Wednesday, 30 January 2013

High glycemic index starch promotes hypersecretion of insulin

High glycemic index starch promotes hypersecretion of insulin and higher body fat in rats without affecting insulin sensitivity.

I think im approaching a pretty convincing model for diabesity. Some additional clues come from this paper. 

The major finding here is that 7 weeks of a high GI diet in rats leads to increased insulin secretion in response to an intravenous-glucose tolerance test. Importantly this increased insulin secretion is NOT a response to insulin resistance because glucose tolerance was not impaired.

So the insulin-hypersecretion is primary.

In the discussion the researchers are not sure why a high GI diet leads to insulin hyper-secretion and speculate that it may have to do with triglyceride accumulation in the beta cells. But from JJ's paper we learned that there is positive feedback mechanism between the pancreas and insulin secretion. More insulin can easily lead to MORE insulin during future hyperglycemic challenges from your plain boiled potatoes.

Oh, and the insulin hyper-secreting rats on the high GI diet also had increased fat mass. But im sure thats just coincidence. ( feeding regime was isocaloric, just before you CICO nutters try to jump in. )

The high GI diet promoted a high insulin response during an intravenous glucose tolerance test (IVGTT) (14), which increased with the duration of feeding (15) and eventually led to fasting hyperinsulinemia

So if the results of JJ's study says that hyperinsulinemia drives obesity, we have a connection, for the above quote says that consumption of a high GI diet leads to hyperinsulinemia.

Which, according to JJ's paper says, drives obesity.

I.E. spiking your blood sugar makes you fat. 

But, most of us ( educated ) fatties already know this. So lets move on...........

It has been reported that the mRNA expression and activity of fatty acid synthase, a key lipogenic enzyme, increase in adipose tissue after only 3 wk of wheat starch feeding

hhhhhmmmm, what about 3 weeks of plain boiled potato feeding?

We speculate that this hypersecretion of insulin in response to a glucose challenge after only 7 wk of feeding may alter fuel utilization and patterns of energy disposition, irrespective of changes in insulin sensitivity.

Indeed, this study  says that  "fatty acid oxidation was significantly blunted as early as 3 wk after beginning of the high-GI intervention" and occurred before any significant increase in fat mass, indicating a possible causal role. ( only "possible"?! lol )

Bottom line, I think the idea that insulin feeds back positively to increase beta cell mass and insulin secretion is a missing part of the "Insulin Hypothesis".

Monday, 28 January 2013

Calorie restriction for weight loss?

I am strongly against calorie restriction. All the evidence I have seen indicates that, even if weight loss does occur, it changes your physiology and sets you up for future weight gain. Heres an introduction to "wet your appetite".

If an animal is in energy balance, its body mass and body composition generally remain stable. Although animals can adjust for subtle alterations in energy budget over the short term, prolonged imbalances can cause weight gain or loss. Dietary restriction has been advocated as a treatment for obesity for over 2500 years (Hippocrates, 5th century B.C.). Yet, despite the fact that caloric restriction is the oldest, most frequently prescribed and self-prescribed treatment for overweight and obesity, the strategy is seldom successful. Rates of weight loss under restriction are rarely sustained for any protracted period. Moreover, the lost weight is frequently regained when the period of restriction ends. ( link )

This paper does a good job of laying out what happens with calorie restriction, here are the best bits.....

  • There are 3 primary mechanisms how organisms cope with reduced calorie intake, increased digestive efficiency, reduced basal metabolic rate, and third, reduced activity.
  • There are 2 phases to calorie restriction, first, an adaption phase, where energy parameters are adjusting ( reducing ) to match the new energy availability of the diet. And second, a maintenance phase where the adjustments are now complete and energy balance is established. ( i.e. weight loss has finished, you are now weight stable at a reduced calorie intake, welcome to hypo-metabolism )
  • Body temperature declines during calorie restriction, shown for both rodents and monkeys.
  • During calorie restriction, not all weight lost is fat mass, a significant amount is also fat-free mass.
  • Different things happen depending on the severity of the calorie restriction. For example in rats, 25% reduction allowed only temporary weight loss before compensatory mechanisms adapted and body mass increased again. Meanwhile 50% reduction wasn't able to be compensated for and body mass continued to decline.
  • In Monkeys, After 30% calorie restriction for 5 years only fat-free mass showed reductions, fat mass was comparable to controls.

