Hepatic Glucose Metabolism

During infection, the liver increases glucose production to defend against hypoglycemia. In fact, the increase in hepatic glucose production is the major reason why patients with infection have an elevated blood glucose concentration. For example, patients with active malaria can have an increase in fasting glucose concentration due to an increase in gluconeo-genesis and overall glucose production. Approximately 75% of cancer patients, like patients with infection, also have an elevated rate of glucose production. Cancer patients also have a mild form of injury; approximately 75% have an elevated rate of hepatic glucose production. In 18 studies, hepatic glucose production for normals ranges between 1.6 and 3.0mg/kg/min, with an average of 2.1 mg/kg/min. Glucose production for cancer patients without weight loss ranges from 1.7 to 5.1 mg/kg/min, with a mean of 2.75 mg/kg/min. This is a 30% increase in the fasting rate of hepatic glucose production. For cancer patients with weight loss, glucose production ranges from 2.3 to 3.3 mg/kg/min, with a mean of 2.96 mg/kg/min. This represents a 41% increase in the rate of hepatic glucose production. Not all cancer types have an elevation in hepatic glucose production. For example, head and neck cancer patients may not have an elevation in fasting hepatic glucose production, but it is commonly elevated in lung cancer patients, probably because they have an increased injury response. In cancer patients, the etiology for the elevated rate of fasting hepatic glucose production is not known. Early studies tested whether excessive growth hormone (GH) release in cancer patients might be responsible. However, there was no direct correlation between GH secretion pattern and hepatic glucose production. Furthermore, the administration of GH to cancer patients for a 3-day period failed to increase the rate of glucose production. Koea and Shaw suggested that the rate is related to the bulk of the tumor, and others have suggested it is related to cytokines or other factors. Earlier studies on normal volunteers demonstrated that the loss of the first-phase insulin response causes a delay in the normal inhibition of glucose production. Although the latter effect may explain postprandial hyperglycemia, it is an unlikely explanation for fasting hepatic glucose production.

Gluconeogenesis is elevated in head and neck cancer patients and also in lung cancer patients. Gluconeogen-esis accounts for approximately 50% of the overall glucose production after an overnight fast. It was demonstrated that glucose carbon recycling was elevated in five of seven published studies. Glucose carbon recycling is an indicator of increased gluconeogenesis. The ability to measure gluconeogenesis was not possible in humans until recently, when a method using [U-13C] glucose and isotopomer analysis was developed. The Cori cycle is increased in cancer patients and has been estimated to account for 300 kcal of energy loss per day. In 70% of published studies, cancer patients have a significant elevation in the rate of gluconeogenesis compared to normal weight-matched controls. Gluconeo-genesis was directly related to the morning blood cortisol concentration in both the normal volunteers (r = 0.913, p < 0.01) and the cancer patients (r = 0.595, p < 0.05). In the septic host, the increase in glucose production is likely due to an elevation of multiple counterregulatory hormones (cortisol, GH, catecholamines, and glucagon) and cytokines (interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a), etc.).

It is important to note that unlike diabetic patients with an elevated blood glucose concentration, cancer patients with an elevated glucose production rate frequently have a normal blood glucose concentration. Fasting glucose concentrations may be 110-120 mg/dl, which may be overlooked as a subtle indicator of an elevated glucose production rate. The increased rate may contribute to an increased energy cost. Data indicate that the resting energy expenditure is elevated in lung cancer patients and those with other types of cancer compared to weight-matched controls. As expected, energy expenditure is increased in most critically ill patients a few days after admission. However, the precise measurement of energy expenditure is difficult in this setting. Early in the course of critically ill patients, one should focus on excellent blood glucose control. A total caloric intake of 20-25 kcal/kg/day should be provided to the nonthermal injured patient. Protein intake should be 1.5g/kg body weight/day.

Unlike the normal fasting blood glucose that is seen in cancer patients, patients with injury or infection most commonly have an increase in blood glucose. This has been associated with a large increase in hospital mortality (Table 1). Hyperglycemia as a marker of intensive care unit (ICU) mortality may be greater in surgical patient compared to medical ICU patients. In a prospective randomized clinical trial in which intravenous insulin was provided to surgical patients, preventing the increase in blood glucose associated with injury and infection, there was significantly reduced mortality.

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