Category Archives: Advanced nutrition

Research studies, hypotheses, data, etc.

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

Diet, diabetes, and death (oh my)

Posted on March 6, 2012 | 7 comments

Fatty acid face off: saturation vs. chain length
or
an homage to pioneers of nutrition research

While both fats contain a lot of 8-12 carbon fatty acids (C8-C12), coconut oil contains more of the 12-carbon fatty acid “lauric acid” whereas medium-chain triacylglycerols (MCT) have more of the 10-carbon fatty acid “capric acid.” Both exhibit remarkably protective effects against diabetes and this has been known for quite a while. Coconut and MCT oils are also phenomenally ketogenic, which contributes to their healthful effects (although this eluded early researchers).

Experimental diabetes and diet (Houssay and Martinez 1947 Science)

This study used alloxan to deplete insulin-producing beta-cells rendering these rats essentially type I diabetic. In the first experiment, they injected alloxan and counted how many rats were still alive after one week. This study is cruel by today’s standards, but things were different in 1947. It does, however, provide valuable information as the rats were also being fed one of 16 (16!) different diets. The major finding was that all the rats fed lard died (d, e, and i in the table below), while all those fed coconut oil survived (o in the table). And additional coconut oil, methionine, or thiouracil, but not protein, sulfanilamide, or choline reduced the deadliness of lard. Both lard and coconut oil contain saturated fat, but lard has longer chain fatty acids and more unsaturated fat than coconut oil suggesting fatty acid chain length and/or degree of unsaturation may be important.

In the follow-up experiment, rats were rendered diabetic by surgical removal of 95% of their pancreas and fed high carb, high protein, or high lard diets (a, b, and d from the table above). In agreement with the first experiment, lard is bad news. On the other hand, whereas a high protein diet wasn’t helpful for alloxan diabetes, it was remarkably protective in pancreatic diabetes.

Influence of diet on incidence of alloxan diabetes (Rodriguez and Krehl 1952)

These researchers measured mortality and diabetes incidence in alloxan-treated rats and found that: 1) coconut oil is protective against mortality and diabetes; 2) lard is not; and 3) high protein is modestly protective. IOW, these data confirm Houssay’s from 5 years earlier.These authors added some information to the picture by measuring body weight and showing that the protective effect of coconut oil is not due to reduced body weight, because these coconut oil-fed rats weighed as much as those fed a low protein diet, and low protein diet-fed rats fared rather poorly.

To add yet more information to the picture (kudos!), they fed rats diets containing the most abundant fatty acids found in coconut oil (caprylic acid) or lard (palmitic acid) and showed that coconut oil’s benefits may be due to caprylic acid because this fatty acid alone was similarly protective against mortality and diabetes. They also showed lard’s malevolence is not due to palmitic acid because these rats were almost just as protected as those fed caprylic acid. This somewhat excludes a role of fatty acid length as caprylic acid has 8 carbons while palmitic acid has 16, but both are fully saturated (suggesting a possible detrimental role for unsaturated fatty acids [?]).

So why is coconut oil so good?

One possible reason: saturated fatty acids are protective, which is supported by the beneficial effect of coconut oil, caprylic acid, and palmitic acid. Similarly, lard and Swift’ning have a lot of unsaturated fats and both were detrimental.

Unsaturated fatty acids and alloxan diabetes (Rodriguez et al., 1953 Journal of Nutrition)

Rats fed saturated fats of varying chain length were remarkably more protected than those fed unsaturated fats. Lard has a lot of oleic acid, and rats fed oleic acid didn’t do so well; corn oil is predominantly unsaturated fat and rats fed corn oil were phenomenally unhealthy. They also showed that rats fed stearic acid (18-carbons, fully saturated) were much healthier than those fed oleic acid (18-carbons, monounsaturated). While none of these studies explored the ketogenic effects of C8-12 fatty acids, they clearly demonstrated that saturated fatty acids of any chain length are good for diabetics, while unsaturated fatty acids are bad. Good sources for C8-10 fatty acids are MCT oil and goat’s milk, and a good source for C12 fatty acids is coconut oil.

