Richard over at Free the Animal has done all of the donkey work on the latest TEE study. I'd just like to add a happenyworth.
Dr Micheal Eades in 2007:
"...what we’re talking about as a metabolic advantage is at the max about 300 kcal per day."
Ludwig's group using stable isotope doubly labeled water for Total Energy Expenditure assessment in 2012:
"During isocaloric feeding following weight loss, REE was 67 kcal/d higher with the very lowcarbohydrate diet compared with the low-fat diet. TEE differed by approximately 300 kcal/d between these 2 diets..."
I'm no great fan of metabolic advantage arguments. I like uncoupling proteins and the way that feeding electrons in to the respiratory chain at the FADH2/CoQ couple is significantly less efficient than feeding them in as NADH at complex I. Calories out can be in to heat (or in to adipocytes if you are so inclined). Your body can't harvest heat from the respiratory chain. We radiate that. There is a modest emphasis on NADH production from glucose and on FADH2 generation from beta oxidation... They feed in differently.
There have been some ugly arguments on the net over the years about metabolic advantage. Eventually the numbers give you some sort of idea as to who is correct and who is talking bollocks.
Quite why fat metabolism should be intrinsically more thermogenic than glucose metabolism is very interesting. Maybe there will be time to go in to this some day. But I live with a core body temperature at well above ambient, most of the time.
But for now, I simply find the number match between 2007 and 2012 rather gratifying.
Peter
Friday, June 29, 2012
Monday, June 25, 2012
The Flatline Days
Almost done with insulin infusions, thankfully. This post follows on from the initial post here.
It's time to discuss the discussion and then leave this paper for ever. Here's your starter for 10, and I quote:
"These three studies suggest the following: (1) insulin limits meal size when blood levels are modestly elevated for prolonged periods of time in the rat, (2) this decrease in meal size is not compensated for by an increase in meal frequency and, hence, total daily food ingestion and body weight gain are reduced, and (3) this effect appears to be a heightening of satiety rather than an induction of illness."
and at the end of the discussion:
"...it seems probable that our prolonged, modest elevations of insulin resemble the elevated basal plasma insulin induced by prolonged overfeeding and perhaps, obesity."
Let's combine suggestions (1) and (2) and drop down to our local McMuffin restaurant to watch the people eat. I've never tried this, so you have to realise I'm making all of this up, in its entirety.
In comes Jo Blob at 400kg, fasting plasma insulin at 100microIU/ml. Obviously this fasting hyperinsulinaemia blunts his appetite and he turns down the "you wanna supersize that?" offer, sits picking at his fries and soda for half an hour and eventually pushes the burger-in-a-bun away after three mouthfuls as his satiety hormone has kicked in, to even higher levels than it was when he was fasting.
Across the aisle sits Dr Guyvernment at 55kg with a fasting insulin of 5microIU/ml. Where is his satiety? Obviously he is ravenous and after the double baked potato with a baked potato on the side and three baked potatoes to follow, he's still ravenous because he is so insulin sensitive that he can't get his satiety hormone level over diddly squat.
It's the age old story. Skinny people overeat because their insulin levels are low and and fat people are chronically over sated so refuse food. Have you noticed anything along these lines? No? Somewhere along the line we do have to have a reality check!
The next statement from the discussion which caught my attention was this one:
"As pointed out earlier, some animals which received the higher dosage of insulin showed hyperphagia, as has been reported in numerous other studies [3. 8, 9, 11, 15]. It is probable that animals which became hyperphagic were more insulin sensitive and perhaps increased food intake to counteract hypoglycemia."
Okaaaay. This suggests that the animals on 6iu/24h over-ate. On average. I hate to query the obvious but does this imply the animals on 1iu/24h didn't overeat? So of course this means that the 6iu/24h animals must have gained more weight due to their hyperphagia. So did the 6iu/24h group really gain extra weight compared to the 1iu/24h group? Go look at Fig 1. Here it is again if you've forgotten:
Duuuuh. The 1iu/24h group gained more weight than the (partially hyperphagic) 6iu/24h group, even if p never got below 0.05. The people who wrote the quoted text are the same people who drew the graph... They have the daily food intakes and weight gains for each individual rat...
And finally, before I leave this execrable paper for ever, are the animals on insulin pumps just ill from their insulin infusion? Let's quote the authors again:
"We realize that a simpler explanation for our results might be that the animals become sick following the release of the insulin, however, we offer two arguments against this. First, water intakes were not decreased by insulin infusions from the Minipumps but were elevated by an average of 47.3% during the first 2 days following pump implantation and then returned to normal. Following this initial elevation, water intakes were not significantly different from controls (0 U/day animals) and the pump-implanted animals’ own baselines..."
Never mind the second argument. Let's think about polydipsia (and presumably polyuria because weight didn't increase) as markers of robust good health in a patient, any patient. I'll use a make-believe, utter fantasy, clinical setting:
Dr Insulin: Ah, hello Mrs Ratty, how are you since I implanted your insulin infusor pump two days ago, to help control your appetite?
Mrs R: I can't seem to stop drinking. I've always got to have a bottle of Evian by my side and I'm spending 47.3% more on the stuff. I wake up in the night to have a drink and I always seem to be spending a penny.
Dr I: Excellent, a good thirst is always my first maker of robust health.
Mrs R: Oh, so you won't need this urine sample I've brought?
Dr I: Oh no, no need to check your urine if you have a healthy thirst.
Mrs R: So I can throw it away?
Dr I: Of course. By the way, is that your sample in the five litre container? Could I oblige you by assisting with its disposal?
Mrs R: Thank you so much, it is quite heavy. You are so helpful. Goodbye.
Dr I: Goodbye (and after Mrs R has left): Igor, IGOR! Come, never mind the LIRKO mice, we have jam a-plenty tonight. Boil down this sample at once...
Okay. If a rat on a pump giving a constant rate infusion of insulin gets Somogyi overswing, how long does it take for the overswing to correct itself, while ever insulin levels are held constant?
I would guess two, at the most three, days. The Flatline Days. When glucose is high and appetite is consequently low. Pure speculation. It would have taken 30 seconds on a urine glucose test stick to check this. They had the sticks.
Peter
It's time to discuss the discussion and then leave this paper for ever. Here's your starter for 10, and I quote:
"These three studies suggest the following: (1) insulin limits meal size when blood levels are modestly elevated for prolonged periods of time in the rat, (2) this decrease in meal size is not compensated for by an increase in meal frequency and, hence, total daily food ingestion and body weight gain are reduced, and (3) this effect appears to be a heightening of satiety rather than an induction of illness."
and at the end of the discussion:
"...it seems probable that our prolonged, modest elevations of insulin resemble the elevated basal plasma insulin induced by prolonged overfeeding and perhaps, obesity."
Let's combine suggestions (1) and (2) and drop down to our local McMuffin restaurant to watch the people eat. I've never tried this, so you have to realise I'm making all of this up, in its entirety.
In comes Jo Blob at 400kg, fasting plasma insulin at 100microIU/ml. Obviously this fasting hyperinsulinaemia blunts his appetite and he turns down the "you wanna supersize that?" offer, sits picking at his fries and soda for half an hour and eventually pushes the burger-in-a-bun away after three mouthfuls as his satiety hormone has kicked in, to even higher levels than it was when he was fasting.
