Welcome to the all-new Vetlearn

  • Vetlearn is becoming part of NAVC VetFolio.
    Starting in January 2015, Compendium and
    Veterinary Technician articles will be available on
    NAVC VetFolio. VetFolio subscribers will have
    access to not only the journals, but also:
  • Over 500 hours of CE
  • Community forums to discuss tough cases
    and networking with your peers
  • Three years of select NAVC Conference
  • Free webinars for the entire healthcare team

To access Vetlearn, you must first sign in or register.


  Sign up now for:
Become a Member

Compendium June 2007 (Vol 29, No 6)

Hyperglycemia in Critically Ill Patients

by Melissa Knieriem, DVM, DACVECC, Cynthia Otto, DVM, PhD, Douglass K. Macintire, DVM, MS, DACVIM, DACVECC

    CETEST This course is approved for 2.0 CE credits

    Start Test


    Hyperglycemia is common in critically ill humans. Recent clinical trials have shown a significant reduction in morbidity and mortality rates with the use of intensive insulin therapy to maintain strict normoglycemia in critically ill patients. Hyperglycemia is associated with many detrimental effects, including reduced immune function, increased inflammation and coagulation, and modulation of the endothelium. Most of the evidence regarding the adverse effects of hyperglycemia is derived from humans with diabetes, cardiac failure, or traumatic brain injury. In addition to its anabolic effects on metabolism, insulin has antiinflammatory properties. To define the potential risks and benefits of intensive insulin therapy in critically ill animals, prospective, randomized clinical trials are necessary.

    Recent human clinical trials1-4 have shown a significant reduction in morbidity and mortality rates in a wide range of critically ill patients when insulin therapy is used to maintain normoglycemia within a narrow range (80 to 110 mg/dl). Specific subpopulations in which glycemic control appears to be of particular importance include patients with cardiac disease, neurotrauma, or sepsis. The mechanism(s) associated with the detrimental effects of hyperglycemia and the improvement associated with strict glycemic control are currently under investigation. This article reviews the normal mechanisms of glucose control, causes of hyperglycemia in critically ill patients, potential detrimental effects of hyperglycemia, and implications for clinical veterinary practice.

    Normal Glucose Metabolism

    Glucose is produced from carbohydrate digestion in the small intestine, glycogenolysis in muscle and the liver, gluconeogenesis in the liver resulting from glycerol fat mobilization, amino acid breakdown, and lactate metabolism through the Cori cycle5 (Figure 1).

    Normoglycemia is important for cellular function. For glucose to be transported into a cell, it must bind to one of several available carrier proteins, which then work through an active or a passive transport mechanism. One active carrier is the sodium-glucose cotransporter, which is used for glucose uptake in the proximal tubule of the kidneys and in the small intestine.6 Several glucose transport proteins (GLUTs) use facilitated diffusion.7 GLUT 1 is responsible for basal glucose uptake and is especially important in the brain and placenta.8 The high glucose affinity of GLUT 1 ensures transport during hypoglycemia.7 GLUT 2, which is found in the liver, kidneys, small intestine, and pancreatic beta cells, mediates glucose uptake and release in hepatocytes.8 GLUT 4 is present in tissues in which glucose uptake is insulin mediated (e.g., muscle, adipose tissue, cardiac tissue).8 Under basal conditions, GLUT 4 is normally found mostly in intracellular vesicles.9 When insulin binds to the insulin receptor on the cell membrane, intracellular signaling pathways are stimulated, causing the GLUT 4-containing vesicles to move to the cell membrane.9

    Following transport into the cell, glucose is either transformed into pyruvate through the process of glycolysis or stored as glycogen. Glycolysis can provide energy in the form of ATP through aerobic (i.e., pyruvate oxidation to carbon dioxide and water) or anaerobic (i.e., pyruvate conversion to lactate) metabolism. Alternatively, pyruvate can be transaminated to alanine or recycled to glucose via oxaloacetate10; these gluconeogenic substrates maintain glucose availability (Figure 2). Lactate metabolism through the Cori cycle provides a constant source of glucose, which is especially important in wounded tissue, leukocytes and erythrocytes, and brain cells11 (Figure 3). Increased glycolysis occurs when phosphofructokinase, the rate-limiting enzyme for glycolysis, is stimulated by increased cellular uptake of glucose, increased turnover of ATP, and increased AMP production, all of which occur during physiologic stress.12

    Glycogen is the storage form of glucose. When glucose is taken up by hepatocytes through GLUT-2 receptors, it is converted to glucose-6-phosphate by glucokinase.5 This is an energy-dependent process requiring ATP. Glucose, once phosphorylated, cannot diffuse out of the cell. Glucose-6-phosphate is then converted to glycogen through a series of enzymatic reactions. Glycogenolysis begins when glycogen is degraded into glucose-1-phosphate by phosphorylase and then converted to glucose-6-phosphate. Phosphorylase is activated by epinephrine and glucagon.5 Glucose phosphatase then splits glucose-6-phosphate into glucose and phosphate. Glucose can then exit the liver cell into systemic circulation (Figure 4).

