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.
Highlights
In the United States, type 2 diabetes (T2D) impacts the lives of ∼10% of the population [1] by increasing their risk of developing severe health complications associated with micro- and macro-vascular disease
The rise in glucose had little effect on glucagon, but its fall increased glucagon levels in the hepatic portal vein by 50%. These innovative studies sum up perfectly the widely accepted model of how blood glucose homeostasis is normally regulated during fasting; namely that euglycemia is maintained by plasma glucose-induced minuteto-minute changes in insulin and glucagon secretion which, in turn, modify hepatic glucose production (HGP) so that it equals the rate of whole-body glucose utilization
Because the expression of both enzymes are reciprocally regulated by insulin and glucagon [where insulin increases and decreases GK and G6Pase expression, respectively, and glucagon does the opposite [32]], insulin resistance or hyperglucagonemia can impact the relative activities of these enzymes, favoring the production of glucose over G6P in the liver
Summary
In the United States, type 2 diabetes (T2D) impacts the lives of ∼10% of the population [1] by increasing their risk of developing severe health complications associated with micro- and macro-vascular disease. While the etiology of T2D is often complex and multi-factorial, it is almost universally characterized by wholebody insulin resistance and the dysregulation of a number of key glucoregulatory organs [2] Among these organs, impaired function of the liver is one of the earliest contributors to impaired blood glucose homeostasis in patients with T2D due to its central role in regulating blood sugar levels during fasting and in response to glucose ingestion. As recent as the mid-nineteenth century, it was accepted that humans could not make their own metabolic substrates to fuel life This dogma was rejected through the pioneering work of Claude Bernard who, among others, discovered that one of the liver’s most important responsibilities is to make glucose and release it into the blood during fasting [for review see reference [3]]. Studies that directly measured hepatic glucose metabolism (e.g., A-V sampling and isotopic dilution studies) will be highlighted, with a reliance on human subject studies, and periodic references to more mechanistic studies using large and small animal models when necessary
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