Across the aisle sits Dr Guyvernment at 55kg with a fasting insulin of 5microIU/ml. Where is his satiety? Obviously he is ravenous and after the double baked potato with a baked potato on the side and three baked potatoes to follow, he's still ravenous because he is so insulin sensitive that he can't get his satiety hormone level over diddly squat.
It's the age old story. Skinny people overeat because their insulin levels are low and and fat people are chronically over sated so refuse food. Have you noticed anything along these lines? No? Somewhere along the line we do have to have a reality check!
The next statement from the discussion which caught my attention was this one:
"As pointed out earlier, some animals which received the higher dosage of insulin showed hyperphagia, as has been reported in numerous other studies [3. 8, 9, 11, 15]. It is probable that animals which became hyperphagic were more insulin sensitive and perhaps increased food intake to counteract hypoglycemia."
Okaaaay. This suggests that the animals on 6iu/24h over-ate. On average. I hate to query the obvious but does this imply the animals on 1iu/24h didn't overeat? So of course this means that the 6iu/24h animals must have gained more weight due to their hyperphagia. So did the 6iu/24h group really gain extra weight compared to the 1iu/24h group? Go look at Fig 1. Here it is again if you've forgotten:
Duuuuh. The 1iu/24h group gained more weight than the (partially hyperphagic) 6iu/24h group, even if p never got below 0.05. The people who wrote the quoted text are the same people who drew the graph... They have the daily food intakes and weight gains for each individual rat...
And finally, before I leave this execrable paper for ever, are the animals on insulin pumps just ill from their insulin infusion? Let's quote the authors again:
"We realize that a simpler explanation for our results might be that the animals become sick following the release of the insulin, however, we offer two arguments against this. First, water intakes were not decreased by insulin infusions from the Minipumps but were elevated by an average of 47.3% during the first 2 days following pump implantation and then returned to normal. Following this initial elevation, water intakes were not significantly different from controls (0 U/day animals) and the pump-implanted animals’ own baselines..."
Never mind the second argument. Let's think about polydipsia (and presumably polyuria because weight didn't increase) as markers of robust good health in a patient, any patient. I'll use a make-believe, utter fantasy, clinical setting:
Dr Insulin: Ah, hello Mrs Ratty, how are you since I implanted your insulin infusor pump two days ago, to help control your appetite?
Mrs R: I can't seem to stop drinking. I've always got to have a bottle of Evian by my side and I'm spending 47.3% more on the stuff. I wake up in the night to have a drink and I always seem to be spending a penny.
Dr I: Excellent, a good thirst is always my first maker of robust health.
Mrs R: Oh, so you won't need this urine sample I've brought?
Dr I: Oh no, no need to check your urine if you have a healthy thirst.
Mrs R: So I can throw it away?
Dr I: Of course. By the way, is that your sample in the five litre container? Could I oblige you by assisting with its disposal?
Mrs R: Thank you so much, it is quite heavy. You are so helpful. Goodbye.
Dr I: Goodbye (and after Mrs R has left): Igor, IGOR! Come, never mind the LIRKO mice, we have jam a-plenty tonight. Boil down this sample at once...
Okay. If a rat on a pump giving a constant rate infusion of insulin gets Somogyi overswing, how long does it take for the overswing to correct itself, while ever insulin levels are held constant?
I would guess two, at the most three, days. The Flatline Days. When glucose is high and appetite is consequently low. Pure speculation. It would have taken 30 seconds on a urine glucose test stick to check this. They had the sticks.
Peter
Tuesday, June 19, 2012
Insulin, are you hungry?
An apology. This is a dry post, I had to edit the zombies out as it was getting way too long, maybe another day. It's a bit difficult to know where to start on quite how bad this paper is. Obviously, having read the abstract, we can flick down pretty well immediately to Fig 1 in the full text.
There are a few oddities. First is the flat line in weight gain on days 1, 2 and 3. This is the suppression of hunger by insulin, maybe. There was a full seven days on insulin. This I will return to in the next post.
Next is the sudden increase in weight gain through days 4, 5, 6 and 7 in the insulin infused groups, giving a final set of weight gains on day 7 which are not statistically distinguishable from controls. Except in the group on 2iu/24h of course. The group receiving 2iu/24h is special.
Then there are the data from days 11, 12, 13 and 14. By this time the insulin infusion had stopped (which occurred around day 7ish). Look at the 2iu/24h group. Waaaay after the insulin infusion had stopped their weight gain was still much slower per day than the other three groups. Oddly this didn't reach p < 0.05, despite standard errors which were far from overlapping those of the other three groups. But trying to see what the final weights gains were is difficult because these "post pump" weight gains have been, err, umm, sort of, err. I'm not sure what the word I need is...
You see the data from these last four time points are slightly moved. Each plot has been pulled down, and by a different amount each. No one is going to say by how much. It's pretty obvious that the control line can simply be moved back up to show a linear increase in weight from the insulin infusion period as these rats never got any insulin. But all lines have been shifted down so their day 11 values are set to their day 7 values, whatever the intermediate weight gain on days 8, 9 and 10 was. It is quite likely that the 6iu/24h and the 1iu/24h rats gained weight fairly linearly and so possibly ended up on day 14 at exactly the same weight as the control group. Or heavier.
It's also very likely that the 2iu/24h group also gained weight fairly linearly but slowly, ie their "pulling down" of day 11 values to those of day 7 didn't involve much of a drop compared to the other three groups. Who knows outside the lab?
Here are the data from Fig 1 in tabular form:
Anyhoo, the 2iu/24h rats, however much they did or didn't eat/gain on days 8, 9 and 10, only gained 1.39g/d on days 11, 12, 13,and 14. Food intake per day was down significantly through this later period, 27.7g/d vs at least 30g/d in all other groups. This is very important. The implication is that if you get yourself set up with just the right insulin infusion for a week, then you still won't be hungry a week later! Wow. Insulin is a satiety hormone blah blah blah.
But if you under-dose at 1iu/24h then it's, oh-oh, back up to pre-infusion weight gain rate, or possibly slightly more. Ditto if you over-dose at 6iu/24h, just the same thing happens. Fascinating. Do you think there might be something odd about this 2iu/24h group? Perhaps someone should repeat the experiment at this infusion rate? Then we might see if the result for these rats, on which the whole concept of suppression of weight gain over 7 days rests, was a quirk. No stats were done on the zero weight gain days, ie days 1-3 on insulin. The only p< 0.05, on which the title of the paper rests, was the 2iu/24h group at day seven.
If we lose the 2iu/24h group all we can say is that an insulin infusion reduces weight gain for three days, with complete restoration of any lost weight gain by the seventh day of a continuing infusion.
So, has the experiment been repeated? Luckily it has. By this very group. And the results are in this very same paper! But well buried. You have to be a dissonant pedant to find it. It's all in Figure 4.
This not quite the same experiment as Fig 1, the timings are slightly changed, but the basic design with insulin at 2iu/24h for seven days is identical.
In the main experiment time "on pump" was 7 days and they looked at all of these days, averaging everything over this time.
In Fig 4 they did the same 2iu/24h pump for seven days but only analysed days 3, 4 and 5 as time "on pump". Go figure. They also chose days 8, 9 and 10 as their "post pump" days vs days 11-14 in the first part of the study. Again, go figure. But eyeballing the graphical weight changes in Fig 1, I doubt this matters.
The data in Fig 4 look at meal size and meal frequency because that's how you bury data. But we can reverse engineer Fig 4 to get total food intake per day. Take a ruler to the graph. Multiply meal size by meal frequency and you get food intake per day, neat huh?
