Overfeeding and Elevated Insulin

It's commonly accepted in the obesity research community that fat gain causes insulin resistance and an increase in circulating insulin, and that this is a major reason why obese people usually have insulin resistance and high circulating insulin. Part of the rationale is that substantial fat loss by almost any means improves insulin sensitivity and causes circulating insulin to decline, and substantial fat gain from deliberate overfeeding causes insulin sensitivity to decline and circulating insulin to increase.  I recently cited three references to support this contention on another blog, and was challenged, so I decided to revisit these references to make sure I had understood them correctly (1, 2, 3).  Since I took the time to do this, I figured I may as well write it up for my readers, since these studies are quite informative.

As I had recalled, in all three studies, overfeeding and fat gain caused an increase in circulating insulin (1, 2, 3).  But there's an even older overfeeding study I didn't cite at the time, much of which appears in a 1968 review paper in AJCN, which is quite interesting as well.  The full text of the paper is available for free, so please have a look if you're interested (4).  This is an old school study design that probably wouldn't pass a modern human subjects research review board.  Volunteers (sort of-- they were prisoners) were intensely overfed for a period of 3-5 months, gaining a full 26 percent of their initial body weight.  Investigators found that these volunteers experienced an increase in fasting and post-meal insulin that was similar to what is observed in common obesity:

As in spontaneous obesity the fasting immunoassayable serum insulin as well as the ratio of insulin to glucose is increased in experimental obesity. 

Our findings in experimental obesity are consistent with those of Perley and Kipnis and Kreisberg et al. in spontaneous obesity in that there is greater secretion of insulin, in response to a comparable stimulus than in the normal [lean person].

For our purposes, the most interesting study of the three I cited originally was published by Drs. Johannes Erdmann and colleagues in 2007 (1).  There are several reasons why I like this study:

1. Weight gain occurred gradually over a period of 4.5 months
2. Overfeeding was only by a relatively modest 300-500 calories per day, in contrast to the more intense overfeeding in certain other studies
3. They measured body fat directly
4. They measured both circulating insulin and insulin sensitivity

This study started with lean, ostensibly healthy people.  Here is the overfeeding protocol:

The subjects were instructed by a dietitian to increase daily food intake by 300–500 kcal in addition to what they were consuming. 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.

Basically it sounds like they replicated roughly what has happened spontaneously in the US over the last 50 years: more calorie-dense, highly palatable foods, more snacks, and more sweetened beverages, leading to a higher overall calorie intake and fat gain.

After 4.5 months of overfeeding, participants gained an average of 13.6 pounds (6.2 kg) of body weight, and 7.1 pounds (3.2 kg) of body fat.  Not nearly as much as in the previous study, but nothing to sneeze at.  Fasting insulin increased more than two-fold from 11.5 to 25.1 pmol/L, and post-meal insulin also increased substantially.  At the same time, insulin sensitivity decreased substantially.  Here's the authors' summary (basically, a more detailed version of what I just said):

The present study demonstrates for the first time that intentional weight gain within the normal range of subjects who are lean to begin with leads to a significant elevation of basal plasma insulin, C-peptide, and glucose concentrations, whereas after ingested or injected stimuli only insulin levels were raised. An increase of insulin resistance is indicated by HOMA-IR in the basal state, by comparable glucose levels despite higher insulin concentrations following oral stimulation, and by a reduced rate of glucose disposal despite higher insulin concentrations during a glucose clamp at physiological hyperglycemia.

Here's another key quote (hang with me, I'll explain it):

Following a meal or glucose-induced stimulation of insulin secretion the glucose response above baseline remained unchanged after weight gain. This indicates that in the postprandial state the augmented insulin resistance can be counterbalanced, most likely via an alteration of hepatic insulin metabolism so that postprandial glucose homeostasis remains unchanged. When changes of body weight and the degree of insulin resistance become greater, the previously demonstrated augmentation of postprandial insulin secretion apart from clearance is additionally required for maintenance of glucose homeostasis in overweight and obese subjects.

For our purposes here, the main point they're suggesting is that fat gain causes insulin resistance, and the body adjusts insulin levels upward to compensate.  To be fair, their data can't really tell us whether elevated insulin is a reaction to insulin resistance, or the reverse, but overall the evidence supports the former scenario. In any case, it doesn't matter much because both were caused by overfeeding and fat gain.

Body fatness isn't the only influence on circulating insulin, so the correspondence between the two is far from perfect on an individual level (though it is quite strong on a population level).  But it does appear to be a major factor.