Review Article
Hyperglycemia, Insulin, and Insulin Resistance in Sepsis

https://doi.org/10.1016/j.amjms.2020.11.007Get rights and content

Abstract

Critically ill patients frequently have hyperglycemia. This event may reflect severe stress with an imbalance between anabolic hormones and catabolic hormones. Alternatively, it may reflect alterations in either insulin levels or insulin function. Insulin is a pleiotropic hormone with multiple important metabolic effects. In patients with sepsis, insulin levels are increased but insulin sensitivity is decreased. However, there is variability in insulin sensitivity, and this creates variability in glucose levels and insulin requirements and increases the frequency of hypo- and hyperglycemia. The factors that influence insulin sensitivity are complex and include inhibition of tyrosine kinase activity of the beta subunit, increased proteolytic activity resulting in loss of receptors from the plasma membrane, and possibly the transfer of insulin receptors into the nucleus where they bind to gene promoters. Better understanding of the role of insulin in critically ill patients requires prospective studies measuring insulin levels in various patient groups and the development of a simple measure of insulin sensitivity.

Introduction

Insulin is an essential hormone with multiple biochemical effects. Clinical studies typically focus on glucose metabolism and consider situations in which there is inadequate insulin production or insulin resistance. Patients with sepsis and other acute medical disorders frequently have hyperglycemia; this develops acutely and does not require the premorbid condition of diabetes. Potential explanations include an imbalance between anabolic hormones (insulin) and catabolic hormones and the acute development of insulin resistance. These complex events make it difficult to know whether high glucose levels just reflect the severity of the acute stress or whether they contribute directly to poor outcomes. Studies on insulin levels and insulin resistance in patients with acute systemic illness have the potential to clarify the role of various factors relevant to hyperglycemia and the potential utility of insulin administration independent of glucose levels.

Section snippets

Insulin

Insulin is an anabolic hormone with three main functions: modulation of cellular metabolism, cell growth and differentiation, and receptor internalization. Its release is stimulated by glucose entering the beta cells via GLUT-2 facilitated diffusion, and it is mainly cleared by insulinase in the liver and kidneys.1 In cellular metabolism, insulin has a role in carbohydrate, protein, and lipid homeostasis. It increases glucose uptake in adipose and muscle tissues by promoting the translocation

Insulin receptors

Increases in blood glucose levels stimulate the pancreas to secrete insulin; its signaling is initiated through binding to insulin receptors located mostly on the surface of liver, muscle, adipose cells, pancreatic beta cells, and pancreatic alpha cells. The insulin receptor is composed of an extracellular domain made of 2 alpha subunits and an intracellular domain made of 2 beta subunits. The binding of insulin to the alpha domain results in conformational changes in membrane-bound

Insulin resistance

Systemic insulin resistance refers to impaired biologic responses to insulin; it manifests with decreased glucose transport and metabolism in skeletal muscle and adipose tissue, failure of insulin to suppress gluconeogenesis in the liver, and failure of insulin to suppress lipolysis in the adipose tissue. Processes that interfere with the phosphorylation of the insulin receptor and insulin receptor substrates result in insulin resistance. Central adiposity is a known factor associated with

Glucose levels and insulin in clinical studies

Glucose metabolism is commonly impaired in patients with acute illness, even in non-diabetic patients. Van Vught and coworkers studied the relationship between admission glucose levels > 70 mg/dL and outcomes in 987 patients with sepsis.7 Glucose values were collected within the timeframe of 4 h before admission to 4 h after admission. Two hundred one patients had severe hyperglycemia defined as a glucose level ≥ 200 mg/dL, and these patients developed acute kidney injury and acute myocardial

Clinical studies managing glucose levels

The metabolic mechanisms that take place during a hyperglycemic state, such as muscle glycolysis and lipolysis, are indicators of poor outcomes in septic shock patients. These metabolic disturbances limit the body's host defenses against infection by inhibiting chemotactic factors for leukocytes, impairing phagocytosis, altering cytokine patterns with increased concentrations of the early proinflammatory cytokines, tumor necrosis factor-α, and interleukin (IL)-6, and reducing endothelial nitric

Conclusions

The available literature does not provide definitive answers to questions about the association between insulin levels and outcomes in patients with sepsis or septic shock. Several studies have reported that insulin levels are increased in patients with sepsis and septic shock. Limited information suggests that there is an immediate change in insulin sensitivity that varies over the first several days in patients with sepsis. C-peptide levels are higher in patients with sepsis, and the ratio of

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