Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.

We assessed the association of intravenous insulin and glucose infusion with intensive care unit (ICU) and hospital mortality.

For this retrospective association study, we used data from all patients admitted to a medical-surgical ICU between January 2012 and September 2017. We excluded patients admitted < 24 h, patients with a diabetic ketoacidosis, patients with a therapy restriction upon ICU admission and readmissions. Using multivariate logistic regression, we examined the relation between intravenous insulin and glucose infusion and ICU and hospital mortality for all patients. Additionally, we used the same model to analyze the outcomes for patients admitted > 72 h.

Of 9507 eligible patients, 3966 were included. After correction for potential confounders, intravenous insulin was associated with ICU and hospital mortality in patients admitted > 24 h (n = 3966) (odds ratio (OR) 1.09 [95% CI 1.05–1.13] and 1.09 [95% CI 1.06–1.13] per 0.1 IU/kg added, respectively). Likewise, intravenous glucose was associated with ICU mortality (OR 1.01 [95% CI 1.00–1.01]) but not with hospital mortality and (OR 1.00 [95% CI 1.00–1.01]) per g/day added, respectively. In patients admitted > 72 h (n = 1550), insulin dose was associated with both ICU and hospital mortality (p = 0.002 and p < 0.001, respectively), but glucose infusion was not (p = 0.08 and p = 0.2, respectively).

Intravenous insulin administration is associated with an increased risk of ICU and hospital mortality, after correction for potential confounders. Parenteral glucose administration was limited in amount but was still associated with ICU mortality. However, based on these results, it is unknown whether this association is an epiphenomenon, or represents a true harm of insulin and glucose administration.

The online version of this article (10.1186/s13613-019-0507-x) contains supplementary material, which is available to authorized users.

• Critical illness
• Glucose
• Glycemic control
• Hyperglycemia
• Insulin
• Intensive care unit
• Mortality

• critical illness
• glucose metabolism
• incretins
• insulin resistance
• systemic inflammation

Hyperglycemia is common in critically ill patients and can be caused by various mechanisms, including nutrition, medications, and insufficient insulin. In the past, hyperglycemia was thought to be an adaptive response to stress, but hyperglycemia is no longer considered a benign condition in patients with critical illnesses. Indeed, hyperglycemia can increase morbidity and mortality in critically ill patients. Correction of hyperglycemia may improve clinical outcomes. To date, a definite answer with regard to glucose management in general intensive care unit patients, including treatment thresholds and glucose target is undetermined. Meta-analyses of randomized controlled trials suggested no survival benefit of tight glycemic control and a significantly increased incidence of hypoglycemia. Studies have shown a J- or U-shaped relationship between average glucose values and mortality; maintaining glucose levels between 100 and 150 mg/dL was likely to be associated with the lowest mortality rates. Recent studies have shown glycemic control < 180 mg/dL is not inferior to near-normal glycemia in critically ill patients and is clearly safer. Glycemic variability is also an important aspect of glucose management in the critically ill patients. Higher glycemic variability may increase the mortality rate, even in patients with the same mean glucose level. Decreasing glucose variability is an important issue for glycemic control in critically ill patients. Continuous measurements with automatic closed-loop systems could be considered to ensure that blood glucose levels are controlled within a specific range and with minimal variability.

• Critical care
• Glycemic control
• Hyperglycemia
• Hypoglycemia
• Insulin

Laboratory routine procedures such as handling, injection, gavage or transportation are stressful events which may influence physiological parameters of laboratory animals and may interfere with the interpretation of the experimental results. Here, we investigated if female BALB/c mice derived from in-house breeding and BALB/c mice from a vendor which were shipped during their juvenile life differ in their HPA axis activity and stress responsiveness in adulthood.