    Glucose Regulation

    A number of hormones are involved in glucose metabolism and the maintenance of normoglycemia. The blood glucose concentration reflects the balance between hepatic glucose production and cellular glucose uptake.

    In dogs and cats, mild hyperglycemia is defined as a glucose concentration of 130 to 180 mg/dl and severe hyperglycemia as a glucose concentration of greater than 180 mg/dl.13 When the amount of glucose filtered by the glomerulus exceeds the renal threshold for glucose, glucos­uria occurs. The renal transport maximum for glucose is 180 to 220 mg/dl in dogs and 260 to 310 mg/dl in cats.14 Glucosuria results in osmotic diuresis. Although glucos­uria can lower the magnitude of hyperglycemia, it can also result in significant dehydration.

    Hyperglycemia can result from increased circulating glucocorticoids, catecholamines, and insulin resistance in critically ill patients. Adrenocorticotropic hormone (ACTH) and thus cortisol levels can be increased by multiple mechanisms. Following injury, afferent pain pathways to the hypothalamus trigger the release of corticotropin-releasing hormone, which stimulates ACTH release from the anterior pituitary.15 ACTH, in turn, stimulates the adrenal gland to release cortisol from the zonae fasciculata and reticularis.16 ACTH is also stimulated by volume depletion sensed by baroreceptors in the carotid bodies and aortic arch.16 In addition, catecholamine release is stimulated by decreased blood volume and afferent stimulation of the hypothalamus by pain pathways from the site of injury.16 The reticular formation and spinal cord transmit signals to postganglionic sympathetic nerve endings to release epinephrine and norepinephrine from the adrenal medulla15 (Figure 5).

    The end result of these metabolic processes associated with stress in critically ill patients is an increase in counterregulatory hormones. This response causes insulin resistance, a clinical state characterized by appropriate levels of insulin but an inability to maintain normoglycemia. It is a prominent feature of critical illness and allows hyperglycemia to develop. One mechanism for insulin resistance is a decrease in GLUT-4 activity by cortisol and glucagon.17 There is also impairment of insulin-stimulated GLUT-4 movement from intracellular vesicles to the plasma membrane despite a normal GLUT-4 concentration.18,19 This defect may be due to tumor necrosis factor-α (TNF-α) acting in a paracrine fashion20,21 and increased glucose22 and/or free fatty acid concentrations.23 Another mechanism for insulin resistance is decreased activity of the muscular enzymes glycogen synthase24 and pyruvate dehydrogenase.25 These enzymes normally function to convert glucose to glycogen and pyruvate, respectively. When their function is impaired, intracellular glucose concentrations rise, creating an unfavorable concentration gradient for glucose uptake into the cells.

    Insulin is released in response to hyperglycemia. Insulin promotes fat synthesis and storage, enhances amino acid transport into cells for protein synthesis and storage, decreases gluconeogenesis, and inhibits proteolysis.26 Insulin is the primary hormone that stimulates glucose uptake into cells, thus potentially promoting hypoglycemia.

    Hypoglycemia is defined as a blood glucose level less than 60 mg/dl. Hypoglycemia can result from increased insulin, increased peripheral glucose uptake, decreased glycogen stores, decreased glycogenolysis, and decreased gluconeogenesis. The counterregulatory hormones (e.g., glucagon, cortisol, growth hormone, catecholamines) are responsible for preventing hypoglycemia (Figure 6). Glucagon is released in response to decreased blood ­glucose or increased amino acid and cortisol concentrations.26 Glucagon stimulates liver glycogenolysis and gluconeogenesis and, in high concentrations, increases free fatty acid concentrations.26 Cortisol is released in response to ACTH secretion. Cortisol stimulates gluconeogenesis by mobilizing amino acids into the liver and decreases glucose uptake and use in most cells, particularly myocytes and adipocytes.16 Cortisol decreases glucose uptake through a number of mechanisms, including decreased number or efficiency of GLUT-4 transporters17 and increased glucagon and free fatty acid concentrations.16 Growth hormone reduces glucose uptake in myocytes and adipocytes and stimulates glycogenolysis.27 In response to severe hypoglycemia, the hypothalamus activates the sympathetic nervous system to release epinephrine and norepinephrine.26 These catecholamines stimulate β2-adrenergic receptors in the liver, resulting in glycogenolysis and in­creased glucose release.5 α-Adrenergic stimulation of pancreatic beta cells causes decreased insulin release and decreased use of glucose by hepatocytes, myocytes, and adipocytes.26

    In addition to being caused by the sympathetic and stress responses, hyperglycemia in critically ill patients can be caused by certain medical interventions, such as total parenteral nutrition (TPN), dextrose supplementation, surgery, and administration of glucocorticoids, vasopressors, and anesthesia (see box). In one study28 of critically ill humans, elevated glucose levels caused by TPN were associated with an increased risk for cardiac complications, infection, sepsis, acute renal failure, and death. The relationship between elevated blood glucose levels and adverse outcomes suggests that tight glycemic control might benefit these patients. In a retrospective study29 of cats and dogs receiving TPN, 30% of patients became hyperglycemic. In cats, hyperglycemia 24 hours after initiation of TPN has been associated with a poor prognosis.30 In contrast, in a retrospective study31 of cats and dogs that received partial parenteral nutrition, 15% became hyperglycemic, but this had no effect on the morbidity and mortality rates.

