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.

Several studies have associated the presence of residual insulin secretion capability (also referred to as being C-peptide positive) with lower risk of insulin-induced hypoglycemia in patients with type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that C-peptide infusion would enhance glucagon secretion in response to hyperinsulinemia during euglycemic and hypoglycemic conditions in dogs (5m/4f). After a 2 hr basal period, an IV-infusion of insulin was started, and dextrose was infused to maintain euglycemia for 2 hrs. At the same time, an IVinfusion of either saline (SAL) or C-peptide (CPEP) was started. After this euglycemic period, the insulin and SAL/CPEP infusions were continued for another 2 hrs, but the glucose was allowed to fall to ~50 mg/dL. In response to euglycemic-hyperinsulinemia, glucagon secretion decreased in SAL, but remained unchanged from basal in CPEP. During hypoglycemia, glucagon secretion in CPEP was two times higher than SAL, which increased net hepatic glucose output and reduced the amount of exogenous glucose required to maintain glycemia. These data suggest that the presence of C-peptide during IV insulin infusion can preserve glucagon secretion during euglycemia, and enhance it during hypoglycemia, which could explain why T1D patients with residual insulin secretion are less susceptible to hypoglycemia.

Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control individuals. Counterregulatory responses to insulin-induced hypoglycemia were measured in 12 healthy people during 2 metabolic studies. During one study, participants ate breakfast and lunch, after which they underwent a 2-hour bout of insulin-induced hypoglycemia (FED). During the other study, participants remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.