Vitamin C intake potentially lowers total cholesterol to improve endothelial function in diabetic patients at increased risk of cardiovascular disease: A systematic review of randomized controlled trials

Background: Vitamin C is one of the most consumed dietary compounds and contains abundant antioxidant properties that could be essential in improving metabolic function. Thus, the current systematic review analyzed evidence on the beneficial effects of vitamin C intake on cardiovascular disease (CVD)-related outcomes in patients with diabetes or metabolic syndrome. Methods: To identify relevant randomized control trials (RCTs), a systematic search was run using prominent search engines like PubMed and Google Scholar, from beginning up to March 2022. The modified Black and Downs checklist was used to assess the quality of evidence. Results: Findings summarized in the current review favor the beneficial effects of vitamin C intake on improving basic metabolic parameters and lowering total cholesterol levels to reduce CVD-risk in subjects with type 2 diabetes or related metabolic diseases. Moreover, vitamin C intake could also reduce the predominant markers of inflammation and oxidative stress like C-reactive protein, interleukin-6, and malondialdehyde. Importantly, these positive outcomes were consistent with improved endothelial function or increased blood flow in these subjects. Predominantly effective doses were 1,000 mg/daily for 4 weeks up to 12 months. The included RCTs presented with the high quality of evidence. Conclusion: Clinical evidence on the beneficial effects of vitamin C intake or its impact on improving prominent markers of inflammation and oxidative stress in patients with diabetes is still limited. Thus, more RCTs are required to solidify these findings, which is essential to better manage diabetic patients at increased risk of developing CVD

Coenzyme Q10 supplementation improves adipokine levels and alleviates inflammation and lipid peroxidation in conditions of metabolic syndrome : a meta-analysis of randomized controlled trials

CITATION: Dludla, P. V., et al. 2020. Q10 Supplementation Improves Adipokine Levels and Alleviates Inflammation and Lipid Peroxidation in Conditions of Metabolic Syndrome: A Meta-Analysis of Randomized Controlled Trials. International Journal of Molecular Sciences. 2020; 21(9). doi:10.3390/ijms21093247The original publication is available at https://www.mdpi.com/journal/ijmsEvidence from randomized controlled trials (RCTs) suggests that coenzyme Q10 (CoQ10) can regulate adipokine levels to impact inflammation and oxidative stress in conditions of metabolic syndrome. Here, prominent electronic databases such as MEDLINE, Cochrane Library, and EMBASE were searched for eligible RCTs reporting on any correlation between adipokine levels and modulation of inflammation and oxidative stress in individuals with metabolic syndrome taking CoQ10. The risk of bias was assessed using the modified Black and Downs checklist, while the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to evaluate the quality of evidence. Results from the current meta-analysis, involving 318 participants, showed that CoQ10 supplementation in individuals with metabolic syndrome increased adiponectin levels when compared to those on placebo (SMD: 1.44 [95% CI: −0.13, 3.00]; I2 = 96%, p < 0.00001). Moreover, CoQ10 supplementation significantly lowered inflammation markers in individuals with metabolic syndrome in comparison to those on placebo (SMD: −0.31 [95% CI: −0.54, −0.08]; I2 = 51%, p = 0.07). Such benefits with CoQ10 supplementation were related to its ameliorative effects on lipid peroxidation by reducing malondialdehyde levels, concomitant to improving glucose control and liver function. The overall findings suggest that optimal regulation of adipokine function is crucial for the beneficial effects of CoQ10 in improving metabolic health.https://www.mdpi.com/1422-0067/21/9/3247/htmPublishers versio

Expression of Caspase-3 in Circulating Innate Lymphoid Cells Subtypes Is Altered by Treatment with Metformin and Fluvastatin in High-Fat Diet Fed C57BL/6 Mice

The current study aimed to determine the expression levels of caspase-3 in circulating innate lymphoid cell subtypes (ILCs) in a high-fat diet (HFD)-induced prediabetes mouse model. Another critical point was to assess the therapeutic effects of metformin and fluvastatin in modulating caspase-3 activation in ILCs within these HFD-fed mice. Prominent results showed that mice exposed to HFD for 14 weeks displayed impaired glucose tolerance that was accompanied by elevated levels of low-density lipoprotein cholesterol (LDL-c) and altered haematological profile as characterised by significantly increased concentrations of red blood cell count, white cell count and lymphocytes when compared to those fed a low-fat diet (LFD). Moreover, the expression of caspase-3 in ILC1 and ILC3 was significantly increased in the HFD groups in comparison to the LFD-fed group. Notably, six-week treatment with metformin and fluvastatin reduced the caspase-3 activation in ILC subtypes. The reduced caspase-3 activation in ILC1 was inversely associated with HDL-c levels following metformin treatment. Interestingly, the reduced caspase-3 activation in ILC3 was associated with lower total cholesterol following fluvastatin treatment in these HFD-fed mice. However, there were no differences in activation of caspase-3 on ILC2 or any association between caspase-3 activation and changes in body weight or fasting blood glucose. Thus, while HFD-feeding clearly modulates ILCs, potentially leading to pro-apoptotic mechanisms, metformin and fluvastatin may play a major role in protecting against such metabolic disturbances

