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PURPOSE OF REVIEW: Glucagon is known as a key hormone in the control of glucose and amino acid metabolism. Critical illness is hallmarked by a profound alteration in glucose and amino acid metabolism, accompanied by muscle wasting and hypoaminoacidemia. Here we review novel insights in glucagon (patho)physiology and discuss the recently discovered role of glucagon in controlling amino acid metabolism during critical illness. RECENT FINDINGS: The role of glucagon in glucose metabolism is much more complex than originally anticipated, and glucagon has shown to be a key player in amino acid metabolism. During critical illness, the contribution of glucagon in bringing about hyperglycemia appeared to be quite limited, whereas increased glucagon availability seems to contribute importantly to the typical hypoaminoacidemia via stimulating hepatic amino acid breakdown, without affecting muscle wasting. Providing amino acids further increases hepatic amino acid breakdown, mediated by a further increase in glucagon. SUMMARY: Glucagon plays a crucial role in amino acid metabolism during critical illness, with an apparent feedback loop between glucagon and circulating amino acids. Indeed, elevated glucagon may, to a large extent, be responsible for the hypoaminoacidemia in the critically ill and infusing amino acids increases glucagon-driven amino acid breakdown in the liver. These novel insights further question the rationale for amino acid administration during critical illness. ispartof: CURRENT OPINION IN CRITICAL CARE vol:24 issue:4 pages:228-234 ispartof: location:United States status: published

Supplemental Digital Content is available in the text, Background and Aims: Elevated markers of cholestasis are common in response to critical illness, and associated with adverse outcome. The role of illness duration and of nutrient restriction on underlying molecular pathways of such cholestatic responses have not been thoroughly investigated. Methods: In a mouse model of surgery- and sepsis-induced critical illness, molecular pathways of cholestasis were investigated up to 7 days. To assess which changes are explained by illness-induced lack of feeding, nutrient-restricted healthy mice were studied and compared with ad libitum fed healthy mice. Furthermore, serum bile acid (BA) concentrations were quantified in 1,114 human patients with either short or long intensive care unit (ICU) stay, matched for type and severity of illness, up to ICU-day-7. Results: In critically ill mice, either evoked by surgery or sepsis, circulating and hepatic BA-levels progressively increased with time from day-3 onward, preceded by unsuppressed or upregulated CYP7A1 and CYP27A1 protein expression. From 30 h onward, nuclear farnesoid-X-receptor-retinoid-X-receptor staining was significantly suppressed in both critically ill groups, followed from day-3 onward by decreased gene expression of the apical exporter BA-specific export pump and increased expression of basolateral exporters multidrug resistance-associated protein 3 (MRP3) and MRP4. Nutrient restriction in healthy mice only partly mirrored illness-induced alterations in circulating BA and BA-transporters, without changing nuclear receptors or synthesis markers expression. Also in human critically ill patients, serum BA increased with time in long-stay patients only, similarly for patients with or without sepsis. Conclusions: Circulating BA concentrations rose days after onset of sepsis- and surgery-induced, critical illness, only partially explained by lack of feeding, preceded by suppressed nuclear feedback-sensors and ongoing BA synthesis. Expression of transporters suggested ongoing reversed BA-flow toward the blood.

Background ICU-acquired weakness is a debilitating consequence of prolonged critical illness that is associated with poor outcome. Recently, premorbid obesity has been shown to protect against such illness-induced muscle wasting and weakness. Here, we hypothesized that this protection was due to increased lipid and ketone availability. Methods In a centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we compared markers of lipolysis and fatty acid oxidation in lean and obese septic mice (n = 117). Next, we compared markers of muscle wasting and weakness in septic obese wild-type and adipose tissue-specific ATGL knockout (AAKO) mice (n = 73), in lean septic mice receiving either intravenous infusion of lipids or standard parenteral nutrition (PN) (n = 70), and in lean septic mice receiving standard PN supplemented with either the ketone body 3-hydroxybutyrate or isocaloric glucose (n = 49). Results Obese septic mice had more pronounced lipolysis (p ≤ 0.05), peripheral fatty acid oxidation (p ≤ 0.05), and ketogenesis (p ≤ 0.05) than lean mice. Blocking lipolysis in obese septic mice caused severely reduced muscle mass (32% loss vs. 15% in wild-type, p

