Low‐glucose‐sensitive TRPC6 dysfunction drives hypoglycemia‐induced cognitive impairment in diabetes

He, Chengkang; Gao, Peng; Cui, Yuanting; Li, Qiang; Li, Yingsha; Lu, Zongshi; Ma, Hongxia; Zhao, Yu; Li, Li; Sun, Fang; Chen, Xiaowei; Jia, Hongbo; Liu, Daoyan; Yang, Gangyi; Wang, Cong-Yi; Zhu, Zhiming

doi:10.1002/ctm2.205

Cited by 19 publications

(21 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Currently, there are some controversial results on this issue, because insulin could cause hypoglycemia related cognitive damage in patients with T2DM. 31 , 32 Importantly, GLP‐1 RA activation was found to increase in the cAMP levels leading to the modulation of downstream kinases that are related to growth factor signaling, which may thereby restore brain insulin resistance and reduce levels of amyloid‐β peptide. 26 …”

Section: Discussionmentioning

confidence: 99%

Activation of Glucagon‐Like Peptide‐1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism‐Independent Pathway

Jia

Yan

et al. 2021

JAHA

Self Cite

View full text Add to dashboard Cite

Background Patients with hypertension and diabetes mellitus are susceptible to dementia, but regular therapy fails to reduce the risk of dementia. Glucagon‐like peptide‐1 receptor agonists have neuroprotective effects in experimental studies. We aimed to assess the effect of liraglutide, a glucagon‐like peptide‐1 receptor agonist, on cognitive function and whether its effect was associated with metabolic changes in patients with type 2 diabetes mellitus. Methods and Results Fifty patients with type 2 diabetes mellitus were recruited in this prospective study. All patients underwent cognitive assessment and brain activation monitoring by functional near‐infrared spectroscopy. At 12 weeks, patients in the glucagon‐like peptide‐1 group acquired better scores in all cognitive tests and showed remarkable improvement in memory and attention ( P =0.040) test compared with the control group after multivariable adjustment. Compared with the control group, liraglutide significantly increased activation of the dorsolateral prefrontal cortex and orbitofrontal cortex brain regions ( P =0.0038). After liraglutide treatment, cognitive scores were significantly correlated with changes in these activating brain regions ( P <0.05), but no correlation was observed between the changes in cognitive function and changes of body mass index, blood pressure, and glycemic levels. Conclusions We concluded that liraglutide improves cognitive decline in patients with type 2 diabetes mellitus. This beneficial effect is independent of its hypoglycemic effect and weight loss. The optimal intervention should be targeted to cognitive decline in the early stages of dementia. Registration URL: https://www.ClinicalTrials.gov ; Unique identifier: NCT03707171.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of Glucagon‐Like Peptide‐1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism‐Independent Pathway

Jia

Yan

et al. 2021

JAHA

Self Cite

View full text Add to dashboard Cite

show abstract

“…TRPC6 is expressed in many different brain regions, such as the cortex, hippocampus, cerebellum, basal ganglia, thalamus, hypothalamus, and dorsal root ganglia [ 57 ]. Numerous studies have documented that the expression of TRPC6 in primary cultured neurons or neuronal cell lines is protective under various stress conditions [ 48 , 58 , 59 , 60 , 61 , 62 ].…”

Section: Cell-specific Roles Of Trpc6mentioning

confidence: 99%

Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke

Shekhar

Liu

Wang

et al. 2021

IJMS

View full text Add to dashboard Cite

Ischemic stroke is one of the most disabling diseases and a leading cause of death globally. Despite advances in medical care, the global burden of stroke continues to grow, as no effective treatments to limit or reverse ischemic injury to the brain are available. However, recent preclinical findings have revealed the potential role of transient receptor potential cation 6 (TRPC6) channels as endogenous protectors of neuronal tissue. Activating TRPC6 in various cerebral ischemia models has been found to prevent neuronal death, whereas blocking TRPC6 enhances sensitivity to ischemia. Evidence has shown that Ca2+ influx through TRPC6 activates the cAMP (adenosine 3’,5’-cyclic monophosphate) response element-binding protein (CREB), an important transcription factor linked to neuronal survival. Additionally, TRPC6 activation may counter excitotoxic damage resulting from glutamate release by attenuating the activity of N-methyl-D-aspartate (NMDA) receptors of neurons by posttranslational means. Unresolved though, are the roles of TRPC6 channels in non-neuronal cells, such as astrocytes and endothelial cells. Moreover, TRPC6 channels may have detrimental effects on the blood–brain barrier, although their exact role in neurovascular coupling requires further investigation. This review discusses evidence-based cell-specific aspects of TRPC6 in the brain to assess the potential targets for ischemic stroke management.

show abstract

“…A growing body of evidence indicates a link between impaired glucose metabolism in the central nervous system and AD [17,[64][65][66]. It was shown that reduced glucose availability in the brain directly triggers behavioral deficits by promoting the development of tau neuropathology and synaptic dysfunction [17,18].…”

Section: Comparative Analysis Of the Gene Network Of Hypoglycemia Cognitive Decline And Admentioning

confidence: 99%

Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks

Saik

Климонтов

2021

IJMS

View full text Add to dashboard Cite

Hypoglycemia has been recognized as a risk factor for diabetic vascular complications and cognitive decline, but the molecular mechanisms of the effect of hypoglycemia on target organs are not fully understood. In this work, gene networks of hypoglycemia and cardiovascular disease, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, cognitive decline, and Alzheimer’s disease were reconstructed using ANDSystem, a text-mining-based tool. The gene network of hypoglycemia included 141 genes and 2467 interactions. Enrichment analysis of Gene Ontology (GO) biological processes showed that the regulation of insulin secretion, glucose homeostasis, apoptosis, nitric oxide biosynthesis, and cell signaling are significantly enriched for hypoglycemia. Among the network hubs, INS, IL6, LEP, TNF, IL1B, EGFR, and FOS had the highest betweenness centrality, while GPR142, MBOAT4, SLC5A4, IGFBP6, PPY, G6PC1, SLC2A2, GYS2, GCGR, and AQP7 demonstrated the highest cross-talk specificity. Hypoglycemia-related genes were overrepresented in the gene networks of diabetic complications and comorbidity; moreover, 14 genes were mutual for all studied disorders. Eleven GO biological processes (glucose homeostasis, nitric oxide biosynthesis, smooth muscle cell proliferation, ERK1 and ERK2 cascade, etc.) were overrepresented in all reconstructed networks. The obtained results expand our understanding of the molecular mechanisms underlying the deteriorating effects of hypoglycemia in diabetes-associated vascular disease and cognitive dysfunction.

show abstract

Low‐glucose‐sensitive TRPC6 dysfunction drives hypoglycemia‐induced cognitive impairment in diabetes

Cited by 19 publications

References 71 publications

Activation of Glucagon‐Like Peptide‐1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism‐Independent Pathway

Activation of Glucagon‐Like Peptide‐1 Receptor Ameliorates Cognitive Decline in Type 2 Diabetes Mellitus Through a Metabolism‐Independent Pathway

Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke

Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks

Contact Info

Product

Resources

About