    Anesthesia and surgery both modulate normal metabolic function.32-36 Anesthetic drugs known to cause transient hyperglycemia include ketamine, α2-agonists, and opioids. Ketamine stimulates epinephrine release.33 α2-Adrenergic agonists, xylazine,34 and medetomidine35 can cause hyperglycemia by binding to α2-adrenergic receptors on pancreatic beta cells and thereby inhibiting insulin release. Morphine stimulates the release of growth hormone and ACTH,36 thereby promoting hyperglycemia.

    Hyperglycemia is common in people1,37 and animals38 in the early stages of sepsis. Studies24,39,40 have found conflicting results on whether this is due to decreased glucose oxidation during sepsis or to increased glucose production. Hepatic glucose production is significantly increased.41 Current evidence suggests that overall glucose uptake is also increased but insulin-mediated glucose uptake by skeletal and adipose tissue is decreased24 and glucose uptake by the reticuloendothelial system and leukocytes is increased.39,40

    Critically ill patients are in a catabolic state in which the increased demand for energy substrates is met by degrading endogenous sources of glycogen. This state is characterized by hyperglycemia, hyperlactatemia, and increased oxygen demand.10 In the past, this catabolic state was believed to be beneficial by providing extra energy substrates to glucose-dependent tissues (i.e., the brain, erythrocytes, leukocytes).10 Evidence now suggests that hyperglycemia produced during critical illness can have various detrimental effects on patients.

    Potential Detrimental Effects of Hyperglycemia

    Research into the mechanisms that cause the detrimental effects of hyperglycemia has mainly focused on modulation of inflammation, changes in vascular tone, and alteration of coagulation (see box). The effects of hyperglycemia on the heart, brain, and endothelium have been the most researched.


    Unfortunately, most studies that have evaluated the mechanisms of inflammatory response modulation under hyperglycemic conditions have been conducted in laboratory animal models and in humans with diabetes and do not necessarily represent events in critical illness. However, it has been well documented that humans with diabetes have a decreased ability to fight infection.42,43

    Based on studies in laboratory animals and humans with diabetes, inflammation is increased but essential function of the inflammatory response is impaired by hyperglycemia. Both migration and phagocytic ability of polymorphonuclear cells are hampered,44,45 leading to an increased risk for bacterial proliferation. Another aspect of hyperglycemia-associated immune impairment may be related to nonenzymatic glycosylation of immuno­globulins, which causes their inactivation, contributing to an increased risk for infection.46,47 As in many inflammatory responses, hyperglycemia induces nuclear factor κβ (NF-κβ), a transcription factor that increases production of cytokines, particularly TNF-α, interleukin-1β, and interleukin-6.48-50 Production of complement, a family of serum proteins critical in bacterial killing and inflammation, is increased, but its function is impaired.45,46,51,52 Hyperglycemia causes increased interactions among endothelial cells, monocytes, lymphocytes, and neutrophils through induction of adhesion molecules.45 Hyperglycemia also results in increased expression of protein kinase Cabo. These intracellular messengers activate NF-κβ, thereby increasing adhesion molecule expression and inhibiting complement- and immunoglobulin-mediated phagocytosis.45,51

    Coagulation and Endothelium

    Research53 has demonstrated an important relationship between inflammation and coagulation. Hyperglycemia stimulates not only inflammation but also coagulation. Procoagulant effects of hyperglycemia include activation of the tissue factor pathway,54 inhibition of proteins C55 and S,48 increase in blood levels of clotting factors,56,57 platelet activation,58,59 and inhibition of the fibrinolytic system.57 Hyperglycemia also stimulates interleukin-6, an inflammatory cytokine with procoagulant effects.48

    In addition to promoting inflammation and coagulation, hyperglycemia interferes with normal endothelial function.60-62 Local activation of the endothelium is necessary for the migration and adhesion of leukocytes to the site of inflammation. Hyperglycemia activates the endothelium.60 Studies61,62 have attempted to determine how hyperglycemia is detrimental to the endothelium. Whether hyperglycemia results in vasoconstriction or vasodilation varies, depending on the tissue studied and the amounts and types of mediators and receptors involved.

