Diabetes and Sepsis: Risk, Recurrence, and Ruination

Abstract

Sepsis develops when an infection surpasses local tissue containment. A series of dysregulated physiological responses are generated, leading to organ dysfunction and a 10% mortality risk. When patients with sepsis demonstrate elevated serum lactates and require vasopressor therapy to maintain adequate blood pressure in the absence of hypovolemia, they are in septic shock with an in-hospital mortality rate >40%. With improvements in intensive care treatment strategies, overall sepsis mortality has diminished to ~20% at 30 days; however, mortality continues to steadily climb after recovery from the acute event. Traditionally, it was thought that the complex interplay between inflammatory and anti-inflammatory responses led to sepsis-induced organ dysfunction and mortality. However, a closer examination of those who die long after sepsis subsides reveals that many initial survivors succumb to recurrent, nosocomial, and secondary infections. The comorbidly challenged, physiologically frail diabetic individuals suffer the highest infection rates. Recent reports suggest that even after clinical “recovery” from sepsis, persistent alterations in innate and adaptive immune responses exists resulting in chronic inflammation, immune suppression, and bacterial persistence. As sepsis-associated immune defects are associated with increased mortality long-term, a potential exists for immune modulatory therapy to improve patient outcomes. We propose that diabetes causes a functional immune deficiency that directly reduces immune cell function. As a result, patients display diminished bactericidal clearance, increased infectious complications, and protracted sepsis mortality. Considering the substantial expansion of the elderly and obese population, global adoption of a Western diet and lifestyle, and multidrug resistant bacterial emergence and persistence, diabetic mortality from sepsis is predicted to rise dramatically over the next two decades. A better understanding of the underlying diabetic-induced immune cell defects that persist following sepsis are crucial to identify potential therapeutic targets to bolster innate and adaptive immune function, prevent infectious complications, and provide more durable diabetic survival.

Obesity and type 2 diabetes mellitus drive immune dysfunction, infection development, and sepsis mortality

“…In addition, given the growing knowledge in the field of metabolic‐induced immune dysfunction in obesity and T2D, possible interventions that curb inflammation may also offer therapeutic benefits in these patient populations. Some current antidiabetic medications are known to have anti‐inflammatory properties . Moreover, immune modulatory therapies are commonplace in other disease states, such as severe burns, advanced cancers, and autoimmune diseases, where combinations of therapies are used to reduce inflammation, optimize metabolism, and decrease infections .…”

“…Moreover, immune modulatory therapies are commonplace in other disease states, such as severe burns, advanced cancers, and autoimmune diseases, where combinations of therapies are used to reduce inflammation, optimize metabolism, and decrease infections . Immune modulatory therapies have not been used in obesity and T2D; however, given that these patients are at the highest risk of mortality from infections that lead to sepsis, immune modulatory therapies have a potential role . Combinations of immune modulators that target the chronically affected pathways in obesity and T2D and the acutely affected signaling pathways in sepsis have the potential to offer meaningful clinical improvements in overall survival.…”

Outcomes of hyperglycemia in patients with and without diabetes hospitalized for infectious diseases

“…Few rare infections such as invasive otitis externa, rhinocerebral mucormycosis, and emphysematous cholecystitis occur almost exclusively in patients with DM . The increased predisposition of patients with DM to infections can be explained by the interplay between the immune dysfunction and the complications of the disease …”

“…In patients without DM hyperglycemia is the result of stress‐mediated activation of sympathetic nervous system and hypothalamic‐pituitary‐adrenal axis. Proinflammatory cytokines, including interleukins 1 and 6 and tumour releasing factor, increase glucose levels by stimulating liver gluconeogenesis and insulin resistance …”

“…7 The increased predisposition of patients with DM to infections can be explained by the interplay between the immune dysfunction and the complications of the disease. 8 Hyperglycemia is frequently observed in patients with and without DM, hospitalized for infectious diseases. [9][10][11] In patients without DM hyperglycemia is the result of stress-mediated activation of sympathetic nervous system and hypothalamic-pituitary-adrenal axis.…”