Background The ‘obesity paradox’ of critical illness refers to better survival with a higher body mass index. We hypothesized that fat mobilized from excess adipose tissue during critical illness provides energy more efficiently than exogenous macronutrients and could prevent lean tissue wasting. Methods In lean and premorbidly obese mice, the effect of 5 days of sepsis-induced critical illness on body weight and composition, muscle wasting, and weakness was assessed, each with fasting and parenteral feeding. Also, in lean and overweight/obese prolonged critically ill patients, markers of muscle wasting and weakness were compared. Results In mice, sepsis reduced body weight similarly in the lean and obese, but in the obese with more fat loss and less loss of muscle mass, better preservation of myofibre size and muscle force, and less loss of ectopic lipids, irrespective of administered feeding. These differences between lean and obese septic mice coincided with signs of more effective hepatic fatty acid and glycerol metabolism, and ketogenesis in the obese. Also in humans, better preservation of myofibre size and muscle strength was observed in overweight/obese compared with lean prolonged critically ill patients. Conclusions During critical illness premorbid obesity, but not nutrition, optimized utilization of stored lipids and attenuated muscle wasting and weakness.

Perioperative hyperglycemia, aggravated by cardiopulmonary bypass, is associated with adverse outcome in adult and pediatric patients. Whereas hyperglycemia was originally perceived as an adaptive response to surgical stress, it is now clear that glycemic control is a strategy to reduce adverse outcomes after cardiac surgery and cardiopulmonary bypass. The optimal blood glucose target, whether or not glycemic control should be initiated already intraoperatively, and whether or not perioperative glucose administration affects the impact of glycemic control on ischemia-reperfusion damage remain open questions. Hypoglycemia, the risk of which is increased with glycemic control, is also associated with adverse outcomes. However, it remains controversial whether brief episodes of hypoglycemia, rapidly corrected during glycemic control, have adverse effects on outcome. This review gives an overview of the currently available literature on glycemic control during and after cardiac surgery and focuses on the indicated open questions about this intervention for this specific patient population. publisher: Elsevier articletitle: Glycemic control and outcome related to cardiopulmonary bypass journaltitle: Best Practice & Research Clinical Anaesthesiology articlelink: http://dx.doi.org/10.1016/j.bpa.2015.03.003 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved. ispartof: Baillière's Best Practice & Research. Clinical Anaesthesiology vol:29 issue:2 pages:177-187 ispartof: location:Netherlands status: published

RATIONALE: Critical illness is hallmarked by muscle wasting and disturbances in glucose, lipid, and amino acid homeostasis. Circulating concentrations of glucagon, a catabolic hormone that affects these metabolic pathways, are elevated during critical illness. Insight in the nutritional regulation of glucagon and its metabolic role during critical illness is lacking. OBJECTIVES: To evaluate whether macronutrient infusion can suppress plasma glucagon during critical illness and study the role of illness-induced glucagon abundance in the disturbed glucose, lipid, and amino acid homeostasis and in muscle wasting during critical illness. METHODS: In human and mouse studies, we infused macronutrients and manipulated glucagon availability up and down to investigate its acute and chronic metabolic role during critical illness. MEASUREMENTS AND MAIN RESULTS: In critically ill patients, infusing glucose with insulin did not lower glucagon, whereas parenteral nutrition containing amino acids increased glucagon. In critically ill mice, infusion of amino acids increased glucagon and up-regulated markers of hepatic amino acid catabolism without affecting muscle wasting. Immunoneutralizing glucagon in critically ill mice only transiently affected glucose and lipid metabolism, did not affect muscle wasting, but drastically suppressed markers of hepatic amino acid catabolism and reversed the illness-induced hypoaminoacidemia. CONCLUSIONS: These data suggest that elevated glucagon availability during critical illness increases hepatic amino acid catabolism, explaining the illness-induced hypoaminoacidemia, without affecting muscle wasting and without a sustained impact on blood glucose. Furthermore, amino acid infusion likely results in a further breakdown of amino acids in the liver, mediated by increased glucagon, without preventing muscle wasting. Clinical trial registered with www.clinicaltrials.gov (NCT 00512122). ispartof: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE vol:196 issue:9 pages:1131-1143 ispartof: location:United States status: published

