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Hyperinsulinemia: Crusade Or Consequence Of Obesity?

Is Elevated Insulin the Cause or Effect of Obesity?

The saccharide hypothesis, inward its most pop electrical flow incarnation, states that elevated insulin acts on obese cells to campaign obese storage, leading to obesity.  This is due to its powerfulness to increment the activity of lipoprotein lipase as well as decrease the activity of hormone-sensitive lipase, thus creating a internet flux of obese into obese cells.  I'm withal non sure why this would hold upward the case, considering that obese tissue becomes to a greater extent than insulin resistant equally trunk obese accumulates, thence insulin activeness on it is non necessarily increased.  Total obese liberate from obese tissue increases alongside full obese volume (1), demonstrating that insulin is non able to reach its chore of suppressing obese liberate equally effectively inward people who bear excess fat.  But let's set that job aside for the 2nd as well as compass off trucking.

Elevated insulin (hyperinsulinemia) as well as elevated obese volume typically move together.   It is by as well as large accepted inward the scientific community that hyperinsulinemia is the resultant of obesity.  However, others take away maintain argued that researchers may take away maintain the causality backward, as well as obesity may instead hold upward the resultant of hyperinsulinemia.  If this is the case, so interventions that suppress hyperinsulinemia should reliably preclude obese gain.  Let's come across if that's true.

One hypothesis of obesity-associated insulin resistance suggests that during the evolution of obesity, inflammation inward obese tissue causes insulin resistance throughout the body.  One potential instrumentalist is a cytokine called tumor necrosis factor-alpha (TNF-alpha).  Knocking out the TNF-alpha factor completely prevents hyperinsulinemia as well as insulin resistance inward mice during exposure to a fattening diet.  If hyperinsulinemia causes obesity, so these mice should stay lean, but they reach not.  They larn obese at nearly the same charge per unit of measurement equally normal mice (2).

Researchers take away maintain generated mice that are missing jun kinase 1 (JNK1), a poly peptide involved inward inflammatory signaling, specifically from blood cells including circulating immune cells.  When exposed to a fattening diet, these mice reach non develop hyperinsulinemia, retain a normal insulin sensitivity, but gain obese at the same charge per unit of measurement equally normal mice when placed on a fattening diet (3).

How nigh mice that lack inducible nitric oxide synthase (iNOS), some other poly peptide involved inward inflammation?  They reach non develop hyperinsulinemia, or insulin resistance, but genuinely gain to a greater extent than obese than normal mice when fed a fattening diet (4).

Influenza A virus subtype H5N1 mutual articulatio genus jerk reaction is to dismiss these results because they were obtained inward mice.  But see this: mice take away maintain insulin.  They take away maintain hormone-sensitive lipase as well as lipoprotein lipase on their obese cells, as well as they are regulated past times insulin inward the same mode equally they are inward humans.  Insulin goes upward temporarily alongside carbohydrate, as well as chronically upward alongside obesity, precisely similar inward humans.  So if the proposed machinery is that insulin causes obese gain past times acting on HSL as well as LPL inward obese tissue, why would i facial expression the association betwixt insulin as well as trunk fatness to hold upward whatsoever dissimilar inward mice than inward humans?

But let's facial expression at some other species anyway: dogs.  Clonidine is a blood pressure level drug that targets the a2 adrenergic receptor.  When dogs are made obese via diet, clonidine prevents an increment inward fasting insulin as well as insulin resistance without attenuating the evolution of obesity at all (5).

If elevated insulin is a major component subdivision inward obesity, i would facial expression to come across elevated insulin inward all, or nearly all, obese people.  However, in that location is a subgroup of obese people who are considered "metabolically healthy" as well as take away maintain normal fasting insulin as well as insulin sensitivity.  Likewise, in that location is a subset of lean, "metabolically obese" people who take away maintain high insulin as well as depression insulin sensitivity despite a normal obese volume (6).

If the correlation betwixt obesity as well as hyperinsulinemia is non real tight, as well as the 2 phenomena tin hold upward completely dissociated inward experimental models past times a diverseness of means, this indicates that elevated insulin is non a major contributor to obesity, as well as is sure enough non required for it.  This bear witness is consistent alongside the prevailing hypothesis that elevated insulin as well as insulin resistance are the resultant of excess obese accumulation, rather than the cause. 

Miscellaneous Observations

In this section, I'd similar to utter over some of the observations that look to back upward the thought that insulin regulates trunk fatness.  I flora these ideas convincing at i point, but I volition explicate why, upon closer examination, they reach non offering much if whatsoever back upward to the hypothesis. 

