Category Archives: Energy balance

Paleo schmaleo, Op. 69

Posted on April 12, 2012 | 2 comments

Brief refresher:

Paleo: lean meat, fish, fruits, vegetables, potatoes, eggs, and nuts; NO grains or dairy

Paleo carbs: fruits, veggies, nuts, and beans… NO starches, cereals, whole grains, added sugars, etc.

Paleo is GFCF-friendly

Atkins is similar to Paleo but allows fewer carbs

Mediterranean diet (from last week): whole grains, low-fat dairy, vegetables, fruits, fish, oils, and margarines (the Paleo diet improved insulin sensitivity WAY more than the Mediterranean diet in patients with CHD).

Diabetic diet (this week; see below): vegetables, root vegetables, dietary fibre, whole-grain bread and other whole-grain cereal products, fruits and berries, and decreased intake of total fat with more unsaturated fat.

Paleo vs. the “diabetic diet” in type II diabetics (Jonsson et al., 2009 Cardiovascular Diabetology).  Lindeberg designed this particular Paleo diet with a much lower carb content (32% vs. 40%) than in the previous study with CHD patients.  A cynic, who might think that some of Paleo’s benefits are due to its low carb content, might think that since traditional Paleo and the comparison “diabetic diet” have a similar carb content (42% and 40%, respectively), Lindeberg intentionally modified Paleo for this study to make sure carbs were significantly lower than in the “diabetic diet” (stacking the deck in Paleo’s favor, according to the cynic).  I can’t find any reason to disagree with the cynic, but it didn’t work out so well for Lindeberg et al.

As detailed in a series of posts about crossover studies (part I and part II), this one was botched due to: 1) what appears to be improper randomization (baseline glucose values were 7.1 and 8.6 mM); and 2) a washout period that was too short to allow one of the primary endpoint variables (HbA1C) to return to baseline.  As such, data presentation was convoluted, which said cynic might think was intentional.  But if we take it at face value, Paleo still fails.  For example, according to this figure (which is NOT crossover data), although Paleo has a lower final HbA1C, the HbA1C reduction is much greater on the diabetic diet.Paleo: 0

Diabetic diet: 1

AND weight loss was similar despite Paleo dieters consuming significantly less food (1581 vs. 1878 kcal/d):So yes, in accord with the Jonsson study (above), Paleo may have been more satiating (i.e., spontaneously lower food intake), but no, this didn’t translate to greater weight loss.  Someone needs to measure energy expenditure in Paleo dieters because it looks like this pattern of food intake either lowers basal metabolic rate or simply makes people tired (though this conclusion would be vehemently denied by Paleo loyalists).  The reduced leptin levels (Jonsson study) may have caused lower energy expenditure, but this would not entirely align with my lower-leptin-equals-higher-leptin-sensitivity hypothesis and thus cannot POSSIBLY be true :/   Alternatively, perhaps the Paleo diet really does lower energy expenditure; this would’ve been irrelevant and possibly even beneficial in Paleolithic times because: 1) they would’ve conserved more energy for “hunting” (hunter-gathers) or fleeing; and 2) weight loss was much less a concern compared to starving or being predated.

The Paleo diet is interesting in that it eludes low-carb status by selectively excluding grains, and I’m pleased that high quality studies (randomized crossover) are at least being attempted, but data thus far suggest we haven’t found anything magical about Paleo (yet)… just need better studies, especially those controlling for total carb content.

Paleo:

+1 for excluding grains, but not much else

 

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Posted in Advanced nutrition, Dietary fat, empty calories, Energy balance, Grains, Leptin, Uncategorized

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

 

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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)

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

Red meat won’t kill you. It will make you stronger.

Posted on March 24, 2012 | 4 comments

While statisticians try to wheedle causation from observational data, they really just end up showing us what health conscious people are like.  They exercise more and smoke less, eat more fruit and less red meat, etc.  This doesn’t “prove” those habits actually make health conscious people healthy.  Intervention studies, where healthy and non-healthy people are randomly assigned one of those habits, are required in order to achieve any reasonable amount of “proof.”  With regard to red meat, findings from such studies frequently stand in contrast to the observational data.
-end soapbox-

Divide and conquer

Serum lipids in humans fed diets containing beef or fish and poultry (Flynn et al., 1981 AJCN)

randomized crossover study: 1 egg + 5 oz. of red meat or fish/poultry for three months

The red meat group ate significantly more cholesterol than the poultry/fish group (540 vs. 477 mg/d), fat (104 vs. 83 g/d) and saturated fat (40 vs. 27 g/d).  Despite these differences, there were no changes in serum cholesterol or HDL.  In women but not men, red meat decreased and poultry/fish increased serum triacylglycerols, an effect that was consistent regardless of the order in which the diets were consumed (it was a crossover study).  This is significant because according to the Framingham studies, serum triacylglycerols are a more important predictor of heart disease in women than men.  And interestingly, carb intake, which usually regulates serum triacylglycerols, was similar in both groups suggesting that red meat has a triacylglycerol-lowering effect independent from simply displacing carbs from the diet.  Furthermore, the red meat group consistently ate about 200 more kilocalories then the poultry/fish group yet body weight was stable and similar in both groups.

