Bitter melon fruit extract enhances intracellular ATP production and insulin secretion from rat pancreatic ß-cells.

Bitter melon (Momordica charantia L.) has been shown to have various health-promoting activities, including antidiabetic and hypoglycaemic effects. Improvement in insulin sensitivity and increase in glucose utilisation in peripheral tissues have been reported, but the effect on insulin secretion from pancreatic ß-cells remains unclear. In this study, we investigated the effect of bitter melon fruit on insulin secretion from ß-cells and the underlying mechanism. The green fruit of bitter melon was freeze-dried and extracted with methanol. The bitter melon fruit extract (BMFE) was fractionated using ethyl acetate (fraction A), n-butanol (fraction B) and water (fraction C). Insulin secretory capacity from INS-1 rat insulinoma cell line and rat pancreatic islets, as well as glucose tolerance in rats by oral glucose tolerance test (OGTT), was measured using BMFE and fractions. ATP production in ß-cells was also examined. BMFE augmented insulin secretion from INS-1 cells in a dose-dependent manner. The significant augmentation of insulin secretion was independent of the glucose dose. Fraction A (i.e. hydrophobic fraction), but not fractions B and C, augmented insulin secretion significantly at the same level as that by BMFE. This finding was also observed in pancreatic islets. In OGTT, BMFE and fraction A decreased blood glucose levels and increased serum insulin levels after glucose loading. The decrease in blood glucose levels was also observed in streptozotocin-induced diabetic rats. In addition, BMFE and fraction A increased the ATP content in ß-cells. We concluded that hydrophobic components of BMFE increase ATP production and augment insulin secretion from ß-cells, consequently decreasing blood glucose levels.

Effect of Lupinus rotundiflorus gamma conglutin treatment on JNK1 gene expression and protein activation in a rat model of type 2 diabetes.

CONTEXT: Gamma conglutin (Cγ) from lupine species represents a potential complementary treatment for type 2 diabetes mellitus (T2DM) because of its hypoglycaemic effect. However, its underlying mechanism of action is not fully known. OBJECTIVE: To evaluate whether Cγ from Lupinus rotundiflorus M. E. Jones (Fabaceae) modulates c-Jun N-terminal kinase 1 (JNK1) expression and activation in a T2DM rat model. MATERIALS AND METHODS: Gamma conglutin isolated from L. rotundiflorus seeds was characterized by SDS-PAGE. Fifteen Wistar rats with streptozotocin-induced T2DM (HG) were randomized into three groups (n = 5): vehicle administration (HG-Ctrl), oral treatment with Cγ (120 mg/kg/day) (HG-Lr) for one week, and treatment with metformin (300 mg/kg/day) (HG-Met); a healthy group (Ctrl, n = 5) was included as control. The levels of glucose and biomarkers of renal and hepatic function were measured pre- and post-treatment. Hepatic Jnk1 expression and phosphorylation of JNK1 were evaluated by qRT-PCR and western blot, respectively. RESULTS: Oral treatment with either Cγ or metformin reduced serum glucose level to 86.30 and 74.80 mg/dL, respectively (p ˂ 0.05), from the basal levels. Jnk1 expression was 0.65- and 0.54-fold lower (p ˂ 0.05) in the HG-Lr and HG-Met groups, respectively, than in HG-Ctrl. Treatment with Cγ decreased JNK1 phosphorylation. However, Cγ did not change the levels of kidney and liver biomarkers. DISCUSSION AND CONCLUSIONS: Treatment with Cγ from L. rotundiflorus inhibited Jnk1 expression, in vivo, suggesting JNK1 as a potential therapeutic target in diabetes and revealing one mechanism underlying the hypoglycaemic effect of lupine Cγ. Nevertheless, further studies are required.

Hypoglycaemic activity of ethanolic extract of Garcinia mangostana Linn. in normoglycaemic and streptozotocin-induced diabetic rats.

