GLP-1R Agonists and Endothelial Dysfunction: More Than Just Glucose Lowering?

Lovshin, Julie A.; Cherney, David Z.I.

doi:10.2337/db15-0366

Cited by 15 publications

(13 citation statements)

References 21 publications

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“…Further studies are required to clarify the exact loci of actions for GLP-1R agonists. Due to multiple GLP-1R expression sites 32,[36][37][38] and capability of GLP-1R agonists to cross the BBB 80,81 , it remains to be determined whether the neurovascular benefits of GLP-1R agonist treatment may depend on vascular or glial cell GLP-1R, or acts by modulating immune cells or altering compositions in the peripheral circulation.…”

Section: Discussionmentioning

confidence: 99%

“…Originally developed to potentiate glucose-induced insulin release and treatment of diabetes, glucagon-like 1-peptide receptor (GLP-1R) agonists were reported to have therapeutic efficacy in multiple animal models of neurodegenerative diseases including AD, ALS, PD [28][29][30][31][32][33] and in human trials of AD and PD 34,35 . In the brain, GLP-1R is expressed by multiple cell types, including neurons, microglia and potentially vascular cells 32,[36][37][38] . It remains to be tested, whether GLP-1R agonists may act partly via reversal of neurovascular ageing, accounting for the general applicability as potential therapeutics for multiple neurodegenerative conditions.…”

Section: Introductionmentioning

confidence: 99%

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Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Zhao

Vong

et al. 2019

Preprint

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With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail 1,2 , yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases 3-7 remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed -the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions [8][9][10][11][12][13][14][15][16][17] . Furthermore, an overrepresentation of Alzheimer's disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with 2 exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Zhao

Vong

et al. 2019

Preprint

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“…The reasons for differences in impact between DPP-4 inhibitors and GLP-1 agonists on endothelial function could be related to several factors like differences in study design, including timing of measurements relative to meals and differences in the activity of comparator therapies 42–44 . Native GLP-1 is released in response to meals.…”

Section: Discussionmentioning

confidence: 99%

Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy

et al. 2017

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Cell culture and animal work indicate that dipeptidyl peptidase-4 (DPP-4) inhibition may exert cardiovascular benefits through favorable effects on the vascular endothelium. Prior human studies evaluating DPP-4 inhibition have shown conflicting results that may in part be related to heterogeneity of background anti-diabetes therapies. No study has evaluated the acute response of the vasculature to DPP-4 inhibition in humans. We recruited 38 patients with type 2 diabetes on stable background metformin therapy for a randomized, double-blind, placebo-controlled crossover trial of DPP-4 inhibition with sitagliptin (100 mg/day). Each treatment period was eight weeks long separated by four weeks of washout. Endothelial function and plasma markers of endothelial activation (ICAM-1 and VCAM-1) were measured prior to and two hours following acute dosing of sitagliptin or placebo, as well as following eight weeks of intervention with each pill. Thirty subjects completed the study and were included in analyses. Neither acute nor chronic sitagliptin therapy resulted in significant changes in vascular endothelial function. While post-acute sitagliptin ICAM-1 levels were lower than that post-chronic sitagliptin, the ICAM-1 concentration was not significantly different than pre-acute sitagliptin levels or levels measured in relationship to placebo. There were no significant changes in plasma VCAM-1 levels at any time point. Acute and chronic sitagliptin therapies have neutral effects on the vascular endothelium in the setting of metformin background therapy. Our findings suggest DPP-4 inhibition has a neutral effect on cardiovascular risk in patients without a history of heart failure or renal insufficiency.

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“…Recent novel treatments also suggest a role for effects on microvascular function. Notably, glucagon-like peptide 1 receptor agonists may improve endothelial function in arterioles through an AMPK-dependent pathway (144,145) and are also associated with improved recruitment of skeletal muscle and cardiac microvasculature (146,147). Recent outcome trials have shown that glucagon-like peptide 1 receptor agonists can improve renal outcomes in T2D in a way not clearly explained by improved glycemic control (148), but their effects on retinopathy need further clarification (149).…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

Microvascular Dysfunction and Hyperglycemia: A Vicious Cycle With Widespread Consequences

2018

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Microvascular and metabolic physiology are tightly linked. This Perspective reviews evidence that ) the relationship between hyperglycemia and microvascular dysfunction (MVD) is bidirectional and constitutes a vicious cycle;) MVD in diabetes affects many, if not all, organs, which may play a role in diabetes-associated comorbidities such as depression and cognitive impairment; and ) MVD precedes, and contributes to, hyperglycemia in type 2 diabetes (T2D) through impairment of insulin-mediated glucose disposal and, possibly, insulin secretion. Obesity and adverse early-life exposures are important drivers of MVD. MVD can be improved through weight loss (in obesity) and through exercise. Pharmacological interventions to improve MVD are an active area of investigation.

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GLP-1R Agonists and Endothelial Dysfunction: More Than Just Glucose Lowering?

Cited by 15 publications

References 21 publications

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

Impact of DPP-4 inhibition on acute and chronic endothelial function in humans with type 2 diabetes on background metformin therapy

Microvascular Dysfunction and Hyperglycemia: A Vicious Cycle With Widespread Consequences

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