The Third International Consensus Definitions for Sepsis and Septic Shock Report defines sepsis as life-threatening organ dysfunction caused by a dysregulated host response to an infection. This is associated with a >10% in-hospital mortality. Septic shock is defined as sepsis associated with profound circulatory, cellular, and metabolic abnormalities. Patients with septic shock have serum lactate levels >2 mmol/L (>18 mg/dL) and require vasopressors to maintain a mean arterial pressure of 65 mmHg or greater in the absence of hypovolemia. Compared to sepsis alone, it has a much higher in-hospital mortality rate of >40% (1).

Long-term sepsis mortality is abysmal at 60–80%. Despite substantial advances in immune pathophysiology, this number has not considerably improved (2). In intensive care units, sepsis remains the leading cause of death (3). Considering the rapidly expanding elderly population with extensive comorbid burdens, physiological frailty, and immune senescence (4), over the next couple of decades, sepsis mortality is predicted to rise at a frightening rate (5). Just as terrifying are the mounting costs associated with treating septic patients. The United States spends ~$17 billion on sepsis-associated medical care (6).

Despite over 100 therapeutic clinical trials in sepsis, there are no current FDA-approved therapies that improve sepsis survival (7). In contrast, advancements in clinical treatment protocols (8) have resulted in increased in-hospital survival from life-threatening sepsis and organ dysfunction. However, a substantial portion of these in-hospital survivors will then die in the months to years following the acute event. A trimodal pattern of death during and after sepsis has been described. The first peak occurs at several days and is likely secondary to inadequate resuscitation. The second peak occurs at several weeks and is secondary to persistent organ injury and/or failure (9). The late (months to years) deaths comprise the largest mortality group and are speculated to be the consequence of improvements in intensive care medicine that keep elderly and comorbidly challenged patients alive despite persistent immune, physiological, biochemical, and metabolic aberrations (10). In 2008, over 800,000 Medicare patients survived admissions for severe sepsis. This population of survivors is composed of individuals with significant comorbidities that are at risk for hospital readmission (11). Several reports suggest that it is the synergistic effect of patients’ advanced age, comorbidities, and persistent organ injury that create this damaging state of ongoing immune dysfunction, immune suppression, catabolism, and inflammation (12–14), leading to long-term sepsis mortality. Patients with Type II diabetes (T2D) are physiologically frail and comprise the largest population of patients who experience post-sepsis complications and rising mortality.

Type II diabetes is a common and devastating disease frequently encountered by clinicians who care for critically ill patients. With increasing globalization of the western diet and lifestyle, the worldwide incidence and prevalence of T2D is approaching pandemic proportions. In the United States, the prevalence has almost doubled from 11.9 million in 2000 to 21.9 million people in 2014, and the incidence has more than tripled from 1980 to 2014 (15). Globally, T2D is no longer a disease of high-income countries. In 2014, an estimated 422 million adults worldwide had T2D, compared to 108 million in 1980. The largest growth in prevalence can be found in low- and middle-income countries (16). From 1980 until 2014, China, India, and United States had the largest T2D patient populations. However, recently, the global share of people with T2D has dramatically increased in India and China while United States share has decreased. As the growth trends in T2D prevalence continue, the number of adults with T2D will surpass 700 million worldwide in the near future (17).

As medical management strategies improve, patients with T2D live longer with their disease. In addition, the increasingly young age at diagnosis results in prolonged exposure to glucolipotoxicity, low-grade inflammation, and increased oxidative stress, creating a metabolic milieu conductive to cancer growth (18). This represents a major public heath challenge. Delayed diagnosis, inadequate follow-up, and suboptimal care of T2D patients predisposes them to develop acute and chronic complications, leading to further burden on the patient, health-care system, and society as a whole (19). A 2012 global systematic analysis of disease and injury epidemiology identified T2D as a leading cause of years lived with disability (YLD), with a 67.2% increase in YLD from 1990 to 2010 (20). Furthermore, T2D has been shown to be a significant cause of mortality. Stokes and Preston performed a cohort study of National Health Interview Survey and National Health and Nutrition Examination Survey participants between 1997 and 2010 and estimated the proportion of deaths attributable to T2D to be 11.5–11.8% (21). These numbers underestimate the burden of T2D, as an estimated one in four people with T2D are unaware that they have the disease (22). As the sedentary, calorie-rich western lifestyle continues to infiltrate the global landscape, T2D will continue to become a more common comorbidity encountered in the hospital setting.

