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Hyperglycemia, Insulin, and Insulin Resistance in Sepsis

Published:November 08, 2020DOI:https://doi.org/10.1016/j.amjms.2020.11.007

      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.

      Key Indexing Terms

      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.

      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.
      • Yaribeygi H
      • Farrokhi FR
      • Butler AE
      • et al.
      Insulin resistance: review of the underlying molecular mechanisms.
      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 of GLUT-4 receptors from the intracellular space to the cell membrane. In muscle, insulin increases protein synthesis and inhibits its degradation, promoting muscle hypertrophy, and it inhibits lipolysis and promotes lipid storage by enhancing triglyceride synthesis using glucose as a precursor in adipose tissue. Finally, at the liver, it suppresses gluconeogenesis and glycogenolysis and enhances de novo lipogenesis and glycogen and lipid synthesis, and at the pancreas it suppresses glucagon secretion from α cells. Glucagon and cortisol promote a catabolic state and reverse all the anabolic processes stimulated by insulin.
      • Kahn C
      • Ferris HA
      • O'Neill BT
      Williams textbook of endocrinology.

      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 glycoprotein and activation of the tyrosine kinase domains on the beta subunits. This tyrosine kinase phosphorylates intracellular enzymes, including mitogen activated protein kinase (MAP-kinase) and phosphatidylinositol–3 kinase (PI-3K) initiating signaling for insulin action. The activation of MAP-kinase promotes cell growth and differentiation; the activation of PI-3K produces the metabolic effects described above.
      • Yaribeygi H
      • Farrokhi FR
      • Butler AE
      • et al.
      Insulin resistance: review of the underlying molecular mechanisms.
      • Kahn C
      • Ferris HA
      • O'Neill BT
      Williams textbook of endocrinology.
      • Belfiore A
      • Frasca F
      • Pandini G
      • et al.
      Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.
      Insulin resistance develops when these biochemical processes are inhibited.

      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 insulin resistance, mediated by inflammatory substances released from fat (IL-6, TNF alpha), fatty acids, and lipopolysaccharides. Moreover, excess nutrients are ultimately stored as triglycerides in adipose tissue, and when its storage capacity is exceeded, ectopic lipid accumulates in the liver and muscle and also contributes to insulin resistance through the production of toxic lipid metabolites, including diacylglycerol or ceramides.
      • Hardy OT
      • Czech MP
      • Corvera S
      What causes the insulin resistance underlying obesity?.
      • Schwartsburd P
      Insulin resistance is a two-sided mechanism acting under opposite catabolic and anabolic conditions.
      • Bastard JP
      • Maachi M
      • Lagathu C
      • et al.
      Recent advances in the relationship between obesity, inflammation, and insulin resistance.
      Finally, high insulin concentrations, which can develop during excess carbohydrate intake or with insulin resistance, result in the down regulation of insulin receptors. Other phenomena that have been proposed to contribute to the development of insulin resistance are an altered balance of insulin receptor isoforms expressed on cell surfaces and accelerated insulin degradation.
      • Yaribeygi H
      • Farrokhi FR
      • Butler AE
      • et al.
      Insulin resistance: review of the underlying molecular mechanisms.
      ,
      • Belfiore A
      • Frasca F
      • Pandini G
      • et al.
      Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.
      This brief paragraph summarizes some of the important ideas about insulin resistance in patients with type 2 diabetes; additional factors relevant to insulin resistance in sepsis will be discussed below.

      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.
      • van Vught LA
      • Wiewel MA
      • Klein Klouwenberg PM
      • et al.
      Admission hyperglycemia in critically ill sepsis patients: association with outcome and host response.
      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 infarction more frequently than other patients in the ICU. In addition, they had an increased risk for mortality by day 30. These effects were observed in patients with and without diabetes. Studies on hospitalized patients have demonstrated that hyperglycemic individuals without known diabetes have significantly greater morbidity and mortality than either patients with known diabetes or patients with normal glucose tolerance.
      • Smith FG
      • Sheehy AM
      • Vincent JL
      • et al.
      Critical illness-induced dysglycaemia: diabetes and beyond.
      These observations and other important studies, such as those from Belgium, raise important questions regarding hyperglycemia, insulin levels, insulin resistance, and the management of hyperglycemia in critically ill patients (Table).
      • van den Berghe G
      • Wouters P
      • Weekers F
      • et al.
      Intensive insulin therapy in critically ill patients.
      TABLEAn overview of the physiopathology of glucose metabolism during sepsis.
      Van Vught et al
      • van Vught LA
      • Wiewel MA
      • Klein Klouwenberg PM
      • et al.
      Admission hyperglycemia in critically ill sepsis patients: association with outcome and host response.


