Current Medicinal Chemistry - Volume 22, Issue 1, 2015

Diabetes mellitus is one of the most serious diseases in the world. The levels of glycated proteins in the blood of diabetics are higher than that of non-diabetic subjects. The glycation of proteins is believed to link to the occurrence of diabetic complications and related diseases. This review focuses on the influence of glycation of human serum albumin (HSA) on its structure and function. The glycation leads to change the HSA conformation, which will further influence its ligand binding properties. The levels of glycated HSA in hyperglycemic conditions showed a significant relationship to the germination of serious complications for diabetics, especially by affecting various cells functions. The conclusion from individual report is contradictory to each other; therefore, it is very difficult to give an univocal comment on the impact of glycation on the binding behaviors of HSA for small molecules. The influence of glycation of HSA on the binding affinities for small molecules is decided by the assay, the structures of small molecules, as well as the degree of glycation. However, the glycation of HSA is believed to reduce the binding affinities for acidic drugs such as polyphenols and phenolic acids.

Currently, experimental and clinical evidences showed that polyphenols-rich natural products, like nutraceuticals and food supplements, may offer unique treatment modalities in type 2 diabetes mellitus (DM), due to their biological properties. Natural products modulate the carbohydrate metabolism by various mechanisms, such as restoring beta-cells integrity and physiology, enhancing insulin releasing activity, and the glucose using. Sea buckthorn berries, red grapes, bilberries, chokeberries and popular drinks like cocoa, coffee and green tea are all rich in polyphenols and may decrease the insulin response, offerin g a natural alternative of treatment in diabetes. Therefore, researches are now focused on potential efficacies of different types of polyphenols, including flavonoids, phenolic acids, lignans, anthocyans and stilbenes. Animal and human studies showed that polyphenols modulate carbohydrate and lipid metabolism, decrease glycemia and insulin resistance, increase lipid metabolism and optimize oxidative stress and inflammatory processes. It is important to understand the proper dose and duration of supplementation with polyphenols-rich extracts in order to guide effective therapeutic interventions in diabetic patients.

Significant evidence suggests that polyphenol-rich diets have the ability to protect against diabetes. Since several previous reviews focused on the nutrition and health effects including type 2 diabetes of polyphenols in 2007-2008, a number of related original publications have been pulished in this field. This review summarizes important advances related to influence of dietary polyphenols and polyphenol-rich diets on preventing and managing type 2 diabetes, as well as diabetes-mediated changes in bioactivities of dietary polyphenols. It appears that anthocyanins or anthocyanin-rich food intake is related to the risk of type 2 diabetes, but there is no association for other polyphenol subclasses. It is discussed that procyanidins are more active when administered individually than when mixed with food. The benefits of dietary polyphenols for type 2 diabetes can be summarized as: protection of pancreatic β-cells against glucose toxicity, anti-inflammatory and antioxidant effects, inhibition of α-amylases or α- glucosidases and thus decrease of starch digestion, and inhibition of advanced glycation end products formation. Moreover, type 2 diabetes also significantly influences the benefits of dietary polyphenols, although there are very limited studies have been conducted so far. How type 2 diabetes impacts the pharmacology of dietary polyphenols is not well understood. Comprehension of type 2 diabetes-mediated changes in pharmacokinetics and bioactivity of dietary polyphenols might lead to improve the benefits of these phytochemicals and subsequent clinical outcomes for type 2 diabetics.

This review focuses on the role of procyanidins, the main group of flavonoids, on type 2 diabetes mellitus (T2DM) and insulin resistance. We compile the role of procyanidins on several animal models, and we evaluate their effects on target tissues and analyze the mechanisms involved. Procyanidin treatments in fructose or high-fat induced insulin resistant models were found to improve the damage induced by the diet, thus improving glycemia and insulin sensitivity. The same positive effects were also reported in models of late stage T2DM, in which pancreatic β-cells can no longer counteract hyperglycemia. More controversial results were found in genetically obese or cafeteria diet-induced insulin resistant models. Human studies, although limited, further support the hypoglycemic effect of procyanidins. Regarding their mechanisms, procyanidins have been found to target several tissues involved in glucose homeostasis, which is also discussed in the present review. In insulin-sensitive tissues, procyanidins modulate glucose uptake and lipogenesis and improve their oxidative/inflammatory state, the disruption of which is important in T2DM development. In the insulin-producing tissue, the pancreas, procyanidins modulate insulin secretion and production and β-cell mass, although the available results are divergent. Finally, the gut is another potential target for procyanidins. The available data suggest that modulation of the active glucagon-like peptide-1 (GLP-1) levels could partially explain the reported antihyperglycemic effect of these natural compounds.