Patients with T2D have an increased risk of developing infections and sepsis. Although a few rare infections such as Klebsiella liver abscesses, malignant otitis externa, and emphysematous cholecystitis are strongly associated with diabetic patients, most infections that occur in diabetics are also common in the general population (23). T2D also worsens infection prognosis, with T2D patients showing increased morbidity and mortality from sepsis (24). The combination of increased incidence, prevalence, and life expectancy of individuals with T2D, combined with an increased risk of infections is resulting in a rapidly expanding patient population consuming more medical resources.

Some investigators have refocused their efforts to work on understanding the underlying innate and adaptive immune system derangements that facilitate the development of infectious complications, impair recovery from sepsis, and increase long-term mortality (25, 26). However, little effort has focused on the interplay between T2D, sepsis, immunity, and their impact on overall survival. In this review, we highlight the immune system’s interdigitating role in the pathogenesis of T2D and sepsis. We focus on the clinical implications and then explore potential therapeutic interventions available to improve long-term survival in patients with T2D. To combat this pandemic, we hypothesize that disease-modifying therapeutics that have the ability to alter the course of disease have to be utilized, instead of focusing on palliative treatments that merely treat the sequelae of disease. Immune-modulatory therapy has been shown to improve patient survival in cancer, autoimmune diseases, and HIV. However, from these successful therapeutic advances, it has been shown that these therapies need to involve multiple agents, given in combination and introduced at the correct time to dampen disease progression, enhance patient immune responses, and affect host–pathogen interactions. We believe single-agent interventions are the reason why the sepsis literature is littered with failed therapeutic interventions. Combine the immune aberrations in T2D with the immune dysregulation found in sepsis and there are multiple targets for modulatory therapy. We propose that combinations of tailored interventions that focus on specific immune system perturbations that exist in sepsis and T2D will result in a high probability of success.

Type II diabetes is a complex clinical syndrome, depicted by persistent hyperglycemia in the setting of decreased insulin secretion and sensitivity, which results in a compilation of aberrant metabolic changes (24). Key metabolic changes include increased formation of advanced glycation end products (AGEs), activation of protein kinase C isoforms, and increased flux through the polyol and hexosamine pathways (27). These changes lead to increase production of superoxide (28), which activates inflammatory pathways, linking T2D to perturbations of the immune system (28). In addition, individuals with T2D have been shown to have abnormal host responses, including disorders of humoral immunity, defects in neutrophil function, and response of T cells (23, 29, 30). A recent study looking at obese individuals with and without T2D showed that individuals with T2D have specific immunological perturbations compared to metabolically healthy obese individuals, supporting the notion that T2D itself contributes to this identified immune dysfunction (31).

There is considerable clinical evidence that T2D worsens prognosis of pathological infections, with increased mortality from infections and sepsis in patients with T2D (24, 30, 32). This raises the pivotal question: why? The hematopoietic compartment constantly replenishes terminally differentiated innate and adaptive cells that are necessary for wound healing, successful tissue regeneration, and immune surveillance against offending pathogens (9). Sepsis impacts the immune system globally by affecting the lifespan, production, and function of innate and adaptive immune cells, leading to homeostatic perturbations in immune cell repletion (33, 34). In patients with T2D, this homeostasis may be altered secondary to over-nutrition and increased adiposity (35). These metabolic-induced immune perturbations clearly play a substantial role in the increased frequency, severity, and duration of infections (24, 28, 36).

In sepsis, an ongoing debate persists as to whether inflammatory/anti-inflammatory processes or innate/adaptive immune dysfunction are more detrimental to survival (37). Genomic studies on tissue samples from septic and severely injured trauma patients have provided more information (13). These studies have identified an enduring and simultaneous inflammatory and anti-inflammatory state, which is driven by dysfunctional innate and suppressed adaptive immunity. Together, these culminate in persistent organ injury (38), inflammation, and patient death (39, 40). Figure 1 illustrates how the immune system responds to an acute septic episode. At baseline, patients with T2D have an aberrant immune system. After the initial acute septic episode, T2D patients continue to experience significant morbidity and mortality several months to a year later. We believe that it is the enduring derangements in the innate and adaptive immune system cellular functions that contribute to the long-term morbidity and mortality.

