The carbohydrate hypothesis, in its most popular current incarnation, states that elevated insulin acts on fat cells to cause fat storage, leading to obesity.  This is due to its ability to increase the activity of lipoprotein lipase and decrease the activity of hormone-sensitive lipase, thus creating a net flux of fat into fat cells.  I’m still not sure why this would be the case, considering that fat tissue becomes more insulin resistant as body fat accumulates, therefore insulin action on it is not necessarily increased.  Total fat release from fat tissue increases with total fat mass (1), demonstrating that insulin is not able to do its job of suppressing fat release as effectively in people who carry excess fat.  But let’s put that problem aside for the moment and keep trucking.

Elevated insulin (hyperinsulinemia) and elevated fat mass typically travel together.   It is generally accepted in the scientific community that hyperinsulinemia is the result of obesity.  However, others have argued that researchers may have the causality backward, and obesity may instead be the result of hyperinsulinemia.  If this is the case, then interventions that suppress hyperinsulinemia should reliably prevent fat gain.  Let’s see if that’s true.

One hypothesis of obesity-associated insulin resistance suggests that during the development of obesity, inflammation in fat tissue causes insulin resistance throughout the body.  One potential player is a cytokine called tumor necrosis factor-alpha (TNF-alpha).  Knocking out the TNF-alpha gene completely prevents hyperinsulinemia and insulin resistance in mice during exposure to a fattening diet.  If hyperinsulinemia causes obesity, then these mice should remain lean, but they do not.  They become obese at nearly the same rate as normal mice (2).

Researchers have generated mice that are missing jun kinase 1 (JNK1), a protein involved in inflammatory signaling, specifically from blood cells including circulating immune cells.  When exposed to a fattening diet, these mice do not develop hyperinsulinemia, retain a normal insulin sensitivity, but gain fat at the same rate as normal mice when placed on a fattening diet (3).

How about mice that lack inducible nitric oxide synthase (iNOS), another protein involved in inflammation?  They do not develop hyperinsulinemia, or insulin resistance, but actually gain more fat than normal mice when fed a fattening diet (4).

A common knee jerk reaction is to dismiss these results because they were obtained in mice.  But consider this: mice have insulin.  They have hormone-sensitive lipase and lipoprotein lipase on their fat cells, and they are regulated by insulin in the same manner as they are in humans.  Insulin goes up temporarily with carbohydrate, and chronically up with obesity, just like in humans.  So if the proposed mechanism is that insulin causes fat gain by acting on HSL and LPL in fat tissue, why would one expect the association between insulin and body fatness to be any different in mice than in humans?

But let’s look at another species anyway: dogs.  Clonidine is a blood pressure drug that targets the a2 adrenergic receptor.  When dogs are made obese via diet, clonidine prevents an increase in fasting insulin and insulin resistance without attenuating the development of obesity at all (5).

If elevated insulin is a major factor in obesity, one would expect to see elevated insulin in all, or nearly all, obese people.  However, there is a subgroup of obese people who are considered “metabolically healthy” and have normal fasting insulin and insulin sensitivity.  Likewise, there is a subset of lean, “metabolically obese” people who have high insulin and low insulin sensitivity despite a normal fat mass (6).

If the correlation between obesity and hyperinsulinemia is not very tight, and the two phenomena can be completely dissociated in experimental models by a variety of means, this indicates that elevated insulin is not a major contributor to obesity, and is certainly not required for it.  This evidence is consistent with the prevailing hypothesis that elevated insulin and insulin resistance are the result of excess fat accumulation, rather than the cause. 

Miscellaneous Observations

In this section, I’d like to discuss some of the observations that appear to support the idea that insulin regulates body fatness.  I found these ideas convincing at one point, but I will explain why, upon closer examination, they do not offer much if any support to the hypothesis. 

The first is the fact that type 1 diabetics become very lean until they receive insulin replacement, at which point they gain fat.  Type 1 diabetes is a condition in which the pancreas produces little or no insulin.  I think this example illustrates a very important concept: the difference between something that is required for fat storage, and something that regulates fat storage.

Let’s use the metaphor of a car.  Without an engine or wheels, a car can’t drive.  But the engine and wheels aren’t what decide how fast the car goes.  That is determined by the driver pushing the pedals.  If you were to get rid of the engine, the car wouldn’t move, and you might be tempted to say that the engine regulates the speed of the car.  Insulin in type 1 diabetes is a similar case.  You need some basal amount of insulin signaling around for fat cells to store fat properly.  Get rid of the insulin, and they rapidly release all of their fat due to unrestrained lipolysis (not good for health!).  Replace insulin, and the fat cells work properly, allowing them to do their job again, which is to store fat.  Fat cells also require ribosomes and DNA polymerase to store fat, but no one claims that these proteins that are required for basic cellular function regulate body fatness. Type 1 diabetics who receive insulin go from being too thin to having a normal degree of body fatness because their fat cells work again. Also because they are no longer peeing out a large quantity of glucose (glycosuria).