Diabetic retinopathy is one of the most common complications of diabetes. A plethora of literature indicates that oxidative stress may play a central role in the pathogenesis of diabetic retinopathy. One could thus hypothesise that antioxidant therapies may be protective for diabetic retinopathy. Anthocyanins are important natural bioactive pigments responsible for red-blue colour of fruits, leaves, seeds, stems and flowers in a variety of plant species. Apart from their colours, anthocyanins are known to be health-promoting phytochemicals with potential properties useful to protect against oxidative stress in some degenerative diseases. They also have a variety of biological properties including anti-inflammatory, antibacterial, anticancer, and cardio-protective properties. Some reports further suggest a therapeutic role of anthocyanins to prevent and/or protect against ocular diseases but more studies are needed to examine their potential as alternative therapy to diabetic retinopathy. The present article reviews the available literature concerning the beneficial role of anthocyanins in diabetic retinopathy.

Epidemiological studies demonstrate robust correlations between green tea consumption and reduced risk of type 2 diabetes and its cardiovascular complications. However, underlying molecular, cellular, and physiological mechanisms remain incompletely understood. Health promoting actions of green tea are often attributed to epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea. Insulin resistance and endothelial dysfunction play key roles in the pathogenesis of type 2 diabetes and its cardiovascular complications. Metabolic insulin resistance results from impaired insulin-mediated glucose disposal in skeletal muscle and adipose tissue, and blunted insulin-mediated suppression of hepatic glucose output that is often associated with endothelial/ vascular dysfunction. This endothelial dysfunction is itself caused, in part, by impaired insulin signaling in vascular endothelium resulting in reduced insulin-stimulated production of NO in arteries, and arterioles that regulate nutritive capillaries. In this review, we discuss the considerable body of literature supporting insulin-mimetic actions of EGCG that oppose endothelial dysfunction and ameliorate metabolic insulin resistance in skeletal muscle and liver. We conclude that EGCG is a promising therapeutic to combat cardiovascular complications associated with the metabolic diseases characterized by reciprocal relationships between insulin resistance and endothelial dysfunction that include obesity, metabolic syndrome and type 2 diabetes. There is a strong rationale for well-powered randomized placebo controlled intervention trials to be carried out in insulin resistant and diabetic populations.

The beneficial effects of green tea have been confirmed in various diseases, such as different types of cancer, heart disease, and liver disease. The effective components of green tea mainly include tea polysaccharides and tea polyphenols, such as catechin, particularly (-)-epigallocatechin-3-gallate. Increasing in vivo and in vitro evidences have explored the potential molecular mechanisms of green tea as well as the specific biological actions. Moreover, clinical trials have also explored the potential value of green tea components in treating metabolic syndromes, such as obesity, type II diabetes, and cardiovascular disease. This study explores the effects of the two major green tea components on the improvement of type II diabetes. It is concluded that regular consumption of green tea is beneficial for the improvement of high-fat dietary-induced obesity and type II diabetes.

Results of several epidemiological studies have indicated that diabetes mellitus will become a global epidemic in the next decades, being more than 400 million the human subjects in the world affected by this disease in the 2030. Most of these subjects will be affected by type 2 diabetes mellitus (T2DM) whose diffusion is mainly related to excessive caloric upload, sedentary life and obesity. Typically, the treatment for T2DM is diet, weight control, physical activity or hypoglycaemic and/or lipid-lowering drugs. Unfortunately, these drugs often show low effectiveness or adverse side effects, thereby forcing patient to discontinue medical treatment. Nevertheless traditional medicine suggests the use of several formulations or medicinal foods to treat T2DM. Most of them are characterized by safety, low cost, effectiveness, and good availability. Before the advent of modern pharmacology, these remedies were used to treat diabetes and obesity or prevent their onset. Today, we know that their effectiveness is due to the presence of several bioactive compounds able to influence insulin signaling pathway and cellular metabolism. In the last decades, many efforts have been carried out to clarify their action mechanism. Here we provide a classification of the natural compounds that stimulate the insulin pathway, highlighting their effectiveness in controlling glycaemia on diabetic animal models or improving insulin signaling in cellular systems.