Conclusion 1: 5 ounces of red meat (plus more cholesterol, fat, and saturated fat) for three months lowered serum triacylglycerols and didn’t affect cholesterol.  The excess calories consumed in the red meat group (mostly from saturated fat and protein) didn’t cause weight gain.

The effect of short-term diets rich in fish, red meat, or white meat on thromboxane and prostacyclin synthesis in humans (Mann et al., 1997 Lipids)

randomized intervention study: ~8 oz. white meat vs. ~12 oz. red meat vs. ~5 oz. fish for 2 weeks

This study was really trying to compare the effect on inflammatory markers of the high AA content of meat to the high EPA and DHA in fish (AA being pro-inflammatory and EPA/DHA being anti-inflammatory).As expected, the fish diet reduced inflammatory biomarkers (thromboxane and prostacyclin).  The two unexpected findings were: 1) white meat actually increased inflammatory biomarkers, and 2) red meat had no effect.

Conclusion 2: red meat and AA did not impact the inflammatory biomarkers thromboxane and prostacyclin.




Comparison of the effects of lean red meat vs lean white meat on serum lipid levels among free-living persons with hypercholesterolemia (Davidson et al., 1999 Archives of Internal Medicine)

randomized intervention study: ~5 oz/d of red meats (beef, veal, and pork) vs. white meats (poultry and fish) for 36 weeks

As seen in the table below, neither diet had any major effect on plasma lipids.

Fat, cholesterol, and total calorie intake was higher in the red meat group, but again, this didn’t result in any differences in body weight between the groups.

Conclusion 3: red meat had no effect on plasma lipids and the excess calories consumed in the red meat group (mostly from saturated fat and protein) didn’t cause weight gain.

Partial substitution of carbohydrate intake with protein intake from lean red meat lowers blood pressure in hypertensive persons   (Hodgson et al., 2006 AJCN)

randomized intervention study: 2 oz./d red meat vs. starchy carbs for 8 weeks

Conclusion 4: red meat lowered blood pressure and the excess calories consumed in the red meat group (mostly from saturated fat and protein) didn’t cause weight gain.

Increased lean red meat intake does not elevate markers of oxidative stress and inflammation in humans (Hodgson et al., 2007 AJCN)

randomized intervention study: 8 oz./d of red meat vs. carbs for 8 weeks

Subjects were instructed to eat their red meat in place of carb-rich foods such as bread, pasta, rice, potatoes, and breakfast cereals.

Conclusion 5: Biomarkers of oxidative stress (F2 isoprostanes and GGT) and inflammation (CRP and SAA) were reduced in the red meat group.




In sum:

WRT plasma lipids: red meat improved some and had no effect on others

WRT inflammation: red meat had no effect on thromboxane and prostacyclin, and decreased CRP and SAA

WRT oxidative stress: red meat reduced F2 isoprostanes and GGT

WRT energy balance: the excess calories from red meat didn’t cause weight gain.  This was the most consistent finding in all of the above studies and may be at least partially explained by the findings of the recent protein overfeeding study by George Bray and colleagues who showed, in brief, that excess protein had no impact on fat mass and actually increased lean mass.  So if you’re worried that fatty red meat might make you fat, don’t be.

The key to these 5 studies is that they are randomized intervention trials.  It’s not simply looking at what healthy people eat, but rather what happens when one specific dietary component is changed in all kinds of random people.  In other words, it’s what would happen in the real world if you made this dietary change.  And red meat consistently improved a variety of health parameters.

I suspect when the value of intervention trials is realized and fully appreciated, the habits of health conscious people will change.  Until then, we’ll just have to take the media’s reporting of nutrition studies with a grain of salt.

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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.).

 

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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.

 

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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.

 

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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

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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.