The immune system protects against foreign microbial invaders, maintains optimal tissue homeostasis, and facilitates wound healing. These processes are dynamic in nature, changing to meet the needs of the organism. Most immune responses are fueled by cellular metabolism that is regulated by extracellular signals, which direct the uptake, storage, and utilization of glucose, amino acids, and fatty acids (9). When the organism senses an invading pathogen or tissue insult, the innate immune cells secrete cytokines, chemokines, and inflammatory mediators, which influence the expansion of adaptive immune cells (9). Since immune cells do not store nutrients, immune responses are only upregulated and sustained when there is an increased uptake of nutrients from the surrounding microenvironment. Nutrients provide substrates for ATP, RNA, DNA, and protein synthesis, along with the membranes necessary for the immune cell’s proliferation and maturation (41). Over a century ago, it was shown that a successful innate effector response is dependent on glucose metabolism (42), and that mitogen-driven proliferation of adaptive immune cells requires the utilization of extracellular glutamine (43, 44). T2D is a disease characterized by aberrant glucose metabolism. Homeostatic conditions are altered with an environment now characterized by chronic hyperglycemia and an increase in free fatty acids (FFAs) (45). An overall change in glucose metabolism therefore contributes to the immune dysfunction seen in T2D and sepsis.

In homeostatic conditions, immune cells rely on oxidative phosphorylation and β-oxidation as energy sources for ATP production (46). However, after stimulation, leukocytes shift their metabolism toward aerobic glycolysis in a process known as the Warburg effect (47). Subsequently, glycolysis produces cellular energy, followed by lactic acid formation in the cytosol instead of oxidation of pyruvate in mitochondria (48). Upon exposure to lipopolysaccharides (LPS), macrophages demonstrate a shift from oxidative phosphorylation to glycolysis and succinate and induce IL-1β production (49, 50). How T2D affects these processes is unknown, but clearly altering the substrates available for these pathways likely contributes to ongoing immune dysfunction. A better understanding of how hyperglycemic environments affect the metabolic checkpoints that control immune cell function, transition, and maturation is needed. In fact, delineating these pathways may provide targets for modulating systemic inflammation, cellular immunity, and recovery from infectious insults suffered by patients with T2D.

While several investigations have addressed the impact of hyperglycemia on sepsis and trauma outcomes in the critically ill in the ICU (51, 52), there is a paucity of studies that address the complications of T2D during infectious states and sepsis. The studies that do examine the association between T2D and sepsis outcomes are limited in their ability to account for all confounders (53, 54). It has been shown that adequate control of hyperglycemia is associated with improved outcomes and survival in times of critical illness; conversely, too tight of glycemic control has been associated with decreased survival (52). This U-shaped curve between glycemic control and mortality suggest that the ideal glycemic control for T2D patients is at moderately elevated glycemic levels. However, it is unclear that this effect is actually due to moderately elevated glucose levels, instead of confounding variables that lead to both lower glycemic levels and poor outcome (55). Although early glycemic control has been associated with risk reduction in the development of heart disease, hypertriglyceridemia, nephropathy, and cataracts, the biochemical mechanisms responsible for these effects are unknown (56, 57). Therefore, the more important question is: does long-term glycemic control augment immune function, prevent infectious complications, and promote durable survival? Although it makes logical sense that early and improves glycemic control would result in better immune function and reduced infections and sepsis episodes, there are few if any studies investigating this assumption. Moreover, there is a paucity of literature investigating the biochemical and physiological pathways central to immune function that benefit from glycemic control. Much more scientific investigation is necessary to determine the biological effect of glycemic control on immune function to improve long-term T2D survival from sepsis.

