Effects of equivalent sympathetic activation during hypoglycemia on endothelial function and pro-atherothrombotic balance in healthy individuals and obese standard treated type 2 diabetes

Joy, Nino G.; Mikeladze, Maia; Younk, Lisa M.; Tate, Donna B.

doi:10.1016/j.metabol.2016.09.001

Cited by 19 publications

(13 citation statements)

References 55 publications

(68 reference statements)

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“…Although hypoglycemia frequency may be increased in these individuals, this may also lower unwanted and deleterious effects on the vasculature from counterregulatory responses. On the other hand, an isolated severe hypoglycemic event in a less well-controlled individual could provoke a relatively greater counterregulatory response with a proportionally attendant elevated risk for adverse vascular effects (22). In support of this, we previously reported in a subset of VADT participants that despite more frequent serious hypoglycemia in the intensive therapy group, progression of coronary artery calcium scores after severe hypoglycemia only occurred in the standard treatment group (23).…”

Section: Discussionmentioning

confidence: 99%

Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial

et al. 2018

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OBJECTIVETo determine the risk factors for severe hypoglycemia and the association between severe hypoglycemia and serious cardiovascular adverse events and cardiovascular and all-cause mortality in the Veterans Affairs Diabetes Trial (VADT).RESEARCH DESIGN AND METHODSThis post hoc analysis of data from the VADT included 1,791 military veterans (age 60.5 ± 9.0 years) with suboptimally controlled type 2 diabetes (HbA1c 9.4 ± 2.0%) of 11.5 ± 7.5 years disease duration with or without known cardiovascular disease and additional cardiovascular risk factors. Participants were randomized to intensive (HbA1c <7.0%) versus standard (HbA1c <8.5%) glucose control.RESULTSThe rate of severe hypoglycemia in the intensive treatment group was 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P < 0.001). In multivariable analysis, insulin use at baseline (P = 0.02), proteinuria (P = 0.009), and autonomic neuropathy (P = 0.01) were independent risk factors for severe hypoglycemia, and higher BMI was protective (P = 0.017). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = 0.032), cardiovascular mortality (P = 0.012), and total mortality (P = 0.024). However, there was a relatively greater increased risk for total mortality in the standard group compared with the intensive group (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased (P = 0.012).CONCLUSIONSSevere hypoglycemic episodes within the previous 3 months were associated with increased risk for major cardiovascular events and cardiovascular and all-cause mortality regardless of glycemic treatment group assignment. Standard therapy further increased the risk for all-cause mortality after severe hypoglycemia.

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Section: Discussionmentioning

confidence: 99%

Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial

et al. 2018

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“…Furthermore, glibenclamide and glimepiride carry a higher risk of hypoglycemia thangliclazide [36]. Low blood glucose levels increase blood PAI-1 levels [37], which may beanother reason why blood PAI-1 levels are lower after using gliclazide than after using glimepiride. However, in this study, we did not observe that blood PAI-1 levels were lowered more significantly by gliclazide than by the placebo.…”

Section: Discussionmentioning

confidence: 99%

Effects of sulfonylurea treatment on blood plasminogen activator inhibitor-1 levels in patients with type 2 diabetes mellitus: A network meta-analysis

Ida¹,

Murata²,

Kaneko³

2018

J Diab Res Clin Met

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Background: To compare the effects ofthree types of sulfonylureas (glibenclamide, gliclazide, and glimepiride) on blood plasminogen activator inhibitor-1 levels in patients with type2 diabetes mellitus, a network meta-analysis of randomized controlled trialswas performed. Methods: A literature search using MEDLINE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted. Randomized controlled trialsin which the effects of sulfonylureas on blood plasminogen activator inhibitor-1 levels in patients with type 2 diabetes mellitus were evaluated were includes. Outcome assessment included standardized mean differences and 95% confidence intervals. Results: Twelve randomized controlled trials (1,050 subjects) met the inclusion criteria and were included in the network meta-analysis. No significant difference was observedin blood plasminogen activator inhibitor-1 levels after using a placebo compared with those after using glibenclamide, gliclazide, and glimepiride. Blood plasminogen activator inhibitor-1levels were significantly lower after using gliclazide than after using glimepiride (standardized mean difference: -0.52; 95% confidence interval: -0.99%-0.44%). However, no significant difference was observed in blood plasminogen activator inhibitor-1 levels after using glibenclamide compared with those after using gliclazide and glime piride. Conclusions: Regarding the use of sulfonylureas for treating patients with type 2 diabetes mellitus, gliclazide may be preferable because of low blood plasminogen activator inhibitor-1 levels after its use. However, few studies have been published on the use of gliclazide, and the quality of these studies has been generally poor; thus, the results of this study should be interpreted with caution.