The rats on 2iu/24h ate 25.5g/d during "on pump" days 3, 4 and 5. This is pretty much the same as the total 7 day value from Fig 1 and Table 1. Happy researchers? Well done for correct choice of days. But...
Does the depressed food intake continue even after insulin has finished? Do you get sustained appetite control if you get the insulin infusion "just right" for a week? Eyeballing Fig 4's "post pump" values, these are about 3.4g/meal, 9.8 meals/day giving over 33g/d food intake...........
My, those are bloody hungry rats! This is the highest food intake per day in any group in the whole paper. It's the direct opposite of the findings presented in Fig 1 "off pump" section. The sustained depression of food intake shown in both Fig 1 and Table 1 could not be repeated in the Fig 4 experiment.
It doesn't happen.
The 2iu/24h group are no different to any other infusion rate when you look at Fig 4 "post pump" section. Quite why the rats on 2iu/24h used to generate Fig 1 data showed depressed weight gain long term is a complete mystery. Personally I'd want to have had a pathologist check out the pumps in the lowest food intake rats in this group, looking for low grade peritonitis. The pumps are in the abdominal cavity. Maybe some surgeon dribbled in to the wound during implantation. I've worked with surgeons. Ultimately we'll never know.
But ANYONE quoting the data presented of Fig 1 to you WITHOUT even mentioning the results of Fig 4 to you is, well, hmmmmm..... probably in obesity research.
I was going to go on to discuss the flat line of weight gain on days 1, 2 and 3 (at all insulin infusion rates) next but I'll leave that to another post as it has nothing to do with the "insulin at 2iu/24h causes sustained decreased food intake" claim.
Which is complete bollocks.
Peter
There are a few oddities. First is the flat line in weight gain on days 1, 2 and 3. This is the suppression of hunger by insulin, maybe. There was a full seven days on insulin. This I will return to in the next post.
Next is the sudden increase in weight gain through days 4, 5, 6 and 7 in the insulin infused groups, giving a final set of weight gains on day 7 which are not statistically distinguishable from controls. Except in the group on 2iu/24h of course. The group receiving 2iu/24h is special.
Then there are the data from days 11, 12, 13 and 14. By this time the insulin infusion had stopped (which occurred around day 7ish). Look at the 2iu/24h group. Waaaay after the insulin infusion had stopped their weight gain was still much slower per day than the other three groups. Oddly this didn't reach p < 0.05, despite standard errors which were far from overlapping those of the other three groups. But trying to see what the final weights gains were is difficult because these "post pump" weight gains have been, err, umm, sort of, err. I'm not sure what the word I need is...
You see the data from these last four time points are slightly moved. Each plot has been pulled down, and by a different amount each. No one is going to say by how much. It's pretty obvious that the control line can simply be moved back up to show a linear increase in weight from the insulin infusion period as these rats never got any insulin. But all lines have been shifted down so their day 11 values are set to their day 7 values, whatever the intermediate weight gain on days 8, 9 and 10 was. It is quite likely that the 6iu/24h and the 1iu/24h rats gained weight fairly linearly and so possibly ended up on day 14 at exactly the same weight as the control group. Or heavier.
It's also very likely that the 2iu/24h group also gained weight fairly linearly but slowly, ie their "pulling down" of day 11 values to those of day 7 didn't involve much of a drop compared to the other three groups. Who knows outside the lab?
Here are the data from Fig 1 in tabular form:
Anyhoo, the 2iu/24h rats, however much they did or didn't eat/gain on days 8, 9 and 10, only gained 1.39g/d on days 11, 12, 13,and 14. Food intake per day was down significantly through this later period, 27.7g/d vs at least 30g/d in all other groups. This is very important. The implication is that if you get yourself set up with just the right insulin infusion for a week, then you still won't be hungry a week later! Wow. Insulin is a satiety hormone blah blah blah.
But if you under-dose at 1iu/24h then it's, oh-oh, back up to pre-infusion weight gain rate, or possibly slightly more. Ditto if you over-dose at 6iu/24h, just the same thing happens. Fascinating. Do you think there might be something odd about this 2iu/24h group? Perhaps someone should repeat the experiment at this infusion rate? Then we might see if the result for these rats, on which the whole concept of suppression of weight gain over 7 days rests, was a quirk. No stats were done on the zero weight gain days, ie days 1-3 on insulin. The only p< 0.05, on which the title of the paper rests, was the 2iu/24h group at day seven.
If we lose the 2iu/24h group all we can say is that an insulin infusion reduces weight gain for three days, with complete restoration of any lost weight gain by the seventh day of a continuing infusion.
So, has the experiment been repeated? Luckily it has. By this very group. And the results are in this very same paper! But well buried. You have to be a dissonant pedant to find it. It's all in Figure 4.
This not quite the same experiment as Fig 1, the timings are slightly changed, but the basic design with insulin at 2iu/24h for seven days is identical.
In the main experiment time "on pump" was 7 days and they looked at all of these days, averaging everything over this time.
In Fig 4 they did the same 2iu/24h pump for seven days but only analysed days 3, 4 and 5 as time "on pump". Go figure. They also chose days 8, 9 and 10 as their "post pump" days vs days 11-14 in the first part of the study. Again, go figure. But eyeballing the graphical weight changes in Fig 1, I doubt this matters.
The data in Fig 4 look at meal size and meal frequency because that's how you bury data. But we can reverse engineer Fig 4 to get total food intake per day. Take a ruler to the graph. Multiply meal size by meal frequency and you get food intake per day, neat huh?
The rats on 2iu/24h ate 25.5g/d during "on pump" days 3, 4 and 5. This is pretty much the same as the total 7 day value from Fig 1 and Table 1. Happy researchers? Well done for correct choice of days. But...
Does the depressed food intake continue even after insulin has finished? Do you get sustained appetite control if you get the insulin infusion "just right" for a week? Eyeballing Fig 4's "post pump" values, these are about 3.4g/meal, 9.8 meals/day giving over 33g/d food intake...........
My, those are bloody hungry rats! This is the highest food intake per day in any group in the whole paper. It's the direct opposite of the findings presented in Fig 1 "off pump" section. The sustained depression of food intake shown in both Fig 1 and Table 1 could not be repeated in the Fig 4 experiment.
It doesn't happen.
The 2iu/24h group are no different to any other infusion rate when you look at Fig 4 "post pump" section. Quite why the rats on 2iu/24h used to generate Fig 1 data showed depressed weight gain long term is a complete mystery. Personally I'd want to have had a pathologist check out the pumps in the lowest food intake rats in this group, looking for low grade peritonitis. The pumps are in the abdominal cavity. Maybe some surgeon dribbled in to the wound during implantation. I've worked with surgeons. Ultimately we'll never know.
But ANYONE quoting the data presented of Fig 1 to you WITHOUT even mentioning the results of Fig 4 to you is, well, hmmmmm..... probably in obesity research.
I was going to go on to discuss the flat line of weight gain on days 1, 2 and 3 (at all insulin infusion rates) next but I'll leave that to another post as it has nothing to do with the "insulin at 2iu/24h causes sustained decreased food intake" claim.
Which is complete bollocks.
Peter
Thursday, June 14, 2012
The Zombie paper
Just a brief thank you to Julianne and Beth for the full coffin nail paper. I was going to leave zombie rats alone after the last post and didn't think the paper itself was needed to see what was going on. But the quick scan I've had of the coffin nail shows it to be very interesting. Want to read some execrable science? I'll deconstruct it soon but there is an on call night tonight and a family weekend coming up, so I might not be as quick as it deserves. But don't worry, there are still plenty of zombies around...
