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Thursday, March 20, 2014

Insulin Dynamics II: Insulin Secretion & Clearance During Weight Gain

This post will discuss the following paper:  Development of hyperinsulinemia and insulin resistance during the early stage of weight gain (Erdmann). This was yet another paper I came across thanks to this recent review: Body Weight Regulation and Obesity: Dietary Strategies to Improve the Metabolic Profile.  I'm efforting the full text of this that I can share here, but in the mean time, here's the context in which the Erdmann paper is introduced in that paper:
Overweight and obesity represent a worldwide increasing health problem that seriously raises the risk for the development of severe metabolic disorders such as type 2 diabetes (T2D) mellitus and cardiovascular diseases (Erdmann et al. 2008, Klein et al. 2004). As with increasing obesity, insulin action decreases, and the system usually compensates by increasing β-cell function and consequently insulin secretion (Stumvoll et al. 2005). Euglycemia is therefore maintained. Overt hyperglycemia does not develop until later stages, when pancreatic β-cells can no longer compensate for the high levels of insulin resistance in peripheral tissues (Martyn et al. 2008). Moreover, Erdmann et al.’s (2008) study demonstrated for the first time that insulin resistance already develops during weight gain within the normal range of body weight (Erdmann et al. 2008).
Now, the increased insulin secretion is attributed to the Stumvoll paper linked in Insulin Dynamics I, but in the context of the conclusion of that paper -- "a growing body of evidence suggests that dietary strategies with the aim to reduce postprandial insulin response ... have a place in the prevention and
treatment of obesity and associated metabolic disorders." -- and this opening paragraph, the impression is given that increased insulin secretion begins early on.

So Erdmann and colleagues took 10 healthy, normal weight, men in their mid 20's and instructed them to gain weight relatively slowly by consuming a 300-500 calorie per day surplus.  Of note:
The energy surplus was achieved by food items of higher energy density considering individual taste preferences, palatability, etc., or by increasing meal size, portion size of snacks, or the number of meals, respectively. A further alternative to increase energy intake was the exchange of water to energy-containing beverages such as fruit juice or lemonades. 
The men were all described as "unrestrained eaters" with stable body weights for at least a year prior to the study.  Their average beginning weight was 71 kg (156 lb), weight gain was approximately 6 kg (~14 lbs) for an increase in BMI of 2 points and 3% fat mass.  The desired gain was fixed and the time to achieve the increased weight varied, averaging 139 ±  26 days (4-5 months).   Further, weight gain was maintained for 4 weeks on a standard 40–50% carb, 15–20% protein, and 30–40% fat diet prior to "after" measurements.  All experiments were conducted following a 12 hour overnight fast.

Pretty much all the "bad stuff" or things associated with overweight and obesity begin to show up increasing basal insulin, leptin, TC & LDL, and fasting glucose.  It is interesting to note, however, that overall glycemia did not increase significantly as determined by HbA1c.  The HOMA-IR more than doubled, but remains in normal range.  

At first blush this fits right in with the hyperinsulinemia to compensate for the insulin resistance that has been developed.  The compensatory action that was also discussed in Insulin Dynamics I seems to be at play keeping things relatively in check.  Clearly in this experiment the deliberate caloric excess → weight gain → increased insulin.  But the basal insulin secretion increased less than 20% while the basal insulin levels more than doubled.  

Is this the beginning of hepatic insulin resistance?  Is the term "insulin resistance" appropriate even in the sense of the liver here?  We have slightly elevated glucose production in the face of mildly elevated insulin production, so that fits the definition of IR.  However, when only insulin levels are measured it seems far worse than this study demonstrates.   Because the role of reduced clearance in the development of basal hyperinsulinemia seems to be considerably more significant.   The insulin clearance rate was reduced to less than half of baseline levels as insulin secretion increased less than 20%.  

So this is what happened in the fasted state.  Perhaps this was produced by some sort of progressive insulin hypersecretion after eating carbs, as insulin resistance develops.  This turns out not to be the case ... at least in this study.  The subjects were given a test meal (bread, butter, & marmalade, 260 kcal, C/F/P = 62%/32%/6% = 39g/9g/4g), and postprandial glucose, insulin and C-peptide were measured at regular intervals for 3 hours. A standard 75g OGTT was also administered.  The integrated "total exposure" was as follows for these tests both before and after weight gain:

The curves for the OGTT are shown at right.  While the total (integrated = AUC) postprandial insulin is increased by almost 50%, the curves do not track all that differently, and this is due to a modest "insulin spike".  I have edited this shortly after initial publication because yes, this spike is statistically different at the peak.    This is what is measured in most of these metabolic studies.  Of note, the glucose curve looks normal for the OGTT and the insulin response is still normal, just different than before the weight gain.  If just insulin levels are measured, this "spike" or hypersecretion appears to be much worse than it actually is.  The contribution of decreased insulin clearance is considerably more significant than the contribution of increased secretion.

Additionally the investigators did a glucose infusion test and these curves (not shown here) are rather unremarkable thought they demonstrate roughly the same thing:  no change in insulin secretion but increased insulin levels indicating reduced clearance.  


This study highlights one problem with many metabolic studies in that elevated insulin levels are reflexively presumed to be the result of hypersecretion.  At least in these subjects, it is evident that reduced insulin clearance is the major contributor to these elevated insulin levels with little to no change in insulin secretion.  Whatever the cause, glycemic control is maintained in these early stages of weight gain accompanied by alteration in insulin dynamics.    

The reduction in insulin clearance appears to be occurring in both the fasted (basal) and fed (postprandial) state.  I would note that in a future installment in this series this is not seen in the obese, rather clearance is enhanced.  This will be discussed at that point, and is likely due to compensatory increases in organ function that are not yet seen in the early stages of caloric surplus and weight gain.

The results of this study fly in the face of the insulin hypothesis yet again.  Whatever hyperinsulinemia developed was not the result of carbohydrate stimulating insulin secretion and that whole cascade of trapped fat and starving cells.  In this regard, this study brings into serious question the bias of the authors of Body Weight Regulation and Obesity: Dietary Strategies to Improve the Metabolic Profile in which it was prominently cited.  Their conclusion that "dietary strategies with the aim to reduce postprandial insulin response ... have a place in the prevention and treatment of obesity" seems misguided in light of evidence that insulin secretion did not change significantly.  While it was not statistically significant, a more "real life" challenge of a test meal (vs. the 75g glucose challenge) elicited less of an insulin response following weight gain.

The insulin resistance demonstrated in Edelmann appears to be hepatic with both a mild decreased suppression of glucose production and a more profound decrease in the clearance of insulin.

In the next installment I'll tackle a study or two in the obese.


EatLessMoveMoore said...

What's with all the science-y stuff? Why have you decided to start giving Jimmy, Robb, Amy, et al a pass? The hard-hitting critical pieces are why most people read this blog. Just sayin', Evie.

albie_cilliers said...

Nice study thanks , and good post Evelyn !

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