Once the host loses local containment of an infection, the body is systemically exposed to microbes, microbial components, and products of damaged tissue. This induces an inflammatory response and initiates sepsis-like responses through the recognition of pathogens and damaged tissue by way of pattern-recognition receptors (PRRs), which are ubiquitous on immune cell surfaces. PRRs are expressed primarily on immune and phagocytic cells and on many types of somatic tissues. Microbial infections are recognized by pathogen-associated molecular patterns (PAMPs), which are expressed by pathogenic and harmless microbes. PAMPs are recognized by PRRs such as toll-like receptors (TLRs), C-type and mannan-binding lectin receptors, NOD-like receptors, and RIG-I-like receptors (9). Proteins and cellular products released by tissue damage are similarly recognized as damage-associated molecular patterns (DAMPs) (58). During sepsis, systemic activation of the innate immune system by PAMPs and DAMPs results in severe and persistent inflammatory responses characterized by an excessive release of inflammatory cytokines such as IL-1β, TNF, and IL-17, collectively known as the “cytokine storm” (38). This unregulated release of inflammatory cytokines occurs over a relatively short period of time (hours or days). Furthermore, instead of stimulating what should be a normal physiological response to an infection, intense complement activation and innate immune cell stimulation enhance an excessive inflammatory response resulting in tissue damage, compromised cellular responses, and molecular dysregulation. The resulting damage incites organ dysfunction and even multiorgan failure (38).

Type II diabetes is an inflammatory disease within itself. In T2D, FFAs bind to TLR2, a receptor for pathogen lipoproteins, and TLR4, a LPS receptor, to activate the innate immune system (59, 60). In addition, there is indirect activation through TLR signaling (61). This elicits the inflammatory pathways activated in sepsis. In addition, AGEs are DAMPs that activate pro-inflammatory pathways.

Several studies also show that the inflammatory response is altered in patients with T2D. For example, mononuclear cells and monocytes have been found to secrete less IL-1 and IL-6 in response to stimulation by LPS, all of which appears to be secondary to an intrinsic defect in cells (29, 62). Although some patients recover from the inflammatory state during an acute septic episode, for unknown reasons elderly patients with significant comorbidities fail to resolve this initial condition. They instead progress to a state of persistent inflammation, immune cell dysfunction, and catabolic metabolism, all of which degrade the immune system’s ability to clear infections and heal injured tissues (63). In individuals with T2D, the chronically inflamed environment may play a role. Adipose tissue serves as a site of inflammation (28), with an increase in adiposity being associated with upregulation of genes encoding pro-inflammatory molecules resulting in the aggregation and accumulation of immune cells (64). Macrophages then create a pro-inflammatory loop by forming crown-like structures, which promote differentiation to pro-inflammatory M1 macrophages (28) and the associated pro-inflammatory cytokines. Similar to the environment seen in adipocytes, pro-inflammatory conditions have also been seen in the pancreas. In the pancreas, there is β-cell apoptosis from glucose-induced IL-1β (65), and β-cell dysfunction by lipoapoptosis from FFAs acting as effector molecules (28). This stress-induced β-cell death results in the release of autoantigens and alarmins, which are endogenous molecules released by necrotic cells resulting in stimulation of the immune system through self-antigen presentation (28). This leads to an enhanced adaptive immune response (66).

Given the growing knowledge in the field of metabolic-induced immune dysfunction in T2D, possible interventions that curb inflammation may offer therapeutic benefits in T2D. In sepsis, recent investigations have suggested that therapeutic interventions that curb hyperinflammation, shift catabolism toward anabolism, and bolster immune function may be beneficial in combination, once the initial episode of sepsis has subsided (25, 67, 68). Although in other disease states, such as severe burns, advanced cancers, and autoimmune diseases, combination therapies that reduce inflammation, optimize metabolism, and decrease infections are common-place, in sepsis there currently is no clear plan for the routine use of these or similar strategies (9). Combinations of immune modulators that target affected pathways in T2D and sepsis have the potential to offer clinically significant improvements in overall survival.

