Anti-diabetic drugs and weight loss in patients with type 2 diabetes.

INTRODUCTION: Obesity is frequently a comorbidity of type 2 diabetes. Even modest weight loss can significantly improve glucose homeostasis and lessen cardiometabolic risk factors in patients with type 2 diabetes, but lifestyle-based weight loss strategies are not long-term effective. There is an increasing need to consider pharmacological approaches to assist weight loss in the so called diabesity syndrome. Aim of this review is to analyze the weight-loss effect of non-insulin glucose lowering drugs in patients with type 2 diabetes. MATERIAL AND METHODS: A systematic analysis of the literature on the effect of non-insulin glucose lowering drugs on weight loss in patients with type 2 diabetes was performed. For each class of drugs, the following parameters were analyzed: kilograms lost on average, effect on body mass index and body composition. RESULTS: Our results suggested that anti-diabetic drugs can be stratified into 3 groups based on their efficacy in weight loss: metformin, acarbose, empagliflozin and exenatide resulted in a in a mild weight loss (less than 3.2% of initial weight); canagliflozin, ertugliflozin, dapagliflozin and dulaglutide induces a moderate weight loss (between 3.2% and 5%); liraglutide, semaglutide and tirzepatide resulted in a strong weight loss (greater than 5%). CONCLUSIONS: This study shows that new anti-diabetic drugs, particularly GLP1-RA and Tirzepatide, are the most effective in inducing weight loss in patients with type 2 diabetes. Interestingly, exenatide appears to be the only GLP1-RA that induces a mild weight loss.

Idebenone is a cytoprotective insulin sensitizer whose mechanism is Shc inhibition.

When insulin binds insulin receptor, IRS1 signaling is stimulated to trigger the maximal insulin response. p52Shc protein competes directly with IRS1, thus damping and diverting maximal insulin response. Genetic reduction of p52Shc minimizes competition with IRS1, and improves insulin signaling and glucose control in mice, and improves pathophysiological consequences of hyperglycemia. Given the multiple benefits of Shc reduction in vivo, we investigated whether any of 1680 drugs used in humans may function as Shc inhibitors, and thus potentially serve as novel anti-diabetics. Of the 1680, 30 insulin sensitizers were identified by screening in vitro, and of these 30 we demonstrated that 7 bound Shc protein. Of the 7 drugs, idebenone dose-dependently bound Shc protein in the 50-100 nM range, and induced insulin sensitivity and cytoprotection in this same 100 nM range that clinically dosed idebenone reaches in human plasma. By contrast we observe mitochondrial effects of idebenone in the 5,000 nM range that are not reached in human dosing. Multiple assays of target engagement demonstrate that idebenone physically interacts with Shc protein. Idebenone sensitizes mice to insulin in two different mouse models of prediabetes. Genetic depletion of idebenone's target eliminates idebenone's ability to insulin-sensitize in vivo. Thus, idebenone is the first-in-class member of a novel category of insulin-sensitizing and cytoprotective agents, the Shc inhibitors. Idebenone is an approved drug and could be considered for other indications such as type 2 diabetes and fatty liver disease, in which insulin resistance occurs.

Efficacy and risk profile of anti-diabetic therapies: Conventional vs traditional drugs-A mechanistic revisit to understand their mode of action.

An increasing array of anti-diabetic drugs are available today, yet Type-2 diabetes mellitus (T2DM) - remains a life threatening disease, causing high mortality and morbidity in developing and developed countries. As of now, no effective therapy is available for the complete eradication/cure of diabetes and its associated complications. Therefore, it is time to re-think and revisit molecular pathways and targets of each existing drug in order to identify multiple targets from different signaling pathways that may be manipulated simultaneously to treat or manage T2DM effectively. Bearing this goal in mind, the article reviews the mechanisms of action of available anti-diabetic drugs with in-depth mechanistic analysis of each therapy. The conventional and herbal strategies are analysed and compared for their benefits and the associated possible side effects. This critical information is necessary not only for the development of better, novel and potent anti-diabetic therapy in future but also for best possible combinational therapies and strategies with the available drugs.