      Smith et al
      • Smith FG
      • Sheehy AM
      • Vincent JL
      • et al.
      Critical illness-induced dysglycaemia: diabetes and beyond.


      Severe hyperglycemia (glucose >200 mg/dL) can occur in patients admitted for sepsis with and without diabetes and has been associated with a higher risk of acute kidney injury and acute myocardial infarction and a higher risk of 30-day mortality.
      Khan et al
      • Khan S
      • Gutch M
      • Kumar S
      • et al.
      Insulin resistance as a prognostic indicator in severe sepsis, septic shock and multiorgan dysfunction syndrome.


      Gupta et al
      • Gupta R
      • Singh S
      • Nithin R
      The role of insulin resistance in outcome of patients with multi organ dysfunction syndrome.


      White et al
      • White RH
      • Frayn KN
      • Little RA
      • et al.
      Hormonal and metabolic responses to glucose infusion in sepsis studied by the hyperglycemic glucose clamp technique.


      Pretty et al
      • Pretty CG
      • Le Compte AJ
      • Chase JG
      • et al.
      Variability of insulin sensitivity during the first 4 days of critical illness: implications for tight glycemic control.


      Chambrier et al
      • Chambrier C
      • Laville M
      • Rhzioual Berrada K
      • et al.
      Insulin sensitivity of glucose and fat metabolism in severe sepsis.
      Insulin resistance occurs in patients with sepsis and with organ dysfunction, resulting in lower glucose utilization. The level of insulin resistance increases in direct proportion to the number of dysfunctional organs.



      Khan et al
      • Khan S
      • Gutch M
      • Kumar S
      • et al.
      Insulin resistance as a prognostic indicator in severe sepsis, septic shock and multiorgan dysfunction syndrome.
      Higher degrees of insulin resistance have been associated with higher mortality.
      Pretty et al
      • Pretty CG
      • Le Compte AJ
      • Chase JG
      • et al.
      Variability of insulin sensitivity during the first 4 days of critical illness: implications for tight glycemic control.


      Verhoeven et al
      • Verhoeven JJ
      • den Brinker M
      • Hokken-Koelega AC
      • et al.
      Pathophysiological aspects of hyperglycemia in children with meningococcal sepsis and septic shock: a prospective, observational cohort study.


      Das et al
      • Das S
      • Misra B
      • Roul L
      • et al.
      Insulin resistance and beta cell function as prognostic indicator in multi-organ dysfunction syndrome.
      Insulin sensitivity improves during recovery phase of acute illness, resulting in lower blood sugars and lower insulin requirements.
      Vanhorebeek
      • Vanhorebeek I
      • De Vos R
      • Mesotten D
      • et al.
      Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients.
      Intensive insulin therapy does not have a uniform effect on all tissues. It appears to protect the mitochondria in the liver and not to skeletal muscle. The effect of intensive insulin therapy may reflect a direct effect of insulin itself or reductions in glucose toxicity.