The pathogenesis of T2D can be described as insulin resistance associated with inactivity, obesity, and aging (69, 70). Initially, the pancreatic islet cells respond to this decrease in insulin-stimulated glucose uptake by increasing cell mass and secretory activity. When functional expansion of the islet β cells fails to compensate for the insulin resistance, insulin deficiency, and subsequent T2D develop. The hypothesized mechanisms behind insulin resistance and islet β-cells dysfunction focus on molecular changes that influence the pathogenesis of T2D. Specifically, most research centers on lipotoxicity, glucotoxicity, oxidative stress, endoplasmic reticulum stress, amyloid deposition in the pancreas, and ectopic lipid deposition in the muscle, liver, and pancreas (70). The contribution of each of these mechanisms remains unclear, but, interestingly, all of these cellular stresses can be caused by over-nutrition (71) and are induced or exacerbated by an inflammatory response (72).

Obesity-induced inflammation is chronic and indolent, differing from the more acute type of inflammation commonly associated with infections (70). Current observations in sepsis show that sepsis-induced organ dysfunction occurs primarily though cellular and molecular dysregulation of signaling pathways, as opposed to gross tissue damage. This may result in multiple organ failure even in the context of preserved cell morphology and in the absence of significant cell injury. Therefore, immune dysfunction in sepsis is associated with molecular alterations that alter cellular phenotype and function. How the molecular changes in T2D and sepsis interact and influence each other resulting in worse clinical outcomes is unclear. Below we outline several important pathways of cellular dysfunction that impact immune function in diabetics and sepsis, illuminating gaps in knowledge, which could influence why patients with T2D have infections that are difficult to treat and are associated with significant morbidity and mortality (70).

Below we will summarize the alterations seen in the majority of innate and adaptive immune cells in T2D. Furthermore, we highlight how these cells types are affected by sepsis and try to illustrate how T2D and sepsis together may interact to exacerbate long-term mortality.

As related to infection, inflammation is generally followed by inflammation resolution. In sepsis, compensatory anti-inflammatory pathways are activated shortly after sepsis initiation (37). The hallmark cytokine in these anti-inflammatory pathways is IL-10. IL-10 suppresses IL-6 and IFNγ, while stimulating the production of soluble TNF receptor and IL-1 receptor antagonist (IL-1RA). At the subcellular level, autophagy eliminates DAMPs and PAMPs by packaging pathogen components, damaged organelles, and cellular proteins into vesicles targeted for lysosomal degradation. This results in reduced inflammation and cellular activation (179). After a severe infection, resolution of inflammation involves an interdigitating, complex, and coordinated array of cellular processes and molecular signals. The offending pathogen needs to be eliminated from the host, while damaged tissues, cells, and leukocytes need to be removed. These processes occur through activation of anti-inflammatory pathways with production of IL-10 and transforming growth factor β.

Sepsis differs from obesity and T2D since the latter has persistent inflammation that does not resolve. The secretion of pro-inflammatory adipokines [IL-6, TNF, and monocyte chemoattractant protein-1 (MCP-1)] is increased while the secretion of anti-inflammatory and insulin-sensitizing adiponectin is reduced (180). The formation of pro- and anti-inflammatory lipid mediators is also deregulated in obesity (181). In addition, deficiencies in IL-10 expression or IL-10 receptor signaling results in inflammatory diseases (182, 183). A recent study showed that T2D patients have decreased IL-10 function, through downstream signaling in the IL-10 pathway (184). Moreover, expression of IL-1RA is decreased in β cells from T2D patients, with an IL-1RA being a current FDA-approved therapeutic (185).

Type II diabetes patients have an increased susceptibility to pathological infections. These patients also have some of the worst long-term morbidity and mortality. This is secondary to the inability to eradicate pathological infections. In sepsis, in addition to immune activation, a component of immune suppression concomitantly exists, which enables individuals to develop recurrent, secondary, and nosocomial infections. This leads to worse outcomes and increased long-term mortality (26). The combination of chronic immune suppression from T2D, combined with sepsis-induced immune suppression, leads to innate and adaptive immune system changes that the human body cannot overcome. As illustrated in Figure 2, both the innate and adaptive immune systems are affected in T2D and sepsis, altering homeostasis. It is not known how these aberrant pathways interact when they are superimposed. However, we do know that these superimposed pathways lead to worsened morbidity and mortality.

