Why fasting matters: more on IGF-1

(Originally appeared on Medium)

I have received several comments for my previous post regarding the fact that, based on the body composition data, in the IF group was in a slight calorie deficit and that therefore, the arguments presented in the post were unwarranted. If you haven’t read that post, its a discussion on the apparent effect that IF has on IGF-1 and adipocytokine levels seen in this study. I discussed the influence of weight loss on the latter, so here I will focus mainly on IGF-1.

But first things first. Let’s see at the body composition data from the study.

  • The IF group lost 0.9 kg in 8 weeks. This represents 1% of body weight. They lost 15% of body fat mass.
  • In kcal/lb (a rough measure of energy intake level), at the end of the study, the IF group was consuming around 14.97 kcal/lb, while the control group was consuming 15.47 kcal/lb. Generally, a good estimate for maintenance calories is between 14–16 kcal/lb.
  • In the IF group, subjects went from consuming 2826 to 2735 kcal/day. In the control group, it went from 3007 to 2910 kcal/day. There was no significant difference between calorie intake between groups. But for the sake of the argument, lets say that they were in calorie deficit. Energy restriction was thus 3% from baseline in both groups. This level of restriction is well within errors in estimation and in all practical purposes, not considered as “energy restriction”. However, if we assume that it indeed is considered an energy restricted diet, then no one can argue that the deficit was small and almost non-significant. This also agrees with the small amount of weight loss, which is well within normal daily variation.
  • Protein intake was increased compared to baseline and not significantly different between groups (1.93 g/kg in the IF group vs. 1.89 g/kg in the control group).

Based on the above, one can rely on the lack of statistical significance in energy intake between groups and mean calorie intake per day to assume that both groups consumed the same number of calories, which were around maintenance. However, the calorie difference might be biologically significant as suggested by the greater loss of body fat in the IF group. Given that the focus of the criticism is in the latter, I will consider the IF group to be in a slight calorie deficit and show how it doesn’t change the main argument of the original post.

What we know about IGF-1, calorie restriction (CR) and weight/fat loss

As mentioned in the other post, it is well established than in humans, dietary protein intake is the main determinant of serum IGF-1 levels. So in theory, the higher the protein intake, the higher the IGF-1 levels. CR has a modest effect. On the other hand, CR, by definition, will result in weight loss, which could also modulate IGF-1. Thus, the significant reduction of IGF-1 in the IF group, if not because of the temporal restriction of food to a short window, could be due to:

a) Lower protein intake than the control group.

b) Lower caloric intake or greater CR than the control group.

b) Greater weight/fat loss than the control group.

Protein intake was not different between groups and was high, so if anything, it should have increased IGF-1 levels.

The CR level in both groups was 3%, so the level of restriction for both was the same (the absolute level of restriction was 91 kcal for the IF group and 97 kcal for the control group). The difference in basal energy intake between groups was due to different initial mean body weight, which was not statistically significant (83.9 kg in the IF group vs. 85.3 kg in the control group), but at the end of the study was 175 kcal. Again, the difference was not statistically significant, both diets were on maintenance levels and restricted from basal levels by the same amount. But for the sake of the argument, we will assume that this difference could account for the change in IGF-1.

The IF group lost significantly more body fat than the control group. Thus, it could also be that this loss of body fat explains the difference in IGF-1 between groups.

In summary and for further comparisons, the IF group was 3% CR, lost 1% of body weight and lost 15% of body fat mass in 8 weeks. The appropriate way to calculate the calorie deficit should be to subtract the intervention calories from basal calories (which is 91 kcal), but as people have focused on the 175 kcal difference with the control group, we will use this number as the calorie deficit (-175 kcal).

Because CR and weight loss are invariably linked, I will discuss them together.

I already mentioned that long-term (6 years) CRON results in a modest decrease in IGF-1, with average levels compared to what achieved in 8 weeks in the IF group. This population is the most relevant for discussion of independent effects of CR on metabolic markers as they are weight-stable (so no confounding due to weight loss).

There is also data from the CALERIE study, at 1 and 2 years. In this intervention, normal weight subjects were calorie restricted for 2 years to a goal of 20% CR. After 1 year, subjects achieved only 12% of CR (-279.5 kcal), reduced body weight by 10.7%, fat mass by 24%, improved insulin sensitivity and some inflammatory markers, but didn’t reduce IGF-1 significantly. The same results were seen after 2 years: body weight was reduced by 10.4%, fat mass by 22.5% with a similar CR level (-216.3 kcal), but IGF-1 levels were only reduced by 8.6%. Importantly, protein intake increased in this period to 1.28 g/kg.

I have put these differences in a table to make it easier to compare:

All changes are with respect to baseline values and just a rough difference between means.

Achieving 10% of weight loss, 22.5% of fat loss and 10% CR in 2 years didn’t produce the same reduction in IGF-1 as 8 weeks with IF with 3% CR, despite higher weight/fat loss and lower protein and calorie intake. Even if we consider that the calorie reduction was 175 kcal (which was not), it still falls short compared to that in Fontana et al., 2016 (175 kcal vs 216 kcal, or 6% CR vs 10% CR).