Perhaps best not comment on this post, comments can stay on the last one all grouped together. I'll take this one down as the next one comes through.
Oh, Hi Melchior. Nice to see you about. It's good when facts plus logical consistency ultimately win through. As they must.
Peter
Perhaps best not comment on this post, comments can stay on the last one all grouped together. I'll take this one down as the next one comes through.
Oh, Hi Melchior. Nice to see you about. It's good when facts plus logical consistency ultimately win through. As they must.
Peter
Wednesday, June 13, 2012
Insulin, the Un-dead and coffin nails
Things keep getting in the way of the next post, which is roughed out but needs tidying. I've also been meaning to post on the Somogyi overswing effect in diabetes treatment for some time, so here is a minor diversion down that route, mostly because it's very illuminating.
The Somogyi effect is quite common in those unstable diabetic dogs which tend to get shunted in my direction at work. Any clinician will recognise the effect. A dog is given 8iu of lente insulin at 7am with a meal of utter crap (ultra low fat Chappie usually). Blood glucose spikes to 22mmol/l by 9am from the carb load then falls progressively until about mid day, as the slow onset insulin struggles with the hyperglycaemia. It looks like there is a nadir at about 6mmol/l around mid day. The 1pm reading is unexpectedly high at 30mmol/l. No food, no behavioural signs. Just sudden hyperglycaemia. The Somogyi overswing. This fades slowly to around 15mmol/l by the next meal time at 7pm. The cycle repeats.
Management (if you can't change anything else) is to reduce the dose rate of insulin, which stops that sudden surge in blood glucose at 1pm. Somogyi attributed the effect to a reflex release of glucose from the liver to prevent catastrophic hypoglycaemia in response to insulin overdose. Most clinicians seem to still think in these terms.
Logical but incorrect. The advent of continuous glucose meters has pretty well disposed of the "hidden hypo" explanation and people are now looking at the effects of hyperinsulinaemia per se. The sudden rise in blood glucose appears to be associated with progressively rising or even peak levels of insulin in the blood.
Let's have a think about what is happening. Under insulin deficiency conditions glucose can still be used as a fuel, in a somewhat unregulated manner, using concentration driven supply through GLUT1, independent of insulin. Hyperglycaemia is essential for this. It's not good. The poorly regulated glucose supply generates free radicals in the electron transport chain. Superoxide is the main one and this appears to be the key to causing insulin resistance. Hyperglycaemia causes insulin resistance. This is not controversial, as far as I am aware.
As the insulin kicks in we have a period where glucose levels are falling so GLUT1 transport is decreasing and insulin regulated GLUT4 transport is increasing. Initially excess glucose above cellular needs diverts to glycogen and the respiratory chain is kept happy by insulin. As insulin levels continue to rise above physiological needs we end up with a situation where insulin is putting a ton of GLUT4s out, far more than are needed. This happens because we have inadvertently injected a supraphysiological dose of insulin.
All those excess GLUT4s allow glucose molecules to pour in to the cells. You might as well have hyperglycaemia and GLUT1 mediated oversupply, as far as the respiratory chain is concerned. Glucose in excess of the cell needs generates superoxide. Superoxide triggers, as an antioxidant defence mechanism, insulin resistance. With thanks to Dr Guyenet. Again. It is difficult to emphasise how good this paper is.
Somogyi overswing is likely to be caused by acute onset insulin resistance occurring as a direct result of excess glucose uptake in to cells due to supraphysiological insulin concentrations.
The temporal association with hypoglycaemia, which misled Somogyi, comes from the time course of switching sources of glucose oversupply. The hypoglycaemia is not causative, it is just common for it to occur at around the same time that insulin/GLUT4s oversupply substrate to the mitochondria and they say no to it, using insulin resistance.
Let's summarise. This is very, very important:
Excess insulin causes insulin resistance
End summary.
This is just day to day internal medicine. You have to pay the mortgage somehow.
If anyone is interested there is a rather nice discussion paper here, it's pay per view and doesn't say much more than is in the abstract but it has a nice set of references. I have access to a great Athens account. All the comments on insulinomas ring so true to clinical life too.
It's also interesting to go back to the controversies around the Somogyi effect, you can read Somogyi's ideas here and the continuous glucose monitoring evidence here. All very fascinating stuff (well it is to me!) but what does it have to do with shooting fish in a barrel?
Question: Who are the Un-dead?
Which can be rephrased as: Can we control the Somogyi effect?
If we take the average bodybuilder from a few years ago and watch him self-inject with insulin for its anabolic effects and then forget to eat the carb load needed to balance it, we can see the acute effects of insulin overdose. Insulin rises very rapidly from the regular insulin used and every GLUT4 receptor in his body pops on to every cell surface which uses them. There is a free fall of glucose from plasma in to the cells, blood glucose plummets and the chap ends up in A&E or, quite possibly, in a mortuary. There is no time for the massive cellular caloric overload from over-translocation of GLUT4s to generate enough insulin resistance to stop the hypoglycaemia. Glucose pours out of the bloodstream until it drops to levels low enough to kill the brain. Sad but true. Somogyi effect is too late, too little. Insulin overdosed bodybuilders are not the Un-dead.
So who really are the Un-dead?
What if you give insulin as a constant rate infusion, initially at a low rate and gradually crank it up?
Think it through. Progressively increasing insulin levels allow progressively greater amounts of glucose in to cells. If the cellular glucose supply is greater than cellular needs there is increased generation of superoxide by the respiratory chain which signals the cell to become resistant to insulin. A balance is achieved. Increase the insulin CRI, overcome the insulin resistance, generate more superoxide, generate greater insulin resistance, achieve a balance. Do it again. And again. More. Again. How high can you get plasma insulin by playing this sort of game? Here's the table we need:
Okay, they stopped at a total of 6iu/24h/per rat. They could possibly have gone higher but hell, we have here a set of rats with a mean insulin level of 588.9microIU/ml. No, that is not a typo. The SEM was 89.7. Anyone like to guess how high the highest insulin level measured was? Quite high perhaps?
These are the Un-dead. They walk around, without any genetic modification, with an insulin level which, if achieved acutely, would have put them rapidly in to a clinical waste bag. They are very, very, very, (repeat ad nauseam) insulin resistant, otherwise they would look like the bodybuilder in the mortuary.
*****************************************************************
WARNING: There is a black box paradox warning about the paper providing Table 1. I'll stick an addendum on the end of the post.
*****************************************************************
Soooooooo. They are, undoubtedly, hyperinsulinaemic. Are they fat? Of course not. Why should they be fat? They are the Un-dead. If they were remotely sensitive to insulin they would be not be the Un-dead, quite the contrary. But insulin induced insulin resistance does not spare adipocytes. These have mitochondria and generate superoxide. They too will ignore insulin, to a level determined by their mitochondrial superoxide production.