When looking at immune suppression in the innate immune system, there are several key pathways to mention. Neutrophils are essential for bacterial eradication. In T2D and sepsis, neutrophils display defects in chemotaxis and recruitment to sites of infection (186, 187). This leads to the reduced ability to eradicate bacteria (99). T2D-associated hyperglycemia also increases cytosolic calcium in neutrophils, which inhibits the synthesis of ATP leading to reduced chemotactic, phagocytic, and bactericidal activity. The production and release of essential effector molecules, such as ROS and cytokines, is significantly impaired leading to bacterial persistence and the development of infectious complications (133, 187, 188). In addition, T2D is associated with elevated FFAs from dysregulated carbohydrate metabolism, which cause EC dysfunction and pathological cytokine fluctuations (189). In T2D, the antioxidant systems and humoral immunity are also depressed. Furthermore, T2D predisposes patients to micro- and macrovascular comorbidities leading to environments susceptible to infections (190).

In addition to diminished innate function, adaptive immunity is similarly impaired. Splenocytes harvested from deceased sepsis patients demonstrate reduced numbers of CD4⁺ and CD8⁺ lymphocytes, due to substantial apoptosis (13). Apoptosis of lymphocytes and APCs (DCs, T cells, and B cells) is considered a hallmark of septic immune suppression (191, 192). Moreover, CD4⁺ cell loss is associated with a reduced ability to mount immune responses to viral infections after septic insults (193). However, reduced lymphocyte numbers are not just reflective of the risk for viral reactivation following sepsis. Lymphopenia 4 days after the onset of sepsis is associated with the development of secondary infections and is predictive of long-term mortality at 1 year after sepsis (194).

Several studies have examined the link between increased infectious morbidity and T2D. It is hypothesized that T2D patients are predisposed to infection due to impaired neutrophil function, decreased adaptive immune response, and dysfunctional immune cell function through high serum levels of inflammatory mediators (195). The cellular alterations observed in T2D and sepsis combine to create a chronic state of immune suppression, characterized by recurrent, secondary, and nosocomial infectious complications (196). These infectious complications often result in hospital readmissions (197–199) and poor long-term survival (200). Compared to patients without sepsis, sepsis survivors require more antibiotics, have more ICU days, and consume more hospital resources (201). T2D patients are also associated with bacterial pathogens with increased antibiotics resistance, such as MRSA, Pseudomonas, and Acinetobacter, which are associated with ICU-related mortality (202).

It is evident that sepsis induces a pathological state of immune suppression that prompts the development of secondary infections while still in the ICU setting (203). In addition, several reports demonstrate that sepsis survivors and T2D patients experience dramatically higher rates of subsequent infections long after the initial episode of sepsis has abated (204, 205). The increased hospital readmission rates due to infectious complications among T2D patients and sepsis survivors is a sign of ongoing immune suppression and dysregulation that if not corrected, diminishes life quality and durable survival. With the ever increasing, comorbidity challenged, elderly T2D population experiencing persistent inflammation, immune suppression, and immune senescence, the number of T2D sepsis survivors who develop subsequent infections is predicted to rise substantially in the next decades (200, 206).

Below we will address immune modulators/modulatory pathways that deserve further consideration as disease-modifying therapeutics. These immune modulators, their proposed benefits, and some possible combinations are also listed in Table 1.

Type II diabetes is a disease of altered immunity that results in protracted inflammation, immune suppression, and significant infection morbidity. Clinically, it is obvious that patients with T2D are more susceptible to infections. In sepsis, despite the best goal-directed therapies that control hyperglycemia, administer antibiotics early, and prevent organ damage, T2D patients still have worse morbidity and mortality for reasons that are poorly understood. However, the link between the two appears to be the dysregulated immune pathways. We believe that immune-modulatory therapies that are strategically introduced and influence the interdigitating immune derangements between these two diseases have the potential to substantially improve the overall morbidity and mortality that these individuals experience.

All authors have made substantial contributions to all phases of manuscript development. MD and LF conceived the larger project. FF, KH, and PW helped conceive the focus of the paper. LF drafted the first version, figures, and table, with all authors providing substantive and editorial feedback on multiple revisions. We have all approved the final version prior to submission.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.