Novel methylated flavoalkaloids from Echa 1 green tea inhibit fat accumulation and enhance stress resistance in Caenorhabditis elegans.

Methylation is a common structural modification of catechins in tea, which can improve the bioavailability of catechins. Flavoalkaloids are catechin derivatives with a nitrogen containing five-membered ring at the C-6 or C-8 position. Here we isolated three new methylated flavoalkaloids from Echa 1 green tea (Camellia sinensis cv. Echa 1) and synthesized another four new methylated flavoalkaloids. The structures of the new ester-type methylated catechins (etmc)-pyrrolidinone A-G (1-7) were elucidated by various spectroscopic techniques, including nuclear magnetic resonance (NMR), optical rotation, infrared, UV-vis, experimental and calculated circular dichroism (CD) spectra, and high-resolution mass. Among them, 6 and 7 showed the strongest α-glucosidase inhibitory activity and significantly lowered lipid content of Caenorhabditis elegans with 73.50 and 67.39% inhibition rate, respectively. Meanwhile, 6 and 7 also exhibited strong antioxidant activity in vitro and stress resistance to heat, oxidative stress, and UV irradiation in nematodes.

α-Glucosidase inhibitors from brown rice bound phenolics extracts (BRBPE): Identification and mechanism.

Brown rice bound phenolics extracts (BRBPE) have been reported to possess α-glucosidase inhibitory effects, the specific enzyme inhibitors involved in this process were unknown. Here, α-glucosidase inhibitors in BRBPE were screened using bioaffinity ultrafiltration methods, and seven phenolic compounds - three monomers (p-coumaric acid, ferulic acid and methyl ferulate), three dimers (8-5', 5-5' and 8-O-4' diferulic acid) and a trimer (5-5'/8-O-4″ dehydrotriferulic acid) were identified as exact inhibitors, among which 5-5'/8-O-4″ dehydrotriferulic acid and 5-5'diferulic acid exhibited the best inhibitory activity. Enzyme kinetic analysis suggested that the inhibitory mechanism of these seven inhibitors including competitive, noncompetitive, uncompetitive and mixed manner. Molecular docking analysis revealed that the seven inhibitors bind with α-glucosidase mainly by hydrogen bonding interaction, hydrophobic force and ionic bond. Molecular dynamics simulation further explored the structure and molecular property of phenolic-glucosidase complex. This work provided a deep insight into brown rice bound phenolics acting as potent α-glucosidase inhibitors.

Role of nutraceutical starch and proanthocyanidins of pigmented rice in regulating hyperglycemia: Enzyme inhibition, enhanced glucose uptake and hepatic glucose homeostasis using in vitro model.

Dysregulation of glucose homeostasis result in hyperglycemia and pigmented rice, unique combination of high quality starch and phenolics has the potential in regulating it. In this study, pigmented rice was characterized in terms of nutraceutical starch (NS) and phenolic content. Further the effect of rice phenolics on carbolytic enzyme inhibition, glucose uptake, hepatic glucose homeostasis and anti-glycation ability was analyzed in vitro. The most relevant effect on enzyme inhibition (α-amylase: IC50-42.34 µg/mL; α-glucosidase: IC50:63.89 µg/mL), basal uptake of glucose (>39.5%) and anti-glycation ability (92%) was found in red rice (RR), than black rice (BR). The role of RR phenolics in regulating glucose homeostasis was deciphered using hepatic cell line system, which found up-regulation of glucose transporter 2 (GLUT2) and glycogen synthase 2 (GYS2); while expression of gluconeogenic genes were found down regulated. To our knowledge this study is the first report validating the role of starch-phenolic quality towards anti-hyperglycemic effect of RR.

Characterization of α-glucosidase inhibitory constituents of the fruiting body of lion's mane mushroom (Hericium erinaceus).