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR), mediate critical illness-induced organ failure, often affecting the liver. Autophagy is known to alleviate both and suppressed or insufficiently activated autophagy in prolonged illness has shown to associate with organ failure. Whether insufficient autophagy contributes to organ failure during critical illness by affecting these underlying mechanisms is incompletely understood. In this study, we investigated whether the inability to acutely activate hepatic autophagy during critical illness aggravates liver damage by increasing hepatic mitochondrial dysfunction and affecting the UPR. In a mouse model of critical illness, induced by surgery and sepsis, we investigated the impact of inactivating hepatic autophagy on markers of hepatic mitochondrial function, the UPR and liver damage in acute (1 day) and prolonged (3 days) critical illness. Hepatic autophagy inactivation during critical illness acutely worsened mitochondrial dysfunction and time-dependently modulated the hepatic UPR. Furthermore, autophagy inactivation aggravated markers of liver damage on both time points. In conclusion, the inability to acutely activate autophagy in liver during critical illness worsened hepatic mitochondrial damage and dysfunction, partially prohibited acute UPR activation and aggravated liver damage, indicating that autophagy is crucial in alleviating critical illness-induced organ failure. ispartof: Scientific Reports vol:7 issue:1 ispartof: location:England status: published

Patients with critical illness-induced multiple organ failure suffer from a very high morbidity and mortality, despite major progress in intensive care. The pathogenesis of this condition is complex and incompletely understood. Inadequate tissue perfusion and an overwhelming inflammatory response with pronounced cellular damage have been suggested to play an important role, but interventions targeting these disturbances largely failed to improve patient outcome. Hence, new therapeutic perspectives are urgently needed. Cellular dysfunction, hallmarked by mitochondrial dysfunction and endoplasmic reticulum stress, is increasingly recognized as an important contributor to the development of organ failure in critical illness. Several cellular defense mechanisms are normally activated when the cell is in distress, but may fail or respond insufficiently to critical illness. This insight may open new therapeutic options by stimulating these cellular defense mechanisms. This review summarizes the current understanding of the role of mitochondrial dysfunction and endoplasmic reticulum stress in critical illness-induced multiple organ failure and gives an overview of the corresponding cellular defense mechanisms. Therapeutic perspectives based on these cellular defense mechanisms are discussed. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis - edited by Raghavan Raju. ispartof: Biochimica et Biophysica Acta. Molecular Basis of Disease vol:1863 issue:10 pages:2534-2545 ispartof: location:Netherlands status: published

Hyperglycemia during critical illness is associated with adverse outcome. Three landmark randomized control trials have shown that maintaining normoglycemia (80–110 mg/dl) with continuous insulin infusion reduces mortality and morbidity of critically ill patients. Subsequent confirmation studies showed mixed results. Several studies, especially in the surgical intensive care unit confirmed the positive effect of targeting normoglycemia, whereas other studies did not or even showed adverse outcome. Several important methodological differences between the studies may explain the discrepant findings. Targeting normoglycemia in the intensive care unit remains to be advocated, provided that adequate monitoring tools and expertise are available.

Fibroblast growth factor 21 (FGF21) is a recently identified hormone that regulates metabolic homeostasis, with a potential role as a stress hormone [1]. Critical illness is hallmarked by insulin resistance and mitochondrial damage, metabolic alterations that increase circulating levels of FGF21 via the integrated stress response (ISR) [2]. Targeting normoglycemia during critical illness has shown to attenuate mitochondrial damage in the liver, the main source of FGF21 [3].

