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Fat Tissue Insulin Sensitivity In Addition To Obesity

In this post, I'll hash out a few to a greater extent than facts pertaining to the thought that elevated insulin promotes the accumulation of obese mass.  

Insulin Action on Fat Cells Over the Course of Fat Gain

The thought that insulin acts on obese cells to promote obesity requires that insulin suppress obese release inwards people alongside to a greater extent than obese (or people who are gaining fat) to a greater extent than inwards lean people.  As I receive got written before, this is non the case, together with inwards fact the opposite is true.  The obese tissue of obese people fails to commonly suppress obese acid release inwards reply to an increment inwards insulin caused past times a repast or an insulin injection, indicating that insulin's mightiness to suppress obese release is impaired inwards obesity (1, 2, 3).  The argue for that is simple: the obese tissue of obese people is insulin resistant.

There has been some interrogation some the blogosphere almost when insulin resistance inwards obese tissue occurs.  Is it exclusively observed inwards obese people, or does it occur to a lesser extent inwards people who deport less excess obese volume together with are maybe on a trajectory of obese gain?  To respond this question, let's plow the clocks dorsum to 1968, a twelvemonth earlier Neil Armstrong showtime laid human foot on the moon. 

The interrogation was showtime investigated past times doc Jules Hirsch's grouping (4).  They took obese biopsies from people alongside a arrive at of dissimilar obese masses, exposed them to insulin, together with determined the marker of insulin sensitivity of the biopsies.  They constitute that insulin sensitivity of obese tissue declines as the size of obese cells increases.  This was truthful across all jail cellular telephone sizes, non exclusively the largest ones.  As torso obese gain mostly involves an increment inwards obese jail cellular telephone size rather than number, this suggests that obese tissue insulin sensitivity progressively declines as obese volume increases.

But they went further.  They caused weight loss inwards their obese subjects using a calorie-restricted diet (15:45:40 protein:carb:fat), which shrunk their obese jail cellular telephone size.  Following this intervention, insulin sensitivity inwards obese tissue increased, together with both the blood glucose together with insulin reply to an oral glucose charge improved considerably.  They concluded:
Weight loss together with reduction inwards adipose jail cellular telephone size restored plasma insulin concentration to normal, concomitant alongside the provide of normal tissue insulin sensitivity.
These information are consistent alongside the residue of the literature suggesting that elevated insulin together with insulin resistance are the final result of obesity.  They advise that excess obese mass, especially enlarged obese cells, is the ultimate crusade of insulin resistance.  This hypothesis has been buttressed farther since 1968.

The Relationship Between Fasting Insulin together with Future Weight Gain

As a farther information point, consider the review newspaper published inwards 2007 past times Hivert together with colleagues (5).  They reviewed all the studies that examined the human relationship betwixt fasting and/or post-meal insulin aeroplane together with hereafter weight gain (there are a number of them).  Here's what they found:
The bulk of prospective studies that included non-obese adults failed to exhibit an association betwixt insulin aeroplane at baseline together with hereafter weight gain.
On the other hand, other large cohort studies receive got shown that insulin resistance, which is usually associated alongside high plasma insulin levels, could endure protective against weight gain.
High insulin does non mostly predict hereafter weight gain, together with sometimes it fifty-fifty predicts lower hereafter weight gain. This could endure because of insulin's anti-obesity activeness inwards the brain, although that isn't clear because nosotros don't know how hypothalamic insulin sensitivity tracks alongside hyperinsulinemia. 

The Case of Diazoxide

Much fuss has been made almost a report showing that the potassium channel activating drug diazoxide accelerates weight loss inwards obese people (6).  One of the effects of this drug is a substantial reduction inwards insulin secretion, which is why it's used to process hypoglycemia. 

There are a number of problems alongside using this report to back upward the insulin hypothesis of obesity.  One occupation is that the finding has non ever been replicated past times other investigators (7). Also, this drug is already approved past times the FDA for the handling of hypoglycemia together with hypertension.  If it's together with so effective for obese loss, why isn't it beingness used as a obese loss drug?

