous leptin (Roth et al., 2008 PNAS):This graph is showing a proxy for leptin sensitivity in rat brain.  The black bars are vehicle-treated, the white bars are leptin-treated.  Amylin-alone increased sensitivity to both endogenous leptin (second to the last bar) and exogenous leptin (last bar).  And indeed, amylin-alone (open triangles in the figure below) reduced body weight; the addition of exogenous leptin further reduced body weight (compare inverted triangles [leptin alone] to squares [leptin plus amylin]).

Similar results are obtained in humans (figure on the right).

The intermediate effects in mice illustrate an important point.  Amylin-induced sensitization to endogenous leptin, as seen in rats and humans but not mice, is required to reap the full benefits of leptin re-sensitivation.  This didn’t occur in mice, but occurred in all species (including mice) when exogenous leptin was administered to restore leptin to an adequate level.

In sum, restoration of leptin sensitivity is required for glycemic improvement and weight loss regardless of whether it is achieved by gastric bypass (Korner study, above), amylin treatment (Kusakabe study in mice; Roth study in rats and humans), a sugar-free diet (Shapiro study, discussed HERE), or a low-carbohydrate diet (Brehm et al., 2003 JCEM – greater weight loss and glycemic improvement despite eating more calories [associated with lower leptin levels]).  Personally, I’d attempt either of the latter prior to gastric bypass or pharmacological therapy with an experimental cocktail of metreleptin and pramlintide.  But that’s just me.

Just like insulin, you gotta get leptin levels down, not up, to see benefits.

calories proper

Leave a comment

Posted in Advanced nutrition, Energy balance, Leptin, Sugar

USDA vs. nutrition, round II

Posted on January 26, 2012 | 2 comments

The school lunch program is screwed.

First the USDA modifies the definition of a vegetable to include pizza.  Now they significantly altered their standards for school lunches to include fewer healthy foods and more USDA-approved ones (see report at the USDA’s website).  In brief, this move further reduces the nutrition of school lunches and will likely do more harm than good.  Here’s why:

In this cross-sectional Swedish study, parents recorded 7-day food diaries for their 4-year old children who then went in for a regular checkup.

Metabolic markers in relation to nutrition and growth in healthy 4-y-old children in Sweden (Garemo et al., 2006 AJCN)

On a 1,400 kcalorie diet, these children were consuming roughly 15% protein, 33% fat, and 52% carbs (about 20% of which came from sucrose).  That seems like a lot of calories, but besides playing all day, 4 year old children are also growing at an incredible rate.

Interesting finding numbers 1 & 2:  Children who got most of their calories from fat had the lowest BMI (i.e., they were the leanest), and the opposite was observed for carbs.

When divided into groups of normal weight vs. overweight and obese, some interesting and non-intuitive patterns emerged.  For example, lean kids don’t eat less food; but they do eat fewer carbs and less sucrose (and make up the difference by eating more fat and saturated fat).

Some of the weaker correlations showed:
-total calorie intake was associated with growth (logical)
-total carbohydrate intake was associated with increased fat mass (unfortunate yet also logical)
-total fat intake was associated with decreased fat mass (interesting)

And those who ate the most saturated fat had the least amount of excess body fat. (more on this below)

Fortunately, in a young child, a poor diet hasn’t had enough time to significantly impact their metabolic health; as such no macronutrient was associated, either positively or negatively, with insulin resistance [yet].

In a more appropriately titled follow-up, Swedish pre-school children eat too much junk food and sucrose (Garemo et al., 2007 Acta Paediatrica), Garemo reported that most of their carbs came from bread, cakes, and cookies, while most of the sucrose came from fruit, juices, jam, soft drinks, and sweets.  And WOW, go figure- most of the fat came from meat, chicken, sausage, liver, eggs, and dairy; NOT vegetable oils.