    Cardiac Effects

    In humans or animal models with cardiac disease, hyperglycemia has been found to cause detrimental effects via increased inflammation, vasoconstriction, and elevated free fatty acid concentration.63 Increased free fatty acids can be cytotoxic to the myocardium.63 In human studies of congestive heart failure, the mechanisms of hyperglycemia include reduced insulin-mediated glucose uptake,64 impaired insulin signal transduction, and antagonism at insulin receptors.65

    Traumatic Brain Injury

    Numerous mechanisms have been proposed to explain the relationship between hyperglycemia and enhanced damage in patients with traumatic, hypoxic, or ischemic brain injury.66-70 Current opinions differ as to whether hyperglycemia simply reflects more severe injury or truly causes direct harm to brain-injured patients.71-73

    During hypoxemia or ischemia, the brain develops lactic acidosis as end products of anaerobic metabolism accumulate. Hyperglycemia allows more anaerobic metabolism to occur and more by-products to accumulate. Lactic acid is cytotoxic to neuronal and glial cells.66 Glial cells produce myelin to protect neurons. Hyperglycemia in patients with traumatic brain injury is associated with increases in free radical production,67 excitatory amino acid release,68 cerebral edema,69 and cerebral vasoconstriction.70

    Human clinical studies71-73 have shown a relationship between hyperglycemia and a worse outcome in brain-injured patients. Studies68,74 have also demonstrated that hyperglycemia worsens secondary brain injury in laboratory animal models of ischemia and hemorrhage associated with traumatic brain injury.


    In the veterinary literature, there is little research relating serum glucose to outcome in clinical patients. Few studies32,75-77 have attempted to correlate glucose levels with outcome in specific conditions (e.g., head trauma, congestive heart failure, sepsis).

    One clinical retrospective veterinary study78 of head trauma in dogs and cats found an association between hyperglycemia and severity of injury but not outcome. A few studies have investigated hyperglycemia in veterinary cardiac patients. Brady et al75 reported higher glucose levels associated with worse outcome (median glucose levels: 101 mg/dl in survivors and 120 mg/dl in nonsurvivors). Freeman et al76 found elevated glucose and TNF-a levels in dogs with congestive heart failure, but TNF-a levels did not directly correlate with the level of hyperglycemia found. In a study32 that compared the glucose levels of septic and nonseptic dogs and cats before and after surgery, there was a trend toward higher mortality rates with severe postsurgical hyperglycemia in cats and dogs with sepsis compared with those with mild postsurgical hyperglycemia. These findings did not reach clinical significance. Meaningful clinical studies to relate hyperglycemia with outcome are difficult to conduct in animals because of the wide spectrum of disease severity and the many interventions that can affect glucose levels.

    Intensive Insulin Therapy for Glycemic Control

    Recent clinical studies1-4,50,77 in humans have shown decreased mortality rates with strict glycemic control using insulin therapy not only in patients with diabetes but also in patients with hyperglycemia that was associated with critical illness. Maintenance of normogly­cemia using insulin therapy decreased not only the mortality rate but also the rates of acute renal failure, ventilatory support, transfusions, polyneuropathy, and infections.1 Several clinical cardiac studies79-81 have shown improved outcome and de­creased complications with glycemic control in both diabetic and nondiabetic patients. In a recent human clinical trial82 in a surgical intensive care unit, a subpopulation with isolated traumatic brain injury had a reduced risk for prolonged mechanical ventilation, had decreased intracranial pressure, and maintained cerebral perfusion pressure with an eight-fold lower dose of vasopressors through strict glycemic control. No other published human clinical trials have demonstrated improved outcome when glucose has been strictly controlled in hyperglycemic patients with traumatic brain injury. A rabbit model of traumatic burn injury found that using insulin to maintain normoglycemia prevented much of the weight loss, lactic acidosis, and monocyte dysfunction that occurred in the hyperglycemic group.83 Whether the maintenance of normoglycemia or the use of insulin is responsible for the beneficial effects in clinical trials remains under investigation.79


    Insulin has several antiinflammatory effects.84,85 Insulin suppresses the generation of numerous inflammatory mediators, including TNF-α,86,87 macrophage migration inhibitory factor,88 superoxide anions,89 and NF-κβ.84

    The primary approach to maintenance of glycemic control in critically ill patients is intensive insulin therapy. To date, attempts at hypocaloric nutrition as a means of decreasing hyperglycemia do not appear beneficial.90 It is important to remember that numerous drugs, such as glucocorticoids, catecholamines, and certain anesthetics (ketamine, α2-agonists, morphine),33-36 as well as supplements, such as dextrose and TPN,28-31 may exacerbate hyperglycemia. Avoiding or limiting the use of these treatments may be indicated in certain situations to prevent hyperglycemia.

