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Is It Fourth Dimension To Re-Write The Textbooks On Insulin Together With Obesity?

A recent study inward Cell Metabolism past times doc Arya Mehran as well as colleagues constitute a number that, according to a press release, "could overturn widely accepted notions almost well for yous eating habits" (1), as well as has gear upwards the Internet abuzz.

In this study, researchers generated mice that lack i re-create of the pancreatic insulin gene, as well as compared them to mice carrying both copies (2).  Then, they exposed both groups to a fattening diet, as well as constitute that mice lacking i re-create of the insulin cistron secreted less insulin than the comparing grouping (i.e., they did non railroad train the same grade of hyperinsulinemia).  These mice were also completely resistant to fatty gain, spell the comparing grouping became obese.  The authors came to some rather large conclusions based on these results, suggesting that the "accepted model" that hyperinsulinemia is the number of obesity is "incompatible amongst our results that seat the insulin hypersecretion genetically upstream of obesity".  Ergo, diet causes hyperinsulinemia, which causes fatty gain.  It's a familiar declaration to those who frequent Internet diet-health circles, except inward this representative the hyperinsulinemia is caused past times a high-fat diet.

The occupation is that the "accepted model" they desire to supersede overnight didn't come upwards out of sparse air-- it emerged from a large trunk of research, which was almost completely ignored past times the authors.  When carefully considered, this bear witness suggests an choice explanation for the results of doc Mehran as well as colleagues.

In a landmark newspaper published inward the magazine Nature inward 1997, doc Teoman Uysal as well as colleagues studied a mouse draw of piece of work lacking the inflammatory cistron TNF-alpha (3).  Due to a suppression of inflammatory signaling, these animals create non railroad train insulin resistance when placed on a fattening diet.  As a result, they create non railroad train hyperinsulinemia at all-- insulin levels stay the same every bit lean controls fed a normal diet.  This suggests that the hyperinsulinemia of obesity is indeed a compensatory reply to insulin resistance.  Get rid of insulin resistance, as well as yous larn rid of hyperinsulinemia.  Meanwhile, inward the comparing grouping fed the same fattening diet, fasting insulin increased past times five-fold.  Yet despite these huge differences inward fasting insulin, both groups of mice developed "marked obesity".  Here are the relevant figures:


The same thing was reported for the iNOS knockout mouse, which also does non railroad train insulin resistance for a like argue (4).  In that case, the mice amongst normal insulin genuinely became fatter than the hyperinsulinemic comparing group, but both groups gained fat.  The finding that obesity does non depend on hyperinsulinemia has been replicated multiple times inward other brute models that create non railroad train insulin resistance on fattening diets (5, 6).  It is unfortunate that doc Mehran as well as colleagues did non advert these papers or sweat to reconcile them amongst their ain findings.

Roughly 20% of obese humans are insulin sensitive as well as possess got normal circulating insulin levels, an number I discussed inward my 2012 AHS beak (7).  Consistent amongst the bear witness inward brute models I but discussed, this demonstrates that hyperinsulinemia is non required for obesity inward humans.  If the interpretation of doc Mehran as well as colleagues were correct, this should last impossible or at to the lowest degree real rare.  Observational studies inward humans overall possess got constitute that elevated insulin levels create non predict time to come fatty make (8), offering farther bear witness against the sentiment that hyperinsulinemia is required for obesity.  Since at that spot possess got been a lot of studies, they tin last cherry picked, but if yous reckon them every bit a whole, the bulk of studies that constitute an association genuinely reported that higher insulin predicts less fatty make over time (8).

Well, where create nosotros larn from here?  We tin either stand upwards on reverse sides of the draw of piece of work as well as yell at i another, or nosotros tin examine to seat the pieces together into a cohesive framework that explains ALL the evidence.  Luckily, such a framework exists as well as it's pretty simple.

The elevated insulin levels that accompany obesity are a compensatory reply to insulin resistance-- this is clear from the papers I cited above, amid many others.  Therefore, when insulin resistance develops, insulin secretion goes upwards inward parallel, maintaining but about the same human relationship betwixt insulin secretion as well as insulin sensitivity, then that relatively normal metabolic command is maintained (if this didn't happen, life-threatening metabolic havoc would speedily ensue, e.g. diabetes or hypoglycemia).  This explains why suppressing insulin resistance as well as hyperinsulinemia inward parallel has picayune or no impact on fatty gain.  In that case, amount insulin activity on fatty tissue (i.e., the normal human relationship betwixt insulin secretion as well as insulin sensitivity) is preserved.

However, when yous uncouple insulin secretion from insulin sensitivity, yous alter the normal ease betwixt the two, as well as yous tin comport on fatty mass.  That's why the fat-specific insulin receptor knockout mouse is resistant to obesity (9).  It's also i of the reasons why people lose fatty when they railroad train diabetes, which is a (relative or absolute) deficiency of insulin action.  Correcting the insulin deficiency of diabetes oft causes fatty make for the same reason.  In the newspaper past times doc Mehran as well as colleagues, they suppressed insulin secretion without increasing insulin sensitivity, creating an insulin deficiency dry ground like to mild diabetes, as well as the number was the same: elevated blood glucose as well as resistance to fatty gain.  I neglect to come across why this is globe shattering.

Although the number is interesting from an academic perspective, it isn't relevant to mutual obesity where insulin resistance as well as insulin secretion parallel i another, as well as it for sure does non erase all previous bear witness suggesting that hyperinsulinemia isn't required for obesity inward mice or humans.  I intend nosotros tin concur off on re-writing those textbooks for the fourth dimension being.


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