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Low grade inflammation is associated with the progression of atherosclerosis. Patients with type 2 diabetes (T2D) have altered cholesterol levels, which are targeted by free radicals to promote lipid peroxidation. Elevated levels of monocyte-associated cytokines such as interleukin (IL)-6, monocyte chemoattractant protein 1 (MCP-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and tumor necrosis factor-alpha (TNF-α), subsequently drive endothelial tissue injury. In fact, the levels of circulating platelet-monocyte aggregates in patients with T2D is a robust marker for atherosclerosis and a cardiovascular disease (CVD)-risk factor. To identify eligible studies, we searched the major online databases using PubMed and Google Scholar. The cumulative evidence synthesized in the current review suggests that, traditional therapies which include thiazolidinediones, statins and some calcium channel blockers can be useful in the primary prevention of atherosclerosis by inhibiting the formation of monocyte-derived microparticles, and pro-inflammatory cytokines such as IL-6, TNF-α, MCP-1, and NF-κB in patients with T2D. Future studies are needed to ascertain whether the combination of dietary interventions and glucose or lipid lowering agents can provide an enhanced cardioprotection in patients with T2D., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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]; I 2 = 4%, p = 0.39) and insulin (SMD: -0.08 [95% CI: -0.50, 0.34], I 2 = 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], I 2 = 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]; I 2 = 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.

Food-derived bioactive compounds such as resveratrol are increasingly explored for their protective effects against metabolic complications. Evidence supports the strong antioxidant properties and therapeutic effects of resveratrol in managing diabetes and its associated complications. However, evidence informing on the comparative or combination effects of this natural compound with an accomplished and well-characterized antidiabetic agent like metformin has not been revised. Thus, we conducted a comprehensive systematic search of the major electronic databases which included MEDLINE, Cochrane Library, and EMBASE. The cumulative evidence strongly supports the comparative effects of metformin and resveratrol in ameliorating diabetes-associated complications in preclinical settings. In particular, both compounds showed strong ameliorative effects against hyperglycemia, dyslipidemia, insulin resistance, a pro-inflammatory response, and lipid peroxidation in various experimental models of diabetes. Enhancing intracellular antioxidant capacity in addition to activating NAD-dependent deacetylase sirtuin-1 (SIRT1) and AMP-activated protein kinase (AMPK) are the prime mechanisms involved in the therapeutic effects of these compounds. Of interest, preclinical evidence also demonstrates that the combination treatment with these compounds may have a greater efficacy in protecting against diabetes. Thus, confirmation of such evidence in well-organized clinical trials remains crucial to uncover novel therapeutic strategies to manage diabetes and its linked complications.

We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor ( Insr ) and insulin receptor substrate 1 and 2 ( Irs1 and Irs2 ), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.

The epidemic of cardiovascular diseases is a global phenomenon that is exaggerated by the growing prevalence of diabetes mellitus. Coronary artery disease and diabetic cardiomyopathy are the major cardiovascular complications responsible for exacerbated myocardial infarction in diabetic individuals. Increasing research has identified hyperglycemia and hyperlipidemia as key factors driving the augmentation of oxidative stress and a pro-inflammatory response that usually results in increased fibrosis and reduced cardiac efficiency. While current antidiabetic agents remain active in attenuating diabetes-associated complications, overtime, their efficacy proves limited in protecting the hearts of diabetic individuals. This has led to a considerable increase in the number of natural products that are screened for their antidiabetic and cardioprotective properties. These natural products may present essential ameliorative properties relevant to their use as a monotherapy or as an adjunct to current drug agents in combating diabetes and its associated cardiovascular complications. Recent findings have suggested that triterpenes isolated from Protorhus longifolia (Benrh.) Engl., a plant species endemic to Southern Africa, display strong antioxidant and antidiabetic properties that may potentially protect against diabetes-induced cardiovascular complications. Thus, in addition to discussing the pathophysiology associated with diabetes-induced cardiovascular injury, available evidence pertaining to the cardiovascular protective potential of lanosteryl triterpenes from Protorhus longifolia will be discussed.