    The use of insulin therapy to provide strict glycemic control in critically ill animals has been reported only in animals with diabetic ketoacidosis.91 In these patients, a constant-rate infusion of regular insulin was shown to gradually reduce hyperglycemia and ketogenesis over a period of 10 to 24 hours.91 In diabetic animals, regular insulin is usually administered at a dose of 1 to 2 U/kg/day (0.04 to 0.08 U/kg/hr) mixed in 250 ml of saline at a rate of 10 ml/hr. Although the routine use of insulin therapy in critically ill hyperglycemic veterinary patients cannot currently be recommended, a modified protocol can be used to provide strict glycemic control in select nondiabetic hyperglycemic patients with head trauma or sepsis: a lower dose of insulin (0.25 to 1 U/kg/day) is used, and the infusion rate is decreased by 50% to 75% when the glucose level drops below 150 mg/dl. Blood glucose levels must be monitored frequently to prevent hypoglycemia. Ideally, the constant-rate infusion should be adjusted to maintain a blood glucose concentration of 85 to 130 mg/dl. The insulin should be discontinued when the blood glucose level drops below 85 mg/dl. Animals receiving insulin therapy are prone to hypoglycemia, hypokalemia, hypophosphatemia, and hypomagnesemia.92 Hypoglycemia can result in seizures, coma, and death.13 Hypokalemia and hypomagnesemia cause muscular weakness and cardiac arrhythmias.13 Hypophosphatemia causes muscular weakness and hemolysis.13 Adequate nutrition should be provided to prevent hypoglycemia, and intravenous fluids should be supplemented with potassium, phosphorus, or magnesium, as needed. Interventions that can cause hyperglycemia, such as TPN infusions, should be avoided in critically ill patients with head trauma or cardiovascular disease.


    Maintenance of normal blood glucose concentrations is important for normal cellular function. Persistent hyperglycemia indicates a significant loss of one or more major homeostatic mechanisms. It may indicate increased hepatic glucose production, insulin resistance, or decreased cellular uptake of glucose. In humans and animal models, persistent increased blood glucose has been shown to have numerous detrimental effects, including increased inflammation, immune system dysfunction, stimulation of coagulation, and modulation of the endothelium. In critical illness, hyperglycemia can theoretically have detrimental effects on many different organs, particularly the brain, heart, and endothelium.

    Many mechanisms for hyperglycemia have been explored in laboratory animal models and humans with diabetes. In critical illness, not all of these models necessarily apply. There may be major differences in the metabolic mechanisms of disease between critically ill humans and cats or dogs. A reduced mortality rate with the use of intensive insulin therapy for glycemic control in critically ill humans does not necessarily imply the same results for cats and dogs. Further research is warranted to determine the incidence of hyperglycemia in various subgroups of critically ill animals and whether strict glycemic control is indicated to reduce morbidity and mortality rates. Although the risk:benefit ratio of active interventions, such as intensive insulin therapy to maintain glycemic control, has not been evaluated in animals, management strategies to avoid hyperglycemia, when possible, are likely indicated. However, until prospective clinical studies have been conducted in critically ill cats and dogs, intensive insulin therapy should be used cautiously and only with intensive monitoring.

    See the Key Points box.

    Downloadable PDF

    1. Van den Berghe G, Wouters PJ, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Engl J Med 345(19):1359-1367, 2001.

    2. Krinsley JS: Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc 78(12):1471-1478, 2003.

    3. Krinsley JS: Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clin Proc 79(8):992-1000, 2004.

    4. Finney SJ, Zekveld C, Elia A, Evans TW: Glucose control and mortality in critically ill patients. JAMA 290(15):2041-2047, 2003.

    5. Guyton AC, Hall JE: Metabolism of carbohydrates, and formation of adenosine triphosphate, in Guyton AC, Hall JE (eds): Textbook of Medical Physiology. Philadelphia, WB Saunders, 2000, pp 772-780.

    6. Guyton AC, Hall JE: Transport of substances through the cell membrane, in Guyton AC, Hall JE (eds): Textbook of Medical Physiology. Philadelphia, WB Saunders, 2000, pp 40-51.

    7. Marik PE, Raghavan M: Stress-hyperglycemia, insulin and immunomodulation in sepsis. Intensive Care Med 30(5):748-756, 2004.

    8. Pessin JE, Bell GI: Mammalian facilitative glucose transporter family: Structure and molecular regulation. Annu Rev Physiol 54:911-930, 1992.

    9. Sheperd PR, Kahn BB: Glucose transporters and insulin action: Implications for insulin resistance and diabetes mellitus. N Engl J Med 341(4):248-257, 1999.

    10. Mizock BA: Alterations in carbohydrate metabolism during stress: A review of the literature. Am J Med 98(1):75-84, 1995.

    11. Amaral JF, Shearer JD, Mastrofrancesco BS, et al: Can lactate be used as a fuel by wounded tissue? Surgery 100(2):252-261, 1986.

    12. Hotchkiss RS, Karl IE: Reevaluation of the role of cellular hypoxia and bioenergetic failure in sepsis. JAMA 267(11):1503-1519, 1992.

    13. Nelson RW: Diabetes mellitus, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, ed 5. Philadelphia, WB Saunders, 2000, pp 1438-1460.

    14. Feldman EC, Nelson RW: Diabetes mellitus, in Canine and Feline Endocrinology, ed 2. Philadelphia, WB Saunders, 1996, pp 339-391.