ETHNOPHARMACOLOGICAL RELEVANCE: Hericium erinaceus, commonly called lion's mane mushroom, is an edible and medicinal mushroom that has been traditionally used for the treatment of metabolic disorders, gastrointestinal diseases and memory impairment. In this study, potential anti-hyperglycemic constituents were identified to support the traditional usage of H. erinaceus. MATERIALS AND METHODS: The components of H. erinaceus were purified using various column chromatography techniques. The structure of the separated compounds was determined based on spectroscopic data analysis, i.e., 1D and 2D NMR analysis. The anti-hyperglycemic activity of the isolated compounds was evaluated by measuring the inhibitory effects on α-glucosidase activity. Molecular docking analysis was also conducted for elucidation of α-glucosidase inhibitory activity of isolated compounds. RESULTS: Ten compounds including four new compounds, erinacenols A-D (1-4), were isolated from the fruiting bodies of H. erinaceus. Investigation of the anti-hyperglycemic effect of isolated compounds demonstrated that erinacenol D (4), 4-[3',7'-dimethyl-2',6'-octadienyl]-2-formyl-3-hydroxy-5-methyoxybenzylalcohol (6), hericene A (7), hericene D (8) and hericenone D (9) strongly inhibited α-glucosidase activity with IC50 values of <20 µM. The structure activity relationship suggested the importance of long side chain for α-glucosidase inhibitory activity. Further analysis by molecular docking demonstrated the interaction of α-glucosidase and isolated compounds, which supported the inhibitory activity of α-glucosidase. CONCLUSION: Our present study demonstrated the beneficial effect of H. erinaceus by characterization of α-glucosidase inhibitory compounds, including four new compounds. This approach can be valuable support for the traditional use of H. erinaceus for the treatment of diabetes and metabolic diseases, which needs to be clarified by further in-vivo study.

Effects of ultrasound irradiation on the characterization and bioactivities of the polysaccharide from blackcurrant fruits.

In this study, the influence of ultrasound irradiation on the characterization and bioactivities of the polysaccharide from blackcurrant fruits (BCP, molecular weight: Mw = 3.26 × 104 kDa) was investigated. Two degraded polysaccharides (U-400, Mw = 1.89 × 104 kDa, and U-600, Mw = 1.32 × 104 kDa) were obtained by different ultrasound powers of 400 W and 600 W, respectively. Compared with BCP, U-400 and U-600 showed 63.52% and 68.85% reductions in the particle size (Zavg), respectively; moreover, the dynamic viscosity of BCP was reduced by 27.88%, and 33.63%, separately. The reducing sugar content and thermal stability increased with the increase of ultrasound intensity. The degraded polysaccharides contained the same monosaccharide species as those of BCP but at different molar ratios. Fourier transform infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopic analysis confirmed that the degraded polysaccharides and BCP exhibited the similar structural features, which were mainly composed of six glycosidic bonds. A reduction in surface area of the flake-like structure was observed in the degraded polysaccharides compared to that of BCP, and they had no triple helix structure. Furthermore, the precise structural characteristics of U-600 were identified by 2D NMR analysis. The results of the bioactivity assays indicated that the ultrasound irradiation could evidently enhance the antioxidant (hydroxyl and superoxide radicals scavenging, lipid peroxidation inhibition, and DNA damage protection activities), α-amylase and α-glucosidase inhibition activities of BCP. These activities increased in the order of U-600 > U-400 > BCP. In particular, the DNA protection and α-amylase inhibition activities for U-600 were 52.19 ±â€¯1.34% and 75.98 ±â€¯0.77%, respectively, which were 2 times higher than those of BCP. U-600 prepared with the higher-intensity ultrasound exhibited the best physicochemical properties and bioactivities among the three polysaccharides. These results suggested that ultrasound irradiation was an efficient, green method to produce value-added polysaccharide for use in functional food or medicine.