I believe the most adequate comparison is the one above, because it compares normal weight subjects. But there is also data from obese subjects undergoing weight loss.

In overweight women, 25% of energy restriction either continuously (CER, 1500 kcal daily) or intermittently (IER, 647 kcal for 2 days per week) resulted in similar body weight loss after 6 months. Neither of the interventions reduced significantly IGF-1. However, there is a clear trend in the IER group for reducing IGF-1 levels (baseline=201.3; 6 months=191.6 ng/mL) that was not seen in the CER (baseline=202.9; 6 months= 203.7 ng/mL) and didn’t appear to correlate with weight or fat loss. But the IER protocol is more similar to the 5:2 diet than to a 16/8 IF protocol (and it involves less overall fasting period). Nevertheless, it shows that 6 months of 25% CR that produced significant changes in body weight and fat loss didn’t reduce IGF-1 levels. Similar results have been observed by the same authors: no change in IGF-1 with 25% daily or intermittent energy restriction despite significant weight/fat loss.

In other group of obese subjects, dietary restriction (1200 kcal/day) increased IGF-1 levels after 8 weeks but returned to baseline after 16 weeks, despite 5.8 and 8.1 kg of body weight lost (8 vs. 16 weeks, respectively). A similar increase in IGF-1 after weight loss has been observed in other study with obese women, as well as in an intervention with or without orlistat.

As described, there is no clear relationship between body weight/fat loss and degree of CR on serum IGF-1 levels in normal or obese subjects. Only after a long period of time (2 years) and constant, significant CR (10–12%) a small change in IGF-1 is observed. Thus, it is highly unlikely that the change seen in the IF group is due to either CR or weight/fat loss, specially with a high protein intake, almost no CR and short duration of the intervention (8 weeks). Even if one assumes that the IF group was in significant calorie deficit, the degree of IGF-1 reduction in such a short time and with the amount of protein is remarkable. As mentioned in the other post, comparable reductions have only been observed after 3 cycles of a Fasting-Mimicking Diet (13%) or reducing protein from 1.67 g/kg to 0.95 g/kg for 3 weeks (22%), the latter being the most effective.

Finally, I want to mention something important that was not part of the original post as the study didn’t measure it: IGFBP (IGF-binding proteins). The activity of IGF-1 depends on its bioavailability, which in turn is determined by the ratio of IGF-1 to IGFBP (IGF-1:IGFBP ratio). Simply put, the concentration of IGFBP determines the amount of free serum IGF-1, which in the end is the available hormone in circulation. 2 years of CR increased IGFBP-1 (one isoform of IGFBP that is regulated by metabolic status) by 20–25%, which in turn reduced the IGF-1:IGFBP-1 ratio by 42%. So even though CR didn’t reduce IGF-1 significantly, it did reduce the amount of free IGF-1.

Why it makes sense

Quoting Fontana et al., 2016 (my emphasis):

In fact, serum concentration of IGFBP-1, unlike IGFBP-3 which binds 75–90% of circulating IGF-I, is heavily influenced by the metabolic (i.e., insulin resistance, and insulin and glucagon levels) and nutritional (fasting and refeeding) state of the individual. Excessive adiposity-induced insulin resistance and compensatory hyperinsulinemia have been shown to decrease hepatic synthesis of IGFBP-1, which translates into increased concentrations of bioavailable IGF-1, without modifications in serum total IGF-1 levels (Lukanova et al., 2001; Maddux et al., 2006). Patients with type 1 diabetes have higher serum IGFBP-1 concentrations than normoglycemic controls (Suikkari et al., 1988), and acute steady state hyperinsulinemia lowers serum IGFBP-1 levels by 40–70% in normal individuals (Yeoh & Baxter, 1988; Snyder & Clemmons, 1990). Moreover, it has been shown that circulating levels of IGFBP-1 are acutely increased by 3–4 fold in response to overnight fasting and decline rapidly after a meal (Busby et al., 1988; Smith et al., 1995).

Indeed, IGFBP-1 has been proposed as a marker of hepatic insulin sensitivity. While IGF-1 levels are primarily determined by dietary protein intake, IGFBP-1 levels are regulated by insulin secretion. It appears that fasting decreases IGF-1 and increases IGFBP-1, effectively reducing IGF-1 bioavailability. In normal subjects after 36 hours of fasting, IGF-1 levels are reduced from 249.5 to 219.4 ng/mL (-12%) and IGFBP-1 levels are increased from 27.4 to 205.2 ng/mL (+649%).

A note on adipocytokines

In the previous post I presented evidence that the relationship between weight loss and levels of adipocytokines is equivocal. However, I found information on TNF-a in non-obese subjects. From the same CALERIE study, TNF-a was reduced by 22% after 2 years, compared to only 8% in the IF group, which is almost the same reduction observed for the CR subjects in CALERIE after 1 year (8.5%) with a higher CR level. Still, absolute values are significantly lower in long-term CRONers.

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