BACKGROUND: Various parts of Garcinia mangostana Linn., including its pericarp, have been traditionally used to treat a variety of ailments. In an attempt to establish its medicinal value, the present study was carried out to determine the hypoglycaemic potential of G. mangostana pericarp ethanolic extract (GME) using the streptozotocin-induced (STZ) diabetic rats. METHODS: GME at 2,000 mg/kg was subjected to a single-dose acute toxicity test. Following this, the effect of GME (50, 100, and 200 mg/kg) on blood glucose level of normoglycaemic and STZ-induced diabetic rats was determined using single-dose (acute) and multiple-dose (subacute) approaches. Subsequent to the multiple-dose study, serum biochemical analysis and liver histopathological examination were also performed. Throughout the experiments, the effect of GME was compared against the standard hypoglycaemic drug, glibenclamide. RESULTS: GME was safe for oral consumption up to the dose of 2,000 mg/kg. In both single- and multiple-dose studies, GME significantly (p < 0.05) reduced the blood glucose level in normoglycaemic rats and STZ-induced diabetic rats when compared against the normal control group or diabetic control group, respectively. Moreover, GME also significantly (p < 0.05) increased the rats' body weight in comparison to the diabetic control group in the multiple-dose study. GME also significantly (p < 0.05) reduced the levels of certain biochemical parameters [i.e., triglycerides (TG), total cholesterol (TC), low density lipoprotein (LDL), very low density lipoprotein (VLDL), serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), urea, and creatinine] while increased the others [i.e., high density lipoprotein (HDL) and total protein (TP)] when compared to the diabetic control group. Histopathological assessment of the collected liver revealed a mild increase in the population of ß-cells in the diabetic rats. CONCLUSION: GME exerts the hypoglycaemic activity possibly by increasing the population of insulin-producing ß-cells. This activity could be attributed to the presence of antioxidant-bearing tannins like epicathecin, and xanthones like α-mangostin. Thus, the findings demonstrated that GME could be a potential candidate in the management of diabetes owing to its hypoglycaemic effect.

Functional and physiological properties of total, soluble, and insoluble dietary fibres derived from defatted rice bran.

Enzymatic- gravimetric method was used to obtain three fractions of dietary from defatted rice bran. The functional and physiological properties such as viscosity, cation exchange capacity (CEC), and glucose dialysis retardation index (GDRI), cholesterol and bile salt adsorption capacity of the resultant fractions were evaluated. Insoluble dietary fibre (IDF) and soluble dietary fibre (SDF) when compared showed that SDF exhibited significantly (p < 0.05) higher viscosity (2.35 mPa.s), greater GDRI value (17.65 %) at 60 min and significantly lowered concentration of cholesterol at pH 7 (29.90 %, p < 0.05). However IDF showed the highest CEC and its adsorption capacity of bile salt was higher than SDF (18.20 % vs. 13.76 %; p < 0.05), while CEC and cholesterol absorption capacity of TDF were similar to SDF. These properties indicate that rice bran soluble, insoluble and total fibres are functional ingredients which can be added to various food products and dietetic, low-calorie high-fiber foods to enhance their nutraceutical properties and health benefits.

A comparative evaluation of cardiac and neurological safety status of two commonly used oral hypoglycaemic agents in T2-DM Swiss albino mice model.