      Insulin studies in critically ill patients

      Several investigators have measured glucose and insulin levels in critically ill patients and calculated insulin resistance in these patients. These studies usually involved patients in a fasting state; insulin resistance was calculated using the Homeostasis Model Assessment method (HOMA). Khan et al. measured fasting glucose and insulin levels and calculated insulin resistance in 81 patients with severe sepsis, septic shock, or multiorgan dysfunction syndrome.
      • Khan S
      • Gutch M
      • Kumar S
      • et al.
      Insulin resistance as a prognostic indicator in severe sepsis, septic shock and multiorgan dysfunction syndrome.
      Mean fasting insulin levels and insulin resistance were higher in patients (n = 39) with hyperglycemia than in patients (n = 42) with euglycemia, but there was no difference in mortality outcomes in the two groups. Insulin resistance levels were higher in patients who died and were lower in survivors. Gupta et al. measured fasting insulin and glucose levels and calculated insulin resistance using HOMA in 75 patients with multiorgan dysfunction syndrome.
      • Gupta R
      • Singh S
      • Nithin R
      The role of insulin resistance in outcome of patients with multi organ dysfunction syndrome.
      Twenty-six patients (34.7%) with multiorgan dysfunction syndrome had insulin resistance; fasting glucose and insulin levels were higher in these patients. Thirty-one patients died, and 20 (64.5%) had insulin resistance. In this study, the level of insulin resistance increased in direct proportion to the number of dysfunctional organs. Das and colleagues also measured insulin resistance and beta cell function using HOMA models in 80 patients with multiorgan dysfunction syndrome; all patients had increased insulin levels and insulin resistance on the first day of hospitalization.
      • Das S
      • Misra B
      • Roul L
      • et al.
      Insulin resistance and beta cell function as prognostic indicator in multi-organ dysfunction syndrome.
      On follow-up 7 days later insulin resistance had decreased and beta cell function had increased. They interpreted these results to indicate that beta cell exhaustion occurs in critically ill patients because these patients are required to secrete more insulin to offset prevailing insulin resistance. Verhoeven et al. studied glucose levels and insulin parameters in 78 children, including shock non-survivors, shock survivors, and sepsis survivors, with meningococcal disease.
      • Verhoeven JJ
      • den Brinker M
      • Hokken-Koelega AC
      • et al.
      Pathophysiological aspects of hyperglycemia in children with meningococcal sepsis and septic shock: a prospective, observational cohort study.
      On admission 62% of the hyperglycemic children had insulin resistance, 17% had beta-cell dysfunction, and 21% had both insulin resistance and beta-cell dysfunction. Blood glucose levels normalized within 48 h typically without insulin treatment. Patients with shock or with sepsis who survived had higher glucose levels than patients with shock who did not survive. This association may be explained by unique features of meningococcal infections.
      Other investigators have used more complicated methods to measure glucose utilization in critically ill patients. White et al. studied the initial hormone and metabolic responses to high glucose levels in five patients with sepsis using a hyperglycemic glucose clamp protocol.
      • White RH
      • Frayn KN
      • Little RA
      • et al.
      Hormonal and metabolic responses to glucose infusion in sepsis studied by the hyperglycemic glucose clamp technique.
      Plasma glucose levels were raised to 12 mmol/L (218 mg/dL) for 2 h and whole body glucose utilization was measured. This was decreased in patients compared to controls despite similar plasma insulin levels. Glucose uptake in the forearm was also decreased. Since insulin levels were similar in the 2 groups, these results indicated patients with sepsis had decreased insulin sensitivity. Pretty and co-workers calculated insulin sensitivity in 164 critically ill patients using information collected during a tight glycemic control protocol that recorded glucose levels, insulin infusion doses, and nutrition.
      • Pretty CG
      • Le Compte AJ
      • Chase JG
      • et al.
      Variability of insulin sensitivity during the first 4 days of critical illness: implications for tight glycemic control.
      They demonstrated that insulin sensitivity was low and more variable early in this course and improved during the next four days. They attributed this improvement in sensitivity to a reduction in catabolic hormones during the recovery phase of an acute illness and suggested that variable insulin sensitivity explains the glucose variability seen in critically ill patients and the increased frequency of hypoglycemia. Chambrier et al measured endogenous glucose production, glucose utilization, plasma fatty acid concentrations, and ketone body concentrations in 5 septic patients using an isoglycemic clamp protocol with increasing levels of exogenous insulin.
      • Chambrier C
      • Laville M
      • Rhzioual Berrada K
      • et al.
      Insulin sensitivity of glucose and fat metabolism in severe sepsis.
      Endogenous glucose production was completely suppressed in control subjects at the first level of insulin infusion, but higher levels of insulin infusion were required in patients with sepsis for suppression. Glucose utilization was lower in patients with sepsis. Free fatty acid levels and ketone body levels were not suppressed in patients with sepsis to the same extent as control subjects. Consequently, patients with sepsis had decreased responses to insulin in both glucose and fat metabolism. Bitker et al. studied 31 adult patients with type 2 diabetes mellitus who were critically ill and admitted to an ICU.
      • Bitker L
      • Cutuli SL
      • Cioccari L
      • et al.
      Sepsis uncouples serum C-peptide and insulin levels in critically ill patients with type 2 diabetes mellitus.
      They measured serum C-peptide and insulin levels during the first 3 days of the ICU stay and the effect of exogenous insulin on these levels. C-peptide levels were higher in these patients than in healthy subjects. Patients with sepsis who did not receive any exogenous insulin had a higher C-peptide levels and C-peptide/insulin ratios. These ratios were positively associated with white blood counts and the severity of illness in septic patients who did not receive insulin. These results indicate that sepsis stimulates a release of both C-peptide and insulin from the pancreas. The elevated C-peptide/insulin ratio may reflect more rapid metabolism (clearance) of insulin in comparison to C-peptide. Higher C-peptide levels have the potential to contribute to the anti-inflammatory responses in patients with sepsis and need more study in critically ill patients.
      In summary, these studies demonstrate that patients with sepsis have elevated insulin levels and insulin resistance. Based on the HOMA methodology, they can have both insulin resistance and decreased pancreatic beta cell function. HOMA calculations can be done in non- fasting patients and could provide serial measurements of insulin resistance and pancreatic function.
      • Hancox RJ
      • Landhuis CE
      Correlation between measures of insulin resistance in fasting and non-fasting blood.
      Insulin sensitivity is lowest during the first one to two days of hospital admission for sepsis and variability in insulin sensitivity is greatest during the early phase or first 1–2 days of the hospitalization.