Polyphenols are members of a very large family of plant-derived compounds that may have beneficial effects on human health, and thus their study has become an increasingly important area of human nutrition research. Considering that it is increasingly accepted that chronic sub-acute inflammation plays an important role in the development of insulin resistance and of diabetes in animals and in humans, the aim of the present review is to compile information concerning the anti-inflammatory effects of non-flavonoid polyphenols on diabetes prevention and/or treatment. Most of these studies have been carried out with different cultured cells and using animal models displaying different types of diabetes, such as diabetes induced by streptozotocin or streptozotocin-nicotinamide, genetic diabetes or diabetes induced by high-fat feeding. In general terms, non-flavonoid polyphenols reduce the production of inflammatory mediators, such as IL-1β, IL-8, MCP-1, COX-2 or iNOS in these animal models of diabetes. This effect is accompanied in the vast majority of these studies by improved insulin action. In addition, some of the non-flavonoid polyphenols are also able to ameliorate or prevent several pathological alterations associated with the development of diabetes, such as nephropathy, cardiopathy or retinopathy. Very little information has been reported with regard to human studies to date. Thus, new studies are needed to confirm if the beneficial effects observed in preclinical studies can apply to human beings.

Flavonoids are well known as antibacterial agents against a wide range of pathogenic microorganism. With increasing prevalence of untreatable infections induced by antibiotic resistance bacteria, flavonoids have attracted much interest because of the potential to be substitutes for antibiotics. In this review, the structure-relationship of flavonoids as antibacterial agents is summarized, and the recent advancements on the antibacterial mechanisms of flavonoids are also discussed. It is concluded that hydroxyls at special sites on the aromatic rings of flavonoids improve the activity. However, the methylation of the active hydroxyl groups generally decreases the activity. Besides, the lipopholicity of the ring A is vital for the activity of chalcones. The hydrophobic substituents such as prenyl groups, alkylamino chains, alkyl chains, and nitrogen or oxygen containing heterocyclic moieties usually enhance the activity for all the flavonoids. The proposed antibacterial mechanisms of flavonoids are as follows: inhibition of nucleic acid synthesis, inhibition of cytoplasmic membrane function, inhibition of energy metabolism, inhibition of the attachment and biofilm formation, inhibition of the porin on the cell membrane, alteration of the membrane permeability, and attenuation of the pathogenicity.

During the last years, the list of resveratrol effects has grown in parallel with the number of other members of the polyphenol family described to modulate glucose or lipid handling. In the same time, more than ten human studies on the influence of resveratrol supplementation on two related metabolic diseases, obesity and diabetes, have indicated that impressive beneficial effects co-exist with lack of demonstration of clinical relevance, irrespective of the daily dose ingested (0.075 to 1.5 g per capita) or the number of studied patients. Such contrasting observations have been proposed to depend on the degree of insulin resistance of the patients incorporated in the study. To date, no definitive conclusion can be drawn on the antidiabetic or antiobesity benefits of resveratrol. On the opposite, studies on animal models of diabesity consistently indicated that resveratrol impairs diverse insulin actions in adipocytes, blunting glucose transport, lipogenesis and adipogenesis. Since resveratrol also favours lipolysis and limits the production of proinflammatory adipokines, its administration in rodents results in limitation of fat deposition, activation of hexose uptake into muscle, improvement of insulin sensitivity, and facilitation of glucose disposal. Facing to a somewhat disappointing extrapolation to man of these promising antidiabetic and antiobesity properties, attention must be paid to re-examine resveratrol targets, especially those attainable after polyphenol ingestion and to re-define the responses to low doses. In this context, human adipocytes are proposed as a convenient model for the screening of "novel" polyphenols that can reproduce, outclass, or reinforce resveratrol metabolic actions, Moreover, the use of combination of polyphenols is proposed to treat diabesity complications in view of recently reported synergisms. Lastly, multidisciplinar approaches are recommended for future investigations, considering the wide range of polyphenol actions that induce body fat reduction, liver disease mitigation, muscle function improvement, cardiovascular and renal protection.