And lets not forget our 5% calorie restricted mice that straight out gain fat mass. In general it appears mild calorie restriction serves only to increase fat mass.

A recent study has examined the neuroendocrine changes that occur with diet-induced weight loss. ( Lets put aside the well known affect of leptin insufficiency for the moment ). One of the things that occurs in diet-induced obesity is ghrelin resistance in the AgRP neurons. Normally, ghrelin serves to increase AgRP.

So anyway, this study starts off with making some rodents fat, ( high-fat diet again ) then, after obesity is established, they switch the diet of the rodents back to chow, or chow with 40% calorie restriction. Heres a graph of the final body weights...

Both sets of rodents switched back to chow and chow with 40% calorie restriction lost weight. The calorie restriction group lost more weight than the Ad libitum chow group. Although this just barely made statistical significance. This is 40% calorie restriction btw, if you live on 2000 calories per day this is equivalent to putting you on a diet of 1200 calories per day, and you loosing only slightly more weight than someone eating 2000 calories per day.  Sounds fair right?

Now here is the really interesting part, despite both the chow and chow + 40% calorie restricted groups both losing weight, ONLY the 40% calorie restricted group experienced a ( very ) significant increase in hypothalamic AgRP expression. See next graph.....

Despite the 40% calorie restricted group weighing the same as never obese controls, they have marked increased AgRP. Hence, just because they weigh the same as controls, they are NOT metabolically the same as controls. The increased AgRP means their bodies perceive their current weight to be too low and in a state of starvation even though they are actually of normal weight.

But look at HF-C, this is the group that lost weight eating Ad Libitum. They had the same level of AgRP as controls, indicating that their bodies did not perceive their new reduced weight as a state of starvation. This result suggests that weight loss without enforced calorie restriction does not increase AgRP, and so should hopefully make you less vulnerable to weight regain. Indeed, the authors make the point that it is the detection of negative energy balance that leads to increased AgRP following weight loss, and not the actual weight loss itself. If you can lose weight without your body detecting the negative energy balance, without stimulating an increase in AgRP, your probably more likely to maintain the weight loss.

In short, this study says weight loss must be achieved without enforced calorie restriction to be sustainable. Weight loss with enforced calorie restriction increases AgRP, which is NOT sustainable unless you prefer to live in misery.

Infact we saw this same thing back in the ketogenic diet unique state study.  Mice subjected to 35% calorie restriction had a nasty increase in AgRP despite similar bodyweight compared to ketogenic fed mice eating Ad Lib. Although these mice did not start off from an obese state.

This increase in AgRP in response to calorie restriction is very prominent in the literature, and make no mistake, AgRP WILL make you gain weight.

Lets re-iterate how potent AgRP is, courtesy of this paper.

  • Agouti-related protein acts as an inverse agonist for the melanocortin receptors, MC3R/MC4R
  • The integral role of the melanocortin system in body weight homeostasis is supported by the fact that any mutation in the melanocortin signaling pathway including MC3R- or MC4R-null mutants and ectopic expression of MCR3/4 antagonist, AgRP, results in hyperphagia, hypometabolism, hyperinsulinemia, and hyperglycemia in both rodents and humans
  • The release of α-MSH by POMC neurons and its binding to G-coupled MCR’s initiates the central anorexic signaling pathway that results in decreased food intake and increased energy expenditure while AgRP exerts its orexigenic action partly by blocking the binding of α-MSH to its receptor there by preventing the α-MSH-induced anorexic pathway
  • Thyroid-releasing hormone (TRH)-, oxytocin (OT)-, and corticotropin-releasing hormone (CRH)-expressing neurons located in the PVN all express MC4R. The binding of α-MSH to MC4R on these neurons has a positive action onto the hypothalamic–pituitary–thyroid (HPT) axis and the hypothalamic–corticotropic axis (HPA). During fasting ( or calorie restriction as we learned in this post ), increased release of AgRP by AgRP neurons has been demonstrated to be a key mechanism for fasting-induced down regulation of the HPT axis and the consequent adaptation during negative energy balance
  • AgRP neurons are necessary and sufficient to initiate the full feeding sequence.
  • extinction of α-MSH signaling cascade was not necessary for AgRP neurons to initiate feeding. ( basically this is saying an increase in AgRP will always initiate feeding, regardless of what the POMC neurons are doing )
  • Lack of AgRP neurons results in death from starvation because mice lose all interest in food and stop eating.
  • AgRP decreases fertility ( link )
  • AgRP increases respiratory quotient, making you oxidize carbohydrate and preserve fat. ( link

"Starvation mode" is a mythical bro-science term that would commonly be stated to be a mode that you get into if you chronically restrict food intake. Well to me, it looks like "starvation mode" is actually a very real phenomenon and is mediated by AgRP.

