Acute and chronic neuroinflammation is triggered by diabetic ketoacidosis in a rat model

Abstract

IntroductionCognitive decline is common in patients with type 1 diabetes and has been attributed to the effects of chronic hyperglycemia and severe hypoglycemia. Diabetic ketoacidosis (DKA) has only recently been suspected to be involved in causing cognitive decline. We hypothesized that DKA triggers both acute and chronic neuroinflammation, contributing to brain injury.Research methods and designWe measured concentrations of cytokines, chemokines and matrix metalloproteinases (MMP) in serum and brain tissue lysates in juvenile rats during and after DKA (during acute DKA, 24 hours and 7 days after DKA), and compared these to healthy controls and hyperglycemic controls. We also measured cytokine, chemokine and MMP concentrations in serum and brain tissue of adult rats (70 days) that had experienced DKA as juveniles and compared these measurements to those of adult diabetic rats without exposure to DKA.ResultsDuring acute DKA in the juvenile rats, serum concentrations of CCL3, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and MMP-9 were significantly increased. Serum concentrations of IL-2 and IL-17A increased 7 days after DKA recovery. In brain tissue lysates, concentrations of CCL3, CCL5, interferon (IFN)-γ and MMP-9 were significantly elevated during acute DKA. In adult rats that had DKA as juveniles (28 days previously), serum concentrations of IL-1ß and brain concentrations of IL-10 and IL-12p70 were elevated in comparison to diabetic rats without prior DKA. Composite scores for highly correlated cytokines and chemokines (mean z-scores for IL-10, IL-1ß, TNF-α, IL-17A, IFN-γ, CXCL-1 and CCL5) were also significantly elevated in adult rats with prior DKA.ConclusionsThese data confirm that DKA causes acute systemic inflammation and neuroinflammation in a rat model. Importantly, the neuroinflammatory response triggered by DKA is long-lasting, suggesting the possibility that DKA-induced chronic neuroinflammation could contribute to long-term cognitive decline in individuals with diabetes.

Association of Acute Kidney Injury During Diabetic Ketoacidosis With Risk of Microalbuminuria in Children With Type 1 Diabetes

“…DKA causes a hyperinflammatory state with elevations of several cytokines that have also been implicated in the pathogenesis of DKD . Interestingly, animal data suggest that DKA might trigger a chronic neuroinflammatory response; however, persistent kidney inflammation after DKA has not been investigated.…”

Diabetic ketoacidosis and oxidative stress: pathophysiological mechanisms

“…Несколько экспериментальных и клинических исследований показали, что развитие острой гипергликемии на фоне ДКА приводит к выраженному воспалительному ответу, характеризующемуся повышением уровня провоспалительных цитокинов и маркеров ОС [19,38]. Индуцированная тяжелой гипергликемией при ДКА продукция макрофагами провоспалительных цитокинов, таких как ФНО-α, ИЛ-6, ИЛ-1β, С-реактивный белок, приводит к нарушению секреции инсулина, а также снижению чувствительности к инсулину [39]. Инсулиноре-SIBERIAN SCIENTIFIC MEDICAL JOURNAL 2023; 43 (6): 6−13 зистентность в данном случае, по-видимому, обусловлены выраженной глюкозотоксичностью при ДКА на фоне сильной воспалительной реакции, в результате чего снижается выработка инсулина [39].…”

“…Индуцированная тяжелой гипергликемией при ДКА продукция макрофагами провоспалительных цитокинов, таких как ФНО-α, ИЛ-6, ИЛ-1β, С-реактивный белок, приводит к нарушению секреции инсулина, а также снижению чувствительности к инсулину [39]. Инсулиноре-SIBERIAN SCIENTIFIC MEDICAL JOURNAL 2023; 43 (6): 6−13 зистентность в данном случае, по-видимому, обусловлены выраженной глюкозотоксичностью при ДКА на фоне сильной воспалительной реакции, в результате чего снижается выработка инсулина [39]. Показано, что значительное повышение уровня ИЛ-6, ИЛ-1β, ИЛ-8, ФНО-α и других цитокинов после манифестации ДКА существенно снижает ответ на инсулинотерапию [19].…”

Systemic Inflammatory Response Index (SIRI) as a Predictive Marker for Adverse Outcomes in Children with New-Onset Type 1 Diabetes Mellitus

“…Among these, the most evaluated index in diabetic patients has been the neutrophil-to-lymphocyte ratio (NLR) [22][23][24][25]. However, while much of the research has centered on the role of neutrophils and lymphocytes, monocytes also appear to exert a notable impact on the pathogenesis of T1DM [26][27][28][29] and its complications, such as cerebral edema and AKI [30,31]. Consequently, investigating an index that integrates monocytes seems useful.…”