Here's a bit of an aside: The process is physiological. It involves a careful titration of cellular insulin resistance to the cellular energy needs. This is no blanket insulin blocking drug. The responsiveness to insulin is carefully adjusted to just allow enough glucose in to cells to meet their needs. This applies to adipocytes as well as well as to muscle cells. With the number of GLUT4s being translocated by the residual insulin sensitivity, in an environment of 588microIU/ml of insulin, you don't need much of a blood glucose level to supply glucose needs. Table 1 suggests the body settles to a plasma glucose of about 71mg/dl, as opposed to 148mg/dl in the control rats. Metabolism is still largely glucose based, with some responsiveness to insulin preserved despite the need for resistance to survive at 588microIU/ml. Transplanting tissues to a petri-dish allows you to pick up this responsiveness. Free fatty acid release from adipocytes is not significantly inhibited because the adipocytes are insulin resistant to a level where they maintain normal function. Weight gain is similar to that of control rats.
And another BTW. The process is cellular. Bugger the hypothalamus.
A nail in someone's coffin?
Apparently these rats are a nail in the coffin of the insulin hypothesis of obesity.
The actual coffin nail [nb if the link comes up with a failed log-in just refresh the page] is a pay per view article in a journal not covered by Pubmed and I'm unwilling to shell out $40 for it. Perhaps I could ask The Good Doctor for a copy. Fortunately the information on CRI rodent models is freely available in the paper which provided Table 1 above. What is crashingly obvious is the utter lack of understanding of insulin induced insulin resistance by people who are fixated on insulin as a satiety hormone.
This might have been acceptable in 1980 when the physiology of insulin resistance was completely unknown. But to see this explanation promoted by the same obesity researcher who provides us with the concept of insulin resistance as a cellular antioxidant defence mechanism, mediated through superoxide, is utterly depressing. We are, after all, talking about a complete failure to understand the basic physiology of insulin resistance, with the key paper sitting as a free download from Pubmed.
Does the Good Doctor not understand his own citations or is he stuck with terminal cognitive dissonance?
Or perhaps he's just utterly confused.
I feel the coffin nail is misplaced.
Peter
OK the paradox: In the paper providing Table 1 the rats have a blood insulin level of 588microIU/ml with physiological blood glucose levels. BUT isolated muscle and fat cells taken from these rats are highly insulin sensitive, more so than those from the control rats. How is this possible? I can imagine the Good Doctor or some other idiot shouting that the rats aren't insulin resistant at all, because the paper clearly shows their tissues are extra insulin sensitive, ergo the insulin hypothesis of obesity is wrong. Peter is misquoting a paper, you know what I'm like!!!! Gotta read all those papers cited, the Good Doctor knows how few people follow the links.
But the rats are definitely Un-dead.
If you culture adipocytes at consistently supra maximal insulin levels they behave exactly as the whole rats do. So if you pull out a muscle or fat cell from an Un-dead rat, having made it an un-Un-dead rat by decapitation, how long will the insulin resistance last? This is probably determined by the elimination half life of superoxide. Which is, err, not very long... Actually, it's probably determined by the cellular redox state providing the superoxide, which should last at least a few seconds after decapitation.
The Somogyi effect is quite common in those unstable diabetic dogs which tend to get shunted in my direction at work. Any clinician will recognise the effect. A dog is given 8iu of lente insulin at 7am with a meal of utter crap (ultra low fat Chappie usually). Blood glucose spikes to 22mmol/l by 9am from the carb load then falls progressively until about mid day, as the slow onset insulin struggles with the hyperglycaemia. It looks like there is a nadir at about 6mmol/l around mid day. The 1pm reading is unexpectedly high at 30mmol/l. No food, no behavioural signs. Just sudden hyperglycaemia. The Somogyi overswing. This fades slowly to around 15mmol/l by the next meal time at 7pm. The cycle repeats.
Management (if you can't change anything else) is to reduce the dose rate of insulin, which stops that sudden surge in blood glucose at 1pm. Somogyi attributed the effect to a reflex release of glucose from the liver to prevent catastrophic hypoglycaemia in response to insulin overdose. Most clinicians seem to still think in these terms.
Logical but incorrect. The advent of continuous glucose meters has pretty well disposed of the "hidden hypo" explanation and people are now looking at the effects of hyperinsulinaemia per se. The sudden rise in blood glucose appears to be associated with progressively rising or even peak levels of insulin in the blood.
Let's have a think about what is happening. Under insulin deficiency conditions glucose can still be used as a fuel, in a somewhat unregulated manner, using concentration driven supply through GLUT1, independent of insulin. Hyperglycaemia is essential for this. It's not good. The poorly regulated glucose supply generates free radicals in the electron transport chain. Superoxide is the main one and this appears to be the key to causing insulin resistance. Hyperglycaemia causes insulin resistance. This is not controversial, as far as I am aware.
As the insulin kicks in we have a period where glucose levels are falling so GLUT1 transport is decreasing and insulin regulated GLUT4 transport is increasing. Initially excess glucose above cellular needs diverts to glycogen and the respiratory chain is kept happy by insulin. As insulin levels continue to rise above physiological needs we end up with a situation where insulin is putting a ton of GLUT4s out, far more than are needed. This happens because we have inadvertently injected a supraphysiological dose of insulin.
All those excess GLUT4s allow glucose molecules to pour in to the cells. You might as well have hyperglycaemia and GLUT1 mediated oversupply, as far as the respiratory chain is concerned. Glucose in excess of the cell needs generates superoxide. Superoxide triggers, as an antioxidant defence mechanism, insulin resistance. With thanks to Dr Guyenet. Again. It is difficult to emphasise how good this paper is.
Somogyi overswing is likely to be caused by acute onset insulin resistance occurring as a direct result of excess glucose uptake in to cells due to supraphysiological insulin concentrations.
The temporal association with hypoglycaemia, which misled Somogyi, comes from the time course of switching sources of glucose oversupply. The hypoglycaemia is not causative, it is just common for it to occur at around the same time that insulin/GLUT4s oversupply substrate to the mitochondria and they say no to it, using insulin resistance.
Let's summarise. This is very, very important:
Excess insulin causes insulin resistance
End summary.
This is just day to day internal medicine. You have to pay the mortgage somehow.
If anyone is interested there is a rather nice discussion paper here, it's pay per view and doesn't say much more than is in the abstract but it has a nice set of references. I have access to a great Athens account. All the comments on insulinomas ring so true to clinical life too.
It's also interesting to go back to the controversies around the Somogyi effect, you can read Somogyi's ideas here and the continuous glucose monitoring evidence here. All very fascinating stuff (well it is to me!) but what does it have to do with shooting fish in a barrel?
Question: Who are the Un-dead?
Which can be rephrased as: Can we control the Somogyi effect?
If we take the average bodybuilder from a few years ago and watch him self-inject with insulin for its anabolic effects and then forget to eat the carb load needed to balance it, we can see the acute effects of insulin overdose. Insulin rises very rapidly from the regular insulin used and every GLUT4 receptor in his body pops on to every cell surface which uses them. There is a free fall of glucose from plasma in to the cells, blood glucose plummets and the chap ends up in A&E or, quite possibly, in a mortuary. There is no time for the massive cellular caloric overload from over-translocation of GLUT4s to generate enough insulin resistance to stop the hypoglycaemia. Glucose pours out of the bloodstream until it drops to levels low enough to kill the brain. Sad but true. Somogyi effect is too late, too little. Insulin overdosed bodybuilders are not the Un-dead.
So who really are the Un-dead?
What if you give insulin as a constant rate infusion, initially at a low rate and gradually crank it up?
