Introduction:: Type 2 Diabetes (T2D) is a major health problem worldwide. This metabolic disease is indicated by high blood glucose levels due to insufficient insulin production by the pancreas. An inflammatory response occurs as a result of the immune response to high blood glucose levels as well as the presence of inflammatory mediators produced by adipocytes and macrophages in fat tissue. This low and chronic inflammation damages the pancreatic beta cells and leads to insufficient insulin production, which results in hyperglycemia. : Hyperglycemia in diabetes is thought to cause dysfunction of the immune response, which fails to control the spread of invading pathogens in diabetic subjects. Therefore, diabetic subjects are known to more susceptible to infections. The increased prevalence of T2D will increase the incidence of infectious diseases and related comorbidities. Objective: : This review provides an overview of the immunological aspect of T2D and the possible mechanisms that result in increased infections in diabetics. Conclusion: : A better understanding of how immune dysfunctions occur during hyperglycemia can lead to novel treatments and preventions for infectious diseases and T2D comorbidities, thus improving the outcome of infectious disease treatment in T2D patients.

Type 2 Diabetes Mellitus (T2DM) is a rapidly growing global health issue characterized by insulin resistance and chronic inflammation. Beyond regulating glucose homeostasis, insulin plays a pivotal role in modulating immune cell function, linking metabolic dysregulation with immune responses. This review examines the intricate relationship between insulin resistance and immune dysfunction in T2DM, focusing on how impaired insulin signaling pathways, particularly PI3K/Akt and MAPK, contribute to immune cell activation, proliferation, and chronic inflammation. Insulin resistance impacts immune cells such as T cells, B cells, macrophages, and neutrophils, leading to an imbalance between pro-inflammatory and anti-inflammatory responses. Elevated pro-inflammatory cytokines (eg, TNF-α, IL-6) and adipokines (eg, leptin, resistin) exacerbate insulin resistance, promoting a vicious cycle of metabolic and immune dysregulation. This interplay contributes to the chronic low-grade inflammation that underlies T2DM pathogenesis, further impairing insulin signaling and glucose metabolism. Restoration of insulin sensitivity is, therefore, a critical step toward correcting immune imbalance in insulin-resistant states like T2DM. Therapeutic approaches that reduce inflammation could also support improvements in insulin sensitivity, addressing both metabolic and immune disturbances simultaneously. The review also explores therapeutic strategies, including insulin therapy, targeting insulin signaling pathways, and lifestyle interventions. Insulin therapy can reduce pro-inflammatory cytokine production and enhance anti-inflammatory responses, although challenges such as potential immune suppression and hyperinsulinemia remain. Targeting key signaling pathways and transcription factors offers promising avenues for modulating immune responses, while lifestyle interventions, such as dietary modifications, physical activity, and weight management, can improve insulin sensitivity and reduce inflammation. By understanding the dual role of insulin in regulating both metabolic and immune functions, this review underscores the importance of addressing immune dysfunction as part of comprehensive T2DM management. Targeting the interconnected pathways of insulin signaling and immune regulation could lead to more effective therapeutic approaches, ultimately improving patient outcomes and reducing disease complications.

Helminths induce type 2 immune responses and establish an anti-inflammatory milieu in their hosts. This immunomodulation was previously shown to improve diet-induced insulin resistance which is linked to chronic inflammation. In the current study, we demonstrate that infection with the filarial nematode Litomosoides sigmodontis increased the eosinophil number and alternatively activated macrophage abundance within epididymal adipose tissue (EAT) and improved glucose tolerance in diet-induced obese mice in an eosinophil-dependent manner. L. sigmodontis antigen (LsAg) administration neither altered the body weight of animals nor adipose tissue mass or adipocyte size, but it triggered type 2 immune responses, eosinophils, alternatively activated macrophages, and type 2 innate lymphoid cells in EAT. Improvement in glucose tolerance by LsAg treatment remained even in the absence of Foxp3+ regulatory T cells. Furthermore, PCR array results revealed that LsAg treatment reduced inflammatory immune responses and increased the expression of genes related to insulin signaling (Glut4, Pde3b, Pik3r1, and Hk2) and fatty acid uptake (Fabp4 and Lpl). Our investigation demonstrates that L. sigmodontis infection and LsAg administration reduce diet-induced EAT inflammation and improve glucose tolerance. Helminth-derived products may, therefore, offer new options to improve insulin sensitivity, while loss of helminth infections in developing and developed countries may contribute to the recent increase in the prevalence of type 2 diabetes.

