A number of mechanisms lead to hype

A number of mechanisms lead to hyperglycemia and insulin resistance in patients receiving parenteral nutrition. The most obvious is the higher total glucose (carbohydrate ) load; a typical 1,800 nonprotein calorie parenteral formula contains about 350 g of glucose, as compared with 230 g in a standard enteral formula. It is well known that oral glucose administration is associated with a much greater increase in the secretion of insulin, with higher plasma insulin levels, when compared with the same amount of glucose given intravenously. The concept that “factors” produced by the intestinal mucosa in response to nutrient ingestion are capable of stimulating the release of substances from the endocrine pancreas and thereby reducing blood glucose levels was first introduced in the early 1900s. This henomenon has been dubbed the “incretin effect,” and it is estimated to account for approximately 50% to 70% of the total insulin secreted after oral glucose administration. Two incretins (ie, glucose- dependent insulinotropic polypeptide and glucagon- like peptide-1), as well as their receptors, have been identifid, purifid, and sequenced and their gene structure determined. Activation of both incretin receptors on the b cell of the pancreas leads to a rapid increase in the levels of cyclic adenosine monophosphate and intracellular calcium, followed by insulin exocytosis, in a glucose- dependent manner. Glucagon-like peptide-1 also inhibits glucagon secretion and enhances glucose disposal through neural mechanisms. Independent of the incretin effect, hepatic glucose output is affected by the portal venous glucose concentration following enteral feeding. An elegant series of experiments demonstrated that the arterial-portal glucose gradient alters net hepatic glucose balance, such that intraportal glucose administration suppresses hepatic glucose output, whereas peripheral glucose administration increases hepatic glucose output. By these mechanisms, parenteral, as opposed to enteral, nutrition results in significantly higher blood glucose levels with insulin resistance. This results in cellular glucose overload and oxidative injury in those cells that do not require insulin for glucose uptake. By increasing glucose-4 -mediated glucose uptake (muscle and adipose tissue) and decreasing blood glucose levels, insulin decreases glucose uptake in non-glucose transporter-4 cells, thereby decreasing oxidative injury in these cells. This phenomenon has been confirmed by Vanhorebeek and colleagues. The results of our meta analysis and meta regression have demonstrated that “tight glycemic control” may only be of benefit in patients receiving parenteral nutrition, particularly those with a low severity of illness. Tight glycemic control is, however, associated with significant hazards. Severe hypoglycemia (blood glucose , 40 mg/dL) occurs in up to 18% of treated patients, with these patients being at an increased risk of death. Using cerebral microdialysis in patients with traumatic brain injuries, Oddo and colleagues demonstrated that tight glycemic control was associated with a greater risk of brain energy crisis and death. These data suggest that tight glycemic control may result in hypoglycemia and neuroglycopenia at a time of increased cerebral metabolic demand. Most ICUs in the world use bedside capillary blood glucose measurements to monitor insulin infusion regimens. Multiple studies have shown that these devices are inaccurate and tend to overestimate “true” plasma glucose levels. This further increases the risk of hypoglycemia in ICU patients.