Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

Abstract

Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia–metabolism interface.

Microglia at the blood brain barrier in health and disease

“…Additionally, even metabolic factors, like glucose levels can impact microglial activity. Conditions, such as diabetes or hyperglycemia, can lead to increased microglial reactivity, marked by upregulation of various molecules and pathways associated with glucose transport and sensing and inflammation and oxidative stress ( Hsieh et al, 2019 ; Iannucci et al, 2022 ; Vargas-Soria et al, 2023 ).…”

Formulating Treatment to Cure Alzheimer’s Dementia: Approach #2

“…Regarding the mechanism for the association between diabetes and AD, a small but relevant study showed that those with MCI who progressed to dementia had a reduced cerebral metabolic rate of glucose metabolism, which is because cerebral insulin resistance is heightened in diabetics [ 18 ]. Additionally, diabetes affects microglial function; a review that examined 267 articles found that diabetes modulates microglia by affecting their secretion of a wide variety of cytokines and chemokines (NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, and Akt/mTOR), their metabolic reprogramming, and their increased promotion of reactive oxygen species (ROS) [ 19 ]. Brabazon et al showed that insulin reduced the pro-inflammatory M1 microglial phenotype [ 20 ].…”

Thirty Risk Factors for Alzheimer’s Disease Unified by a Common Neuroimmune–Neuroinflammation Mechanism

“…Amongst these, Van Dyken and Lacoste argued that neuroinflammation is one of the key mechanistic connectors between diabetes and AD [71]. Similarly, based on a systematic review of in vitro, preclinical and clinical studies, Vargas-Soria et al concluded that diabetes triggers specific responses that include the upregulation of activated microglia and secretion of a wide variety of pro-inflammatory cytokines and chemokines [72]. Pathways commonly activated by diabetic pathological changes include the NLRP3 inflammasome.…”