Influenza A virus subtype H5N1 2d occupation appears as yous assort through the showtime study's results.  Basal metabolic charge per unit of measurement together with the proportion of saccharide together with obese beingness used for fuel remained unchanged past times diazoxide, suggesting that fifty-fifty if to a greater extent than obese acids were beingness released past times obese cells, they were non beingness burned at a faster rate, together with thus they were also beingness re-incorporated into obese cells at an as high rate.  Think almost this for a moment. Diazoxide decreased fasting insulin past times 36 percent, together with this had no trial whatsoever on obese burning or resting loose energy expenditure.  This report confirms, ironically, that insulin does non regulate the cyberspace obese acid flux of obese cells.  Even if reducing insulin increases obese release from obese cells, if the obese is non burnt, it simply does a loop through the circulation together with ends upward correct dorsum where it started.  This is partially because insulin is non the principal element controlling obese re-incorporation into obese cells-- that project seems to endure held past times acylation-stimulating poly peptide (ASP).

The obese loss coupled alongside unchanged basal metabolic charge per unit of measurement agency that either a) diazoxide made them begin exercising a lot, and/or b) they ate less.  Since I've never heard of a drug that causes obese people to run 3 miles a day, it was almost for certain (b).  So did reduced insulin activeness on their obese cells brand them swallow less?  Given that obese cells don't regulate nutrient intake (except indirectly via their production of leptin, which acts inwards the brain), together with the encephalon does, maybe nosotros should shift our focus to the encephalon for a moment.

But first, what is diazoxide?  It activates ATP-dependent potassium channels, which are required for glucose sensing past times the insulin-secreting pancreatic beta cells.  But as the biologists inwards the crowd may know, these channels seem inwards a lot of places inwards the body.  One of the places they seem is inwards the shine musculus tissue that lines the arteries, which may endure why diazoxide is used to process hypertension.  Another house they seem is inwards the brain, where they regulate the electrical activity that is intrinsic to neuron function. 

As the hypothalamus is a critical expanse regulating nutrient intake, it makes feel to encounter if diazoxide tin influence the activity of neurons there.  It turns out, diazoxide influences the activity of POMC neurons, 1 of the critical jail cellular telephone types that regulates nutrient intake inwards mammals (8).  As these cells are contained inwards the hypothalamus, a part that has a high blood-brain-barrier permeability, it is plausible that diazoxide genuinely exerts its trial there.  The larger indicate is that diazoxide is non a specific drug-- it has effects on many parts of the body, together with so 1 cannot assume that its trial on torso weight inwards some studies is due to a reduction inwards circulating insulin.  The evidence on diazoxide does non back upward the thought that it causes obese loss past times reducing insulin activeness on obese cells.  Other mechanisms are to a greater extent than plausible at this point.  

Drugs that influence nutrient intake and/or torso fatness usually exercise together with so via an trial on the brain.  For example, rosiglitazone is an anti-diabetic drug that increases insulin sensitivity.  One side trial is obese gain.  Originally, it was postulated that obese gain was due to the effects of rosiglitazone on obese cells.  Recently, it was shown past times doc Jerrold Olefsky, inwards collaboration alongside my colleagues at UW, that rosiglitazone exerts its obesity-promoting trial mostly via the encephalon (9).  This same story has repeated itself many times inwards the scientific literature, so whenever an intervention causes a alter inwards nutrient intake or obese mass, the showtime affair I hollo back is "what's happening inwards the brain?" 

Conclusion

High circulating insulin is in all likelihood an adaptive reply to insulin resistance inwards the body, which develops as obese cells enlarge together with larn less effective at trapping obese acids together with keeping them where they should endure (there may also endure a contribution from inflammation that may or may non endure independent of the changes inwards obese acid handling).  Elevated insulin is in all likelihood the body's manner of trying to compensate for this defect together with travel on obese inwards obese cells, but it does non fully compensate for the insulin resistance inwards obese tissue that progressively develops as obese cells enlarge.  Evelyn Kocur has written almost this quite a bit.  This defect tin endure largely reversed past times obese loss, as demonstrated past times the fact that a number of obese loss diets, including low-carbohydrate, low-fat together with calorie restriction diets Pb to improved insulin activeness as long as sufficient obese is lost. 

I receive got pointed out the reasons why the carbohydrate-insulin-fat hypothesis is non mostly considered feasible past times the scientific community.  I experience I receive got convinced those who are able to endure convinced.  I can't convince everyone, together with that's all right.  It's fourth dimension for me to motion on from this topic, together with on to to a greater extent than useful things!
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