Insulin Sensitivity and Exercise

May 2, 2016

Exercise may lower the risk of diabetes, metabolic syndrome, or CV events, but the relationship between exercise and insulin sensitivity is complex.

Most people would agree that exercise does a body good, especially for people with diabetes, and studies support this opinion. Results from large diabetes prevention studies like DPS, DDP, HERITAGE, LookAHEAD, STRRIDE, Da Qing Diabetes Studies, and TULIP suggest that exercise may decrease the risk of diabetes, metabolic syndrome, or cardiovascular events by about 35%.1

Studies also raise many questions, though, about the complex relationship between exercise and insulin sensitivity. Some of these questions remain unresolved, while research has made strides in answering others. 

Do some people benefit from exercise more than others?

Unfortunately, not everyone seems to benefit to the same degree. There is a wide range in variability of response to exercise. Exercise non-response in terms of failure to improve glucose tolerance and insulin sensitivity may range from 7-63%. About 8.3% of people may show adverse responses.1

There is much speculation but no clear evidence about what contributes to nonresponse. Possibilities include: older age, baseline fitness level, heart rate and blood pressure, long duration of diabetes, genetic factors such as a predisposition to obesity, individual variability in mitochondrial pathways involved in fuel oxidation, variability in adipose tissue metabolism, and individual differences in pro-/and   anti-inflammatory cytokines.1

How intense does exercise need to be?

Though research is inconsistent, a recent review has suggested a dose-response effect: the more vigorous the exercise, the greater the benefits.2 A recent meta-analysis supports this view. It included fifty studies of exercise interventions of adults at high risk for T2DM, or who already had the disorder. Compared to control and continuous training, high intensity interval training was linked to a significant reduction in insulin resistance.3

How does weight loss fit into the equation?

Some studies suggest that exercise unaccompanied by weight loss may improve insulin resistance in the short-term, but insulin resistance often comes back to baseline after stopping exercise. Other studies indicate that dieting alone does not improve muscle metabolism, and that exercise-induced weight loss improves insulin sensitivity most effectively. Exercise-induced weight loss may increase mitochondrial oxidative capacity, decrease endogenous glucose production, and change body composition, all of which contribute to improved metabolic parameters. Moreover, exercise-induced changes in body composition may contribute to sustained improvements in glucose sensitivity.2

What’s really going on: underlying mechanisms

Exercise increases lean muscle mass, decreases oxidative stress, and improves mitochondrial function, all of which have been linked to improvements in glucose sensitivity.1,4 Exercise may also have an impact on whole body metabolism via effects on central control mechanisms in the brain that decrease appetite and food consumption. Perhaps most remarkable, though, are the anti-inflammatory effects of exercise, which may help improve the low-grade inflammatory state of metabolic syndrome and diabetes.1

Studies suggest many anti-inflammatory effects of exercise including:

• Macrophages in adipose tissue: Mouse studies suggest that exercise can decrease macrophage infiltration and shift the proportion of proinflammatory macrophages to anti-inflammatory macrophages in adipose tissuse.4

• IL-6: IL-6 is increased in sedentariness and impaired glucose tolerance. During exercise there are transient increases in IL-6 released from contracting muscles, while IL-6 levels decrease in adipose tissue.5 Transient exercise-induced increases in IL-6 stimulate the release of anti-inflammatory cytokines. Animal studies also suggest that IL-6 can downregulate the proinflammatory cytokine TNFα, which plays an important role in peripheral insulin resistance.4 IL-6 may also directly affect glucose and lipid metabolism.

• IL-ira: IL-1ra is induced by IL-6, and inhibits the proinflammatory cytokine IL-1β, which may contribute to beta cell damage and is found at high levels in metabolic diseases.4,6

• IL-10: IL-10 decreases inflammation by downregulating the adaptive immune response; IL-10 levels are increased with exercise, and decreased in obesity.4

• CRP: Some studies suggest that regular exercise can decrease this inflammatory marker.4

• Toll-like receptors: Limited evidence suggests that acute exercise can decrease expression of toll-like receptors; activation of toll-like receptors has been linked to increased proinflammatory signaling associated with sedentariness and systemic inflammation.4  

• Hsp70: Exercise may also induce expression of the 70-kDA heat shock protein (Hsp70), which suppresses inflammation by decreasing activation of proinflammatory NFĸB.

• Regulatory T-cells: Exercise has also been linked to mobilization of regulatory T cells, and suppression of immune responses.4

So, with the weather warming up and levels of outdoor activities increasing, it may be a helpful reminder that there’s proof: exercise does do a body good. Working out the nuances, though, may take longer than the fleeting nature of spring.

Take-home points

• Results from large diabetes prevention trials suggest that exercise may decrease the risk of diabetes, metabolic syndrome, or cardiovascular events, but questions remain about the complex relationship between exercise and insulin sensitivity.

• There is a wide range in variability of response to exercise, and the reasons for non-response are unclear.

• There seems to be a dose-response effect, with higher intensity exercise linked to greater the benefits.

• Dieting alone does not seem to improve muscle metabolism, and exercise-induced weight loss may improve insulin sensitivity most effectively.

• Exercise exerts many anti-inflammatory effects, of which IL-6 is a key player.


1. Böhm A, et al. Exercise and diabetes: relevance and causes for response variability. Endocrine. 2016 Mar;51(3):390-401. doi: 10.1007/s12020-015-0792-6.

2. Keshel TE, Coker RH. Exercise training and insulin resistance: a current review. J Obes Weight Loss Ther. 2015 Jul;5(Suppl 5):pii: S5-003.

3. Jelleyman C, et al. The effects of high-intensity interval training on glucose regulation and insulin resistance: a meta-analysis. Obes Rev. 2015 Nov;16(11):942-961.

4. Codella R, et al. The anti-inflammatory effects of exercise in the syndromic thread of diabetes and autoimmunity. Eur Rev Med Pharmacol Sci. 2015 Oct;19(19):3709-3722.

5. Röhling M, et al. Influence of acute and chronic exercise on glucose uptake. J Diabetes Res. 2016;2016:2868652.

6. Karstoft K, Pedersen BK. Exercise and type 2 diabetes: focus on metabolism and inflammation. Immunol Cell Biol. 2016 Feb;94(2):146-150.