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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

Purpose of review Two large randomized studies demonstrated that maintenance of normoglycemia with intensive insulin therapy for at least a few days decreases morbidity and mortality of critically ill patients. This review gives an overview of the benefits associated with this therapy and highlights the importance of achieving optimal blood glucose levels. It discusses the indications for this therapy and the fear for potential harm. Recent findings A pooled analysis of the two Leuven studies (n = 2748) revealed a significantly reduced morbidity and mortality in critically ill patients for all subgroups, except those with a prior history of diabetes. An absolute reduction in risk of hospital death of 3-4% is to be expected from this therapy in an intention-to-treat analysis. When patients are treated for more than 3 days, the absolute reduction in risk of death increases to approximately 8%. The available data indicate that strict normoglycemia is required to obtain optimal clinical benefit. This increases the risk of hypoglycemia, but it remains unclear whether this is truly harmful in the setting of critical care. Summary Maintaining strict normoglycemia by the use of intensive insulin therapy improves outcome of critically ill patients.

PURPOSE OF REVIEW To summarize the clinical evidence for beneficial effects of ketones, ketogenic diets and intermittent fasting in critical illness, and to review potential mechanisms behind such effects. RECENT FINDINGS Recent evidence demonstrates that activation of a metabolic fasting response may be beneficial to recover from critical insults. Potential protective mechanisms are, among others, activation of ketogenesis and of damage removal by autophagy. Novel feeding strategies, including ketone supplements, ketogenic diets and intermittent fasting regimens, can activate these pathways - at least partially - in critically ill patients. Randomized controlled trials (RCTs) studying these novel feeding strategies as compared with standard care, are scarce and have not shown consistent benefit. Yet, all RCTs were small and underpowered for clinical endpoints. Moreover, in intermittent fasting studies, the duration of the fasting interval may have been too short to develop a sustained metabolic fasting response. SUMMARY These findings open perspectives for the further development of fasting-mimicking diets. Ultimately, clinical benefit should be confirmed by RCTs that are adequately powered for clinically relevant, patient-centered endpoints.