    15. Guyton AC, Hall JE: The autonomic nervous system and the adrenal medulla, in Guyton AC, Hall JE (eds): Textbook of Medical Physiology. Philadelphia, WB Saunders, 2000, pp 697-708.

    16. Guyton AC, Hall JE: The adrenocortical hormones, in Guyton AC, Hall JE (eds): Textbook of Medical Physiology. Philadelphia, WB Saunders, 2000, pp 869-883.

    17. Moller DE, Flier JS: Insulin resistance: Mechanisms, syndromes, and implications. N Engl J Med 325(13):938-948, 1991.

    18. Rea S, James DE: Moving GLUT4: The biogenesis and trafficking of GLUT4 storage vesicles. Diabetes 46(11):1667-1677, 1997.

    19. Zierath JR, He L, Guma A, et al: Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia 39(10):1180-1189, 1996.

    20. Hotamisligil GS, Spiegelman BM: Tumor necrosis factor alpha: A key component of the obesity-diabetes link. Diabetes 43(11):1271-1278, 1994.

    21. Saghizadeh M, Ong JM, Garvey WT, et al: The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest 97(4):1111- 1116, 1996.

    22. Yki-Jarvinen H: Glucose toxicity. Endocr Rev 13(3):415-431, 1992.

    23. Roden M, Price TB, Perseghin G, et al: Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97(12):2859-2865, 1996.

    24. Virkamaki A, Puhakainen I, Koivisto VA, et al: Mechanisms of hepatic and peripheral insulin resistance during acute infections in humans. J Clin Endocrinol Metab 74(3):673-679, 1992.

    25. Beck-Nielsen H, Wright K, Verity L, et al: Reduced glucose oxidation and pyruvate-dehydrogenase activity (PDH) in type I diabetics (insulin-depen­dent) in poor control. Diabetes 36(suppl):30, 1987.

    26. Guyton AC, Hall JE: Insulin, glucagon, and diabetes mellitus, in Guyton AC, Hall JE (eds): Textbook of Medical Physiology. Philadelphia, WB Saunders, 2000, pp 884-897.

    27. Guyton AC, Hall JE: The pituitary hormones and their control by the hypothalamus, in Guyton AC, Hall JE (eds): Textbook of Medical Physiology. Philadelphia, WB Saunders, 2000, pp 846-857.

    28. Cheung NW, Napier B, Zaccaria C, Fletcher JP: Hyperglycemia is associated with adverse outcomes in patients receiving total parenteral nutrition. Diabetes Care 28(10):2367-2371, 2005.

    29. Lippert AC, Fulton RB, Parr AM: A retrospective study of the use of total parenteral nutrition in dogs and cats. J Vet Intern Med 7(2):52-64, 1993.

    30. Pyle SC, Marks SL, Kass PH: Evaluation of complications and prognostic factors associated with administration of total parenteral nutrition in cats: 75 cases (1994-2001). JAVMA 225(2):242-250, 2004.

    31. Chan DL, Freeman LM, Labato MA, Rush JE: Retrospective evaluation of partial parenteral nutrition in dogs and cats. J Vet Intern Med 16(4):440-445, 2002.

    32. Hardie EM, Rawlings CA, George JW: Plasma-glucose concentrations in dogs and cats before and after surgery: Comparison of healthy animals and animals with sepsis. Am J Vet Res 46(8):1700-1704, 1985.

    33. Hsu WH, Hembrough FB: Intravenous glucose tolerance test in cats: Influenced by acetylpromazine, ketamine, morphine, thiopental, and xylazine. Am J Vet Res 43(11):2060-2061, 1982.

    34. Thurmon JC, Tranquili WJ, Benson GJ: Preanesthetics and anesthetic adjuncts, in Thurmon JC, Tranquili WJ, Benson GJ (eds): Lumb and Jones' Veterinary Anesthesia, ed 3. Baltimore, Williams & Wilkins, 1996, pp 183-209.

    35. Ambrisko TD, Hikasa Y, Sato K: Influence of medetomidine on stress-related neurohormonal and metabolic effects caused by butorphanol, fentanyl, and ketamine administration in dogs. Am J Vet Res 66(3):406-412, 2005.

    36. Branson KR, Gross ME, Booth NH: Opioid agonists and antagonists, in Adams HR (ed): Veterinary Pharmacology and Therapeutics, ed 7. Ames, Iowa State University Press, 1995, pp 274-310.

    37. Frankenfield DC, Omert LA, Badellino MM, et al: Correlation between measured energy expenditure and clinically obtained variables in trauma and sepsis patients. J Parenter Enteral Nutr 18:398-403, 1994.

    38. Brady CA, Otto CM: Systemic inflammatory response syndrome, sepsis, and multiple organ dysfunction. Vet Clin North Am Small Anim Pract 31(6):1147- 1162, 2001.

    39. Stoner HB: Metabolism after trauma and in sepsis. Circ Shock 19(1):75-87, 1986.

    40. Meszaros K, Lang CH, Bagby GJ, Spitzer JJ: Contribution of different organs to increased glucose consumption after endotoxin administration. J Biol Chem 262(23):10965-10970, 1987.