      Experimental studies in humans

      Experimental studies evaluating glucose metabolism in humans receiving lipopolysaccharide (LPS) injections to mimic a septic state
      • van der Crabben SN
      • Blumer RM
      • Stegenga ME
      • et al.
      Early endotoxemia increases peripheral and hepatic insulin sensitivity in healthy humans.
      ,
      • Agwunobi AO
      • Reid C
      • Maycock P
      • et al.
      Insulin resistance and substrate utilization in human endotoxemia.
      have demonstrated a biphasic response in glucose metabolism during “sepsis,” which is characterized by increased insulin sensitivity within 2 h of injection of LPS and then the development of insulin resistance several hours later.
      • Agwunobi AO
      • Reid C
      • Maycock P
      • et al.
      Insulin resistance and substrate utilization in human endotoxemia.
      These studies suggest that the initial increased peripheral and hepatic insulin sensitivity, which commonly manifests as hypoglycemia, is strongly driven by increased glucose disposal and decreased endogenous glucose production. The second phase of insulin resistance is less well-understood; it occurs 7 h after LPS administration in human studies and as early as 3–5 h after LPS injected in animal studies in which higher LPS doses are used.
      • Agwunobi AO
      • Reid C
      • Maycock P
      • et al.
      Insulin resistance and substrate utilization in human endotoxemia.
      ,
      • Virkamaki A
      • Yki-Jarvinen H
      Mechanisms of insulin resistance during acute endotoxemia.
      Most patients present after the early phase of endotoxin effects related to sepsis and have insulin resistance. Proposed mechanisms for resistance in sepsis include inhibition of serine phosphorylation from increased fatty acids induced by endogenous glucocorticoids, inhibition of PI-3K pathways by pro-inflammatory cytokines, and decreased insulin-mediated GLUT-4 translocation in cardiac and skeletal muscle plasma membrane through stimulation of adenosine monophosphate-activated protein kinase signaling.
      • Delile E
      • Neviere R
      • Thiebaut PA
      • et al.
      Reduced insulin resistance contributes to the beneficial effect of protein tyrosine phosphatase-1b deletion in a mouse model of sepsis.
      • Li L
      • Messina JL
      Acute insulin resistance following injury.
      • Vanhorebeek I
      • De Vos R
      • Mesotten D
      • et al.
      Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients.
      In a study in which muscle and liver biopsies of rats obtained after injection of LPS with a euglycemic hyperinsulinemia clamp to determine the underlying mechanisms of insulin resistance in endotoxemia,
      • Virkamaki A
      • Yki-Jarvinen H
      Mechanisms of insulin resistance during acute endotoxemia.
      a lower rate of glucose disposal compared to control was observed in the LPS group, which highly correlated with lower muscle and liver glycogen content and glycogen synthase activity. Therefore, hyperglycemia is thought to be partly mediated by a defect in glycogen synthesis. In human studies the development of insulin resistance coincides with the appearance of TNF, which likely has a role in the development of insulin resistance along with other cytokines. Moreover, cortisol, growth hormone, and catecholamine levels increase in sepsis and contribute to the development of insulin resistance.
      • Agwunobi AO
      • Reid C
      • Maycock P
      • et al.
      Insulin resistance and substrate utilization in human endotoxemia.

