The roles of insulin and hyperglycemia in sepsis pathogenesis

Abstract

Hyperglycemia is a risk marker of morbidity and mortality in acute critical illness, and insulin therapy seems to be beneficial in this patient group. Whether this is true for a population of sepsis patients, as such, has not been investigated in clinical trials, but evidence from in vitro studies and experimental sepsis suggests that this may be the case. The endocrinology of septic patients is characterized by a shift in the balance between insulin and its counter-regulatory hormones favoring the latter. This leads to prominent metabolic derangements composed of high release and low use of glucose, amino acids, and free fatty acids (FFA), resulting in increased blood levels of these substrates. Circulating, proinflammatory mediators further enhance this state of global catabolism. Increased levels of glucose and FFA have distinct effects on inflammatory signaling leading to additional release of proinflammatory mediators and endothelial and neutrophil dysfunction. Insulin has the inherent capability to counteract the metabolic changes observed in septic patients. Concomitantly, insulin therapy may act as a modulator of inflammatory pathways inhibiting the unspecific, inflammatory activation caused by metabolic substrates. Given these properties, insulin could conceivably be serving a dual purpose for the benefit of septic patients.

Serial plasma glucose changes in dogs suffering from severe dog bite wounds

“…A positive correlation has been found between the degree of hyperglycaemia and the risk of death in human trauma and cardiac patients 42 . In human critical care medicine, insulin resistance has been implicated as a major contributor to this phenomenon 1,25,26,42 . Aggressive control of even mildly elevated glucose concentrations, using insulin therapy, has shown a significant decline in death rates in human intensive care units, from 20.2 % to 10.6 % 42 .…”

“…Glucose is the primary source of energy for leucocytes and the predominating carbohydrate substrate for fibroblasts in their synthesis of proteoglycan polymers during wound healing 10 . However, excessively high plasma glucose concentrations can potentially inhibit neutrophil function by impairing phagocytosis and diminishing the production of oxygen radicals 1,14 .…”

“…Patients with severe injury therefore undergo an accelerated form of starvation 7,11,37 . During the hypermetabolic state, a number of alterations in carbohydrate metabolism are induced, these include 1,23,34,42 : • Enhanced peripheral uptake and utilisation of glucose by the wound and other organs such as the liver and spleen, which are involved in the immune response; • Increased glucose production stimulated by the release of epinephrine, cortisol, glucagon and growth hormone; • Hyperlactataemia due to hypoperfusion; • Decreased glucose production due to the release of gram-negative bacterial endotoxin, interleukin-6, insulin-like factors and decreased hepatic export or increased utilisation; • Depressed glycogenesis due to the persistent high rate of glycogen breakdown under the influence of epinephrine and glucagon, decreased glycogen synthetase activity or the presence of tumour necrosis factor (TNF); • A rise in extra-cellular glucose concentrations due to defective suppression of gluconeogenesis, glucose intolerance and resistance to the peripheral action of insulin, also termed 'diabetes of injury'. Tissue trauma with or without infection can initiate the systemic inflammatory response syndrome (SIRS), in which multiple inflammatory, immunological, coagulation and fibrinolytic cascades are activated and interact 18,20 .…”

Incidence and Clinical Relevance of Hyperglycemia in Critically Ill Dogs

“…In people, hyperglycemia is known to increase oxidative stress, increase susceptibility to infection, and increase the release of pro-inflammatory mediators. [14][15][16] If these findings are confirmed in dogs and cats, insulin therapy may have a role in the management of hyperglycemia in critically ill hospitalized animals.…”

Microcirculatory dysfunction and tissue oxygenation in critical illness

“…We analyzed the effects of capillary flow disturbance on oxygen uptake, glucose uptake, and ATP production in tumor and brain tissue,84, 85 and discovered that the uptake of glucose becomes limited, yet remains favored over that of oxygen, as CTH increases. Further studies should therefore address whether microcirculatory disturbances contribute to the hyperglycemia,86 aerobic glycolysis,87 and lactate production88, 89 observed in sepsis.…”