Natural Killer Cell Function, an Important Target for Infection and Tumor Protection, Is Impaired in Type 2 Diabetes

Abstract

Patients with Type 2 diabetes (T2D) are highly susceptible to infection and have an increased incidence of some tumors, possibly due to immune system dysfunction. In the innate cellular immune system, Natural Killer (NK) lymphocytes are important effectors responsible for controlling infections and combating tumor development. We analyzed NK cell subsets in 51 patients with long-standing T2D. Compared with healthy blood donors, diabetic patients showed a profound decrease in both NKG2D-positive NK cells (44% vs. 55.5%, P<0.01) and NKp46-positive cells (26% vs. 50%, P<0.01). Decreased expression of these receptors was associated with functional defects, such as reduced NK degranulation capacity when challenged with the tumor target cell line K562 (10.3 vs. 15.8%, P<0.05). This defect could be restored in vitro by stimulating NK cells from T2D patients with IL-15 (P<0.05). NKG2D expression was found to be negatively correlated with HBA1c level (r = −0.50; P = 0.009), suggesting that sustained hyperglycemia could directly influence NK cell defects. We demonstrated that endoplasmic reticulum (ER) stress, an important mediator in diabetes-associated complications, was inducible in vitro in normal NK cells and that tunicamycin treatment resulted in a significant decrease in NKG2D expression (P<0.05). Furthermore, markers of the Unfolded Protein Response (UPR) BiP, PDI and sXBP1 mRNAs were significantly increased in NK cells from T2D patients (P<0.05, P<0.01, P<0.05, respectively), indicating that ER stress is activated in vivo through both PERK and IRE1 sensors. These results demonstate for the first time defects in NK cell-activating receptors NKG2D and NKp46 in T2D patients, and implicate the UPR pathway as a potential mechanism. These defects may contribute to susceptibility to infections and malignancies and could be targetted therapeutically.

Postoperative fungal endophthalmitis caused by Trichosporon asahii treated with voriconazole

“…In addition, they postulated that sarcoidosis may have predisposed their patient to fungal endophthalmitis because patients with this disease may have a form of immune dysfunction. Similarly, our patient had no other immunocompromising risk factors, except for diabetes mellitus, which is associated with impaired leukocyte function (5) . Therefore, diabetes mellitus may have pre disposed our patient to T. asahii endophthalmitis.…”

Risk Factors of Community-Associated Infections in Chinese Patients With Diabetes: A Meta-analysis

“…In detail, the study showed that beside cardiovascular causes and cancer, infectious diseases substantially contribute to the reduced life expectancy of diabetic people. [1,2,15,16] Diabetics were prone to suffer from infections, the mechanisms of which may be as follow: [17][18][19] 1. The body's defense system was weakened: Each stage of the body's defense to invading microorganisms was suppressed in diabetics, including leukocyte chemotaxis, phagocytosis, weakened intracellular bactericidal effect, neutralized toxin, decreased serum opsonin and cellular immune function, etc., 2.…”

Magnesium and lymphoma: opportunities in translation

“…Of interest, also diabetic patients have less NKG2D-expressing NK cells than healthy controls. 5 Especially, patients with uncontrolled hyperglycemia share both a more profound depression of NKG2D expression and a lower intracellular magnesium concentration than diabetic patients with good metabolic control. 5 Hence, the basic findings in XMEN may be highly relevant for other clinical conditions, especially diabetes and posttransplant status.…”