Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: April 10, 2023

Abstract Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on single vascular complication are no longer suitable for the long-term management patients with diabetes. Diabetic panvascular disease (DPD) is clinical syndrome in which vessels various sizes, including macrovessels microvessels cardiac, cerebral, renal, ophthalmic, peripheral systems diabetes, develop atherosclerosis as common pathology. Pathological manifestations DPDs usually manifest macrovascular atherosclerosis, well microvascular endothelial function impairment, basement membrane thickening, microthrombosis. Cardiac, microangiopathy coexist microangiopathy, while renal retinal predominantly microangiopathic. The following associations exist between DPDs: numerous similar molecular mechanisms, risk-predictive relationships diseases. Aggressive glycemic control combined early comprehensive intervention key prevention treatment. In addition widely recommended metformin, glucagon-like peptide-1 agonist, sodium-glucose cotransporter-2 inhibitors, latest aldose reductase peroxisome proliferator-activated receptor-γ agonizts, glucokinases mitochondrial energy modulators, etc. under active development. proposed obtain more systematic care requires center focusing This would leverage advantages cross-disciplinary approach achieve better integration pathogenesis therapeutic evidence. Such strategy confer benefits promote development DPD discipline.

Language: Английский

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Association of Sodium–Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study

Diabetes Care, Journal Year: 2022, Volume and Issue: 46(2), P. 297 - 304

Published: Dec. 12, 2022

OBJECTIVE Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate risk remains lacking. This population-based retrospective cohort study aimed determine whether new use of sodium–glucose cotransporter (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) was associated lower risk. RESEARCH DESIGN AND METHODS Ontario residents aged ≥66 years who were users an SGLT2 inhibitor or a DPP-4 from 1 July 2016 31 March 2021 entered the cohort. Incident identified using validated algorithm for Alzheimer’s disease and related dementias. Propensity score–weighted Cox proportional hazards models used obtain adjusted hazard ratios (aHR) CIs time incident dementia. To address reverse causality latency, observation window started at 1-year lag entry. The primary analysis followed intention-to-treat exposure definition, secondary as-treated performed. RESULTS Among 106,903 individuals, (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71–0.89]) over mean follow-up 2.80 When stratified by different inhibitors, dapagliflozin exhibited lowest (aHR 0.67 0.53–0.84]), empagliflozin 0.78 0.69–0.89]), whereas canagliflozin showed no association 0.96 0.80–1.16]). observed larger 0.66 0.57–0.76]) than analysis. CONCLUSIONS in older people T2D. Randomized controlled trials are warranted.

Language: Английский

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Metabolic Syndrome as a Risk Factor for Alzheimer’s Disease: A Focus on Insulin Resistance

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4354 - 4354

Published: Feb. 22, 2023

Alzheimer's disease (AD) is the main type of dementia and a with profound socioeconomic burden due to lack effective treatment. In addition genetics environmental factors, AD highly associated metabolic syndrome, defined as combination hypertension, hyperlipidemia, obesity 2 diabetes mellitus (T2DM). Among these risk connection between T2DM has been deeply studied. It suggested that mechanism linking both conditions insulin resistance. Insulin an important hormone regulates not only peripheral energy homeostasis but also brain functions, such cognition. desensitization, therefore, could impact normal function increasing developing neurodegenerative disorders in later life. Paradoxically, it demonstrated decreased neuronal signalling can have protective role aging protein-aggregation-associated diseases, case AD. This controversy fed by studies focused on signalling. However, action other cell types, astrocytes, still unexplored. Therefore, worthwhile exploring involvement astrocytic receptor cognition, well onset and/or development

Language: Английский

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Newer glucose‐lowering drugs and risk of dementia: A systematic review and meta‐analysis of observational studies

Journal of the American Geriatrics Society, Journal Year: 2023, Volume and Issue: 71(7), P. 2096 - 2106