The impact of metformin and aspirin on T-cell mediated inflammation: A systematic review of in vitro and in vivo findings

Chronic inflammation and hyperglycaemia are well-established aspects in the pathogenesis of type 2 diabetes mellitus (T2D), including the progression of its associated complications such as cardiovascular diseases (CVDs). In fact, emerging evidence shows that dysfunctional immune responses due to dysregulated T-cell function aggravates CVD-related complications in T2D. However, there is a lack of specific therapeutic interventions that protect patients with diabetes who are at risk of heart failure. Metformin and aspirin are among the leading therapies being used to protect or at the very least slow the progression of CVD-related complications. The current review made use of major electronic databases to identify and systematically synthesise emerging experimental data on the impact of these pharmacological drugs on T-cell responses. The quality and risk of bias of include evidence were independently assessed by two reviewers. Overwhelming evidence showed that both metformin and aspirin can ameliorate T-cell mediated inflammation by inducing regulatory T-cells (Tregs) polarisation, inhibiting T-cell trafficking and activation as well as signal transducer and activator of transcription (STAT)3 signalling. As a plausible mechanism to mediate T-cell function, metformin showed enhanced potential to regulate mechanistic targets of rapamycin (mTOR), STAT5 and adenosine-monophosphate-activated protein kinase (AMPK) signalling pathways. Whilst aspirin modulated nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-kB) and co-stimulatory signalling pathways and induced T-cell anergy. Overall, synthesised data prompt further investigation into the combinational effect of metformin and aspirin for the management of T2D-related cardiovascular complications

Elevated T-helper 2 cytokine levels in high fat diet-fed C57BL/6 mice are attenuated by short-term 6-week treatment with a combination of low-dose aspirin and metformin

Objective: To evaluate T-helper cytokine responses in a short-term high fat diet (HFD) induced impaired glucose metabolism. To further evaluate the modulation of T-helper 1 (Th1) and T-helper 2 (Th2) cytokines using short-term low-dose aspirin in combination with metformin. Design: Two experiments were carried out in this study in order to evaluate the T-helper cytokine profiles in a state of impaired glucose metabolism. A total of 28 six-week-old male C57BL/6 mice were used in this study. In the first experiment, mice were fed either a high fat diet or low fat diet for a duration of 10 weeks. We then determined the Th1, Th2 and T-helper 17 (Th17) cytokine profiles. In the second experiment, we evaluated whether the short term 6-week treatment with low-dose aspirin in combination with metformin modulates T-helper cytokine profiles of the HFD-fed mice. Measurements: In the first experiment, we measured the body weights, blood glucose levels, insulin levels, lipid profiles and haematological parameters. We further performed oral glucose tolerance testing following an 8-hour fast and serum Th1, Th2 and Th17 cytokine levels were also determined following short-term 8-week diet-feeding and 6-week low-dose aspirin and combined metformin with low-dose aspirin treatment. Results: High fat diet-feeding caused a marked increase in circulating peripheral blood lymphocytes, which was attenuated by short-term low-dose aspirin treatment. Moreover, the HFD feeding resulted in 2-fold increase in total cholesterol and a 4-fold increase in low-density lipoprotein cholesterol when compared to the low-fat diet-fed group (p 0.05). While the combination of low-dose aspirin with metformin considerably reduced the levels of serum IFN-Ƴ (P < 0.05). Furthermore low-dose aspirin treatment showed the modest attenuation of the selected Th2 cytokines, IL-10 and IL-13 when compared to low-dose aspirin with metformin (P < 0.01). Conclusion: The early immunological and metabolic changes that occur in a state impaired glucose tolerance are accompanied by the increased production of Th2 cell cytokines. The short-term treatment using low-dose aspirin combined with metformin may provide therapeutic benefits in preventing complications associated with dysregulated Th2 cell responses

Adipokines as a therapeutic target by metformin to improve metabolic function: A systematic review of randomized controlled trials