Think it through. Progressively increasing insulin levels allow progressively greater amounts of glucose in to cells. If the cellular glucose supply is greater than cellular needs there is increased generation of superoxide by the respiratory chain which signals the cell to become resistant to insulin. A balance is achieved. Increase the insulin CRI, overcome the insulin resistance, generate more superoxide, generate greater insulin resistance, achieve a balance. Do it again. And again. More. Again. How high can you get plasma insulin by playing this sort of game? Here's the table we need:
Okay, they stopped at a total of 6iu/24h/per rat. They could possibly have gone higher but hell, we have here a set of rats with a mean insulin level of 588.9microIU/ml. No, that is not a typo. The SEM was 89.7. Anyone like to guess how high the highest insulin level measured was? Quite high perhaps?
These are the Un-dead. They walk around, without any genetic modification, with an insulin level which, if achieved acutely, would have put them rapidly in to a clinical waste bag. They are very, very, very, (repeat ad nauseam) insulin resistant, otherwise they would look like the bodybuilder in the mortuary.
*****************************************************************
WARNING: There is a black box paradox warning about the paper providing Table 1. I'll stick an addendum on the end of the post.
*****************************************************************
Soooooooo. They are, undoubtedly, hyperinsulinaemic. Are they fat? Of course not. Why should they be fat? They are the Un-dead. If they were remotely sensitive to insulin they would be not be the Un-dead, quite the contrary. But insulin induced insulin resistance does not spare adipocytes. These have mitochondria and generate superoxide. They too will ignore insulin, to a level determined by their mitochondrial superoxide production.
Here's a bit of an aside: The process is physiological. It involves a careful titration of cellular insulin resistance to the cellular energy needs. This is no blanket insulin blocking drug. The responsiveness to insulin is carefully adjusted to just allow enough glucose in to cells to meet their needs. This applies to adipocytes as well as well as to muscle cells. With the number of GLUT4s being translocated by the residual insulin sensitivity, in an environment of 588microIU/ml of insulin, you don't need much of a blood glucose level to supply glucose needs. Table 1 suggests the body settles to a plasma glucose of about 71mg/dl, as opposed to 148mg/dl in the control rats. Metabolism is still largely glucose based, with some responsiveness to insulin preserved despite the need for resistance to survive at 588microIU/ml. Transplanting tissues to a petri-dish allows you to pick up this responsiveness. Free fatty acid release from adipocytes is not significantly inhibited because the adipocytes are insulin resistant to a level where they maintain normal function. Weight gain is similar to that of control rats.
And another BTW. The process is cellular. Bugger the hypothalamus.
A nail in someone's coffin?
Apparently these rats are a nail in the coffin of the insulin hypothesis of obesity.
The actual coffin nail [nb if the link comes up with a failed log-in just refresh the page] is a pay per view article in a journal not covered by Pubmed and I'm unwilling to shell out $40 for it. Perhaps I could ask The Good Doctor for a copy. Fortunately the information on CRI rodent models is freely available in the paper which provided Table 1 above. What is crashingly obvious is the utter lack of understanding of insulin induced insulin resistance by people who are fixated on insulin as a satiety hormone.
This might have been acceptable in 1980 when the physiology of insulin resistance was completely unknown. But to see this explanation promoted by the same obesity researcher who provides us with the concept of insulin resistance as a cellular antioxidant defence mechanism, mediated through superoxide, is utterly depressing. We are, after all, talking about a complete failure to understand the basic physiology of insulin resistance, with the key paper sitting as a free download from Pubmed.
Does the Good Doctor not understand his own citations or is he stuck with terminal cognitive dissonance?
Or perhaps he's just utterly confused.
I feel the coffin nail is misplaced.
Peter
OK the paradox: In the paper providing Table 1 the rats have a blood insulin level of 588microIU/ml with physiological blood glucose levels. BUT isolated muscle and fat cells taken from these rats are highly insulin sensitive, more so than those from the control rats. How is this possible? I can imagine the Good Doctor or some other idiot shouting that the rats aren't insulin resistant at all, because the paper clearly shows their tissues are extra insulin sensitive, ergo the insulin hypothesis of obesity is wrong. Peter is misquoting a paper, you know what I'm like!!!! Gotta read all those papers cited, the Good Doctor knows how few people follow the links.
But the rats are definitely Un-dead.
If you culture adipocytes at consistently supra maximal insulin levels they behave exactly as the whole rats do. So if you pull out a muscle or fat cell from an Un-dead rat, having made it an un-Un-dead rat by decapitation, how long will the insulin resistance last? This is probably determined by the elimination half life of superoxide. Which is, err, not very long... Actually, it's probably determined by the cellular redox state providing the superoxide, which should last at least a few seconds after decapitation.
Thursday, June 07, 2012
Confused
Oh dear,
Back in this post I discussed the study by Knudsen et al on forced overfeeding. It found, very clearly, that acute overfeeding produces acute fasting hyperinsulinaemia, provided you feed utter crap.
The hyperinsulinaemia moderates progressively over the next two weeks, at which time the study ended.
In comments after the post this one came up from Dr Guyenet:
"You are utterly confused Peter. These people only gained 0.8 kg of fat mass. Over the course of the study, they went from lean to slightly less lean. If you look at studies where overfeeding produced greater fat gains, you see a consistent increase in fasting insulin that corresponds with fat gain, just as those silly obesity researchers would predict:
www.ncbi.nlm.nih.gov/pubmed/18171910
www.ncbi.nlm.nih.gov/pubmed/20814413
www.ncbi.nlm.nih.gov/pubmed/21127472
In animal models of diet-induced obesity (rodents and dogs), blocking the hyperinsulinemia has no effect on the rate of fat gain. The carbohydrate-insulin-obesity hypothesis is dead and buried, and all that remains are rearguard attempts to salvage it using increasingly complex theories. Just let go of the cognitive dissonance man."
with those three studies to back up the comment.
So, being a bit of a dissonant pedant, I checked the studies for information on changes in fasting insulin with time. Here they are, with Knudsen's data at the top:
nm stands for not measured.
As you can see 18171910 covers none of the acute changes in insulin levels discussed in the post. I've spent a great deal of time discussing adipocyte distension induced insulin resistance and this will be the end effect of sustained adipocyte distension. It will kick in eventually and certainly affects fasting insulin levels.
The second study clearly shows on day 14 and day 28 EXACTLY the same changes seen by Knudsen et al in their 14 day study. Anyone want to how high fasting insulin peaked on day 3 in 20814413? Not measured, but answers on a postcard to... Hint, probably very high.
The third study measured, but doesn't report, fasting insulin only at > day 56 of overfeeding. Oh, and day 0 of course.
These are the classic half truths so typical of modern obesity research, technically correct but comprehending nothing.
But here's the real giggle, again quoting the Good Doctor:
"These people only gained 0.8 kg of fat mass"
These people gained 1.5kg of fat mass. From 10.5kg to 12.0kg. The drop to 11.29kg of fat mass occurred AFTER the overfeeding had finished.
I don't suppose reading the studies matters that much in obesity research.
Personally, I'd be embarrassed to be Dr Guyenet.
Peter, as confused as always.
Back in this post I discussed the study by Knudsen et al on forced overfeeding. It found, very clearly, that acute overfeeding produces acute fasting hyperinsulinaemia, provided you feed utter crap.
The hyperinsulinaemia moderates progressively over the next two weeks, at which time the study ended.
