Abstract
Type 2 diabetes is a significant health concern in the United States and its prevalence is expected to triple by 2050. Both metformin and exercise have shown to be effective in the management of blood glucose control. The pharmacological mechanism of action of metformin is largely based on the activation of AMPK to induce glucose transport. Likewise, the physiological actions of exercise appear to be a potent activator of AMPK, resulting in glucose uptake by the muscle. Research shows that metformin may control blood glucose slightly better than exercise in persons with type 2 diabetes. However, it appears that lifestyle interventions outperform metformin when trying to prevent the onset of diabetes. Both metformin and exercise have a positive and significant role in the management of type 2 diabetes and appear to work similarly to help manage blood glucose control.
Much has been written over the past several years about the increasing prevalence of type 2 diabetes in the United States. Currently, about 10% of US adults have type 2 diabetes, and if current trends continue, the Centers for Disease Control and Prevention predicts that as many as 1 in 3 adults will have the condition by the year 2050. 1
The Centers for Disease Control and Prevention predicts that as many as 1 in 3 adults will have the condition [type 2 diabetes] by the year 2050.
The diabetes treatment recommendations published in 2012 by the American Diabetes Association recommends that at the time of type 2 diabetes diagnosis, metformin therapy (unless contraindicated) along with lifestyle interventions should be the treatment of choice. 2 Among US adults currently diagnosed with diabetes (types 1 and 2), 12% are taking insulin only, 14% take both insulin and oral medication, 58% take oral medication only, and 16% do not take either insulin or oral medication to manage the condition. 3 Of the oral medications used to treat diabetes, metformin is the most widely used. When looking at all medications dispensed in the United States, metformin ranks as the ninth most frequently prescribed medication, accounting for 48.3 million prescriptions in 2010. 4
Exercise is a fundamental recommendation for individuals with type 2 diabetes to help manage their condition and decrease the risk for comorbidities. The purpose of this article is to briefly show the relationship between the pharmacological actions of metformin to that of the physiological actions of exercise relative to the management of type 2 diabetes.
Pathophysiology of Type 2 Diabetes
Type 2 diabetes is characterized by altered lipid and glucose metabolism as a result of a combination of peripheral insulin resistance and inadequate insulin secretion by pancreatic beta cells. 5 Insulin resistance occurs in the liver, peripheral muscle, and peripheral adipocyte locations. Insulin resistance leads to decreased glucose transport into muscle cells, elevated hepatic glucose production, and increased breakdown of fat. It has also shown to increase levels of free fatty acids and proinflammatory cytokines in the plasma. 5 Approximately 80% of total body glucose uptake occurs in the muscle and, therefore, is the major site of glucose disposal. 5 The primary site of insulin resistance for individuals with type 2 diabetes is in the muscle tissue. 5
The progression of type 2 diabetes occurs as individuals usually experience an asymptomatic period of insulin resistance. Pancreatic beta cells initially compensate for insulin resistance with a hypersecretion of insulin. However, with time, progressive pancreatic beta cell failure occurs and an insufficient amount of insulin is secreted to meet the metabolic demand, resulting in hyperglycemia. 5
AMP-Activated Protein Kinase
AMP-activated protein kinase (AMPK) is a phylogenetically conserved fuel sensing enzyme. It plays an important role in the regulation of cellular and whole-body energy homeostasis and is a common link between the actions of metformin and exercise in the regulation of blood glucose. 6 AMPK belongs to a family of energy sensing enzymes that are activated by cellular stress that occurs when adenosine triphosphate (ATP) are depleted. On activation, AMPK functions to restore cellular ATP by both inhibiting ATP consumption processes as well as accelerating ATP generation processes. 7 AMPK has been referred to as a cellular “fuel gage” and a “metabolic master switch.”6,7 Among other activities, AMPK stimulation results in muscle glucose uptake, skeletal muscle fatty acid oxidation, and the modulation of insulin secretion by pancreatic beta cells. 6
Skeletal muscle is the main site for glucose disposal in the body. 6 Insulin increases glucose uptake in the muscle by stimulating the translocation of glucose transporter GLUT4 from intracellular vesicles to the cell surface. It has been shown that muscular AMPK activation stimulates muscle glucose uptake in a manner distinct from this insulin signaling pathway. The stimulation of muscular AMPK appears to increase glucose uptake in an insulin-independent manner that bypasses the defective insulin signaling that occurs in type 2 diabetes. AMPK has been shown to increase glucose transport in people with and without type 2 diabetes. 6
It is now well accepted in biochemistry and exercise physiology research that AMPK activation occurs through muscle contraction.6,8 In addition, the mechanism of action of metformin is largely based on its ability to activate AMPK.2,9 Both are discussed in further detail below.