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“…We next asked whether the glycemic modulations could affect IRF5 expression in macrophages. Notably, both hyperglycemia [ 33 , 34 ] and hypoglycemia [ 35 , 36 ] have been implicated in the progression of T2D-associated pathologies. Therefore, to test the effects of both high and low glucose concentrations on IRF5 expression, we cultured the THP-1-derived macrophages under five different glycemic conditions as described in the Materials and Methods section.…”

Section: Resultsmentioning

confidence: 99%

Repetitive Intermittent Hyperglycemia Drives the M1 Polarization and Inflammatory Responses in THP-1 Macrophages Through the Mechanism Involving the TLR4-IRF5 Pathway

Al-Rashed

Sindhu

Arefanian

et al. 2020

Cells

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Repetitive intermittent hyperglycemia (RIH) is an independent risk factor for complications associated with type-2 diabetes (T2D). Glucose fluctuations commonly occur in T2D patients with poor glycemic control or following intensive therapy. Reducing blood glucose as well as glucose fluctuations is critical to the control of T2D and its macro-/microvascular complications. The interferon regulatory factor (IRF)-5 located downstream of the nutrient sensor toll-like receptor (TLR)-4, is emerging as a key metabolic regulator. It remains unclear how glucose fluctuations may alter the IRF5/TLR4 expression and inflammatory responses in monocytes/macrophages. To investigate this, first, we determined IRF5 gene expression by real-time qRT-PCR in the white adipose tissue samples from 39 T2D and 48 nondiabetic individuals. Next, we cultured THP-1 macrophages in hypo- and hyperglycemic conditions and compared, at the protein and transcription levels, the expressions of IRF5, TLR4, and M1/M2 polarization profile and inflammatory markers against control (normoglycemia). Protein expression was assessed using flow cytometry, ELISA, Western blotting, and/or confocal microscopy. IRF5 silencing was achieved by small interfering RNA (siRNA) transfection. The data show that adipose IRF5 gene expression was higher in T2D than nondiabetic counterparts (p = 0.006), which correlated with glycated hemoglobin (HbA1c) (r = 0.47/p < 0.001), homeostatic model assessment of insulin resistance (HOMA-IR) (r = 0.23/p = 0.03), tumor necrosis factor (TNF)-α (r = 0.56/p < 0.0001), interleukin (IL)-1β (r = 0.40/p = 0.0009), and C-C motif chemokine receptor (CCR)-2 (r = 0.49/p < 0.001) expression. IRF5 expression in macrophages was induced/upregulated (p < 0.05) by hypoglycemia (3 mM/L), persistent hyperglycemia (15 mM/L–25 mM/L), and RIH/glucose fluctuations (3–15 mM/L) as compared to normoglycemia (5 mM/L). RIH/glucose fluctuations also induced M1 polarization and an inflammatory profile (CD11c, IL-1β, TNF-α, IL-6, and monocyte chemoattractant protein (MCP)-1) in macrophages. RIH/glucose fluctuations also drove the expression of matrix metalloproteinase (MMP)-9 (p < 0.001), which is a known marker for cardiovascular complication in T2D patients. Notably, all these changes were counteracted by IRF5 silencing in macrophages. In conclusion, RIH/glucose fluctuations promote the M1 polarization and inflammatory responses in macrophages via the mechanism involving TLR4-IRF5 pathway, which may have significance for metabolic inflammation.

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Effects of equivalent sympathetic activation during hypoglycemia on endothelial function and pro-atherothrombotic balance in healthy individuals and obese standard treated type 2 diabetes

Cited by 19 publications

References 55 publications

Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial

Effects of Severe Hypoglycemia on Cardiovascular Outcomes and Death in the Veterans Affairs Diabetes Trial

Effects of sulfonylurea treatment on blood plasminogen activator inhibitor-1 levels in patients with type 2 diabetes mellitus: A network meta-analysis

Repetitive Intermittent Hyperglycemia Drives the M1 Polarization and Inflammatory Responses in THP-1 Macrophages Through the Mechanism Involving the TLR4-IRF5 Pathway

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