The essential role of exercise in the management of type 2 diabetes

Liver

The liver regulates fasting glucose through gluconeogenesis and glycogen storage. The liver is also the primary site of action for pancreatic hormones during the transition from pre- to postprandial states.

As with skeletal muscle and adipose tissue, insulin resistance is also present within the liver in patients with type 2 diabetes. Specifically, impaired suppression of HGP by insulin is a hallmark of type 2 diabetes, leading to sustained hyperglycemia.⁴⁴

Approaches using fasting measures of glucose and insulin do not distinguish between peripheral and hepatic insulin resistance.⁴⁵ Instead, hepatic insulin sensitivity and HGP are best assessed by the hyperinsulinemic-euglycemic clamp technique, along with isotopic glucose tracers.¹⁵

Although more elaborate, magnetic resonance spectroscopy may also be used to assess intrahepatic lipid content, as its accumulation has been shown to drive hepatic insulin resistance.⁴⁶ Indirect measures of hepatic dysfunction may be made from increased levels of the circulating hepatic enzymes alkaline phosphatase, alanine transaminase, and aspartate transaminase.¹⁶

From an exercise perspective, we have shown that 7 days of aerobic training, in the absence of weight loss, improves hepatic insulin sensitivity.¹⁵ It has also been shown that hepatic AMPK is stimulated during exercise, suggesting that an AMPK-induced adaptive response to exercise may facilitate improved suppression of HGP.⁴⁷ We have also shown that a longer 12-week aerobic exercise intervention reduces hepatic insulin resistance, with and without restricted caloric intake.⁴⁸ Further, HGP correlated with reduced visceral fat, suggesting that this fat depot may play an important mechanistic role in improved hepatic function.

Pancreas

Insulin resistance in adipose tissue, muscle, or the liver places greater demand on insulin secretion from pancreatic beta cells. For many, this hypersecretory state is unsustainable, and the subsequent loss of beta-cell function marks the onset of type 2 diabetes.⁴⁹ Fasting plasma glucose, insulin, and glucagon levels are generally poor indicators of beta-cell function.

Clinical research studies typically use the oral glucose tolerance test and hyperglycemic clamp technique to more accurately measure the dynamic regulation of glucose homeostasis by the pancreas.⁵⁰ However, few studies have examined the effects of exercise on beta-cell function in type 2 diabetes.

Dela and colleagues⁵¹ showed that 3 months of aerobic training improved beta-cell function in type 2 diabetes, but only in those who had some residual function and were less severely diabetic. We have shown that a 12-week aerobic exercise intervention improves beta-cell function in older obese adults and in patients with type 2 diabetes.^52,53 We have also found that improvements in glycemic control that occur with exercise are better predicted by changes in insulin secretion as opposed to peripheral insulin sensitivity.⁵⁴ It has also been shown that a relatively short (8-week) HIIT program improved beta-cell function in patients with type 2 diabetes.⁵⁵ And we recently found that a 6-week CrossFit training program improved beta-cell function in adults with type 2 diabetes.³⁰

SUMMARY, CONCLUSIONS, AND FUTURE DIRECTIONS

Regular exercise produces health benefits beyond improvements in cardiovascular fitness. These include enhanced glycemic control, insulin signaling, and blood lipids, as well as reduced low-grade inflammation, improved vascular function, and weight loss.

Both aerobic and resistance training programs promote healthier skeletal muscle, adipose tissue, liver, and pancreatic function.¹⁸ Greater whole-body insulin sensitivity is seen immediately after exercise and persists for up to 96 hours. While a discrete bout of exercise provides substantial metabolic benefits in diabetic cohorts, maintenance of glucose control and insulin sensitivity are maximized by physiologic adaptations that only occur with weeks, months, and years of exercise training.^15,33

Exercise intensity,¹¹ volume, and frequency⁵⁶ are associated with reductions in HbA1c; however, a consensus has not been reached on whether one is a better determinant than the other.

The most important consideration when recommending exercise to patients with type 2 diabetes is that the intensity and volume be optimized for the greatest metabolic benefit while avoiding injury or cardiovascular risk. In general, the risk of exercise-induced adverse events is low, even in adults with type 2 diabetes, and there is no current evidence that screening procedures beyond usual diabetes care are needed to safely prescribe exercise in asymptomatic patients in this population.¹⁸

Future clinical research in this area will provide a broader appreciation for the interactions (positive and negative) between exercise and diabetes medications, the synergy between exercise and bariatric surgery, and the potential to use exercise to reduce the health burden of diabetes complications, including nephropathy, retinopathy, neuropathy, and peripheral arterial disease.

Moreover, basic research will likely identify the detailed molecular defects that contribute to diabetes in insulin-targeted tissues. The emerging science surrounding cytokines, adipokines, myokines, and, most recently, exerkines is likely to deepen our understanding of the mechanistic links between exercise and diabetes management.

Finally, although we have ample evidence that exercise is an effective, scalable, and affordable approach to prevent and manage type 2 diabetes, we still need to overcome the challenge of discovering how to make exercise sustainable for patients.