The kickoff is the fact that type 1 diabetics larn real lean until they have insulin replacement, at which dot they gain fat.  Type 1 diabetes is a status inward which the pancreas produces trivial or no insulin.  I remember this illustration illustrates a real of import concept: the deviation betwixt something that is required for obese storage, as well as something that regulates obese storage.

Let's job the metaphor of a car.  Without an engine or wheels, a automobile can't drive.  But the engine as well as wheels aren't what determine how fast the automobile goes.  That is determined past times the driver pushing the pedals.  If y'all were to larn rid of the engine, the automobile wouldn't move, as well as y'all powerfulness hold upward tempted to enjoin that the engine regulates the speed of the car.  Insulin inward type 1 diabetes is a similar case.  You request some basal amount of insulin signaling some for obese cells to shop obese properly.  Get rid of the insulin, as well as they speedily liberate all of their obese due to unrestrained lipolysis (not skillful for health!).  Replace insulin, as well as the obese cells piece of work properly, allowing them to reach their chore again, which is to shop fat.  Fat cells also require ribosomes as well as deoxyribonucleic acid polymerase to shop fat, but no i claims that these proteins that are required for basic cellular go regulate trunk fatness. Type 1 diabetics who have insulin go from beingness besides sparse to having a normal aeroplane of trunk fatness because their obese cells piece of work again. Also because they are no longer peeing out a large quantity of glucose (glycosuria).

Another declaration is the instance of type 2 diabetics who require insulin.  Insulin handling is oftentimes associated alongside obese gain inward this scenario (7).  There are a number of problems alongside using this equally back upward for the hypothesis that insulin causes obese gain inward non-diabetics.  People who request insulin are, past times definition, insulin deficient relative to their ain aeroplane of insulin sensitivity.  Therefore, they are inward some respects similar to type 1 diabetics who are non producing plenty insulin.  They may merely hold upward gaining dorsum the weight that they would take away maintain had to laid out with, due to a failure of their ain insulin to compass off obese cells working properly.  The other affair to see is that uncontrolled diabetics lose a lot of calories through their urine.  Insulin therapy corrects this, effectively increasing calorie intake.

Furthermore, insulin therapy is precisely insulin.  It is non accompanied past times the many signals that are released past times the digestive tract as well as pancreas of a salubrious somebody inward reply to saccharide ingestion.  One of these is the hormone amylin, which is co-released past times the pancreas, along alongside insulin, when saccharide is eaten.  It is non entirely a satiety peptide, but is also beingness investigated equally a obese loss handling (Pramlintide, 8).  When injected insulin is administered along alongside amylin to diabetics, it causes weight loss (9, 10).  The larger dot is that y'all can't extrapolate from the effects of isolated insulin injections on diabetics, to the effects of insulin on a salubrious somebody eating carbohydrate.

Influenza A virus subtype H5N1 3rd declaration is the instance of lipomas.  These are obese deposits that cook upward inward diabetics who repeatedly inject insulin into the same spot.  Once again, it is of import to compass off inward heed the deviation betwixt normal as well as abnormal states.  Influenza A virus subtype H5N1 local injection of insulin delivers a massive dose to a real localized surface area of the body.  The dose received past times that minor surface area of obese tissue is hundreds of times what it would come across nether whatsoever normal circumstances.  That suppresses HSL as well as activates LPL to an abnormal degree, resulting inward obese accumulation.  This is essentially the equivalent of a jail mobile telephone civilisation written report where investigators set a massive amount of insulin onto obese cells, as well as sentry nutrients period of time into them from the surrounding medium.  It has real trivial relevance to normal physiology inward my opinion. 

Insulin tin influence the accumulation of obese past times obese tissue if it is manipulated inward an extreme manner, either due to severe insulin deficiency or injecting unnaturally large amounts into i surface area repeatedly.  However, I take away maintain yet to come across whatsoever convincing bear witness that insulin activeness on obese cells is a physiologically relevant regulator of trunk fatness nether normal circumstances, or that it contributes to the evolution of obesity inward whatsoever way.  The hypothesis that insulin, inward a physiological context, increases trunk fatness has been some for a long time.  However, most obesity as well as metabolism researchers considered it defunct past times the mid-1980s, if non before, because of its failure to explicate a number of basic observations (11).  The instance against this hypothesis has expanded considerably since then. 


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