Background: Diabetes mellitus (DM), along with its associated complications, including diabetic neuropathy and hyperlipidemia, has become a global concern in the last few decades. The main objective of our study is to evaluate the comparative neuro-safety status, serum plasma glucose, and lipid-lowering potential of two widely recognized antidiabetic drugs named metformin and glimepiride. Methods: The neurological evaluation was done by open field test, hole board test, forced swimming test, dark and lighthouse test, and elevated plus maze test by employing diazepam as standard. Serum blood glucose level of streptozotocin (STZ)-induced diabetic mice was determined by glucose oxidizing method using a glucometer. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C) levels were estimated by using the reference method where atorvastatin was used as standard. Results: In neurological evaluation, both drugs produce almost the same anxiolytic activity in the open field test, hole board test, light and dark house test, and elevated plus maze test. However, in the forced swimming test, glimepiride produced more antidepressant activity than metformin. Glimepiride was found to remarkably reduce serum glucose and VLDL-C levels more than metformin, whereas, for other parameters, metformin takes over glimepiride sometimes took over the standard atorvastatin. Conclusions: The results of our study indicate that both oral hypoglycaemic drugs alter the lipid index while producing some anxiolytic effects on the central nervous system. Thus, recommended to be carefully administered to patients with low BMI and might be beneficial to patients suffering from peripheral nerve function and anxiety.

Two new compounds from a mangrove sediment-derived fungus Penicillium polonicum H175.

Two new compounds, 6-acetyl-4-methoxy-3,5-dimethyl-2H-pyran-2-one (1) and (2E,4E)-5-((2S,3S,4R,5R)-3,4-dihydroxy-2,4,5-trimethyltetrahydrofuran-2-yl)-2,4-dimethylpenta-2,4-dienal (2), and 22 known compounds were identified from the mangrove-forest-derived fungus Penicillium polonicum H175. The structures of these compounds were elucidated by analysis of the high-resolution electrospray ionisation mass spectroscopy (HR-ESI-MS), 1 D and 2 D nuclear magnetic resonance (NMR) data. The hypoglycaemic effect of compounds was evaluated by the Tg (Ins: htBidTE-ON; LR) zebrafish model. Compound 3 (aspterric acid) exhibited a significant hypoglycaemic effect equivalent to the positive drug rosiglitazone (RSG) at 10 µmol/L.

Goji Berry (Lycium barbarum) Supplementation during Pregnancy Influences Insulin Sensitivity in Rabbit Does but Not in Their Offspring.

This study investigated the effects of Goji berry (Lycium barbarum) dietary supplementation during pregnancy on insulin sensitivity of rabbit does and their offspring. Starting from two months before the artificial insemination, 75 New Zealand White does were fed only commercial standard diet (C) or supplemented with 1% (G1) and 3% (G3) of Goji berries. Their offspring received a standard diet but kept the nomenclature of the mother's group. Fasting and intravenous glucose tolerance test-derived indices were estimated at 21 days of pregnancy on rabbit does and at 90 days of age on the offspring. No difference was found in the fasting indices, while the diet modulated the response to glucose load of rabbit does. In particular, G3 group had the lowest glucose concentrations 5 min after the bolus administration (p < 0.05) and, as a result, differed in the parameters calculated during the elimination phase such as the elimination rate constant (Kel), the half-life of the exogenous glucose load (t1/2), and apparent volume of distribution (Vd; for all, p < 0.05). The high dose of Goji supplementation could thus enhance the first-phase glucose-induced insulin secretion. Findings on the offspring were inconsistent and therefore a long-term effect of Goji supplementation during pregnancy could not be demonstrated. Further study on the effect of Goji on the secretory pathway of insulin could clarify its hypoglycaemic action, while different protocols are needed to investigate its potential effects on foetal programming.

Myrianthus libericus: Possible mechanisms of hypoglycaemic action and in silico prediction of pharmacokinetics and toxicity profile of its bioactive metabolite, friedelan-3-one.

