Hippocampal subfields atrophy contribute more to cognitive impairment in middle-aged patients with type 2 diabetes rather than microvascular lesions

Zhang, Wen; Gao, Cailiang; Qing, Zhao; Zhang, Zhou; Bi, Yan; Zeng, Wenbing; Zhang, Bing

doi:10.1007/s00592-020-01670-x

Cited by 17 publications

(21 citation statements)

References 39 publications

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“…Indeed, brain structures are fairly vulnerable to microvascular disturbances since brain microvessels have low resistance and sensitive auto-regulatory processes, being more vulnerable to phenomena like augmented pulsatile load that occurs with elevated glucose levels 12 . Nonetheless, a recent study suggested that brain atrophy in hippocampal sub elds are associated with cognitive impairment in this disease rather than microstructural lesions, where HbA 1c levels were negatively correlated with hippocampal atrophy but not with the burden of white matter hyperintensities 13 .…”

Section: Discussionmentioning

confidence: 85%

Irreversible atrophy in memory brain regions over 7 years is predicted by glycemic control in type 2 diabetes without cognitive decline

Canário

Crisóstomo

Duarte

et al. 2023

Preprint

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Memory-related impairments in type 2 diabetes maybe be mediated by insulin resistance and hyperglycemia. Previous cross-sectional studies have controversially suggested a relationship between metabolic control and a decrease in hippocampal volumes, but only longitudinal studies can test this hypothesis directly. We performed a longitudinal morphometric study to provide such a direct test of a possible role of higher levels of glycated hemoglobin (HbA1C) with long term brain structural integrity in key regions of the memory system – hippocampus, parahippocampal gyrus and fusiform gyrus. Grey matter volume was measured at two different times – baseline and after ~ 7 years. We found an association between higher initial levels of HbA1C and grey matter volume loss in all three core memory regions, even in the absence of cognitive decline. Importantly, these neural effects persisted in spite of the fact that patients had significantly improved their glicemic control. This suggests that early high levels of HbA1c are irreversibly associated with subsequent long-term atrophy in the medial temporal cortex and that early intensive management is critical.

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Section: Discussionmentioning

confidence: 85%

Irreversible atrophy in memory brain regions over 7 years is predicted by glycemic control in type 2 diabetes without cognitive decline

Canário

Crisóstomo

Duarte

et al. 2023

Preprint

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“…It is worth noting that study focusing on the accurate domain by which RIPK1 interaction with RAGE requires future clari cation. In diabetic humans and animals, impairments of spatial learning, memory, and cognition have been associated with marked changes in the hippocampus, a key brain region for many forms of learning and memory that is sensitive to changes in glucose homeostasis [40]. Cognitive de cit in diabetes is originate from neurophysiological and structural changes in hippocampus [41].…”

Section: Discussionmentioning

confidence: 99%

Binding of RAGE (AAs 362-367) and RIPK1 induces cognitive deficit in chronic hyperglycemia-derived neuroinflammation

Zhou

Zhu

Gao

et al. 2022

Preprint

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Background Chronic hyperglycemia-induced inflammation of the hippocampus is an important cause of cognitive deficit in diabetic patients. The receptor for advanced glycation end products (RAGE), which is widely expressed in the hippocampus of the brain, and is a crucial factor of inflammation and cognitive deficits. However, the precise role of RAGE in neuroinflammation is not fully elucidated. In the present study, we aimed to reveal the underlying mechanism by which RAGE regulates neuroinflammation in the pathogenesis of diabetes-induced cognitive impairment. Methods We employed db/db mice as type 2 diabetic mouse models for investigating whether receptor-interacting serine/threonine protein kinase 1 (RIPK1), which expressed in microglia in the hippocampal region, is a key protein that interacts with RAGE. GST pull-down assay and AutoDock Vina were performed to specify the key structural domain in RAGE that binds to RIPK1. Sophisticated molecular technologies including western blot (WB), co-immunoprecipitation (Co-IP) and immunofuorescence (IF) were applied to detect levels of key protein molecules. Furthermore, cognitive deficit of mice was assessed with Morris water maze (MWM), new object recognition (NOR) and fear conditioning tests. Results RAGE binds directly to RIPK1 via its amino acid sequences (AAs) 362–367, thereby upregulating the phosphorylation level of RIPK1, which is accompanied by the activation of NLRP3 inflammasome in microglia and ultimately leads to cognitive impairment in db/db mice. RAGE AAs 362–367 was mutated to reverse neuroinflammation and improve cognitive function in the hippocampus, suggesting that RAGE AAs 362–367 is a key structural domain that binds directly to PIPK1, while implying that hyperglycemia-induced inflammation in hippocampus is dependent on direct binding of RAGE and RIPK1. Conclusions These findings indicate that direct interaction of RAGE and RIPK1 via AAs 362–367 is an important mechanism for enhanced neuroinflammation in the hyperglycemic environment and is a key node in the development of cognitive deficit in diabetes.

