Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification By Exercise Training

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ByCrossFit June 27, 2019

In this comprehensive 2013 review, C.K. Roberts et al. summarize the mechanisms by which exercise training may affect insulin resistance and thus serve as a tool to either prevent or reverse metabolic syndrome.

As shown in Figure 1 below, insulin sensitivity refers to the body’s ability to dispose of glucose given a fixed insulin load (the x-axis in Figure 1 represents the amount of glucose cleared at a given insulin dose). A variety of evidence has shown that active individuals clear greater glucose with lower insulin secretion than sedentary individuals — that is, active individuals are more insulin sensitive. As sedentary individuals become progressively more insulin resistant, pancreatic beta cells hypertrophy and eventually become unable to secrete sufficient insulin to clear glucose from the blood after a meal. This end state is referred to as glucose intolerance.

Figure 1: Graph depicting the hyperbolic relation between insulin secretion and insulin sensitivity. Insulin secretion rises as insulin sensitivity falls when an individual goes from a state of exercise training/being physically active (point A) to detraining/sedentary (point B) and vice versa, that is, bidirectionality of the two arrows from B to A when undergoing exercise training/increasing physical activity levels. A failure of insulin secretion to compensate for a fall in insulin sensitivity is noted when both insulin secretion and insulin sensitivity decline from points B to C, leading to elevated fasting glucose and prediabetes (impaired glucose tolerance). A progressive decline in both insulin secretion and insulin sensitivity to point D indicates type 2 diabetes. Adapted from reference (9) with permission.

Trial and observational evidence has shown that aerobic training increases whole-body insulin sensitivity (i.e., the ability of insulin to clear glucose from the blood) and muscular insulin sensitivity (i.e., the amount of glucose taken up by the muscle in response to insulin). Similarly, sedentary individuals exhibit lower whole-body and muscular insulin sensitivity than active individuals. Muscular and whole-body insulin sensitivity are closely connected, as skeletal muscle is the primary tissue insulin stimulates to take up glucose. Thus, the improvements in whole-body insulin sensitivity associated with exercise are largely due to improvements in muscular insulin sensitivity.

The dose of activity has proven important in trials as well; low doses of exercise do not lead to an increase in insulin sensitivity, but the particular threshold for benefit seems to depend on a variety of factors specific to each subject. Similarly, the type of activity plays a role, with various forms of interval training showing consistently positive impacts and resistance training showing benefits independent of any coincident improvements in aerobic capacity. Evidence suggests that aerobic and resistance training have additive effects. As shown in Figure 13, this may be because both types of exercise improve insulin signaling, while only resistance training increases lean body mass (thus affecting the amount of tissue that is able to take up glucose in response to insulin).

Figure 13: Schematic diagram of future directions to determine mechanisms by which aerobic training (AT) and resistance training (RT) increase insulin sensitivity. Although there is preliminary evidence, more research is needed to clearly identify the mechanisms that are involved, as denoted by the question marks linking AT and RT to enhance insulin signaling.

These effects are particularly prominent in older individuals. Figure 15 shows the dramatic difference in insulin sensitivity (as measured by response to an oral glucose tolerance test, or OGTT) between active and inactive older men; it also demonstrates that this difference is not as pronounced in younger men. Some studies have suggested that the insulin resistance commonly seen in older individuals is not the inevitable result of aging but is due to lower levels of activity. Continuous exercise is required to maintain improved insulin sensitivity, as insulin sensitivity returns to baseline levels after as few as 10 days of inactivity.

Figure 15: Effects of training and age on area under the curve for (A) glucose and (B) insulin during an oral glucose tolerance test. Adapted, with permission, from reference (577).

In addition to reviewing these findings, Roberts et al. provide an extensive overview of the mechanisms by which insulin sensitivity and/or resistance may develop, some of which have been covered previously on CrossFit.com. One example they discuss is fat accumulation. Figure 5 demonstrates how fat storage in the muscle and liver contributes to insulin resistance in these organs. As the muscle takes on fat, it takes on less glucose in response to the same insulin load, thereby reducing overall insulin sensitivity. As the liver takes on fat, it fails to suppress glucose production in response to an insulin load. In both cases, fat accumulation within the organ has downstream effects that drive chronic elevation of blood glucose levels. Interventions that reduce fat accumulation in these organs — including certain kinds of exercise — may thus improve blood glucose control and insulin sensitivity.

Figure 5: Schematic of adipose tissue-secreted factors that act on muscle and liver to promote insulin resistance.

The paper also discusses the effects of the immune response and a variety of other pathways and regulatory processes. It includes an extensive discussion of the core mechanisms of insulin resistance and the roles different organs, hormones, and signaling mechanisms play in the development of whole-body and organ-specific insulin resistance.

Comments on Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification By Exercise Training

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Gary Taubes
June 28th, 2019 at 5:57 pm
Commented on: Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification By Exercise Training

Regrettably, I'm skeptical. I'd like to believe what the authors say is true and it certainly makes sense, but their presentation makes me nervous and they are still trapped in the dietary fat paradigm of the last century. My bias is that I think the type of food consumed (sugar and sugary beverages, primarily, refined grains, secondarily) is the dominant factor. So when I read this I'm wondering what their biases are, whether the author's are aware that there are multiple hypotheses to explain what they're seeing, and how they treat the evidence.