Sulfated modification of the polysaccharides from blackcurrant and their antioxidant and α-amylase inhibitory activities.

Sulfated modification was conducted to modify a homogenous polysaccharide from blackcurrant (BCP). The sulfated polysaccharides (SBCPs) with different degree of substitution (DS) were synthesized using the aminosulfonic acid (ASA)/4-dimethylaminopyridine method by varying reaction conditions such as the mass ratio of ASA to BCP, temperature, and time. Three sulfated derivatives were chosen for high-performance gel-permeation chromatography, gas chromatography, fourier-transform infrared (FT-IR) spectroscopy, and nuclear magnetic resonance (NMR), and activity studies, designated as SBCP-1, SBCP-2, and SBCP-3 with DS of 1.28, 0.95, and 0.53, respectively. Results showed that the sulfated modification was successful, and SBCPs had an increase in molecular weight compared to BCP. Both SBCPs and BCP were composed of rhamnose, arabinose, xylose, mannose, galactose, and glucose, with different molar ratios. Sulfate substitution was further confirmed by FT-IR and 13C NMR analysis. SBCPs exhibited excellent antioxidant capacities (DPPH, hydroxyl, and superoxide radical scavenging, reducing power, and ferrous metal-chelating capacities) and α-amylase inhibitory activity in vitro, and the activities of SBCPs were significantly improved in positive correlation with the DS value. This study suggested that SBCPs could serve as potential antioxidant agents to be used as alternative supplements or functional foods.

Characterization, antioxidant and hypoglycemic activities of degraded polysaccharides from blackcurrant (Ribes nigrum L.) fruits.

In this study, the degradation of polysaccharides from blackcurrant (BCP) was investigated. Two low-molecular-weight polysaccharides (DBCP-1, DBCP-2) were obtained using Fe2+ with different concentrations of H2O2 solution. IR spectra showed DBCPs had obvious characteristic peaks of polysaccharides. GC analysis confirmed DBCPs were composed of the same monosaccharide units as BCP but with different molar ratios. NMR analysis indicated DBCPs and BCP had similar glycosidic linkage patterns. The surface area of fragmented structure in DBCPs was reduced compared to BCP, and they had no triple helix structure. The results of bioactivity assays indicated that DBCPs exhibited higher antioxidant, α-amylase and α-glucosidase inhibitory activities than BCP, and the degraded polysaccharides with the lower molecular weight possessed higher bioactivities. These results suggested that Fe2+-H2O2 degradation did not change the main structure of polysaccharide and the degree of degradation could play a key role in the bioactivities of the polysaccharides.

Antidiabetic activity and chemical constituents of the aerial parts of Heracleum dissectum Ledeb.

Heracleum dissectum Ledeb. has long been used as a wild edible vegetable by local people in China. The purpose of this study is to investigate the antidiabetic potential of aerial part of H. dissectum methanol extract (HdME) and the chemical constituents. Ten compounds including eight coumarins were isolated and four of them were found from H. dissectum for the first time. HdME potently inhibited the elevation of plasma glucose after its oral administration to glucose-loaded mice, and its petroleum ether (PE) fraction exerted the greatest inhibitory activities. Meanwhile, HdME (125 and 250mg/kg) also significantly decreased the blood glucose level in STZ-induced diabetic mice, but had no effect in normoglycemic mice. Additionally, HdME showed weak inhibitory effects on α-glucosidase activity and DPPH free radicals scavenging. In conclusion, HdME has antidiabetic action and PE fraction is the active part where coumarins possibly play an important role in antidiabetic activity.

Black bean anthocyanin-rich extracts as food colorants: Physicochemical stability and antidiabetes potential.