Tuesday, 15 January 2013

JJ's Insulin Paper and beta-cell expansion

Wow I havent made a post on this paper yet.

By now it seems pointless, everything that could of been discussed has already been discussed about it elsewhere. However the points about beta cell mass expansion in obesity were interesting.

Pancreas and beta cell is an area that I am under-researched in ( I have been focusing alot on the morphology of the adipose tissue ), so I was a bit surprised that learn that beta cell mass increases in obesity. Its worse than I could ever have imagined, one study reports as much 10-30% increase in beta cell mass for each 10kg in weight gain.

One of the best lines in JJ's paper is this...

Together, many lines of evidence from multiple groups support the concept that insulin acts via insulin receptors to mediate the compensatory increase in b cell mass and basal insulin release in the context of high-fat diet

Ignore the bolded part for now. What JJ says in the paper is that there appears to be some kind of positive feedback mechanism between insulin secretion and beta cell expansion. I.E. insulin acts via receptors locally on the pancreas to promote beta cell expansion. Insulin hyper-secretion feeds back positively to the beta cells telling them to increase mass, presumably so that you can become a better insulin hyper-secreter in the future.

more insulin leads to more insulin leads to more insulin.

Yeh something like that.

Ofcourse the beta cells probably dont have any idea in the meantime that all this insulin its learning to pump out is rapidly expanding your fat tissue.

In addition there is this excerpt from the 2004 paper linked above...

In conclusion, obesity is a condition of predominantly β-cell functional upregulation rather than β-cell expansion. This upregulation involves the static responses (i.e., basal and total secretion) much more than the dynamic responses (i.e., glucose sensitivity and potentiation), at least as long as glucose-tolerant subjects are concerned. The insulin hypersecretion of obesity has a primary component, which cannot be explained by adaptation to insulin resistance and can be tracked through the period of weight loss (induced by calorie reduction or restrictive bariatric surgery). The residual insulin hypersecretion of the postobese (or weight-reduced) state may be the equivalent of an inherent insulin hypersecretion of the preobese condition.

So what im getting at is this, did you become obese because your pancreas learned to become an insulin-hypersecreter? All the fucked up stuff that happens with the morphology of your adipose tissue is likely just the result of this insulin-hypersecretion.

But, what provided the positive feedback of insulin hypersecretion to get the snowball rolling in the first place? I think this is a good point to go back to the Jenkins study . Insulin-hypersecretion BEGINS in response to blood sugar spikes.

But what causes blood sugar spikes? Again as shown in the Jenkins study, it is fast absorption of lots of glucose. Jenkins shows that fast absorption of glucose alone is not enough to spike blood sugar, you must also have significant amounts for it to build up in the blood ( I suppose thats obvious really, a single glucose molecule is not going to spike your blood sugar ) . Also we have to consider the degree of hepatic insulin resistance you have and how well you can activate glucokinase in the liver in response to carb ingestion.

All in all, the physiology remains complex, but the cause remains simple. Its the fast digesting, glucose dense foods spiking your blood sugar that is making you fat.

Also what happens with weight loss? Does beta cell mass shrink along with your BMI? Even after youve lost weight, it doesnt change the fact you were an insulin-hypersecreter in the past. And you can be one again in the future. You just need to get the snowball rolling again with some potato.

Saturday, 12 January 2013

Ketones slow heart rate

Ketones slow heart rate, meanwhile short chain fatty acids increase heart rate. Both β-hydroxybutyrate and SCFA act through the receptor gpr41 to decrease or increase sympathetic nervous system activity, respectively. ( yes, much to everyone's surprise, BHB actually decreases sympathetic activity. )

Below are the graphs showing changes in heart rate in mice with infusion of either SCFA or BHB, note that gpr41-/- stands for mice that have knock-out of this receptor and so will not respond to the infusions.

On the left graph we see a gradual decline in heart-rate of wild-type mice in response to BHB infusion. On the right graph we see an increase in heart rate with Propionate infusion.