      The effect of insulin on the adverse effects of sepsis on metabolism

      Recent studies have found that hyperglycemia in critically ill patients triggers mitochondrial dysfunction and disturbs energy production in the liver, skeletal muscle, heart, and diaphragm.
      • Vanhorebeek I
      • De Vos R
      • Mesotten D
      • et al.
      Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients.
      Similarly, mitochondrial dysfunction and bioenergetic failure contribute to multiorgan failure in sepsis.
      • Brealey D
      • Brand M
      • Hargreaves I
      • et al.
      Association between mitochondrial dysfunction and severity and outcome of septic shock.
      Whether this is somehow related to insulin resistance is not known. Vanhorebeek et al analyzed the mitochondrial ultrastructure by electron microscopy in postmortem liver and muscle biopsies in patients with sepsis who had had been treated with either an intensive glucose control protocol or a conventional glucose control protocol.
      • Vanhorebeek I
      • De Vos R
      • Mesotten D
      • et al.
      Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients.
      Patients treated with the conventional protocol had hypertrophic mitochondria with increased numbers of abnormal and irregular cristae. They did not find these changes in patients on the intensive glucose treatment protocol. In addition, patients on the intensive treatment protocol had higher enzymatic activities for respiratory chain complex 1 and complex 4. There was no difference in mitochondrial ultrastructure or enzymatic activity in skeletal muscle when comparing the 2 insulin management groups. The results in hepatic tissue may represent protection from glucose toxicity in patients on intensive insulin therapy and not a direct effect on the liver.
      Whether this increased mortality and metabolic derangements can be prevented or reversed by insulin administration is an important question. Van den Berghe and associates have studied multiple metabolic parameters in critically ill patients treated either with intensive insulin therapy or conventional insulin therapy.
      • Langouche L
      • Van den Berghe G
      Glucose metabolism and insulin therapy.
      • Langouche L
      • Vander Perre S
      • Wouters PJ
      • et al.
      Effect of intensive insulin therapy on insulin sensitivity in the critically ill.
      • Vanhorebeek I
      • Langouche L
      • Van den Berghe G
      Glycemic and nonglycemic effects of insulin: how do they contribute to a better outcome of critical illness.
      • Vanhorebeek I
      • Langouche L
      Molecular mechanisms behind clinical benefits of intensive insulin therapy during critical illness: glucose versus insulin.
      Some of the studies included liver and skeletal muscle biopsies in patients who had just died. The studies indicate that the intensive insulin therapy increases GLUT 4 receptors in skeletal muscle. Intensive insulin therapy did not reduce phosphoenolpyruvate, glucose kinase, or insulin-like growth factor (IGF) binding protein (IGF1-BP) in hepatic tissue. This protein inhibits IGF effects on metabolism and growth, and circulating concentrations are determined largely by the action of insulin, which inhibits its hepatic transcription. In nondiabetic subjects, IGF1-BP levels strongly correlate with insulin action, and IGF1-BP levels decrease by about 50% after 120 min of hyperinsulinemia
      • Maddux BA
      • Chan A
      • De Filippis EA
      • et al.
      IGF-binding protein-1 levels are related to insulin-mediated glucose disposal and are a potential serum marker of insulin resistance.
      Messoten et al compared IGF1-BP levels in ICU patients assigned to intensive or conventional insulin regimens found no significant differences, suggesting that more insulin administration did not increase inhibition and reverse the alterations in this pathway. Serum IGF1-BP concentrations decreased over time in survivors and had a predictive value for mortality similar to that of the APACHE-II score.
      • Mesotten D
      • Delhanty PJ
      • Vanderhoydonc F
      • et al.
      Regulation of insulin-like growth factor binding protein-1 during protracted critical illness.
      Intensive insulin therapy did normalize serum C-peptide levels and increased circulating adiponectin levels. In summary, intensive length insulin therapy with high circulating levels of insulin does not have a uniform effect on tissues in critically ill patients. It increases glucose uptake in muscle tissue but does not inhibit enzymatic activities in the liver that are usually responsive to insulin levels. Consequently, the results in these experiments probably reflect both tissue protection from glucose toxicity and direct insulin effect on various tissues.