In comments after the post this one came up from Dr Guyenet:
"You are utterly confused Peter. These people only gained 0.8 kg of fat mass. Over the course of the study, they went from lean to slightly less lean. If you look at studies where overfeeding produced greater fat gains, you see a consistent increase in fasting insulin that corresponds with fat gain, just as those silly obesity researchers would predict:
www.ncbi.nlm.nih.gov/pubmed/18171910
www.ncbi.nlm.nih.gov/pubmed/20814413
www.ncbi.nlm.nih.gov/pubmed/21127472
In animal models of diet-induced obesity (rodents and dogs), blocking the hyperinsulinemia has no effect on the rate of fat gain. The carbohydrate-insulin-obesity hypothesis is dead and buried, and all that remains are rearguard attempts to salvage it using increasingly complex theories. Just let go of the cognitive dissonance man."
with those three studies to back up the comment.
So, being a bit of a dissonant pedant, I checked the studies for information on changes in fasting insulin with time. Here they are, with Knudsen's data at the top:
nm stands for not measured.
As you can see 18171910 covers none of the acute changes in insulin levels discussed in the post. I've spent a great deal of time discussing adipocyte distension induced insulin resistance and this will be the end effect of sustained adipocyte distension. It will kick in eventually and certainly affects fasting insulin levels.
The second study clearly shows on day 14 and day 28 EXACTLY the same changes seen by Knudsen et al in their 14 day study. Anyone want to how high fasting insulin peaked on day 3 in 20814413? Not measured, but answers on a postcard to... Hint, probably very high.
The third study measured, but doesn't report, fasting insulin only at > day 56 of overfeeding. Oh, and day 0 of course.
These are the classic half truths so typical of modern obesity research, technically correct but comprehending nothing.
But here's the real giggle, again quoting the Good Doctor:
"These people only gained 0.8 kg of fat mass"
These people gained 1.5kg of fat mass. From 10.5kg to 12.0kg. The drop to 11.29kg of fat mass occurred AFTER the overfeeding had finished.
I don't suppose reading the studies matters that much in obesity research.
Personally, I'd be embarrassed to be Dr Guyenet.
Peter, as confused as always.
Wednesday, June 06, 2012
A glimmer of light
For those who do not have the supplies of anti emetic necessary to read main stream nutrition opinion it's worth noting that not all obesity researchers are idiots. I rather like this article. Woo might too, after her last foray on the WHS for the Noddy guide to obesity.
Peter
Peter
Tuesday, June 05, 2012
Insulin and the Rewards of overfeeding
I've been tempted away from the electron transport chain, origins of life and the suspected paleo prompt nuclear criticality on Mars by a neat paper from Liz.
This is what they did in the study: Over-fed 9 slim, young, fit, healthy blokes for two weeks while limiting their exercise. They establish an energy surplus of about 2000kcal/d. Here we go:
Needless to say, they gained weight. Here we go again, Table 3:
A total of about 1.5kg in two weeks.
Now, all you have to do is to go and ask any cutting edge, state of the art obesity researcher and you can be told that hyperinsulinaemia is a consequence of obesity, not a cause, and that carbohydrates are the worlds greatest slimming aid because insulin is a satiety hormone and, oh, did I fall asleep there?????? Sorry.
Back to the paper. The overfeeding was with utter crap
and produced a rise in fasting insulin from 35pmol/l to 74pmol/l in 3 days.
Personally, I found this quite amusing.
Aside: What would have happened if they had overfed with lard? That's another post, it has been done, rather badly, in Schwartz's lab using dogs. They gained weight. End aside.
By 3 days the fat mass had increase by an average of 100g. My, that is potent fat! Here's the table, day nought vs day three is the place to look:
We could leave it at that and just go away scratching our heads about what goes on in the minds of obesity researchers, but it does get quite interesting. Obviously, as obesity progressed the level of insulin should increase if insulin resistance is caused by fat mass. It doesn't. Fasting insulin falls progressively after the initial spike, and in a fairly linear manner, through days 3, 7 and 14, while weight (and especially visceral fat) actually increases over this time period.
So the idea that fasting insulin rises as a consequence of rising fat mass is, well, you know what it is.
Ah, but if insulin stores fat, why should the level of insulin fall progressively during a sustained hypercaloric eating episode? Surely you must need insulin to store those extra calories? In fact, as insulin levels fall, so does the rate of fat storage. The chaps gained, from Table 3, 1kg of fat mass in the first week and only 0.5kg of fat in the second week... Oh, I guess this must be because the subjects either (a) sneaked off to the gym in the second week or (b) flushed their Snicker Bars down the loo in the second week, without passing them through their gastro intestinal tract first (good idea!) or (c) got bored with Snickers and stopped finding them rewarding. And of course they disconnected their Actiheart monitors at the gym.
Otherwise how you can eat 2000kcal over your energy expenditure, equivalent to nearly 200g of fat gain per day, and gain a kilo of fat in the first week, then continue to eat an excess 2000kcal/d for a second week and only gain half a kilo of fat? Calories in, calories out, you know the rules. Hmmm, in the second week there are 14,000 excess calories-in, 5,000 stored, very interesting.
We all know the obese lie about calories. It seems probable that so too must experimental subjects, in direct proportion to the duration of their over eating! Now we know. Bit of a milestone paper this one.
So what is really going on? What appears to be happening is the insulin system working exactly as it should do. Insulin resistance protects cells from caloric excess, when forced in to the body by a study protocol. Think of it in these terms, with thanks to Dr Guyenet from back when I used to read him. The vast majority of free radicals will be generated at complex I.
The mitochondria say they have too many calories. It's easy for mitochondria to refuse calories from glucose by using insulin resistance, working at the whole cell level. In the presence of massive oral doses of glucose this must elevate insulin to maintain normoglycaemia. The elevated insulin diverts calories from dietary fat in to adipocytes, away from muscle cells. And inhibits lipolysis at the same time, look at the FFA levels in Table 3 on days 7 and 14, waaaay down from pre and post study values. I wonder why they didn't measure FFAs on day 3? So insulin goes up to maintain normal blood sugar levels, overcomes insulin resistance to run cells on a reasonable amount of glucose and shuts down FFA release to counterbalance its action in facilitating the entry of glucose in to cells.
Core to this is (a) there is no hyperglycaemia, insulin still successfully controls glucose flux and (b) insulin inhibits lipolysis. So you store fat. These subjects are both young and healthy. They do not have insulin resistant adipocytes, mitochondrial damage or a fatty liver. The system works as it should.
As time goes by fasting insulin levels fall and weight gain slows. Calorie intake doesn't drop. The only plausible explanation is that the subjects generate more heat and radiate that heat during the second week of the study. Total energy expenditure was estimated using the Actiheart device. You have to wonder how well its computer algorithms coped with the massive overfeeding. It looks like the weakest link in the protocol, assuming the the subjects really ate their muffins and Snicker bars. The device is supposed to be very good but where else did those calories-in go? So let's consider uncoupling proteins. These decrease the inner mitochondrial membrane potential and so decrease free radical production, which decreases insulin resistance. You can afford to allow more glucose in to cells when the UCPs are in place and working. More posts on this to come when we get back to the electron transport chain and free radicals. Free radical generation at complex I is VERY dependent on the inner mitochondrial membrane voltage.
Unfortunately the clamp studies were only performed on days 0 and 14, so all we can say about the insulin sensitivity by clamp (gold standard) is that it was worse on day 14 than day 0. Who knows what the results would have been on days 3 and 7? This protocol is understandable as clamps are a pain to do, but there is no way of ascertaining what glucose disposal per unit insulin was through the body of the study.