And in a mammoth dissertation, Eriksson (2009) confirmed many of these findings in a larger cohort of 8-year old Swedish children and had this to say about dairy fat:

The open boxes represent overweight kids, the closed boxes are lean kids.  Going from left to right, in either the open or closed boxes, BMI declines with increasing intake of full fat milk (perhaps parents should reconsider skim milk?).  Eriksson also confirmed that saturated fat intake was strongly associated with reduced body weight.  Interestingly, she mentioned that food intake patterns are established early in life, so it might be prudent to remove sugars and other nutrient poor carb-rich foods, and introduce nutritious whole foods as early as possible.  I’m not exactly sure how she assessed patterns of food intake establishment, but it seems logical.  Especially in light of the following study… we’ve seen 4 year olds, 8 year olds, and now we have 12-19 year olds.  The relationship between diet and health is consistent across all age groups.

Virtually all of the above data in Swedish children seem to suggest dietary saturated fat, whether it’s from beef, sausage, eggs, whole fat dairy, or liver (i.e., WHOLE food sources; NOT hydrogenated vegetable oils), is associated with reduced fat mass.  Metabolic abnormalities were not present, probably because the children were simply too young (although body weight seems to respond relatively quickly, other downstream effects of poor nutrition take years to accumulate before symptoms develop).

An American study about nutrient density and metabolic syndrome was recently published.  These kids were exposed to poor nutrition for just long enough to experience some of those malevolent effects.

Dietary fiber and nutrient density are inversely associated with the metabolic syndrome in US adolescents (Carlson et al., 2011 Journal of the American Dietetic Association)

The figure below divides fiber (a proxy for good nutrition; i.e., leafy vegetables, beans, etc.) and saturated fat into groups of least and most amounts comsumed. The lowest fiber intake was 2.9 grams for every 1,000 kcal, and 9.3% of these kids already had metabolic syndrome; the highest fiber intake was 10.7 grams / 1,000 kcal and 3.2% had metabolic syndrome.  Thus, consuming a fiber-rich [nutrient dense] diet is associated with a significantly reduced risk of metabolic syndrome.

The next rows are saturated fat.  The lowest saturated fat intake was 6.9 grams / 1,000 kcal and 7.2% had metabolic syndrome; the highest saturated fat intake was 18 grams / 1,000 kcal and 6.7% had metabolic syndrome…. huh?  While it didn’t reach statistical significance, the trend for saturated fat paralleled that of a “nutrient dense” diet.  Is it possible that saturated fat might be part of a nutrient dense diet?   if saturated fat comes in the form of red meat, liver, eggs, etc., then yes, it is part of a nutrient dense diet.  This conclusion evaded both the study authors and the media.

In 4 and 8 year old Swedish children, those who ate the most saturated fat had the least excess fat mass.  In 12 – 19 year old American adolescents, those who ate the most saturated fat had the lowest risk for metabolic syndrome.

Is it too much of a stretch to connect these ideas by saying that in the short run, a low saturated fat (nutrient poor, carb-rich) diet predisposes to obesity; and in the long run it predisposes to metabolic syndrome  ???

Collectively, these data suggest a diet based on whole foods like meat and eggs, including animal fats, with nutrient dense sources of fiber (e.g., leafy vegetables) but without a lot of nutrient poor carb-rich or high sugar foods, may be the healthiest diet for children.  

Flashback: recap of “USDA vs. nutrition, round I”
USDA: 1
Nutrition: 0
They made pizza a vegetable and insiders suspect that next they’ll try to make it a vitamin.

USDA vs. nutrition, round II

USDA: replacing normal milk with low fat milk
nutrition: full-fat milk was associated with lower BMI in both lean and obese children (see the Eriksson figure above)

USDA: increasing nutrient poor carb-rich options
nutrition: this was associated with increased fat mass in children (Garumen et al., see figures above)

USDA: reducing saturated fat as much as possible
nutrition: reduced saturated fat was associated with excess fat mass in children and metabolic syndrome in adolescents.

Such changes will have an immeasurable long-term impact if children grow up thinking these are healthy options.  Finally, this blog post does not contain a comprehensive analysis of saturated fat intake and health outcomes in children, but the USDA’s new regulations should have been accompanied by one.  In other words, these regulations should not have been based on the studies discussed above, but the studies discussed above should have been considered when the USDA was crafting their recommendations.  Obviously, they weren’t.

calories proper

2 Comments

Posted in Advanced nutrition, Dietary fat, empty calories, Energy balance, Fructose, Grains, Sugar, Trans fat, Uncategorized