Black beans contain anthocyanins that could be used as colorants in foods with associated health benefits. The objective was to optimize anthocyanins extraction from black bean coats and evaluate their physicochemical stability and antidiabetes potential. Optimal extraction conditions were 24% ethanol, 1:40 solid-to-liquid ratio and 29°C (P<0.0001). Three anthocyanins were identified by MS ions, delphinidin-3-O-glucoside (465.1m/z), petunidin-3-O-glucoside (479.1m/z) and malvidin-3-O-glucoside (493.1m/z). A total of 32mg of anthocyanins were quantified per gram of dry extract. Bean anthocyanins were stable at pH 2.5 and low-temperature 4°C (89.6%), with an extrapolated half-life of 277days. Anthocyanin-rich extracts inhibited α-glucosidase (37.8%), α-amylase (35.6%), dipeptidyl peptidase-IV (34.4%), reactive oxygen species (81.6%), and decreased glucose uptake. Black bean coats are a good source of anthocyanins and other phenolics with the potential to be used as natural-source food colorants with exceptional antidiabetes potential.

In vitro biological assessment of Homalium zeylanicum and isolation of lucidenic acid A triterpenoid.

Homalium zeylanicum (Gardner) Benth. (Flacourtiaceae) is a medicinal plant useful in controlling rheumatism, inflammation and diabetes. The objective of this work evaluates in vitro antioxidant, antidiabetic, and antiinflammatory properties of hydroalcohol extract of bark of H. zeylanicum (HAHZ). It also describes isolation and structure determination of lucidenic acid A, which is the first report in this plant. In order to explain the role of antioxidant principles, DPPH, nitric oxide, hydroxyl, superoxide and metal chelating assays were performed. Antidiabetic and anti-inflammatory activities were investigated by quantifying α-amylase, α-glucosidase and protein denaturation inhibitory activities of HAHZ. Biochemical estimations were performed. The chemical structure of the triterpenoid was elucidated using 1H, 13C NMR and high resolution-MS. IC50 of DPPH, nitric oxide, hydroxyl, superoxide and metal chelating activities were of 36.23 ± 0.27, 40.11 ± 0.32, 35.23 ± 0.57, 43.34 ± 0.22 and 11.54 ± 0.08 µg/mL, respectively. IC50 of α-amylase and α-glucosidase activities were 29.12 ± 0.54, and 18.55 ± 0.15 µg/mL. Total phenolic and total flavonoid contents were recorded at 233.65 mg/g GAE and 172.7 mg/g QE. Regarding kinetic behaviour, HAHZ showed competitive inhibition on α-glucosidase and mixed competitive inhibition on α-amylase. Lucidenic acid A was confirmed by spectroscopic studies. Anti-inflammatory activity of lucidenic acid A was determined by using protein denaturation assay with IC50 13 µg/mL but HAHZ showed 30.34 ± 0.13 µg/mL. Phenols and flavonoids could be attributed to inhibition of intestinal carbohydrases for anti-diabetic activities whereas triterpenoids could be responsible for anti-inflammatory activity of H. zeylanicum.

Optimization of ultrasound-assisted compound enzymatic extraction and characterization of polysaccharides from blackcurrant.

In the present study, an efficient procedure for ultrasound-assisted compound enzymatic extraction of polysaccharides from blackcurrant fruits was investigated using response surface methodology (RSM). The Box-Behnken design was applied to optimize the effects of enzyme concentration (X1), pH (X2) and ultrasonic time (X3). The statistical analysis indicated that the independent variables (X1) and the quadratic terms (X1(2) and X3(2)) had significant effects on the yield of blackcurrant polysaccharides (BCP). The optimal conditions were: enzyme concentration 1.575%, pH 5.3, and ultrasonic time 25.6 min. The experimental yield of BCP was 14.28±0.06%, which was closely matched with the predicted yield of 14.31%. After preliminary purification, BCP I was obtained and characterized by GC, HPLC, and IR. BCP I comprised rhamnose, arabinose, xylose, mannose, glucose, and galactose in a molar ratio of 1.818:1.362:0.377:0.501:1.581:1.722 and its molecular weight was 8146 kDa. BCP I showed notable α-amylase inhibitory activity.