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“…Recent studies show that both GLP-1 receptor agonists and SGLT-2 inhibitors have neuroprotective effects in experimental models of acute brain injury. [15][16][17][18][19] We hypothesized that the two drug classes could protect the cerebral microcirculation of diabetic subjects, and their combination may have additive effects on metabolic and microcirculatory alterations of DM. Therefore, the present study aimed to compare the effects of liraglutide and empagliflozin treatments alone and in combination on brain microcirculation using a rat model of DM.…”

Section: Antidiabetic Drugs Such As Glp-1 Receptor Agonists and Sglt2mentioning

confidence: 99%

“…Recent studies show that both GLP‐1 receptor agonists and SGLT‐2 inhibitors have neuroprotective effects in experimental models of acute brain injury 15–19 . We hypothesized that the two drug classes could protect the cerebral microcirculation of diabetic subjects, and their combination may have additive effects on metabolic and microcirculatory alterations of DM.…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of empagliflozin and liraglutide on the cerebral microcirculation of diabetic rats

d'Avila,

Carlos,

Vieira

et al. 2023

Microcirculation

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ObjectivesThis study aimed to evaluate the effects of the antidiabetics liraglutide, a GLP‐1 analog, and empagliflozin, an SGLT‐2 inhibitor, on the brain microcirculation of diabetic rats.MethodsType 2 diabetes mellitus (DM) was experimentally induced in male Wistar rats by combining a high‐fat diet and a low dose of streptozotocin (35 mg/kg). Liraglutide (100 μg/kg s.c.) and empagliflozin (10 mg/kg, oral) were administered for 5 weeks. Body weight was monitored periodically. Oral glucose tolerance, fasting glycemia, and blood triglycerides were evaluated after the treatments. Endothelial–leukocyte interactions in the brain microcirculation and structural capillary density were assessed.ResultsDM rats presented metabolic and cerebrovascular alterations. Liraglutide treatment decreased body weight and blood triglycerides of DM rats. Empagliflozin treatment improved glucose tolerance but only the combination therapy significantly reduced fasting blood glucose. Both treatments and their combination reduced leukocyte adhesion into the endothelium of brain venules. However, empagliflozin was more effective in preventing DM‐induced microvascular rarefaction.ConclusionThese findings suggest that chronic treatment with SGLT2 inhibitors and GLP‐1 receptor agonists may serve as potential therapeutic approaches to prevent microvascular complications associated with diabetes.

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Hippocampal subfields atrophy contribute more to cognitive impairment in middle-aged patients with type 2 diabetes rather than microvascular lesions

Cited by 17 publications

References 39 publications

Irreversible atrophy in memory brain regions over 7 years is predicted by glycemic control in type 2 diabetes without cognitive decline

Irreversible atrophy in memory brain regions over 7 years is predicted by glycemic control in type 2 diabetes without cognitive decline

Binding of RAGE (AAs 362-367) and RIPK1 induces cognitive deficit in chronic hyperglycemia-derived neuroinflammation

Beneficial effects of empagliflozin and liraglutide on the cerebral microcirculation of diabetic rats

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