    41. Dahn MS, Mitchell RA, Lange MP, et al: Hepatic metabolic response to injury and sepsis. Surgery 117(5):520-530, 1995.

    42. Pozzilli P, Leslie RD: Infections and diabetes: Mechanisms and prospects for prevention. Diabet Med 11(10):935-941, 1994.

    43. McCowen KC, Malhotra A, Bistrian BR: Stress-induced hyperglycemia. Crit Care Clin 17(1):107-124, 2001.

    44. Mowat A, Baum J: Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. N Engl J Med 284(12):621-627, 1971.

    45. Morigi M, Angioletti S, Imberti B, et al: Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kb dependent fashion. J Clin Invest 101(9):1905-1915, 1998.

    46. Black CT, Hennessey PJ, Andrassy RJ: Short-term hyperglycemia depresses immunity through nonenzymatic glycosylation of circulating immunoglobulin. J Trauma 30(7):830-832, 1990.

    47. Hennessey PJ, Black CT, Andrassy RJ: Nonenzymatic glycosylation of immunoglobulin G impairs complement fixation. J Parenter Enter Nutr 15(1):60-64, 1991.

    48. Morohoshi M, Fujisawa K, Uchimura I, Numano F: Glucose-dependent interleukin 6 and tumor necrosis factor production by human peripheral blood monocytes in vitro. Diabetes 45(7):954-959, 1996.

    49. Morohoshi M, Fujisawa K, Uchimura I, Numano F: The effect of glucose and advanced glycosylation end products on IL-6 production by human monocytes. Ann NY Acad Sci 748:562-570, 1995.

    50. Esposito K, Nappo F, Marfella R, et al: Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: Role of oxidative stress. Circulation 106(16):2067-2072, 2002.

    51. Hostetter MK: Handicaps to host defense: Effects of hyperglycemia on C3 and Candida albicans. Diabetes 39:271-275, 1990.

    52. Saiepour D, Sehlin J, Oldenborg PA: Hyperglycemia-induced protein kinase C activation inhibits phagocytosis of C3b- and immunoglobulin g-opsonized yeast particles in normal human neutrophils. Exp Diabesity Res 4(2):125-132, 2003.

    53. Bernard GR, Vincent JL, Laterre PF, et al: Recombinant human protein C worldwide evaluation in severe sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344(10):699-709, 2001.

    54. Rao AK, Chouhan V, Chen X, et al: Activation of the tissue factor pathway of blood coagulation during prolonged hyperglycemia in young healthy men. Diabetes 48(5):1156-1161, 1999.

    55. Vukovich TC, Schernthaner G: Decreased protein C levels in patients with insulin-dependent type I diabetes mellitus. Diabetes 35(5):617-619, 1986.

    56. Patrassi GM, Vettor R, Padovan D, Giorlami A: Contact phase of blood coagulation in diabetes mellitus. Eur J Clin Invest 12(4):307-311, 1982.

    57. Carmassi F, Morale M, Puccetti R, et al: Coagulation and fibrinolytic system impairment in insulin dependent diabetes mellitus. Thromb Res 67(6):643- 654, 1992.

    58. Hughes A, McVerry BA, Wilkinson L, et al: Diabetes, a hypercoagulable state? Hemostatic variables in newly diagnosed type 2 diabetic patients. Acta Haematol 69(4):254-259, 1983.

    59. Garcia Frade LJ, de la Calle H, Alava I, et al: Diabetes mellitus as a hypercoagulable state: Its relationship with fibrin fragments and vascular damage. Thromb Res 47(5):533-540, 1987.

    60. Lin LY, Lin CY, Ho FM, Liau CS: Up-regulation of the association between heat shock protein 90 and endothelial nitric oxide synthase prevents high glucose-induced apoptosis in human endothelial cells. J Cell Biochem 94(1):194-201, 2005.

    61. Langouche L, Vanhorebeek I, Vlasselaers D, et al: Intensive insulin therapy protects the endothelium of critically ill patients. J Clin Invest 115(8):2277-2286, 2005.

    62. Siroen MP, van Leeuwen PA, Nijveldt RJ, et al: Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: A possible explanation of reduced morbidity and mortality? Crit Care Med 33(3):504-510, 2005.

    63. Oliver MF, Opie LH: Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 343(8890):155-158, 1994.

    64. Paolisso G, Tagliamonte MR, Rizzo MR, et al: Prognostic importance of insulin-mediated glucose uptake in aged patients with congestive heart failure secondary to mitral and/or aortic valve disease. Am J Cardiol 83(9):1338-1344, 1999.

    65. Swan JW, Anker SD, Walton C, et al: Insulin resistance in chronic heart failure: Relation to severity and etiology of heart failure. J Am Coll Cardiol 30(2):527-532, 1997.

    66. Staub F, Mackert B, Kempski O, et al: Swelling and death of neuronal cells by lactic acid. J Neurol Sci 119(1):79-84, 1993.