Metformin is a widely used glucose-lowering drug, although its impact on adipose tissue function remains elusive. Adipose tissue-derived molecules regulate diverse physiological mechanisms, including energy metabolism, insulin sensitization, and inflammatory response. Alternatively, it has remained relevant to understand the therapeutic regulation of adipokines in efforts to alleviate inflammation in conditions associated with the metabolic syndrome. The current qualitative analysis of available literature focused on randomized clinical trials (RCTs) assessing the association between administration of metformin and adipokine regulation in individuals with metabolic syndrome. The major electronic databases such as MEDLINE, Cochrane Library, Scopus, and EMBASE were searched for eligible RCTs. Overall, 13 RCTs met the inclusion criteria, with a total of 4605 participants. Patients with metabolic syndrome were characterized by a state of obesity, impaired glucose tolerance, insulin resistance, and type 2 diabetes. Cumulative evidence from these RCTs supported the blood glucose lowering effects of metformin, in addition to promoting weight loss, ameliorating insulin resistance, and reducing pro-inflammatory markers such as interleukin-6 and tumor necrosis factor-α in patients with metabolic syndrome. Importantly, these therapeutic effects are associated with the upregulation of adiponectin and suppression of leptin and resistin

A systematic review on the functional role of Th1/Th2 cytokines in type 2 diabetes and related metabolic complications

The T-helper (Th1/Th2) paradigm is widely studied for its role in modulating an adaptive immune response, especially in relation to the onset of various autoimmune diseases. In fact, emerging evidence clearly shows an inverse relationship between Th1/Th2 cytokines and the development of type 2 diabetes (T2D) complications, which is accelerated by an exacerbated inflammatory state. Here, relevant studies reporting on any association between the levels of Th1/Th2 cytokines and the development of T2D were retrieved through major electronic databases such as The Cochrane Library, Embase and PubMed. Extracted evidence which mostly involved animal models and human subjects with T2D or metabolic syndrome was assessed for quality and risk of bias using the Downs and Black checklist and Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines. Results strongly correlated raised Th1/Th2 cytokines such as interferon-gamma (IFN-γ)/interleukin (IL)-5 and IL-2/IL-5 ratios to T2D, and this was positively linked with the other complications including retinopathy and cardiovascular complications. Further, logistic regression analysis demonstrated that the Th1/Th2 ratios were significantly associated with impaired glucose homeostasis, abnormally enhanced lipid profiles, and insulin resistance. Although more studies making use of a larger sample size are required, current data suggest that optimal modulation of Th1/Th2 cytokines may be an important aspect in the management of T2D and its associated complications

A Meta-Analysis of the Impact of Resveratrol Supplementation on Markers of Renal Function and Blood Pressure in Type 2 Diabetic Patients on Hypoglycemic Therapy

Evidence on the beneficial effects of resveratrol supplementation on cardiovascular disease-related profiles in patients with type 2 diabetes (T2D) is conflicting, while its impact on renal function and blood pressure measurements remains to be established in these patients. The current meta-analysis included randomized controlled trials (RCTs) reporting on the impact of resveratrol supplementation on markers of renal function and blood pressure in patients with T2D on hypoglycemic medication. Electronic databases such as MEDLINE, Cochrane Library, Scopus, and EMBASE were searched for eligible studies from inception up to June 2020. The random and fixed effects model was used in the meta-analysis. A total of five RCTs met the inclusion criteria and involved 388 participants with T2D. Notably, most of the participants were on metformin therapy, or metformin in combination with other hypoglycemic drugs such as insulin and glibenclamide. Pooled estimates showed that resveratrol supplementation in patients with T2D lowered the levels of fasting glucose (SMD: -0.06 [95% CI: -0.24, 0.12]; I2 = 4%, p = 0.39) and insulin (SMD: -0.08 [95% CI: -0.50, 0.34], I2 = 73%, p = 0.002) when compared to those on placebo. In addition, supplementation significantly lowered systolic blood pressure (SMD: -5.77 [95% CI: -8.61, -2.93], I2 = 66%, p = 0.02) in these patients. Although resveratrol supplementation did not affect creatinine or urea levels, it reduced the total protein content (SMD: -0.19 [95% CI: -0.36, -0.02]; I2 = 91%, p = 0.001). In all, resveratrol supplementation in hypoglycemic therapy improves glucose control and lowers blood pressure; however, additional evidence is necessary to confirm its effect on renal function in patients with T2D

The impact of coenzyme Q10 on metabolic and cardiovascular disease profiles in diabetic patients: A systematic review and meta-analysis of randomized controlled trials

Coenzyme Q10 (CoQ10) is well known for its beneficial effects in cardiovascular disease (CVD); however, reported evidence has not been precisely synthesized to better inform on its impact in protecting against cardiovascular-related complications in diabetic patients