Specifically, the authors make definitive statements about sedentary behavior as a cause of MS -- i.e., "Numerous studies have clearly demonstrated that the pathogenesis of the MS is largely attributable to a lack of fitness and physical activity." -- and they imply that the benefits of physical activity are clear ("many studies have demonstrated that AT improved whole body insulin sensitivity"). But the evidence for sedentary behavior as a cause is almost exclusively observational and cannot be used to establish causality. And the "many studies" are a little bit worrisome as well.


Regarding the observational evidence, here are two other possibilities (hypotheses) to explain the correlations: 1) sedentary behavior is an early symptom of MS. A first sign of insulin resistance is a tendency to avoid physical activity. 2) Sedentary behavior associates with a lack health consciousness and so other "unhealthy" behaviors. In other words, folks who are sedentary are folks who haven't gotten the message or have ignored the message that they should be exercising. That's a pretty ubiquitous message and we all know we should do it. if we don't, there's something wrong -- either in body or mind.


In either scenario (and I'm betting on both) you'd see the same correlations.


As for the intervention studies cited, the authors acknowledge they're ambiguous and the review seems to be cherry-picking: i.e., the authors set out to demonstrate that physical activity is beneficial, because that's what they believe, and so they enumerate the positive evidence and seem to be ignoring negative. (A Scottish cardiologist once described this to me as "Bing Cosby epidemiology: i.e., accentuate the positive, eliminate the negative...")


Moreover, it's virtually impossible to do a physical activity intervention trial double-blinded and placebo-controlled. Hence, you'd expect positive effects even if the intervention is useless: i.e., from what's called "performance bias". People who are randomized to intensive physical activity are more likely to adopt other health conscious behaviors than those who are sent home to continue sitting on the couch. There's a reason why double-blinding, randomization and placebo-control are all required in drug studies. Trials that aren't double-blind and placebo-controlled have to be treated with great skepticism, regardless of the reason why they're absent. The fact that comparisons of aerobic training and resistance training saw much the same improvement in insulin resistance leaves open the possibility that the type of training is not important, which might imply that it's some confounding factor in both groups that matters. Along those lines, I'd love to see a trial comparing, say, 40 minutes a day of intensive aerobic activity or resistance training to an equivalent amount of yoga or meditation. They would both promote health conscious behaviors (don't eat or drink sugary crap) and so might balance each other out on that effect, but if they also got the same results it would suggest that something other than the physical activity is responsible.

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Sarah Neidler
June 29th, 2019 at 10:51 am

Great insights, Gary. I haven't been aware of performance bias in physical exercise interventions, but it makes sense. While I don't think it's possible to create a double-blind design, yoga instead of sitting on the couch should eliminate some confounding factors, at least.

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RAPHAEL SIRTOLI
June 28th, 2019 at 9:11 am
Commented on: Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification By Exercise Training

This review raises interesting ideas that are seldom discussed or appreciated, like the following 2 for example:




- how body fat is distributed matters a great deal, not only body fat % (e.g. “women with upper body obesity were far more likely to get heart disease and T2D compared to women with lower body obesity.”)




- Metabolic Syndrome stems from hyperinsulinemia (rather than insulin resistance per se, which is a physiological/normal response to hyperinsulinemia)




However, the review focuses on beta-cell failure as a primary mechanism to explain IR. This is a very late stage phenomenon in type 2 diabetics (or early on in the rarer type 1 diabetes).




A better mechanistic explanation can be found in the too frequent hyperstimulation of insulin; this over-stimulates the generation of new fat cells - called adipocyte hyperplasia - and the expansion of existing ones - known as adipose hypertrophy. With normal insulin levels this doesn’t occur nearly as much. 

2 problems result, together or separately depending on the individuals:


- 

insulin diverts fat towards adipocyte storage, eventually lead to obesity (the increase in caloric intake need not be big, but literally only about 20kcals/day)



- perpetual insulin eventually actual stops fat cells from releasing fatty acids in a timely and controlled manner, eventually leading to diabetes (how? see link: https://www.ncbi.nlm.nih.gov/pubmed/25662011)

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Nathan Jenkins
June 28th, 2019 at 3:53 am
Commented on: Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification By Exercise Training

Great post. Studies going back to at least the early 1980s show that in older master's athletes (endurance specialists), cessation of training for 10 days resulted in a near complete loss of the benefits of exercise on glucose tolerance. Some of those data are discussed in the post. What's not mentioned but is also really important is that the glucose tolerance and insulin sensitivity was largely restored to the 'trained' status after a single training session on the 11th day. Abstract of the original paper here:

https://www.ncbi.nlm.nih.gov/pubmed/6352578 The implication being that exercise-induced effects on insulin sensitivity and glucose tolerance are remarkably labile - they come and go quickly!


Very happy to see some classic exercise physiology from a golden era in the field being discussed on the main site. There are a ton of examples of bad science - of poor quality or corrupted by industry influences or both - in the exercise science literature, but it's refreshing to see and discuss some high quality work. This review is an example of the best the field has to offer.

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