    67. Rovlias A, Kotsou S: The influence of hyperglycemia on neurological outcome in patients with severe head injury. Neurosurgery 46(2):335-342, 2000.

    68. Li PA, Shuaib A, Miyashita H, et al: Hyperglycemia enhances extracellular glutamate accumulation in rats subjected to forebrain ischemia. Stroke 31(1):183-192, 2000.

    69. Song EC, Chu K, Jeong SW, et al: Hyperglycemia exacerbates brain edema and perihematomal cell death after intracerebral hemorrhage. Stroke 34(9):2215-2220, 2003.

    70. Kawai N, Keep RF, Betz AL: Hyperglycemia and the vascular effects of cerebral ischemia. Stroke 28:149-154, 1997.

    71. Jeremitsky E, Omert LA, Dunham CM, et al: The impact of hyperglycemia on patients with severe brain injury. J Trauma 58(1):47-50, 2005.

    72. Cochran A, Scaife ER, Hansen KW, Downey EC: Hyperglycemia and outcomes from pediatric traumatic brain injury. J Trauma 55(6):1035-1038, 2003.

    73. Lam AM, Winn HR, Cullen BF, Sundling N: Hyperglycemia and neurological outcome in patients with head injury. J Neurosurg 75(4):545-551, 1991.

    74. Cherian L, Goodman JC, Robertson CS: Hyperglycemia increases brain injury caused by secondary ischemia after cortical impact injury in rats. Crit Care Med 25(8):1378-1383, 1997.

    75. Brady CA, Hughes D, Drobatz KJ: Association of hyponatremia and hyperglycemia with outcome in dogs with congestive heart failure. J Vet Emerg Crit Care 14(3):177-182, 2004.

    76. Freeman LM, Rush JE, Brown DH, et al: Elevated concentrations of tumor necrosis factor in dogs with congestive heart failure. J Vet Intern Med 8:146, 1994.

    77. Van den Berghe G, Wouters PJ, Bouillon R, et al: Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med 31(2):359-366, 2003.

    78. Syring RS, Otto CM, Drobatz KJ: Hyperglycemia in dogs and cats with head trauma: 122 cases (1997-1999). JAVMA 218(7):1124-1129, 2001.

    79. Furnary AP, Wu Y, Bookin SO: Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: The Portland Diabetic Project. Endocr Pract 10(S2):21-33, 2004.

    80. Furnary AP, Gao G, Grunkemeier GL, et al: Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thoracic Cardiovasc Surg 125(5):1007-1021, 2003.

    81. Capes SE, Hunt D, Malmberg K, Gerstein HO: Stress hyperglycemia and increased risk of death after myocardial infarction in patients with and without diabetes. Lancet 355(9206):773-778, 2000.

    82. Van den Berghe G, Schoonheydt K, Becx P, et al: Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 64(8):1348-1353, 2005.

    83. Weekers F, Giulietti AP, Michalaki M, et al: Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness. Endocrinology 144(12):5329-5338, 2003.

    84. Das UN: Is insulin an antiinflammatory molecule? Nutrition 17(1):409-413, 2001.

    85. Hansen TK, Thiel S, Wouters PJ, et al: Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 88(3):1082-1088, 2003.

    86. Satomi N, Sakurai A, Haranaka K: Relationship of hypoglycemia to tumor necrosis factor production and antitumor activity: Role of glucose, insulin, and macrophages. J Natl Cancer Inst 74(6):1255-1260, 1985.

    87. Fraker DL, Merino MJ, Norton JA: Reversal of the toxic effects of cachectin by concurrent insulin administration. Am J Physiol 256(6):E725-E731, 1989.

    88. Sakaue S, Nishihira J, Hirokawa J, et al: Regulation of macrophage migration inhibitory factor (MIF) expression by glucose and insulin in adipocytes in vitro. Mol Med 5(6):361-371, 1999.

    89. Chen HC, Guh JY, Shin SJ, et al: Insulin and heparin suppress superoxide production in diabetic rat glomeruli stimulated with low-density lipoprotein. Kidney Int Suppl 78:S124-S127, 2001.

    90. McCowen KC, Friel C, Sternberg J, et al: Hypocaloric total parenteral nutrition: Effectiveness in prevention of hyperglycemia and infectious complications: A randomized clinical trial. Crit Care Med 28(11):3606-3611, 2000.

    91. Macintire DK: Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin. JAVMA 202(8):1266-1272, 1993.

    92. Dibartola S: Fluid Therapy in Small Animal Practice, ed 2. Philadelphia, WB Saunders, 2000.

    References »

    NEXT: News Bites (June 2007)

    CETEST This course is approved for 2.0 CE credits

    Start Test


    Did you know... Urate uroliths (in dogs) are amenable to medical dissolution.Read More

    These Care Guides are written to help your clients understand common conditions. They are formatted to print and give to your clients for their information.

    Stay on top of all our latest content — sign up for the Vetlearn newsletters.
    • More