Published: Feb. 23, 2023

Abstract Background Preclinical studies have suggested potential beneficial effects of newer glucose‐lowering drugs (GLDs) including dipeptidyl peptidase (DPP)‐4 inhibitors, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs), and sodium glucose co‐transporter‐2 (SGLT2) in protecting humans against cognitive decline dementia. However, population aiming to demonstrate such benefits from GLDs produced mixed findings. This meta‐analysis aimed evaluate the association between risk dementia adults with type 2 diabetes (T2D). Methods Electronic databases were searched up March 11, 2022 include observational that examined DPP‐4 GLP‐1RAs, SGLT2 inhibitors (including all‐cause dementia, Alzheimer's disease [AD], vascular [VD]) people T2D. We conducted a random‐effects calculate relative (RR) 95% confidence interval (CI) for each class GLD. Results Ten (from nine articles) involving 819,511 individuals T2D included. Three found inhibitor users had lower than non‐SGLT2 (RR, 0.62; CI, 0.39–0.97). Five versus nonusers GLP‐1RAs associated significant reduction 0.72; 0.54–0.97). AD VD was unavailable because only one study included drug. In seven studies, vs. significantly decreased 0.84; 0.74–0.94) 0.59; 0.47–0.75) but not 0.82; 0.63–1.08). Conclusion Newer Because nature heterogeneity results should be interpreted caution. Further research is warranted confirm our

Language: Английский

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Advances in Research on Type 2 Diabetes Mellitus Targets and Therapeutic Agents

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(17), P. 13381 - 13381

Published: Aug. 29, 2023

Diabetes mellitus is a chronic multifaceted disease with multiple potential complications, the treatment of which can only delay and prolong terminal stage disease, i.e., type 2 diabetes (T2DM). The World Health Organization predicts that will be seventh leading cause death by 2030. Although many antidiabetic medicines have been successfully developed in recent years, such as GLP-1 receptor agonists SGLT-2 inhibitors, single-target drugs are gradually failing to meet therapeutic requirements owing individual variability, diversity pathogenesis, organismal resistance. Therefore, there remains need investigate pathogenesis T2DM more depth, identify targets, provide improved glycemic control solutions. This review presents an overview mechanisms action development latest agents targeting years. It also discusses emerging target-based therapies new targets emerged within last three aim our theoretical basis for further advancement targeted T2DM.

Language: Английский

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Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Nervous System Disorders: A Systematic Review and Meta-Analysis

Annals of Pharmacotherapy, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 23, 2025

Background: Adults with type 2 diabetes mellitus (T2DM) are at an increased risk for certain brain or psychiatric disorders, as those without chronic kidney disease heart failure. Whether sodium-glucose cotransporter (SGLT2) inhibitors associated these diseases is unclear. Objective: This systematic review and meta-analysis aimed to investigate the effects of SGLT2 on nervous system disorders. Methods: We searched PubMed, ClinicalTrials.gov, Web Science randomized, double-blind placebo-controlled trials least ≥24 weeks. used Mantel–Haenszel statistical method, ratio (RR), 95% confidence interval (CI) dichotomous variables. Results: included 52 publications/trials covering 111 376 participants (SGLT2 62 192; Placebo 49 184). Sodium-glucose had no significant effect ischaemic stroke (RR = 0.97; CI 0.87-1.09; P 0.64), cerebrovascular accident 1.05; 0.91-1.22; 0.50), dementia 1.29; 0.78-2.12; 0.32), carotid artery occlusion/carotid stenosis 1.18; CI: 0.92-1.53; 0.20), haemorrhagic 0.84; 0.62-1.12; 0.23), transient attack 0.82-1.15; 0.73) compared placebo. No heterogeneity was observed. However, showed slight reduce Parkinson’s (major failure subgroup). Empagliflozin dapagliflozin significantly syncope 1.65; 1.15-2.38; < 0.01) 1.04-2.61; 0.03), respectively. Conclusion Relevance: disorders There reduced Disease observed in some specific populations. In addition, risks empagliflozin concerning worth attention.