We show that already transferring the home cage to another room is a stressful event which causes an increased HPA axis activation for at least 24 hours as well as a loss of circulating lymphocytes which normalizes during a few days after transportation. However and important for the interpretation of experimental data, commercially available strain-, age- and gender-matched animals that were shipped over-night showed elevated glucocorticoid levels for up to three weeks after shipment, indicating a heightened HPA axis activation and they gained less body weight during adolescence. Four weeks after shipment, these vendor-derived mice showed increased corticosterone levels at 45-min after intraperitoneal ACTH challenge but, unexpectedly, no acute stress-induced glucocorticoid release. Surprisingly, activation of monoaminergic pathways were identified to inhibit the central nervous HPA axis activation in the vendor-derived, shipped animals since depletion of monoamines by reserpine treatment could restore the stress-induced HPA axis response during acute stress.

In-house bred and vendor-derived BALB/c mice show a different stress-induced HPA axis response in adulthood which seems to be associated with different central monoaminergic pathway activity. The stress of shipment itself and/or differences in raising conditions, therefore, can cause the development of different stress response phenotypes which needs to be taken into account when interpreting experimental data.

• Acoustic Stimulation
• Acute Disease
• Animals
• Disease Models, Animal
• Drinking Behavior/physiology
• Energy Intake/physiology
• Energy Metabolism
• Female
• Kinetics
• Metabolic Syndrome/etiology
• Mice
• Mice, Inbred BALB C
• Oligonucleotide Array Sequence Analysis
• Polymerase Chain Reaction
• Stress, Psychological/genetics
• Stress, Psychological/physiopathology
• Water

• Adult
• Aged
• Blood Glucose/drug effects
• Female
• Humans
• Hyperglycemia/drug therapy
• Hypoglycemia/etiology
• Insulin/administration & dosage
• Insulin/adverse effects
• Insulin/therapeutic use
• Intensive Care Units
• Male
• Middle Aged
• Retrospective Studies
• Risk
• Risk Assessment

• Acute Disease
• Humans
• Hyperglycemia/complications
• Methicillin Resistance
• Respiratory Tract Infections/etiology
• Respiratory Tract Infections/microbiology
• Risk Factors
• Staphylococcal Infections/etiology
• Staphylococcal Infections/microbiology
• Staphylococcus aureus/growth & development
• Staphylococcus aureus/metabolism

• Critical Care/methods
• Critical Illness/therapy
• Humans
• Hyperglycemia/drug therapy
• Hyperglycemia/etiology
• Insulin/therapeutic use
• Intensive Care Units
• Severity of Illness Index
• Stress, Physiological/complications
• Survival Analysis
• Treatment Outcome

• Gluconeogenesis
• Glucose/metabolism
• Homeostasis
• Hormones/physiology
• Humans
• Infections/metabolism
• Inflammation/metabolism
• Insulin Resistance
• Liver/metabolism
• Nutritional Support

• DK-20593 NIDDK NIH HHS
• DK-43748 NIDDK NIH HHS
• P30-DK-26657 NIDDK NIH HHS

• Blood Glucose/drug effects
• Blood Glucose/metabolism
• Clinical Protocols
• Critical Care/methods
• Critical Care/standards
• Critical Illness/mortality
• Critical Illness/therapy
• Cytokines/immunology
• Drug Monitoring/methods
• Drug Monitoring/nursing
• Humans
• Hyperglycemia/diagnosis
• Hyperglycemia/etiology
• Hyperglycemia/metabolism
• Hyperglycemia/therapy
• Hypoglycemic Agents/pharmacology
• Hypoglycemic Agents/therapeutic use
• Inflammation Mediators/immunology
• Infusions, Intravenous
• Insulin/pharmacology
• Insulin/therapeutic use
• Insulin Resistance/physiology
• Treatment Outcome

• Glucose/metabolism
• Humans
• Hyperglycemia/complications
• Hyperglycemia/epidemiology
• Hyperglycemia/etiology
• Hyperglycemia/physiopathology
• Hyperglycemia/prevention & control
• Insulin/therapeutic use
• Insulin Resistance
• Intensive Care Units
• Risk Factors
• Stress, Physiological/complications