      Additional considerations about insulin resistance in sepsis

      As discussed above, insulin resistance has several possible explanations. The tyrosine kinase activity of the beta subunit may be inhibited by inflammation associated with sepsis and decrease intracellular control of glucose, lipid, and protein metabolism.
      • Yaribeygi H
      • Farrokhi FR
      • Butler AE
      • et al.
      Insulin resistance: review of the underlying molecular mechanisms.
      Proteolytic activity in the serum may release the receptor from the plasma membrane. Bauza-Martinez et al have demonstrated that patients with septic shock have increased proteolytic activity and have plasma peptidomic patterns that are associated with mortality.
      • Bauzá-Martinez J
      • Aletti F
      • Pinto BB
      • et al.
      Proteolysis in septic shock patients: plasma peptidomic patterns are associated with mortality.
      Hiriart and coworkers reported that high levels of insulin are associated with increased soluble insulin receptor levels released from hepatocytes.
      • Hiriart M
      • Sanchez-Soto C
      • Diaz-Garcia CM
      • et al.
      Hyperinsulinemia is associated with increased soluble insulin receptors release from hepatocytes.
      They also demonstrated that both healthy subjects and patients with hyperinsulinemia had elevated levels of soluble insulin receptor and that there was a positive correlation between the insulin level and the level of soluble insulin receptor. Consequently, it is possible that increased proteolytic activity during acute inflammatory stage decreases the number of insulin receptors on the plasma membrane and this contributes to insulin resistance. In this situation circulating insulin receptors could bind insulin and prevent cellular effects. In addition, insulin receptors recycle to the plasma membrane, and this could be inhibited during sepsis.
      • Chen Y
      • Huang L
      • Qi X
      • et al.
      Insulin receptor trafficking: consequences for insulin sensitivity and diabetes.
      Finally, Hancock and coworkers have reported the transfer of insulin receptors into the nucleus and demonstrated that these receptors associate with promoters and regulate gene expression.
      • Hancock ML
      • Meyer RC
      • Mistry M
      • et al.
      Insulin receptor associates with promoters genome-wide and regulates gene expression.
      Multiple genes are potentially affected by this activity, and this could contribute to the inflammatory response seen with acute illness. The transfer of insulin receptors to the nucleus decreases the number of receptors available for the usual activities required for glucose metabolism. These insulin receptors may recycle to the plasma membrane, and this process could be inhibited in patients with sepsis.