Helminths immunomodulate their hosts and induce a regulatory, anti-inflammatory milieu that prevents allergies and autoimmune diseases. Helminth immunomodulation may benefit sepsis outcome by preventing exacerbated inflammation and severe pathology, but the influence on bacterial clearance remains unclear. To address this, mice were chronically infected with the filarial nematode Litomosoides sigmodontis (L.s.) and the outcome of acute systemic inflammation caused by i.p. Escherichia coli injection was determined. L.s. infection significantly improved E. coli-induced hypothermia, bacterial clearance and sepsis survival and correlated with reduced concentrations of associated pro-inflammatory cytokines/chemokines and a less pronounced pro-inflammatory macrophage gene expression profile. Improved sepsis outcome in L.s.-infected animals was mediated by macrophages, but independent of the alternatively activated macrophage subset. Endosymbiotic Wolbachia bacteria that are present in most human pathogenic filariae, as well as L.s., signal via TLR2 and modulate macrophage function. Here, gene expression profiles of peritoneal macrophages from L.s.-infected mice revealed a downregulation of genes involved in TLR signaling, and pulsing of macrophages in vitro with L.s. extract reduced LPS-triggered activation. Subsequent transfer improved sepsis outcome in naïve mice in a Wolbachia- and TLR2-dependent manner. In vivo, phagocytosis was increased in macrophages from L.s.-infected wild type, but not TLR2-deficient animals. In association, L.s. infection neither improved bacterial clearance in TLR2-deficient animals nor ameliorated E. coli-induced hypothermia and sepsis survival. These results indicate that chronic L.s. infection has a dual beneficial effect on bacterial sepsis, reducing pro-inflammatory immune responses and improving bacterial control. Thus, helminths and their antigens may not only improve the outcome of autoimmune and allergic diseases, but may also present new therapeutic approaches for acute inflammatory diseases that do not impair bacterial control. As the human immune system evolved in the presence of helminth infections, it is postulated that improved hygiene and subsequent loss of helminth infections and their immunomodulatory functions contributed to the sharp increase of autoimmune diseases and allergies over the last decades. Accordingly, helminth-induced anti-inflammatory, regulatory immune responses ameliorate allergy and autoimmune diseases and are likely to impact other immunological disorders including sepsis. Sepsis is an exacerbated, systemic inflammatory disease that occurs when pathogens cannot be locally confined and spread via the blood stream. Thus, efficient sepsis therapies should reduce excessive inflammation without impairing protective immune responses. In the present study we demonstrate that chronic filarial infection modulates macrophages to a less pro-inflammatory phenotype with improved phagocytic capacity. This immunomodulation reduces sepsis-induced inflammation and hypothermia and clears bacteria more efficiently thus improving sepsis survival. Moreover, we found that Wolbachia, the endosymbiotic bacteria of filariae, play a crucial role in triggering the correct macrophage response via TLR2. Thus, our observations suggest that helminths and helminth-derived antigens may not only present new treatment options for allergies and autoimmune diseases, but may also allow treatment of sepsis caused inflammation without impairing bacterial control.

Breynia cernua has been used as an alternative medicine for wounds, smallpox, cervical cancer, and breast cancer. This plant is a potential source of new plant-derived drugs to cure numerous diseases for its multiple therapeutic functions. An in vitro study revealed that the methanol extract of B. cernua (stem) exhibits antioxidant activity according to DPPH and SOD methods, with IC₅₀ values of 33 and 8.13 ppm, respectively. The extract also exerts antibacterial activity against Staphylococcus aureus with minimum bactericidal concentration of 1875 ppm. Further analysis revealed that the extract with a concentration of 1–2 ppm protects erythrocytes from the ring formation stage of Plasmodium falciparum, while the extract with a concentration of 1600 ppm induced apoptosis in the MCF-7 breast cancer cell line. GC–MS analysis showed 45 bioactive compounds consisting of cyclic, alkyl halide, organosulfur, and organoarsenic compounds. Virtual screening via a blind docking approach was conducted to analyze the binding affinity of each metabolite against various target proteins. The results unveiled that two compounds, namely, N-[β-hydroxy-β-[4-[1-adamantyl-6,8-dichloro]quinolyl]ethyl]piperidine and 1,3-phenylene, bis(3-phenylpropenoate), demonstrated the best binding score toward four tested proteins with a binding affinity varying from −8.3 to −10.8 kcal/mol. Site-specific docking analysis showed that the two compounds showed similar binding energy with native ligands. This finding indicated that the two phenolic compounds could be novel antioxidant, antibacterial, antiplasmodial, and anticancer drugs. A thorough analysis by monitoring drug likeness and pharmacokinetics revealed that almost all the identified compounds can be considered as drugs, and they have good solubility, oral bioavailability, and synthetic accessibility. Altogether, the in vitro and in silico analysis suggested that the extract of B. cernua (stem) contains various compounds that might be correlated with its bioactivities.