As to the role of ketones, which I think is quite important… to be continued

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Posted in Advanced nutrition, Dietary fat, Ketosis, Protein, Uncategorized

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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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?

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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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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

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

another side of leptin

Posted on January 19, 2012 | 1 comment

Op. 56

Leptin is probably just as important as insulin WRT obesity, and this is as just as good a place as any to learn about this increasingly interesting hormone.

ABCs of Leptin in a nutshell:

A. Fed state: leptin is secreted from adipose and tells the brain to maintain food intake and energy expenditure at a body weight set point, which is likely established by diet.

B. Fasted state: leptin secretion declines, causing hunger to go up and energy expenditure to go down.

In the past, the cause and consequence of leptin resistance received a lot of my attention due to their importance in obesity. Leptin resistance is, in brief, obesity. Or the mouse on the right:

C. Obesity: eating a poor diet causes leptin resistance, which allows the body weight set point to rise until your fat cells stop responding to insulin (it’s kind of complicated)

But there’s another side of leptin that is mostly unknown, frequently overlooked, and poorly understood. And I say this “is as just as good a place as any” to learn about it because while this side of leptin isn’t as popular as the energy expenditure, appetite, etc., stuff, it could very well be just as important, IMHO.

Leptin vs. the pathological hyperglycemia in diabetic state(s) (note the plural form of “state[s]”).

Leptin deficiency causes insulin resistance induced by uncontrolled diabetes (German, Morton, et al., 2011 Diabetes)

Divide and conquer

STZ is a beta-cell toxin used to induce diabetes. STZ-treated mice have low insulin, low leptin, and lose weight despite a voracious appetite (just like type 1 diabetic humans). Their insulin resistance is fully corrected while their marked hyperglycemia is attenuated by leptin injections. Leptin reduces food intake but this doesn’t reduce body weight because energy expenditure paradoxically declines (discussed below). Furthermore, diabetic mice restricted to eat only as much as leptin-treated diabetic mice (STZ-veh-PF) lose significantly more weight because they lack the leptin-induced suppression in energy expenditure.

Summary of energy balance:

Control mice (veh-veh) eat the least but have much lower energy expenditure, causing them to weigh the most. Energy expenditure is the more important variable driving high body weight in these animals (it goes down significantly more than food intake). Diabetic mice (STZ-veh) eat the most food which is balanced by high energy expenditure (explained below), causing an intermediate body weight. When the voracious appetite of diabetic mice is restrained (STZ-veh-PF), they weigh the least (they are starving). Food intake is the more important variable driving low body weight in diabetic mice (energy expenditure is the same in diabetic and diabetic-PF mice). STZ-leptin mice have intermediate food intake, energy expenditure, and body weight. All is well, leptin cures the deranged energy balance of type I diabetes.

As mentioned above, diabetic mice eat more but weigh less because of drastically increased energy expenditure. Energy expenditure is increased, in part, due to out-of-control gluconeogenesis (from hyperglucagonemia). The paradoxical effects of leptin on energy expenditure (increases it in post-obese subjects but decreases it in diabetic mice) may be explained by leptin-induced reduction of this out-of-control gluconeogenesis, mediated via normalization of glucagon.

The authors further demonstrated that leptin restores liver, but not muscle or adipose insulin sensitivity in diabetic mice, independent of food intake.

Thus, insulin-deficiency -> dec. leptin -> inc. glucagon -> inc. hepatic glucose output -> hyperglycemia

Insulin’s primarily role might be to suppress glucagon. STZ-induced “relative” state of starvation causes leptin to plummet; in the basal state, leptin may not have anything to do with glucagon because insulin keeps it under control. But in diabetes, there’s no insulin to suppress glucagon; this is where exogenous leptin struts its stuff.