      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 oxide formation.
      • Jafar N
      • Edriss H
      • Nugent K
      The effect of short-term hyperglycemia on the innate immune system.
      In early 2000, two landmark studies suggested that intensive insulin therapy using IV insulin infusion to achieve tight blood sugar control reduced mortality in critically ill patients.
      • van den Berghe G
      • Wouters P
      • Weekers F
      • et al.
      Intensive insulin therapy in critically ill patients.
      ,
      • Krinsley JS
      Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients.
      However, in 2009, a large multicenter randomized controlled trial (The Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation [NICE-SUGAR]) found higher mortality with tight blood sugar control and more frequent episodes of hypoglycemia.
      • Finfer S
      • Chittock DR
      • Su SY
      • et al.
      NICE-SUGAR investigators
      Intensive versus conventional glucose control in critically ill patients.
      Based on this study, the recommendations by most guidelines have shifted to a less tight blood sugar target of 140–180 mg/dL. The occurrence of hypoglycemia during acute illness has been well described, and severe hypoglycemia is an important complication of intensive insulin therapy in critical illness in most studies. Hypoglycemia is independently associated with increased risk of death in critically ill patients, and understanding the changes of glucose metabolism in acute illness allows the incorporation of measures to help maintain optimal blood sugar control with fewer episodes of hypoglycemia during the different stages of acute illness.
      • Krinsley JS
      Glycemic control in the critically ill: What have we learned since NICE-SUGAR.
      ,
      • Krinsley JS
      The long and winding road toward personalized glycemic control in the critically ill.
      Given the pleiotropic hormonal effects of insulin, it is possible that insulin administration improves outcomes independent of its effect on glucose levels. Song et al. analyzed 12 randomized control trials of intensive insulin therapy in 4100 septic patients. Intensive insulin therapy did not reduce any mortality outcomes but did increase the incidence of hypoglycemia.
      • Song F
      • Zhong LJ
      • Han L
      • et al.
      Intensive insulin therapy for septic patients: a meta-analysis of randomized controlled trials.
      Puskarich et al. published a systematic review and meta-analysis of glucose–insulin–potassium infusions reported in 23 studies with 22,525 critically ill patients and found no effect on mortality.
      • Song JY
      • Eun BW
      • Nahm MH
      Diagnosis of pneumococcal pneumonia: current pitfalls and the way forward.
      In addition, they found no studies on patients in shock or with sepsis. Van der Horst et al also did not identify any evidence of that glucose–insulin–potassium infusions improved outcomes in patients with sepsis, septic shock, or burns.
      • van der Horst IC
      • Ligtenberg JJ
      • Bilo HJ
      • et al.
      Glucose-insulin-potassium infusion in sepsis and septic shock: no hard evidence yet.
      Overall, these studies do not support the routine infusion of insulin independent of glucose levels in patients with sepsis.
      Different factors may explain the discordant results in outcomes of randomized controlled trials of glucose targets in critical illness. Differences in patient populations (medical versus surgical ICU),
      • Griesdale DE
      • de Souza RJ
      • van Dam RM
      • et al.
      Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data.
      the difficulty achieving high rates of time within blood sugar range for most studies, the differences in blood sugar monitoring frequency, and the lack of evaluation of other important variables such as glucose variability potentially explain discordant results in various studies.
      • Krinsley JS
      Glycemic control in the critically ill: What have we learned since NICE-SUGAR.
      Finally, patients in the NICE-SUGAR study received less insulin than those in the previous studies showing benefits of intensive insulin therapy, suggesting that the severity of illness or degree of insulin resistance might differ between study populations.
      • Li L
      • Messina JL
      Acute insulin resistance following injury.
      Moreover, it is possible that blood sugar targets should not be used in a “one size fits all” manner; for example, some studies have suggested that tighter targets might favor hyperglycemic patients without history of diabetes, whereas looser targets can provide better outcomes in some diabetics, especially those with poor blood sugar control. In fact, several studies stratifying patients as diabetics and non-diabetics have found lower mortality with tighter blood sugar control in non-diabetics.
      • Krinsley JS
      The long and winding road toward personalized glycemic control in the critically ill.

      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 C-peptide to insulin is higher. C-peptide needs more investigation to determine whether or not it is preferentially secreted by pancreatic beta cells or whether there is preferential metabolism (clearance) of insulin during acute stress. Measuring insulin levels and/or soluble receptor levels might help classify patients into two groups with good outcomes and poor outcomes and provide prognostic information. C-peptide levels might also predict outcomes. The variability in insulin sensitivity could explain the development of hypoglycemia and attendant management difficulties with conflicting outcomes on insulin protocol studies. The initial answers to these questions will require prospective studies measuring glucose, insulin, and C-peptide levels in patients with sepsis and septic shock. Determining insulin sensitivity or resistance requires more complicated calculations and will also depend on prospective studies. Finally, comparing the characteristics of patients who have better outcomes with tight or tighter glucose control with those who do not could provide better protocols for the management of these patients.

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