Impact of glucocorticoids on insulin resistance in the critically ill

Glucocorticoids (GCs) have been shown to reduce insulin sensitivity in healthy individuals. Widely used in critical care to treat a variety of inflammatory and allergic disorders, they may inadvertently exacerbate stress-hyperglycaemia. This research uses model-based methods to quantify the reduction in insulin sensitivity from GCs in critically ill patients, and thus their impact on glycaemic control. A model-based measure of insulin sensitivity (S(I)) was used to quantify changes between two matched cohorts of 40 intensive care unit (ICU) patients. Patients in one cohort received GC treatment, while patients in the control cohort did not. All patients were admitted to the Christchurch hospital ICU between 2005 and 2007 and spent at least 24h on the SPRINT glycaemic control protocol. A 31% reduction in whole-cohort median insulin sensitivity was seen between the control cohort and patients receiving glucocorticoids with a median dose equivalent to 200mg/d of hydrocortisone per patient. Comparing percentile patients as a surrogate for matched patients, reductions in median insulin sensitivity of 20%, 25%, and 21% were observed for the 25th-, 50th- and 75th-percentile patients, respectively. These cohort and percentile patient reductions are less than or equivalent to the 30-62% reductions reported in healthy subjects especially when considering the fact that the GC doses in this study are 1.3-4.0 times larger than those in studies of healthy subjects. This reduced suppression of insulin sensitivity in critically ill patients could be a result of saturation due to already increased levels of catecholamines and cortisol common in critically illness. Virtual trial simulation showed that reductions in insulin sensitivity of 20-30% associated with glucocorticoid treatment in the ICU have limited impact on glycaemic control levels within the context of the SPRINT protocol.

[1]  P. Bessey,et al.  Early Hormonal Changes Affect the Catabolic Response to Trauma , 1993, Annals of surgery.

[2]  Roger L. Black,et al.  Goodman and Gilman's The Pharmacological Basis of Therapeutics , 1991 .

[3]  S. Ruchat,et al.  Dexamethasone-induced insulin resistance shows no gender difference in healthy humans. , 2004, Diabetes & metabolism.

[4]  R. Wolfe,et al.  Mechanisms of Insulin Resistance Following Injury , 1982, Annals of surgery.

[5]  P. Vollenweider,et al.  Mechanisms of dexamethasone-induced insulin resistance in healthy humans. , 1994, The Journal of clinical endocrinology and metabolism.

[6]  P. Gilon,et al.  Direct glucocorticoid inhibition of insulin secretion. An in vitro study of dexamethasone effects in mouse islets. , 1997, The Journal of clinical investigation.

[7]  Thomas Lotz,et al.  A pilot study of the SPRINT protocol for tight glycemic control in critically Ill patients. , 2006, Diabetes technology & therapeutics.

[8]  J. Geoffrey Chase,et al.  Blood Glucose Controller for Neonatal Intensive Care: Virtual Trials Development and First Clinical Trials , 2009, Journal of diabetes science and technology.

[9]  J. Melby Clinical pharmacology of systemic corticosteroids. , 1977, Annual review of pharmacology and toxicology.

[10]  Thomas Lotz,et al.  A simple insulin-nutrition protocol for tight glycemic control in critical illness: development and protocol comparison. , 2006, Diabetes technology & therapeutics.

[11]  J Geoffrey Chase,et al.  Model-based insulin and nutrition administration for tight glycaemic control in critical care. , 2007, Current drug delivery.

[12]  L. Tappy,et al.  Changes in insulin secretion and glucose metabolism induced by dexamethasone in lean and obese females. , 2005, Obesity research.

[13]  Dominic S. Lee,et al.  Implementation and evaluation of the SPRINT protocol for tight glycaemic control in critically ill patients: a clinical practice change , 2008, Critical care.

[14]  D. Isaacs The Unicorn , 2009, Journal of paediatrics and child health.

[15]  B A Mizock,et al.  Alterations in fuel metabolism in critical illness: hyperglycaemia. , 2001, Best practice & research. Clinical endocrinology & metabolism.

[16]  A Mari,et al.  Dose-response characteristics of insulin action on glucose metabolism: a non-steady-state approach. , 2000, American journal of physiology. Endocrinology and metabolism.

[17]  C. Östenson,et al.  Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids. , 1997, The Journal of clinical investigation.

[18]  R. Hancox,et al.  Interactions between corticosteroids and beta agonists. , 2000, Thorax.

[19]  Liu Xinbing,et al.  Intensive insulin therapy for the critically ill patients with stress hyperglycemia , 2008 .

[20]  Christopher E. Hann,et al.  Monte Carlo analysis of a new model-based method for insulin sensitivity testing , 2008, Comput. Methods Programs Biomed..

[21]  M. Cassader,et al.  An in vivo and in vitro study of the mechanism of prednisone-induced insulin resistance in healthy subjects. , 1983, The Journal of clinical investigation.

[22]  Anna Hart,et al.  Mann-Whitney test is not just a test of medians: differences in spread can be important , 2001, BMJ : British Medical Journal.

[23]  A. Malhotra,et al.  Stress-induced hyperglycemia. , 2001, Critical care clinics.

[24]  Amir H Hamrahian,et al.  Measurements of serum free cortisol in critically ill patients. , 2004, The New England journal of medicine.

[25]  R. Rizza,et al.  Adrenergic mechanisms for the effects of epinephrine on glucose production and clearance in man. , 1980, The Journal of clinical investigation.

[26]  P. Radermacher,et al.  Glucose metabolism and catecholamines , 2007, Critical care medicine.

[27]  R. DeFronzo,et al.  Epinephrine-induced insulin resistance in man. , 1980, The Journal of clinical investigation.

[28]  G. Van den Berghe,et al.  Intensive insulin therapy in the medical ICU. , 2006, The New England journal of medicine.

[29]  B. Ahrén,et al.  Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women. , 1996, The Journal of clinical endocrinology and metabolism.

[30]  H. Gerstein,et al.  Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview , 2000, The Lancet.

[31]  S. Tunn,et al.  Receptor‐Based Pharmacokinetic‐Pharmacodynamic Analysis of Corticosteroids , 1993, Journal of clinical pharmacology.

[32]  Christopher E. Hann,et al.  Development of a Clinical Type 1 Diabetes Metabolic System Model and in Silico Simulation Tool , 2008, Journal of diabetes science and technology.

[33]  M Schetz,et al.  Intensive insulin therapy in critically ill patients. , 2001, The New England journal of medicine.

[34]  V. Giusti,et al.  Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers. , 2002, Obesity research.

[35]  L. Goodman,et al.  The Pharmacological Basis of Therapeutics , 1941 .

[36]  D R Worthington Minimal model of food absorption in the gut. , 1997, Medical informatics = Medecine et informatique.

[37]  W. Stigelman,et al.  Goodman and Gilman's the Pharmacological Basis of Therapeutics , 1986 .

[38]  R. Hancox,et al.  Interactions between corticosteroids and β agonists , 2000 .

[39]  E. Jéquier,et al.  Effects of glucocorticoids and sympathomimetic agents on basal and insulin-stimulated glucose metabolism. , 1995, Clinical physiology.

[40]  J. Connell,et al.  Glucocorticoids and insulin sensitivity: dissociation of insulin's metabolic and vascular actions. , 2003, The Journal of clinical endocrinology and metabolism.

[41]  S. Jacob,et al.  Angiotensin converting enzyme inhibitors and modulation of skeletal muscle insulin resistance , 2003, Diabetes, obesity & metabolism.

[42]  T. Micceri The unicorn, the normal curve, and other improbable creatures. , 1989 .