Blood glucose regulation during prolonged, submaximal, continuous exercise: a guide for clinicians

Abstract

Management of many chronic diseases now includes regular exercise as part of a viable treatment plan. Exercise in the form of prolonged, submaximal, continuous exercise (SUBEX; i.e., approximately 30 min to 1 h, approximately 40-70% of maximal oxygen uptake) is often prescribed due to its relatively low risk, the willingness of patients to undertake, its efficacy, its affordability, and its ease of prescription. Specifically, patients who are insulin resistant or that have type 2 diabetes mellitus may benefit from regular exercise of this type. During this type of exercise, muscles dramatically increase glucose uptake as the liver increases both glycogenolysis and gluco-neogenesis. While a redundancy of mechanisms is at work to maintain blood glucose concentration ([glucose]) during this type of exercise, the major regulator of blood glucose is the insulin/glucagon response. At exercise onset, blood [glucose] transiently rises before beginning to decline after approximately 30 min, causing a subsequent decline in blood [insulin] and rise in blood glucagon. This leads to many downstream effects, including an increase in glucose output from the liver to maintain adequate glucose in the blood to fuel both the muscles and the brain. Finally, when analyzing blood [glucose], consideration should be given to nutritional status (postabsorptive versus postprandial) as well as both what the analyzer measures and the type of sample used (plasma versus whole blood). In view of both prescribing exercise to patients as well as designing studies that perturb glucose homeostasis, it is imperative that clinicians and researchers alike understand the controls of blood glucose homeostasis during SUBEX.

(c) 2010 Diabetes Technology Society.

Figures

Figure 1.

The typical blood glucose response during SUBEX. Error bars were omitted for clarity. Reproduced with permission from Zinker et al.

Figure 2.

Simplified schematic of insulin binding at a skeletal muscle cell membrane and subsequent GLUT4 translocation. The dimerized insulin receptor is shown as four filled-in rectangles. Insulin binds, leading to dimerization and phosphorylation of the intracellular subunits of the insulin receptor. This leads to phosphorylation of many proteins, including IRS-1. This then leads to activation of PI3-K, leading to translocation of GLUT4s to the cell membrane, allowing an increase in glucose uptake. Note that exercise also induces trans-location of GLUT4s, but independently of PI3-K and possibly from a separate intracellular pool.

Figure 3.

The “crossover” concept originally proposed by Brooks and Mercier. As intensity of exercise increases, there is greater and greater reliance on carbohydrate as a fuel source. Reproduced with permission from Brooks and Mercier. CHO, carbohydrate.

Figure 4.

Simplified schematic of glucagon binding at a hepatocyte cell membrane and subsequent signaling that ultimately leads to glucose release into the blood. Glucagon binds its G-protein-coupled receptor, which causes the intracellular Gα subunit to activate adenylate cyclase, which catalyzes cAMP formation, which then activates protein kinase A, which phosphorylates both phosphorylase kinase and the fructose-2,6-bisphosphatase/phosphofructokinase-2 enzyme; the latter leads to a decrease in F26BP, causing a decrease in glycolysis and allowing an increase in gluconeogenesis. Concurrently, phosphorylated phosphorylase kinase phosphorylates glycogen phosphorylase to the more active “a” form, causing a rapid breakdown of glycogen and ultimately leading to release of glucose from the cell to the blood. Note that this figure has been simplified for clarity; not shown are numerous other signaling and metabolic steps involved. AC, adenylate cyclase; PKA, protein kinase A.

Figure 5.

Plasma insulin concentrations during exercise at 60% of VO2max, both before (filled circles/solid curve) and after (filled squares/dotted curve) training. Error bars have been omitted for clarity. Reproduced with permission from Gyntelberg et al.. WR, work rate.

Figure 6.

Plasma glucagon concentrations during exercise at 60% of VO2max, both before (filled circles/solid curve) and after (filled squares/dotted curve/same absolute work rate; empty squares/solid line/same relative work rate) training. Error bars have been omitted for clarity. Reproduced with permission from Gyntelberg et al. WR, work rate.

Figure 7.

Plasma (A) NE and (B) E responses at different work rates between trained (filled bars) and untrained (empty bars) subjects. Error bars omitted for clarity. Asterisks denote significant differences between the groups at any given work rate. Note that the differences seen between trained and untrained are in the NE response but not the E response. Reproduced with permission from Greiwe et al..

Figure 8.

The major systems involved in blood glucose homeostasis during SUBEX. Depicted in the center is a cylinder representing blood [glucose] during exercise. As shown in the figure, during exercise, blood glucose maintenance is a balance between glucose appearance (e.g., from the liver) and glucose disposal (e.g., into the muscles). The central nervous system has direct influence on several organs during exercise via neuronal innervations (dotted line arrows). This figure does not distinguish between autonomic (liver, blood vessels, pancreas) or somatic (skeletal muscle) innervations. Large black arrows pointing in both directions between blood glucose and an organ represent humoral communication. Below each organ's name, the major changes seen during SUBEX are listed. Note that this figure has been simplified for clarity; not shown are other changes/communications, including the brain receiving neuronal feedback from various organs. CNS, central nervous system.