Exercise Physiology and AMPK
When looking specifically at the physiology related to exercise and blood glucose control, it is known that there are 2 well-defined and distinct pathways that stimulate glucose uptake by the muscle. 10 At rest and postprandially, glucose uptake by muscle is insulin dependent. During exercise, however, glucose uptake is insulin independent and occurs due to the action of the muscles contracting to perform the activity. In individuals with type 2 diabetes, the insulin-dependent pathway is impaired, but the insulin-independent pathway functions similarly in those with and without type 2 diabetes. 10
Muscular blood glucose uptake not only occurs during exercise but remains elevated for several hours postexercise. The effects of a single bout of aerobic exercise on improving the action of insulin and blood glucose tolerance can be observed for up to 72 hours postexercise. 10 For this reason and others, the American Diabetes Association recommends that those with type 2 diabetes exercise at least 3 days per week with no more than 2 consecutive days between bouts of physical activity. 10 It should be noted that muscle contractions that occur during resistance training also show a positive effect on glucose uptake in those with type 2 diabetes. 10 A combination of aerobic and resistance training may be more effective for blood glucose management than either activity alone. 10
Biochemical researchers have been able to show that one of the primary reasons for the enhanced glucose uptake during exercise is due to the activation of AMPK. Muscle contraction has been shown to increase multiple and redundant signaling pathways of AMPK causing contraction-induced glucose transport that is insulin independent. 6 Interestingly, because researchers consider muscle contraction to be the prototypical AMPK activator, some are working to mimic the beneficial effects of exercise to develop new drug compounds to be used in the treatment of type 2 diabetes. 6
Metformin Pharmacology
Metformin is in a class of oral antidiabetic medications called biguanides.2,9 It has been shown to improve glucose tolerance and lower basal and postprandial plasma glucose levels. The mechanism of action of metformin is different from other oral antidiabetic agents, and a complete explanation of its action is not fully understood. However, the primary effects of metformin come from reducing hepatic glucose production and increasing peripheral glucose uptake and utilization through the activation of AMPK.2,9 Metformin has been shown to improve glucose utilization in skeletal muscle and adipose tissue by increasing cell membrane glucose transport.
Research has shown that individuals with type 2 diabetes significantly increase AMPK activity in skeletal muscles during metformin treatment with a resulting effect of enhanced peripheral glucose disposal.6,11,12 Additional research has also shown that metformin can restore glucose uptake stimulation in insulin-resistant cardiomyocytes.6,13 This research suggests that AMPK could potentially have a positive therapeutic effect on insulin resistance in the hearts of those with diabetes. 6
Metformin Versus Exercise
The American Diabetes Association recommends that metformin be used as the first line agent along with exercise in those with type 2 diabetes. 2 A meta- analysis reviewing the effects of metformin in those with type 2 diabetes showed that at doses up to 1500 mg per day, hemoglobin A1c levels were reduced by approximately 1% after 3 months of therapy compared with placebo. 14 A meta-analysis reviewing the effects of structured exercise in those with type 2 diabetes showed that hemoglobin A1c levels are reduced by 0.66%, independent of body weight changes, with ≥8 weeks duration of exercise. 15
It is also interesting to look at metformin and exercise comparatively in individuals without type 2 diabetes for their effects at preventing the condition. In 2002, the Diabetes Prevention Program Research Group published the results of an important trial comparing the effects of metformin versus lifestyle intervention in the prevention of type 2 diabetes for individuals at high risk for the development of the disease. 16 Participants were randomly assigned to 1 of 3 interventions: standard lifestyle recommendations plus metformin 850 mg twice daily, standard lifestyle recommendations plus placebo twice daily, or an intensive program of lifestyle modification consisting of a low-fat, low-calorie eating plan and moderate intensity physical activity. The results showed that after 3 years of follow-up, the lifestyle intervention group reduced their incidence of type 2 diabetes by 58% while those in the metformin group reduced their incidence by 31%, compared with placebo. The authors concluded that lifestyle intervention prevented 1 case of diabetes per 7 persons treated for 3 years. 16
Conclusions
Type 2 diabetes is a significant health concern in the United States, and its prevalence is expected to triple by 2050. The American Diabetes Association recommends that newly diagnosed persons with type 2 diabetes take metformin as a first line agent in conjunction with lifestyle interventions to most adequately mange the condition. Both metformin and exercise have shown to be effective in their management of blood glucose control, and their mechanisms of doing so appear to be similar. The pharmacological mechanism of action of metformin is largely based on the activation of AMPK to induce glucose transport. Likewise, the physiological actions of muscle contractions that occur during exercise appear to be a potent activator of AMPK, resulting in glucose uptake by the muscle. Meta-analysis of both treatments in persons with type 2 diabetes shows that metformin may perform slightly better than exercise for lowering hemoglobin A1c levels. However, it appears that lifestyle interventions outperform metformin when trying to prevent the onset of diabetes. Both metformin and exercise have a positive and significant role in the management of type 2 diabetes and appear to work similarly to help manage blood glucose control.