Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress

Metabolic complications in an obese state can be aggravated by an abnormal inflammatory response and enhanced production of reactive oxygen species. Pro-inflammatory response is known to be associated with the formation of toxic reactive oxygen species and subsequent generation of oxidative stress. Indeed, adipocytes from obese individuals display an altered adipokine profile, with upregulated expression and secretion of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin (IL-6). Interestingly, natural compounds, including phenolic enriched foods are increasingly explored for their ameliorative effects against various metabolic diseases. Of interest is gallic acid, a trihydroxybenzoic acid that has progressively demonstrated robust anti-obesity capabilities in various experimental models. In addition to reducing excessive lipid storage in obese subjects, gallic acid has been shown to specifically target the adipose tissue to suppress lipogenesis, improve insulin signaling, and concomitantly combat raised pro-inflammatory response and oxidative stress. This review will revise mechanisms involved in the pathophysiological effects of inflammation and oxidative stress in an obese state. To better inform on its therapeutic potential and improvement of human health, available evidence reporting on the anti-obesity properties of gallic acid and its derivatives will be discussed, with emphases on its modulatory effect on molecular mechanisms involved in insulin signaling, inflammation and oxidative stress.

The present review focuses on preclinical and clinical studies conducted in the last decade that contribute to increasing knowledge on Coenzyme Q₁₀’s role in health and disease. Classical antioxidant and bioenergetic functions of the coenzyme have been taken into consideration, as well as novel mechanisms of action involving the redox-regulated activation of molecular pathways associated with anti-inflammatory activities. Cardiovascular research and fertility remain major fields of application of Coenzyme Q₁₀, although novel applications, in particular in relation to topical application, are gaining considerable interest. In this respect, bioavailability represents a major challenge and the innovation in formulation aspects is gaining critical importance.

Dimethyl sulfoxide (DMSO) is an effective solvent and cytoprotectant agent that can induce diverse actions in experimental settings, ranging from metabolic stress to cytotoxic effects depending on the concentration used. Therefore, for the quality of experiments and reproducibility of results it is essential to establish a precise and non-toxic dose of DMSO within a specific cell system. 3T3-L1 adipocytes, represent a well-established in vitro cell model used to assess the anti-obesity potential of extracts and compounds. Although DMSO is commonly used as a solvent for these experiments, there is limited data available on the compounding effects of using DMSO. The purpose of this study was to assess a concentration-dependent effect of DMSO on lipid content, cell viability and oxidative damage in 3T3-L1 adipocytes. Results showed that DMSO at doses ≥ 0.1% increased mitochondrial membrane potential as measured by JC-1 fluorescent staining, while doses ≥ 10% reduced the lipid content in matured adipocytes. Consistently, higher doses significantly reduced cell viability, elevated reactive oxygen species levels, depleted intracellular glutathione levels, and accelerated apoptosis and cell necrosis. An interesting finding was that a DMSO dose of 0.01% improved glutathione content of 3T3-L1 adipocytes and had minimal effects on cell viability, apoptosis or and necrosis, supporting its antioxidant effect. Therefore, this study provides compelling evidence that precaution should be taken when assessing compounds dissolved in DMSO, particularly doses ≥1% that were shown to induce oxidative stress in 3T3-L1 adipocytes.

Lipid peroxidation, including its prominent byproducts such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE), has long been linked with worsened metabolic health in patients with type 2 diabetes (T2D). In fact, patients with T2D already display increased levels of lipids in circulation, including low-density lipoprotein-cholesterol and triglycerides, which are easily attacked by reactive oxygen molecules to give rise to lipid peroxidation. This process severely depletes intracellular antioxidants to cause excess generation of oxidative stress. This consequence mainly drives poor glycemic control and metabolic complications that are implicated in the development of cardiovascular disease. The current review explores the pathological relevance of elevated lipid peroxidation products in T2D, especially highlighting their potential role as biomarkers and therapeutic targets in disease severity. In addition, we briefly explain the implication of some prominent antioxidant enzymes/factors involved in the blockade of lipid peroxidation, including termination reactions that involve the effect of antioxidants, such as catalase, coenzyme Q₁₀, glutathione peroxidase, and superoxide dismutase, as well as vitamins C and E.