Collectively, these data further support the conclusion that insulin’s major function is to suppress glucagon, as opposed to other effects in skeletal muscle or adipose. It’s been almost a year since Unger’s notorious publication which showed that glucagon receptor knockout mice were immune to type 1 diabetes (discussed here). Diabetic hyperglycemia is partially mediated by insulin resistance, and largely mediated by hyperglucagonemia. But why wasn’t hyperglycemia completely normalized by leptin replacement therapy? These researchers sought simply to normalize leptin levels, but what would’ve happened if they provided a supraphysiological dose of leptin? During physiological leptin replacement therapy, glucagon levels were normalized, but a hint of hyperglycemia remained. Some other [leptin resistant?] member(s) of glucagon’s nefarious cohort must be responsible for the residual diabetic hyperglycemia…

Fortunately for us, the effects of supraphysiological leptin were tested in an identical experimental paradigm:

Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling (Denroche, Kieffer, et al., 2011 Diabetes)

Indeed, supraphysiological leptin therapy overcame whatever diabetic “leptin resistance” remained and totally cured hyperglycemia.

This study repeated much of what was done in the first study, but whereas the first study added that leptin’s effect on food intake was not involved, this study showed that hepatic leptin signaling was not responsible either:

In both cases, hyperglucagonemia appears to be a major cause of diabetic hyperglycemia, and this is cured by leptin. Insulin sensitivity was only partially restored by physiological leptin replacement; this seems to be due to some sort of apparent “leptin resistance,” which is overcome by supraphysiological leptin. Diabetic insulin resistance is most likely caused by hyperglucagonemia-induced increased hepatic glucose output, and this is cured by leptin’s [non-hepatic] effects on reducing glucagon levels. Diabetic insulin resistance may be partially caused by a brain mechanism, but at least one brain mechanism (food intake) was ruled out by the German study.

And oh so interestingly, all of these effects were mimicked by leptin administration directly into the brain, at a dose which caused no change in peripheral leptin levels (German, Morton, et al., 2011 Endocrinology). The “STZ-lep” in the figure below refers to diabetic mice with leptin administered directly into the brain.

Back to the plural form of diabetic “state[s]” mentioned in the intro. All of the above studies were in insulin-deficient SKINNY type 1 diabetic mice. The next study is in OBESE type 2 diabetic rats.

Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats (Cummings, Havel, et al., 2011 PNAS)

N.B. the control rats in this study were pair-fed to the leptin treated animals to control for the leptin-induced satiation. Leptin-treated mice lost less weight most likely because energy expenditure declined (just like in the first study mentioned above).

In agreement with the glucose normalization seen by leptin treatment in skinny type 1 diabetic animals, leptin reduced glucose levels in obese type 2 diabetic rats, and this too was associated with reduced glucagon levels:

In type 1 diabetic animals, there are very low insulin levels regardless of food intake, leptin treatment, and hepatic leptin signaling. Thus, insulin has nothing to do with the effects of leptin in type 1 diabetes. This study showed that insulin levels also have nothing to do with the effects of leptin in obese type 2 diabetes:

So while the efficacy of exogenous leptin administration in established obesity is questionable, it is capable of combating the pathological glucagon-induced hyperglycemia which is responsible for much of the damage incurred by the diabetic state[s].

Leptin, glucagon, and diabetes.

calories proper

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Posted in Advanced nutrition, Energy balance, Leptin, pair-feeding, Sugar

Insulin, the nutrient anti-partitioner.

Posted on January 13, 2012 | 4 comments

“Insulin is a double-edged sword with a pointy tip” discussed the relationship between insulin and visceral fat. In brief, any dietary intervention which lowered insulin concomitantly reduced visceral fat, and this was accompanied by a variety of health improvements. Today’s post focuses more on the connection between insulin and body composition. Current hypothesis: reducing insulin causes weight loss, and this weight is primarily adipose (muscle is spared). IOW, insulin plays a primary [cause], as opposed to secondary [effect] role in regulating fat mass. FYI the alternative hypothesis states that reduced insulin levels are simply one of the many beneficial effects of weight loss.