Language: Английский

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Type 2 diabetes mellitus and cognitive function: understanding the connections

Current Opinion in Endocrinology Diabetes and Obesity, Journal Year: 2022, Volume and Issue: 30(1), P. 7 - 13

Published: Nov. 17, 2022

Purpose of review To the connection between type 2 diabetes and cognitive dysfunction, including its epidemiology, potential mechanisms pathophysiology, risk factors, possible prevention, treatment considerations. Recent findings Diabetes is a factor for mild decline, in addition to Alzheimer's disease vascular dementia. Duration diabetes, concomitant or associated co-morbidities, hyper- hypoglycemia may lead worsening dysfunction. Unfortunately, there lack evidence-based guidance on prevention dysfunction population. Studies medications, metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 inhibitors (SGLT2) have shown some benefit with cardiovascular morbidity affect cognition. In absence clearly defined preventive tools, practice guidelines recommend annual screening as standard care adults aged 65 years older. Summary People living are at significant decline function. Epidemiology factors well defined. Prevention strategies limited require further study.

Language: Английский

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Unlocking the Full Potential of SGLT2 Inhibitors: Expanding Applications beyond Glycemic Control

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6039 - 6039

Published: March 23, 2023

The number of diabetic patients has risen dramatically in recent decades, owing mostly to the rising incidence type 2 diabetes mellitus (T2DM). Several oral antidiabetic medications are used for treatment T2DM including, α-glucosidases inhibitors, biguanides, sulfonylureas, meglitinides, GLP-1 receptor agonists, PPAR-γ DDP4 and SGLT2 inhibitors. In this review we focus on possible effects inhibitors different body systems. Beyond state, have revealed a demonstrable ability ameliorate cardiac remodeling, enhance myocardial function, lower heart failure mortality. Additionally, can modify adipocytes their production cytokines, such as adipokines adiponectin, which enhances insulin sensitivity delays onset. On other hand, been linked decreased total hip bone mineral deposition increased resorption patients. More data needed evaluate role cancer. Finally, neuroprotection appear be both direct indirect, according scientific investigations utilizing various experimental models. improve vascular tone, elasticity, contractility by reducing oxidative stress, inflammation, signaling pathways, endothelial cell proliferation. They also brain synaptic plasticity, acetylcholinesterase activity, reduce amyloid plaque formation, well regulation mTOR pathway brain, reduces damage cognitive decline.

Language: Английский

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Shared biological mechanisms of depression and obesity: focus on adipokines and lipokines

Aging, Journal Year: 2023, Volume and Issue: unknown

Published: June 29, 2023

Depression and obesity are both common disorders currently affecting public health, frequently occurring simultaneously within individuals, the relationship between these is bidirectional. The association depression highly co-morbid tends to significantly exacerbate metabolic related depressive symptoms. However, neural mechanism under mutual control of largely inscrutable. This review focuses particularly on alterations in systems that may mechanistically explain vivo homeostatic regulation link, such as immune-inflammatory activation, gut microbiota, neuroplasticity, HPA axis dysregulation well neuroendocrine regulators energy metabolism including adipocytokines lipokines. In addition, summarizes potential future treatments for raises several questions need be answered research. will provide a comprehensive description localization biological connection better understand co-morbidity depression.

Language: Английский

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The gut microbiota‐astrocyte axis: Implications for type 2 diabetic cognitive dysfunction

CNS Neuroscience & Therapeutics, Journal Year: 2023, Volume and Issue: 29(S1), P. 59 - 73

Published: Jan. 4, 2023

Abstract Background Diabetic cognitive dysfunction (DCD) is one of the most insidious complications type 2 diabetes mellitus, which can seriously affect ability to self‐monitoring blood glucose and quality life in elderly. Previous pathological studies have focused on neuronal dysfunction, characterized by extracellular beta‐amyloid deposition intracellular tau hyperphosphorylation. In recent years, astrocytes been recognized as a potential therapeutic target for important participants central control metabolism. The disorder gut microbiota their metabolites linked series metabolic diseases such mellitus. imbalance intestinal flora has effect promoting occurrence deterioration several diabetes‐related complications. Gut microbes drive astrocyte activation. Aims We reviewed progress DCD related “gut microbiota‐astrocyte” axis terms peripheral inflammation, blood–brain barrier (BBB) systemic brain energy metabolism disorders deepen research explore targets. Conclusion “Gut axis, unique bidirectional crosstalk brain‐gut mediates intermediate process neurocognitive secondary

Language: Английский

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