Metformin is the first line therapy of type 2 diabetics, but continued reduction of their life expectancy warrants further investigation into alternative treatment strategies. This study reports on the combinational use of metformin with aspalathin, a C-glucosyl dihydrochalcone with known glucose lowering and antioxidant properties, as an effective hypoglycemic therapy in a type 2 diabetic (db/db) mouse model. When tested as a monotherapy, a low dose of aspalathin (13 mg/kg) showed no effect, while a high dose (130 mg/kg) has already displayed a better potential than metformin in protecting against diabetes associated symptoms in db/db mice. Thus, it remains of interest to determine whether this dihydrochalcone can improve the efficacy of metformin. The results showed that this combination therapy was more effective than the use of metformin as a monotherapy in ameliorating diabetes associated symptoms, including abnormal raised fasting plasma glucose levels, impaired glucose tolerance, as well as excessively increased body weights and fat content. The treated mice also had reduced food and water consumption when compared to untreated controls, with a pronounced effect evident in the last week of treatment. Therefore, this study supports further investigations into the ameliorative effect of combination therapy of metformin and aspalathin against diabetes associated symptoms.

Accumulative evidence shows that chronic hyperglycaemia is a major factor implicated in the development of pancreatic β-cell dysfunction in diabetic patients. Furthermore, most of these patients display impaired insulin signalling that is responsible for accelerated pancreatic β-cell damage. Indeed, prominent pathways involved in glucose metabolism such as phosphatidylinositol 3-kinase/ protein kinase B (PI3-K/AKT) and 5' AMP-activated protein kinase (AMPK) are impaired in an insulin resistant state. The impairment of this pathway is associated with over production of reactive oxygen species and pro-inflammatory factors that supersede pancreatic β-cell damage. Although several antidiabetic drugs can improve β-cell function by modulating key regulators such as PI3-K/AKT and AMPK, evidence of their β-cell regenerative and protective effect is scanty. As a result, there has been continued exploration of novel antidiabetic therapeutics with abundant antioxidant and antiinflammatory properties that are essential in protecting against β-cell damage. Such therapies include triterpenes, which have displayed robust effects to improve glycaemic tolerance, insulin secretion, and pancreatic β-cell function. This review summarises most relevant effects of various triterpenes on improving pancreatic β-cell function in both in vitro and in vivo experimental models. A special focus falls on studies reporting on the ameliorative properties of these compounds against insulin resistance, oxidative stress and inflammation, the well-known factors involved in hyperglycaemia associated tissue damage., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Type 2 diabetes remains one of the leading causes of death worldwide. Persistent hyperglycemia within a diabetic state is implicated in the generation of oxidative stress and aggravated inflammation that is responsible for accelerated modification of pancreatic beta cell structure. Here we investigated whether a lanosteryl triterpene, methyl-3β-hydroxylanosta-9,24-dien-21-oate (RA-3), isolated from Protorhus longifolia can improve glucose tolerance and pancreatic beta cell ultrastructure by reducing oxidative stress and inflammation in high fat diet and streptozotocin-induced type 2 diabetes in rats. In addition to impaired glucose tolerance, the untreated diabetic rats showed increased fasting plasma glucose and C-peptide levels. These untreated diabetic rats further demonstrated raised cholesterol, interleukin-6 (IL-6), and lipid peroxidation levels as well as a destroyed beta cell ultrastructure. Treatment with RA-3 was as effective as metformin in improving glucose tolerance and antioxidant effect in the diabetic rats. Interestingly, RA-3 displayed a slightly more enhanced effect than metformin in reducing elevated IL-6 levels and in improving beta cell ultrastructure. Although the involved molecular mechanisms remain to be established, RA-3 demonstrates a strong potential to improve pancreatic beta cell ultrastructure by attenuating impaired glucose tolerance, reducing oxidative stress and inflammation., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript and in the decision to publish the results.