Exhibit A: lower insulin is correlated with more fat loss

1. Diet-induced reduction in insulin

A. Glycemic load

Long-term effects of 2 energy-restricted diets differing in glycemic load on dietary adherence, body composition, and metabolism in CALERIE: a 1-y randomized controlled trial (Das et al., AJCN 2007)

In this year-long study, the low glycemic load (GL) diet reduced insulin levels to a greater degree than the high GL diet (-21.2% vs. -18%), and this resulted in more total fat loss (-26.1% vs. -23.5%), and a greater proportion of the total amount of weight lost was comprised of fat (92% vs. 81%). The differences were small, but probably not due to chance given the consistency and specificity of this effect (see below).

B. Calories vs. carbs

The role of energy expenditure in the differential weight loss in obese women on low-fat and low-carbohydrate diets (Brehm et al., 2005 JCEM)

In this 4 month-long study, the low-carb diet lowered insulin over twice as much as the low-fat diet (-36.8% vs. -13.6%), which resulted in significantly more total fat loss (-6.7% vs. -3.8%), and a greater proportion of the total weight lost was comprised of fat (92% vs. 81%). The absolute differences between studies (comparing these results directly to the above results) are big, but this is not unexpected because each study has markedly different 1) patient populations, 2) study durations, and 3) interventions.

2. Exercise-induced reduction in insulin

Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men (Ross et al., 2000 Annals of Internal Medicine)

In this rather complicated 3 month-long study, the exercise group lost weight, and this was compared to a group who lost a similar amount of weight by diet alone. The diet-alone group functioned as a control for the negative energy balance. Exercise lowered insulin levels more than diet alone (-41.4% vs. -17.9%), which resulted in more fat loss (-18.4% vs. -16.9%), and a greater proportion of the total weight lost was comprised of fat compared to diet alone (81.3% vs. 64.9%). If a greater proportion of the total weight lost was comprised of fat, then the intervention selectively spared lean mass resulting in a more favorable body composition; this occurs consistently in every study mentioned in this post.

Exhibit B: pharmacologically lowering insulin causes fat loss

1. Diazoxide

Beneficial effect of diazoxide in obese hyperinsulinemic adults (Alemzadeh et al., 1998 JCEM)

Diazoxide directly targets the pancreatic beta-cells to reduce glucose-stimulated insulin secretion. In this 2 month-long study, diazoxide combined with a low-calorie diet reduced insulin levels more than diet alone (-35.7% vs. -14.7%), which resulted in more fat loss (-19.8% vs. -6.8%), and a significantly greater amount of the total weight lost was comprised of fat compared to diet alone (95% vs. 72%).

2. Octreotide

Efficacy of octreotide-LAR in dieting women with abdominal obesity and polycystic ovary syndrome (Gambineri et al., 2005 JCEM)

Octreotide is a somatostatin analogue which suppresses, among other things, insulin secretion. In this 7 month-long study, octreotide combined with a low calorie diet reduced insulin levels more than diet alone, which resulted in more fat loss (-6.4% vs. -2.4%), and a greater proportion of the total weight lost was comprised of fat.

Exhibit C: insulin increases fat mass

The previous data supported the hypothesis that lowering insulin, by multiple completely different mechanisms, results in reduced fat mass. The next evidence argues against the opposite hypothesis and supports a direct role for insulin in increasing fat mass.

Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus (Makimattila et al., 1999 Diabetologia)

In this year-long study, diabetic hyperglycemia was treated with insulin alone or insulin combined with metformin. All subjects in this study gained weight and fat mass. The addition of metformin to insulin therapy blunted the increase in insulin levels (30.8% vs. 45.5%), which reduced fat gain (11.6% vs. 22.1%), and only 73.7% of the weight gained was fat compared to 91.8% by insulin alone.

Administration of exogenous insulin increases fat mass. Reducing insulin, by a variety of means, burns fat and spares lean mass.

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