CONTEXT: Critical illness is hallmarked by mitochondrial damage, which is attenuated by targeting normoglycemia. Mitochondrial dysfunction induces fibroblast growth factor-21 (FGF21) via the integrated stress response (ISR). OBJECTIVE: We evaluated whether critical illness elevates serum FGF21 concentrations and whether targeting normoglycemia (80-110 mg/dL) with insulin vs tolerating hyperglycemia may lower serum FGF21 by attenuating mitochondrial dysfunction and the ISR. SETTING/DESIGN: We quantified serum FGF21 concentrations in critically ill patients. To allow tissue analyses, including hepatic fgf21 expression in relation with mitochondrial function and ISR markers, we studied critically ill rabbits. Patients and rabbits were randomized to hyper- or normoglycemia. Patients/Other Participants: We studied 405 fed critically ill patients vs 20 matched non-critically ill control subjects as well as 26 critically ill rabbits vs 13 healthy rabbits. INTERVENTIONS: Insulin was infused to control blood glucose. MAIN OUTCOME MEASURES AND RESULTS: Serum FGF21 concentrations upon intensive care unit admission were 8-fold higher than in control subjects (P < .0001), decreased with time, but always remained higher in nonsurvivors than survivors (P ≤ .006). Maintaining normoglycemia lowered serum FGF21 (P = .01), statistically explaining at least part of its mortality benefit. In ill rabbits, hepatic fgf21 expression was substantially increased (P < .0001) and was tightly correlated with mitochondrial dysfunction (all R(2) ≥ 0.49; all P ≤ .0006 for complex I and V) and ISR markers on day 3 (R(2) ≥ 0.73; P ≤ .0001), all lowered by targeting normoglycemia. CONCLUSION: Critical illness is a potent inducer of serum FGF21 and of liver fgf21 expression, possibly driven at least in part by mitochondrial damage and the ISR, which were all attenuated by targeting normoglycemia. ispartof: Journal of Clinical Endocrinology & Metabolism vol:100 issue:10 pages:E1319-E1327 ispartof: location:United States status: published

Dear Editor, Scleromyxedema (SME), a subtype of lichen myxedematosus, is characterized by a generalized sclerodermoid eruption and a monoclonal gammopathy in the absence of thyroid disease. Mucin deposition, fibroblast proliferation, and fibrosis are seen at skin biopsy [1]. The “dermato-neuro syndrome” (DNS) is a rare manifestation of scleromyxedema and only a few cases have been described. It is characterized by a flu-like prodrome, followed by high fever, tonic-clonic convulsions, and coma in the setting of scleromyxedema [2, 3]. We report a case of DNS successfully treated with high-dose melphalan and autologous stem cell transplantation, followed by thalidomide during 1 year and ongoing monthly administration of intravenous immunoglobulins (IVIg). In December 2005, a 39-year-old Caucasian man was referred to our institute after developing a subacute neurological deterioration (increased confusion, agitation, and visual hallucinations) while being treated for pneumonia. Prior to transfer, he developed generalized tonic-clonic seizures. During the 9-month period, before, the patient had two similar episodes of subacute encephalopathy progressing to status epilepticus and coma. Both were preceded by a flu-like prodrome. Upon admission, the patient was disoriented, agitated, and had fever. Due to progressive loss of consciousness, urgent sedation and mechanical ventilation were mandatory. Serum protein electrophoresis revealed an IgG kappa monoclonal protein (15.9 g/L). The bone marrow plasmocytosis was low (3, 7 %). Electrophoresis of CSF showed a monoclonal protein [4]. High-dose dexamethasone and plasmapheresis were started and neurological, hemodynamic, and respiratory improvement occurred. After 8 weeks, the patient was able to leave the hospital with mild residual cognitive impairment and an Mprotein level of 7 g/L. Ten days after discharge, he again developed a flu-like prodrome followed by high fever, confusion, and tonic-clonic convulsions. The M-protein value peaked to 26 g/L in a few days. As a consequence, a relation between the epileptic insult and the rapid increase of paraprotein was suspected. At that time, an erythematous skin induration with longitudinal furrowing of the glabella (leonine facies) was observed (Fig. 1a). The skin biopsy of the glabella showed typical dermal mucin deposition, fibroblast proliferation, and fibrosis, confirming the histological diagnosis of scleromyxedema (Fig. 1c, d). The combination of the dermatologic manifestations, the presence of a monoclonal gammopathy, and the neurologic manifestations led to the diagnosis of DNS [5, 6]. Dexamethasone was resumed in association with IVIg [7]. In February 2006, CAD mobilization chemotherapy (cyclophosphamide 1,000 mg/m2 on day 1; adriamycine 15 mg/m2 on day 1–4; dexamethasone 40 mg on day 1–4) was administered. Three weeks later, high-dose melphalan (200 mg/m) was administrated followed by autologous T. Devos (*) :M. Delforge Department of Hematology, University Hospitals Leuven, Leuven, Belgium e-mail: Timothy.Devos@uzleuven.be