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the metabolic orchestra

Posted on February 3, 2012 | Leave a comment

What’s on YOUR plate?

whenever something goes up, something else goes down.  e.g., compare the fat and carbs in the three 30% protein diets:

It is virtually impossible to study macronutrients in isolation, but by looking collectively at a wide range of diet intervention trials, we can get some insight into the metabolic program orchestrated by fat, protein, and carbohydrates.

the “bar:” if we are to conclude that increasing nutrient “A” causes effect #1, then it must be true if the calories are compensated by 1) lowering nutrient “B” while leaving nutrient “C” unchanged, and 2) lowering “C” while keeping “B” unchanged.  And it doesn’t count if this is accomplished indirectly by abstract statistics.

Divide and conquer

Comparison of high-fat and high-protein diets with a high-carbohydrate diet in insulin-resistant obese women (McAuley et al., 2005 Diabetologia)  

To make a very long story very short, here’s what happened after 24 weeks:

Abbreviations I: kcal, food intake in calories; BW, body weight; FFM, fat-free mass (muscle); FM, fat mass; ‘slin, insulin; CRP, C-reactive protein

Abbreviations II: HC, high carb; HP, high protein; HF, high fat

Abbreviations III: LC, low carb; LP, low protein; LF, low fat

Despite similar calorie reductions, HF lost more BW and FM than HC (HP was intermediate).  Fasting insulin was reduced most in HF and this group lost the most fat.  Anyone as surprised as me about the dramatic reduction in CRP in the HF group?  (+2 for HF)  Fasting insulin was reduced the least by HP but HP lost more fat than the HC.  You might think this undermines the insulin-fat theory, but alas, draw your attention to the kcal’s.  Perhaps the bigger reduction in calories in HP helped them shed a little more fat than HC despite a lower reduction in insulin. Furthermore, HF lowered insulin more and they lost more fat but had the same caloric deficit as HC.

But does it meet the “bar?” IOW, are these results due to the abundance of dietary fat or the lack of carbs?

Alternatively, is HC inferior because of the low fat content or the high carb content?  To address this, we need to compare two diets with similar fat but different carbs.

Effect of an energy-restricted, high-protein, low-fat diet relative to a conventional high-carbohydrate, low-fat diet on weight loss, body composition, nutritional status, and markers of cardiovascular health in obese women (Noakes et al., 2005 AJCN)

This study was half as long (12 weeks vs. 24 weeks), but compensated by a more robust calorie deficit 

Both groups were supposed to undergo an identical degree of calorie restriction, but HP lost slightly more weight despite eating slightly more food than HC.  HP also lost more fat and their insulin was more suppressed.  And importantly, HP lost less muscle than HC.  (and wow, check out those CRP data [+2 for HP]).  This was all confirmed in a much larger year-long study comparing two 30% fat diets, HP vs. HC, with nearly identical results (Due et al., 2004 International Journal of Obesity)

Summary thus far:

McAuley (first study; three moderate protein diets: fat vs. carb)
high fat is superior to high carb     or     low carb is superior to low fat

Noakes (second study; two low fat diets: protein vs. carb)
high protein is superior to high carb     or     low carb is superior to low protein

To bring this around full circle: both HF and HP independently beat HC, so what do you think would happen in a face-off between HF and HP?

Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids (Luscombe-Marsh et al., 2005 AJCN)  

This study was of intermediate duration (16 weeks) but had the greatest weight loss:

HF vs. HP?  It’s a tie!!  Insulin was reduced more by HP and fat mass declined ever so slightly more in this group, but the difference was very small.  When the data were broken down by genders, women did retain more muscle on HP but again, the difference was small.

Luscombe-Marsh (third study; two low carb diets: protein vs. fat)
high protein is equal to high fat     or     low protein is probably just as bad as low fat

So if anyone tries to quiz you about diets and weight loss, like the way my colleagues relentlessly do to me whenever a new diet study is published, armed with this knowledge you should be able to guess the outcome (probably)…

I know what you’re thinking… what if they try to trick me, like comparing the effects of HP to high fiber??  Fiber is supposed to be good for you, green leafy vegetables and all, right?

Just stick to the data outlined above.

Comparison of high protein and high fiber weight-loss diets in women with risk factors for the metabolic syndrome: a randomized trial (Morenga et al., 2011 Nutrition Journal)  

With the exception that the high fiber group was getting 39 grams of fiber per day while HP was only getting 24 grams.

This was the shortest study (8 weeks) and accordingly weight loss was the least.

Victory!  despite a significantly lower reduction in calorie intake, HP lost more weight than high fiber.  HP also lost less muscle, more fat, and insulin declined to a greater degree.

Morenga (fourth study, two mixed diets: protein vs. fiber)
higher protein, higher fat, and lower carbs are superior to high fiber

just don’t gamble with this information

 

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Posted in Advanced nutrition, Dietary fat, Energy balance, Protein