Another argument is the case of type 2 diabetics who require insulin.  Insulin treatment is often associated with fat gain in this scenario (7).  There are a number of problems with using this as support for the hypothesis that insulin causes fat gain in non-diabetics.  People who need insulin are, by definition, insulin deficient relative to their own degree of insulin sensitivity.  Therefore, they are in some respects similar to type 1 diabetics who are not producing enough insulin.  They may simply be gaining back the weight that they would have had to begin with, due to a failure of their own insulin to keep fat cells working properly.  The other thing to consider is that uncontrolled diabetics lose a lot of calories through their urine.  Insulin therapy corrects this, effectively increasing calorie intake.

Furthermore, insulin therapy is just insulin.  It is not accompanied by the many signals that are released by the digestive tract and pancreas of a healthy person in response to carbohydrate ingestion.  One of these is the hormone amylin, which is co-released by the pancreas, along with insulin, when carbohydrate is eaten.  It is not only a satiety peptide, but is also being investigated as a fat loss treatment (Pramlintide, 8).  When injected insulin is administered along with amylin to diabetics, it causes weight loss (9, 10).  The larger point is that you can’t extrapolate from the effects of isolated insulin injections on diabetics, to the effects of insulin on a healthy person eating carbohydrate.

A third argument is the case of lipomas.  These are fatty deposits that build up in diabetics who repeatedly inject insulin into the same spot.  Once again, it is important to keep in mind the difference between normal and abnormal states.  A local injection of insulin delivers a massive dose to a very localized area of the body.  The dose received by that small area of fat tissue is hundreds of times what it would see under any normal circumstances.  That suppresses HSL and activates LPL to an abnormal degree, resulting in fat accumulation.  This is essentially the equivalent of a cell culture study where investigators put a massive amount of insulin onto fat cells, and watch nutrients flow into them from the surrounding medium.  It has very little relevance to normal physiology in my opinion. 

Insulin can influence the accumulation of fat by fat tissue if it is manipulated in an extreme manner, either due to severe insulin deficiency or injecting unnaturally large amounts into one area repeatedly.  However, I have yet to see any convincing evidence that insulin action on fat cells is a physiologically relevant regulator of body fatness under normal circumstances, or that it contributes to the development of obesity in any way.  The hypothesis that insulin, in a physiological context, increases body fatness has been around for a long time.  However, most obesity and metabolism researchers considered it defunct by the mid-1980s, if not before, because of its failure to explain a number of basic observations (11).  The case against this hypothesis has expanded considerably since then. 

Hyperinsulinemia: Cause or Effect of Obesity? ]]> http://www.tediye.com/diet/hyperinsulinemia-cause-or-effect-of-obesity-4/feed/ 0 http://www.tediye.com/diet/hyperinsulinemia-cause-or-effect-of-obesity/ http://www.tediye.com/diet/hyperinsulinemia-cause-or-effect-of-obesity/#comments Thu, 15 Sep 2011 19:05:32 +0000 levent http://www.tediye.com/diet/hyperinsulinemia-cause-or-effect-of-obesity/ Is Elevated Insulin the Cause or Effect of Obesity?

The carbohydrate hypothesis, in its most popular current incarnation, states that elevated insulin acts on fat cells to cause fat storage, leading to obesity.  This is due to its ability to increase the activity of lipoprotein lipase and decrease the activity of hormone-sensitive lipase, thus creating a net flux of fat into fat cells.  I’m still not sure why this would be the case, considering that fat tissue becomes more insulin resistant as body fat accumulates, therefore insulin action on it is not necessarily increased.  Total fat release from fat tissue increases with total fat mass (1), demonstrating that insulin is not able to do its job of suppressing fat release as effectively in people who carry excess fat.  But let’s put that problem aside for the moment and keep trucking.

Elevated insulin (hyperinsulinemia) and elevated fat mass typically travel together.   It is generally accepted in the scientific community that hyperinsulinemia is the result of obesity.  However, others have argued that researchers may have the causality backward, and obesity may instead be the result of hyperinsulinemia.  If this is the case, then interventions that suppress hyperinsulinemia should reliably prevent fat gain.  Let’s see if that’s true.

One hypothesis of obesity-associated insulin resistance suggests that during the development of obesity, inflammation in fat tissue causes insulin resistance throughout the body.  One potential player is a cytokine called tumor necrosis factor-alpha (TNF-alpha).  Knocking out the TNF-alpha gene completely prevents hyperinsulinemia and insulin resistance in mice during exposure to a fattening diet.  If hyperinsulinemia causes obesity, then these mice should remain lean, but they do not.  They become obese at nearly the same rate as normal mice (2).