RATIONALE: Critical illness is characterized by lean tissue wasting, whereas adipose tissue is preserved. Overweight and obese critically ill patients may have a lower risk of death than lean patients, suggestive of a protective role for adipose tissue during illness. OBJECTIVES: To investigate whether adipose tissue could protectively respond to critical illness by storing potentially toxic metabolites, such as excess circulating glucose and triglycerides. METHODS: We studied adipose tissue morphology and metabolic activity markers in postmortem biopsies of 61 critically ill patients and 20 matched control subjects. Adipose morphology was also studied in in vivo biopsies of 27 patients and in a rabbit model of critical illness (n = 22). MEASUREMENTS AND MAIN RESULTS: Adipose tissue from critically ill patients revealed a higher number and a smaller size of adipocytes and increased preadipocyte marker levels as compared with control subjects. Virtually all adipose biopsies from critically ill patients displayed positive macrophage staining. The animal model demonstrated similar changes. Glucose transporter levels and glucose content were increased. Glucokinase expression was up-regulated, whereas glycogen and glucose-6-phosphate levels were low. Acetyl CoA carboxylase protein and fatty acid synthase activity were increased. Hormone-sensitive lipase activity was not altered, whereas lipoprotein lipase activity was increased. A substantially increased AMP-activated protein kinase activity may play a crucial role. CONCLUSIONS: Postmortem adipose tissue biopsies from critically ill patients displayed a larger number of small adipocytes in response to critical illness, revealing an increased ability to take up circulating glucose and triglycerides. Similar morphologic changes were present in vivo. Such changes may render adipose tissue biologically active as a functional storage depot for potentially toxic metabolites, thereby contributing to survival. ispartof: American Journal of Respiratory and Critical Care Medicine vol:182 issue:4 pages:507-516 ispartof: location:United States status: published

Critically ill patients requiring prolonged intensive care are characterized by a profound decrease of lean body mass, evoking weakness and impairing rehabilitation, whereas, paradoxically, adipose tissue is preserved (1, 2). Remarkably, overweight (body mass index [BMI], 25–30 kg/m 2 ) and obese (BMI, 30–40 kg/m 2 ) critically ill patients have recently been shown to have a lower risk of death than patients with a normal BMI (3–5). Morbid obesity (BMI > 40 kg/m 2 ), however, is an independent risk factor for death in the intensive care unit (ICU) (4). These observations suggest that adipose tissue may play a protective role during severe illness in the intensive care setting. The primary metabolic role of adipose tissue is to store excess energy as triglycerides. This excess energy mainly originates from circulating lipids, which are taken up by adipocytes via action of lipoprotein lipase (LPL). A much smaller part of the stored triglycerides in adipocytes is de novo synthesized from circulating carbohydrates through lipogenesis (6). Critically ill patients suffer from dyslipidemia and hyperglycemia, partly due to increased hepatic lipogenesis (7) and gluconeogenesis (8). The severity of these alterations is associated with adverse outcome (9–11). Moreover, elevated circulating glucose (12–14) levels as well as high levels of triglycerides (15–17) can aggravate vital organ dysfunction during critical illness. We hypothesized that adipose tissue can respond to illness by increasing its storage properties for such circulating toxic metabolites, whereby it may enhance the chances of survival. To test this hypothesis, we obtained abdominal subcutaneous and omental adipose tissue biopsies from 61 nonsurviving critically ill patients with a BMI ranging from 16.3 to 31.2 kg/m 2 , and compared these with biopsies from 20 matched control subjects undergoing elective abdominal surgery. More specifically, we studied adipose tissue morphology as well as its ability to take up and metabolize glucose and triglycerides. In addition, we studied adipose tissue morphological changes in response to critical illness in in vivo subcutaneous limb adipose tissue from 27 critically ill patients, and in the controlled setting of an animal model. Some of the results of this study have been previously reported in the form of an abstract (18, 19).