In contrast to BHB, the other ketone bodies acetoacetate and acetone had no affect on gpr41 acitvity, so BHB is the only ketone which decreases energy expenditure.

Something interesting is that the gpr41-/- mice had reduced body temperature. This is because without the gpr41 receptor the SCFA cannot act to increases the sympathetic nervous system, and so thermogenesis in response to feeding is diminished. ( they also report that ucp1 in brown adipose tissue was reduced in gpr41-/- so this is probably another reason for reduced body temp. )

Remember that BHB blocks gpr41, I had a weird idea flash in my head with this, ive seen alot of people complain of feeling cold on long term ketogenic dieting, and attribute it to reduced thyroid or whatever. This study suggests that increased serum ketones/BHB may be contributing to that decreased body temperature by antagonizing gpr41.

In theory this decline in body temperature can be reduced by consuming significant fibre that will go on to ferment in the colon to SCFA, and these SCFA increase sympathetic activity via the gpr41 receptor.

In theory,    that is.........

Heres another thing that comes to mind, the idea of carb refeeds to beat a weight loss plateau. Theres lots of theories as to how this works, including insulin and carbs bumping up leptin. Another idea could be the interplay between insulin and ketones on SNS activity.

Both ketones and insulin inhibit SNS activity, weight loss should be highest when SNS is highest. This must occur when both insulin and ketones are low. The situation of low insulin and low ketones will occur when you are transitioning from a high carb refeed back to a ketogenic state.

Once you have spent a few weeks in ketosis, insulin will be chronically low, ketones will be consistently elevated, and therefore SNS activity will be consistently depressed.


A link I found in the gpr41 paper goes here, where they say acetate, but not butyrate, stimulated leptin secretion from adipocytes. More good news for vinegar then I guess.

Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

Tuesday, 8 January 2013

Random papers on Insulin and FFA

im feeling very cba today, not gonna write anything comprehensive.

The Taubes talk that sidereal linked to sent me on a pubmed crusade and I found some interesting papers im just gonna link here and drop some short thoughts,

Dose-dependent effect of insulin on plasma free fatty acid turnover and oxidation in humans.

If anyone can link the full text of this paper I would very grateful. This is the paper where in the talk, Taubes shows how FFA turnover is strongly activated below a certain insulin threshold.

Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man.

Insulin inhibits net lipid oxidation. Nothing new, but I will read the full paper later.

Insulin causes endothelial dysfunction in humans: sites and mechanisms.

Does insulin cause atherosclerosis?

Modulation of the hepatic malonyl-CoA-carnitine palmitoyltransferase 1A partnership creates a metabolic switch allowing oxidation of de novo fatty acids.

Im not really interested in this study but the stuff in the introduction is relevant. Glucose and insulin inhibit liver fatty acid oxidation, and as I blogged on previously inhibition of liver fat oxidation increases appetite via vagal nerve stimulation ( see Hepatic Oxidation Theory in the literature ).

This is why grazing on carbohydrates is such a vicious cycle, small quantities of carbs inhibit liver fat oxidation stimulating appetite but if you only eat a small portion of food you wont secrete enough incretins to offset that increase in appetite.

I think this is also a prime reason mice get fat on "high-fat diets" ( apart from peter's hypothalamic injury idea ), because usually, they are given Ad Libitum access to the food and tend to graze on it throughout the day, the small amount of carbs in this high-fat diet immediately inhibits liver fat oxidation, so all that fat they are eating is not oxidized and is instead packaged up as triglycerides/cholesterol and exported from the liver.

As demonstrated in the time-restricted feeding study, if you dont give the mice ad libitum access to the food, and make them do some intermittent fasting, their PPAR(alpah) shoots up indicative of increased fat oxidation, which is what you want on a high-fat diet.

BTW im sure animals dont have access to food Ad Libitum in nature, they get sick on such a protocol because there has been no evolutionary selective pressure to adapt to Ad Libitum food access.

Bottom line, if your gonna eat carbs, you gotta get some Intermittent fasting in your protocol.

Increased secretion of very low density lipoprotein triglyceride following inhibition of long chain fatty acid oxidation in isolated rat liver.

Increased secretion of triglyceride and cholesterol following inhibition of long-chain fatty acid oxidation in rat liver.

How do we inhibit liver fat oxidation? I just told you above, you eat carbs and spike insulin.