Researchers have generated mice that are missing jun kinase 1 (JNK1), a protein involved in inflammatory signaling, specifically from blood cells including circulating immune cells.  When exposed to a fattening diet, these mice do not develop hyperinsulinemia, retain a normal insulin sensitivity, but gain fat at the same rate as normal mice when placed on a fattening diet (3).

How about mice that lack inducible nitric oxide synthase (iNOS), another protein involved in inflammation?  They do not develop hyperinsulinemia, or insulin resistance, but actually gain more fat than normal mice when fed a fattening diet (4).

A common knee jerk reaction is to dismiss these results because they were obtained in mice.  But consider this: mice have insulin.  They have hormone-sensitive lipase and lipoprotein lipase on their fat cells, and they are regulated by insulin in the same manner as they are in humans.  Insulin goes up temporarily with carbohydrate, and chronically up with obesity, just like in humans.  So if the proposed mechanism is that insulin causes fat gain by acting on HSL and LPL in fat tissue, why would one expect the association between insulin and body fatness to be any different in mice than in humans?

But let’s look at another species anyway: dogs.  Clonidine is a blood pressure drug that targets the a2 adrenergic receptor.  When dogs are made obese via diet, clonidine prevents an increase in fasting insulin and insulin resistance without attenuating the development of obesity at all (5).

If elevated insulin is a major factor in obesity, one would expect to see elevated insulin in all, or nearly all, obese people.  However, there is a subgroup of obese people who are considered “metabolically healthy” and have normal fasting insulin and insulin sensitivity.  Likewise, there is a subset of lean, “metabolically obese” people who have high insulin and low insulin sensitivity despite a normal fat mass (6).

If the correlation between obesity and hyperinsulinemia is not very tight, and the two phenomena can be completely dissociated in experimental models by a variety of means, this indicates that elevated insulin is not a major contributor to obesity, and is certainly not required for it.  This evidence is consistent with the prevailing hypothesis that elevated insulin and insulin resistance are the result of excess fat accumulation, rather than the cause. 

Miscellaneous Observations

In this section, I’d like to discuss some of the observations that appear to support the idea that insulin regulates body fatness.  I found these ideas convincing at one point, but I will explain why, upon closer examination, they do not offer much if any support to the hypothesis. 

The first is the fact that type 1 diabetics become very lean until they receive insulin replacement, at which point they gain fat.  Type 1 diabetes is a condition in which the pancreas produces little or no insulin.  I think this example illustrates a very important concept: the difference between something that is required for fat storage, and something that regulates fat storage.

Let’s use the metaphor of a car.  Without an engine or wheels, a car can’t drive.  But the engine and wheels aren’t what decide how fast the car goes.  That is determined by the driver pushing the pedals.  If you were to get rid of the engine, the car wouldn’t move, and you might be tempted to say that the engine regulates the speed of the car.  Insulin in type 1 diabetes is a similar case.  You need some basal amount of insulin signaling around for fat cells to store fat properly.  Get rid of the insulin, and they rapidly release all of their fat due to unrestrained lipolysis (not good for health!).  Replace insulin, and the fat cells work properly, allowing them to do their job again, which is to store fat.  Fat cells also require ribosomes and DNA polymerase to store fat, but no one claims that these proteins that are required for basic cellular function regulate body fatness. Type 1 diabetics who receive insulin go from being too thin to having a normal degree of body fatness because their fat cells work again. Also because they are no longer peeing out a large quantity of glucose (glycosuria).

Another argument is the case of type 2 diabetics who require insulin.  Insulin treatment is often associated with fat gain in this scenario (7).  There are a number of problems with using this as support for the hypothesis that insulin causes fat gain in non-diabetics.  People who need insulin are, by definition, insulin deficient relative to their own degree of insulin sensitivity.  Therefore, they are in some respects similar to type 1 diabetics who are not producing enough insulin.  They may simply be gaining back the weight that they would have had to begin with, due to a failure of their own insulin to keep fat cells working properly.  The other thing to consider is that uncontrolled diabetics lose a lot of calories through their urine.  Insulin therapy corrects this, effectively increasing calorie intake.

Furthermore, insulin therapy is just insulin.  It is not accompanied by the many signals that are released by the digestive tract and pancreas of a healthy person in response to carbohydrate ingestion.  One of these is the hormone amylin, which is co-released by the pancreas, along with insulin, when carbohydrate is eaten.  It is not only a satiety peptide, but is also being investigated as a fat loss treatment (Pramlintide, 8).  When injected insulin is administered along with amylin to diabetics, it causes weight loss (9, 10).  The larger point is that you can’t extrapolate from the effects of isolated insulin injections on diabetics, to the effects of insulin on a healthy person eating carbohydrate.