So forced weight gain fits quite nicely with the role of insulin in fat storage. It's a nice study because it looked at insulin before fat gain had occurred, and kept on looking too. But how much does forcing people to overeat tell us about "accidental" weight gain in people who have spent good money on some slimming plan to lose weight temporarily with enormous difficulty? Under these circumstances calories are offered to cells at very reasonable levels, mitochondria are already dysfunctional and signal (using free radicals) excess calorie warnings (free radical leakage) and so induce insulin resistance inappropriately. So calories, especially those from dietary fat, get diverted to adipocytes through the subsequent hyperinsulinaemia. And are kept there due to fasting hyperinsulinaemia.
The situations are quite different, I'm not sure that overfeeding healthy subjects tells us too much about accidental obesity, except that they both seem to work through insulin and mitochondria. But this study does tell us a great deal about the idea of reward.
This study is the ultimate affirmation of the Reward Hypothesis of obesity:
If you reward people with enough Danish Krone for over eating, they gain weight.
Peter
This is what they did in the study: Over-fed 9 slim, young, fit, healthy blokes for two weeks while limiting their exercise. They establish an energy surplus of about 2000kcal/d. Here we go:
Needless to say, they gained weight. Here we go again, Table 3:
A total of about 1.5kg in two weeks.
Now, all you have to do is to go and ask any cutting edge, state of the art obesity researcher and you can be told that hyperinsulinaemia is a consequence of obesity, not a cause, and that carbohydrates are the worlds greatest slimming aid because insulin is a satiety hormone and, oh, did I fall asleep there?????? Sorry.
Back to the paper. The overfeeding was with utter crap
and produced a rise in fasting insulin from 35pmol/l to 74pmol/l in 3 days.
Personally, I found this quite amusing.
Aside: What would have happened if they had overfed with lard? That's another post, it has been done, rather badly, in Schwartz's lab using dogs. They gained weight. End aside.
By 3 days the fat mass had increase by an average of 100g. My, that is potent fat! Here's the table, day nought vs day three is the place to look:
We could leave it at that and just go away scratching our heads about what goes on in the minds of obesity researchers, but it does get quite interesting. Obviously, as obesity progressed the level of insulin should increase if insulin resistance is caused by fat mass. It doesn't. Fasting insulin falls progressively after the initial spike, and in a fairly linear manner, through days 3, 7 and 14, while weight (and especially visceral fat) actually increases over this time period.
So the idea that fasting insulin rises as a consequence of rising fat mass is, well, you know what it is.
Ah, but if insulin stores fat, why should the level of insulin fall progressively during a sustained hypercaloric eating episode? Surely you must need insulin to store those extra calories? In fact, as insulin levels fall, so does the rate of fat storage. The chaps gained, from Table 3, 1kg of fat mass in the first week and only 0.5kg of fat in the second week... Oh, I guess this must be because the subjects either (a) sneaked off to the gym in the second week or (b) flushed their Snicker Bars down the loo in the second week, without passing them through their gastro intestinal tract first (good idea!) or (c) got bored with Snickers and stopped finding them rewarding. And of course they disconnected their Actiheart monitors at the gym.
Otherwise how you can eat 2000kcal over your energy expenditure, equivalent to nearly 200g of fat gain per day, and gain a kilo of fat in the first week, then continue to eat an excess 2000kcal/d for a second week and only gain half a kilo of fat? Calories in, calories out, you know the rules. Hmmm, in the second week there are 14,000 excess calories-in, 5,000 stored, very interesting.
We all know the obese lie about calories. It seems probable that so too must experimental subjects, in direct proportion to the duration of their over eating! Now we know. Bit of a milestone paper this one.
So what is really going on? What appears to be happening is the insulin system working exactly as it should do. Insulin resistance protects cells from caloric excess, when forced in to the body by a study protocol. Think of it in these terms, with thanks to Dr Guyenet from back when I used to read him. The vast majority of free radicals will be generated at complex I.
The mitochondria say they have too many calories. It's easy for mitochondria to refuse calories from glucose by using insulin resistance, working at the whole cell level. In the presence of massive oral doses of glucose this must elevate insulin to maintain normoglycaemia. The elevated insulin diverts calories from dietary fat in to adipocytes, away from muscle cells. And inhibits lipolysis at the same time, look at the FFA levels in Table 3 on days 7 and 14, waaaay down from pre and post study values. I wonder why they didn't measure FFAs on day 3? So insulin goes up to maintain normal blood sugar levels, overcomes insulin resistance to run cells on a reasonable amount of glucose and shuts down FFA release to counterbalance its action in facilitating the entry of glucose in to cells.
Core to this is (a) there is no hyperglycaemia, insulin still successfully controls glucose flux and (b) insulin inhibits lipolysis. So you store fat. These subjects are both young and healthy. They do not have insulin resistant adipocytes, mitochondrial damage or a fatty liver. The system works as it should.
As time goes by fasting insulin levels fall and weight gain slows. Calorie intake doesn't drop. The only plausible explanation is that the subjects generate more heat and radiate that heat during the second week of the study. Total energy expenditure was estimated using the Actiheart device. You have to wonder how well its computer algorithms coped with the massive overfeeding. It looks like the weakest link in the protocol, assuming the the subjects really ate their muffins and Snicker bars. The device is supposed to be very good but where else did those calories-in go? So let's consider uncoupling proteins. These decrease the inner mitochondrial membrane potential and so decrease free radical production, which decreases insulin resistance. You can afford to allow more glucose in to cells when the UCPs are in place and working. More posts on this to come when we get back to the electron transport chain and free radicals. Free radical generation at complex I is VERY dependent on the inner mitochondrial membrane voltage.
Unfortunately the clamp studies were only performed on days 0 and 14, so all we can say about the insulin sensitivity by clamp (gold standard) is that it was worse on day 14 than day 0. Who knows what the results would have been on days 3 and 7? This protocol is understandable as clamps are a pain to do, but there is no way of ascertaining what glucose disposal per unit insulin was through the body of the study.
So forced weight gain fits quite nicely with the role of insulin in fat storage. It's a nice study because it looked at insulin before fat gain had occurred, and kept on looking too. But how much does forcing people to overeat tell us about "accidental" weight gain in people who have spent good money on some slimming plan to lose weight temporarily with enormous difficulty? Under these circumstances calories are offered to cells at very reasonable levels, mitochondria are already dysfunctional and signal (using free radicals) excess calorie warnings (free radical leakage) and so induce insulin resistance inappropriately. So calories, especially those from dietary fat, get diverted to adipocytes through the subsequent hyperinsulinaemia. And are kept there due to fasting hyperinsulinaemia.
The situations are quite different, I'm not sure that overfeeding healthy subjects tells us too much about accidental obesity, except that they both seem to work through insulin and mitochondria. But this study does tell us a great deal about the idea of reward.
This study is the ultimate affirmation of the Reward Hypothesis of obesity:
If you reward people with enough Danish Krone for over eating, they gain weight.
Peter
Saturday, June 02, 2012
Cholesterol: More epidemiology
Too hilarious not to comment on!
Lipitor because your TC "number" is "bad"?.
Ah you can say, but what about psLDL? They never measured psLDL! Mmmm, sucrose...
Thanks to Karl for the heads up
Peter
Lipitor because your TC "number" is "bad"?.
Ah you can say, but what about psLDL? They never measured psLDL! Mmmm, sucrose...
Thanks to Karl for the heads up
Peter
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