Exercise-Induced Improvements to Whole Body Glucose Metabolism in Type 2 Diabetes: The Essential Role of the Liver

Abstract

Type 2 diabetes (T2D) is a metabolic disease characterized by obesity, insulin resistance, and the dysfunction of several key glucoregulatory organs. Among these organs, impaired liver function is recognized as one of the earliest contributors to impaired whole-body glucose homeostasis, with well-characterized hepatic insulin resistance resulting in elevated rates of hepatic glucose production (HGP) and fasting hyperglycemia. One portion of this review will provide an overview of how HGP is regulated during the fasted state in healthy humans and how this process becomes dysregulated in patients with T2D. Less well-appreciated is the liver's role in post-prandial glucose metabolism, where it takes up and metabolizes one-third of orally ingested glucose. An abundance of literature has shown that the process of hepatic glucose uptake is impaired in patients with T2D, thereby contributing to glucose intolerance. A second portion of this review will outline how hepatic glucose uptake is regulated during the post-prandial state, and how it becomes dysfunctional in patients with T2D. Finally, it is well-known that exercise training has an insulin-sensitizing effect on the liver, which contributes to improved whole-body glucose metabolism in patients with T2D, thereby making it a cornerstone in the management of the disease. To this end, the impact of exercise on hepatic glucose metabolism will be thoroughly discussed, referencing key findings in the literature. At the same time, sources of heterogeneity that contribute to inconsistent findings in the field will be pointed out, as will important topics for future investigation.

Keywords: aerobic exercise; fasting blood glucose levels; glucagon; hepatic glucose production; post-prandial glucose; resistance training.

Figure 1

The regulation of fasting blood glucose homeostasis. Subtle changes in fasting glucose levels (FG) entering the pancreas regulate the release of the islet hormones insulin (INS) and glucagon (GGN). In turn, these hormones control the rate of hepatic glucose production (HGP), making HGP equal to the rate at which all other tissues of the body utilize glucose, thereby preserving fasting glucose levels at a steady state. CNS, central nervous system; WBC, white blood cells; RBC, red blood cells.

Figure 2

Effect of exercise training on hepatic glucose production in type 2 diabetes. Obesity and/or inactivity are known to be risk factors for the development of type 2 diabetes (T2D). T2D is associated with increased intrahepatic lipid content (IHL) and resultant insulin resistance, which increases fasting hepatic glucose production (HGP). Increased hepatic glucagon action is also a key contributor to excessive HGP in patients with T2D. Exercise training is known to diminish IHL and hepatic insulin resistance in patients with T2D, thereby enhancing insulin mediated suppression of HGP. However, the metabolic pathway(s) impacted by this enhanced suppression is not yet known. Also unknown is the impact of exercise training on glucagon-mediated HGP in patients with T2D. GNG, gluconeogenesis; GLY, glycogenolysis; GK, glucokinase; G6Pase, glucose-6-phosphatase.

Figure 3

After ingestion, glucose is absorbed into the hepatic portal vein (PV) from the intestine (1). One third of the glucose in the PV is taken up by the liver, after which the remaining fraction is delivered to other tissues of the body by arterial blood. Hepatic glucose uptake is regulated by three factors. The first (1) is an increase in the glucose load to the liver as a result of intestinal glucose absorption-induced hyperglycemia. The second (2) is a negative arterial-PV glucose gradient generated by the absorption of glucose from the intestine into the PV, thereby making its glucose levels higher than that of arterial blood. The third (3) is hyperinsulinemia that occurs as a result of hyperglycemia-induced insulin secretion by islet β-cells. The presence of all three of these signals is required to maximize hepatic glucose uptake. INS, insulin.

Figure 4

Effect of exercise training on hepatic glucose uptake in type 2 diabetes. Obesity and/or inactivity are known to be risk factors for the development of type 2 diabetes (T2D). T2D is associated with increased intrahepatic lipid content (IHL), which decreases post-prandial hepatic glucose uptake, thereby contributing to glucose intolerance. Decreased muscle glucose uptake in patients with T2D is also an important contributor to glucose intolerance in T2D. Exercise training is known to increase muscle glucose uptake in patients with T2D. At the same time, exercise is known to reduce IHL, although the impact of this reduction on hepatic glucose uptake remains controversial and requires further investigation.