A third argument is the case of lipomas.  These are fatty deposits that build up in diabetics who repeatedly inject insulin into the same spot.  Once again, it is important to keep in mind the difference between normal and abnormal states.  A local injection of insulin delivers a massive dose to a very localized area of the body.  The dose received by that small area of fat tissue is hundreds of times what it would see under any normal circumstances.  That suppresses HSL and activates LPL to an abnormal degree, resulting in fat accumulation.  This is essentially the equivalent of a cell culture study where investigators put a massive amount of insulin onto fat cells, and watch nutrients flow into them from the surrounding medium.  It has very little relevance to normal physiology in my opinion. 

Insulin can influence the accumulation of fat by fat tissue if it is manipulated in an extreme manner, either due to severe insulin deficiency or injecting unnaturally large amounts into one area repeatedly.  However, I have yet to see any convincing evidence that insulin action on fat cells is a physiologically relevant regulator of body fatness under normal circumstances, or that it contributes to the development of obesity in any way.  The hypothesis that insulin, in a physiological context, increases body fatness has been around for a long time.  However, most obesity and metabolism researchers considered it defunct by the mid-1980s, if not before, because of its failure to explain a number of basic observations (11).  The case against this hypothesis has expanded considerably since then. 

Hyperinsulinemia: Cause or Effect of Obesity? ]]> http://www.tediye.com/diet/hyperinsulinemia-cause-or-effect-of-obesity/feed/ 0 http://www.tediye.com/deneme/tennessee-women-to-have-fewer-options-for-reproductivehealthaugust-15-2008/ http://www.tediye.com/deneme/tennessee-women-to-have-fewer-options-for-reproductivehealthaugust-15-2008/#comments Fri, 26 Aug 2011 22:54:16 +0000 levent http://www.tediye.com/deneme/tennessee-women-to-have-fewer-options-for-reproductivehealthaugust-15-2008.html

Early this year, I posted on the Knoxville, TN merger of the city’s Baptist Hospital into St. Mary’s (a Catholic system) and the resulting end of access to tubal ligation and vasectomy at Baptist. Access to tubal ligation is now being eliminated at a Nashville, TN Baptist facility as well, as WKRN reports – Baptist Women’s Treatment Center will no longer offer tubal ligation after the end of this year.

WKRN also reports that this change “comes six years after Baptist Hospital and Middle Tennessee Medical Center stopped offering the procedure,” because “the hospitals were acquired by Saint Thomas Health Services, a Catholic health ministry, in 2002.”

A Baptist Hospital spokesperson reportedly issued a statement explaining that “Baptist Hospital and Middle Tennessee Medical Center remain committed to providing and expanding women’s services so more women will have the opportunity to get their care at our hospitals.”

Which sounds like the exact opposite of what has actually happened since 2002 and is happening at the Women’s Treatment Center, unless you believe that “women’s services” only means birthin’ babies – the spokesperson also explained, “Saint Thomas Health Services remains the market leader delivering more babies than any other health system in Middle Tennessee.”

[Thanks to B for letting me know about this]

Tennessee Women to Have Fewer Options for Reproductive Health

The Vagina Of The Grammar Nazi

I *heart* Kat Coble.

Best Blog Post Title of the Week

On August 12th, the American Psychological Association issued a press release regarding the APA Task Force on Mental Health and Abortion’s review of the evidence on abortion and the possibility of negative mental health outcomes. The release states:

“The best scientific evidence published indicates that among adult women who have an unplanned pregnancy, the relative risk of mental health problems is no greater if they have a single elective first-trimester abortion or deliver that pregnancy,” said Brenda Major, PhD, chair of the task force. “The evidence regarding the relative mental health risks associated with multiple abortions is more uncertain.”

The task force found that some studies indicate that some women do experience sadness, grief and feelings of loss following an abortion, and some may experience “clinically significant disorders, including depression and anxiety.” However, the task force found “no evidence sufficient to support the claim that an observed association between abortion history and mental health was caused by the abortion per se, as opposed to other factors.”

The complete report can be freely downloaded as a PDF from the APA website. The Task Force noted a lack of well-designed research on the subject, explaining that “One of the task force’s chief recommendations is for better-designed, rigorously conducted future research on the topic to ‘help disentangle confounding factors and establish relative risks of abortion compared to its alternatives.’”

I’m working on a longer piece on this topic, so will not dissect it in detail for this post, but hope to share the link with you in the months to come.

Eco World Content From Across The Internet.



Featured on EcoPressed


13-Year-Old Designs Efficient Solar Array Inspired By Oak Trees

APA Reports on Abortion and Mental Health