The hypoglycaemic and anti-hyperlipidaemic effects of the 70% ethanol stem bark extract of Myrianthus libericus (MLB), used traditionally in the management of diabetes in Ghana, was evaluated in this study using streptozotocin (45 mg/kg)-induced diabetic rats. In vitro hypoglycaemic activities of the extract and one of its principal compounds, friedelan-3-one were then investigated using α-amylase inhibitory and glucose uptake assay in C2C12 myotubes. In silico analysis of the pharmacokinetic and toxicity properties of the compound was also performed. MLB significantly (p < 0.001) reduced the elevated blood glucose levels and corrected considerably (p < 0.01) the altered serum lipid profiles of the diabetic rats which was comparable to glibenclamide (5 mg/kg). Together with friedelan-3-one, the extract markedly inhibited the activity of α-amylase and promoted glucose uptake in C2C12 cells. Whereas MLB significantly (p < 0.001) up-regulated PI3K and PPARγ transcripts with a corresponding increase in GLUT-4 transcripts within the muscle cells, friedelan-3-one only up-regulated PI3K and GLUT-4 transcripts to promote glucose transport. Friedelan-3-one was shown to be non-carcinogenic, non-hepatotoxic, has decent oral bioavailability and a good compound for optimisation into a drug candidate. The study has demonstrated that MLB possess hypoglycaemic and anti-hyperlipidaemic activities and could be used as a therapeutic agent in the management of diabetes mellitus.

Contribution of fasting and postprandial glucose-lowering mechanisms to the acute hypoglycemic effect of traditionally used Eryngium cymosum F.Delaroche.

ETHNOPHARMACOLOGICAL RELEVANCE: Eryngium cymosum F. Delaroche was detected as a traditional remedy against type 2 diabetes consumed by patients of Tlanchinol in the state of Hidalgo, Mexico. AIM OF THE STUDY: Assessing the hypoglycemic effect and safety of the traditional extract of E. cymosum and relating it to key glucose-lowering mechanisms both in fasting and postprandial state. MATERIALS AND METHODS: The aqueous extract of E. cymosum was subjected to HPLC analysis to identify its main components. Hyperglycaemic STZ-NA Wistar rats were administered with the extract to evaluate its effect on blood glucose levels and a possible dose-dependence. Afterward, it was evaluated in both pyruvate and maltose tolerance tests in STZ-NA rats to characterize its effect on gluconeogenesis and carbohydrate breakdown, two of the main mechanisms responsible for fasting and postprandial hyperglycaemia in type 2 diabetes patients. In addition, the inhibitory capacity of the extract was evaluated on key enzymes involved in gluconeogenesis and a-glucosidases. Moreover, insulin concentrations were measured in normoglycemic rats in both conditions to establish a link between the hypoglycaemic effect of the extract with insulin release and functioning. RESULTS: Caffeic acid (1), chlorogenic acid (2), and rosmarinic acid (3) were identified as the main constituents of the aqueous extract of E. cymosum, which exerted a hypoglycaemic effect in hyperglycaemic STZ-NA rats. It has a significant antihyperglycemic effect in the pyruvate tolerance test, and it was able to reduce the postprandial hyperglycaemia in maltose tolerance tests significantly. Moreover, it effectively reduced the activity of both gluconeogenic enzymes reaching almost 100% of inhibition, while it presented a modest 32% inhibition of aglucosidases. On the other hand, the extract decreased insulin levels after its oral administration in healthy rats in both nutritional states, without affecting normoglycemia in normal curves and reducing the postprandial peak in glucose load curves. CONCLUSIONS: The traditional consumed form of aerial parts of E. cymosum is safe and regulated glucose levels both in fasting and in postprandial state.

Hypoglycaemic effect and mechanism of an RG-II type polysaccharide purified from Aconitum coreanum in diet-induced obese mice.

The present study aimed to explore the effect of an anti-inflammatory RG-II type polysaccharide (KMPS) purified from Aconitum coreanum (Le'vl.) on glucose metabolism in high-fat diet-induced obese (DIO) mice. Treatment with KMPS for 4 weeks significantly reduced the fasting blood glucose, increased the sensitivity to insulin and improved glucose tolerance. Concurrently, KMPS supplementation also markedly inhibited inflammatory cytokine expression in serum and insulin target tissues and decreased the proportion of M1-type macrophages in adipose tissue, which was considered as the potential hypoglycaemic mechanism. In mechanism study, it was found that KMPS reduced the serine phosphorylation of IRS-1 by inhibiting the activation of the NF-κB pathway, thereby restoring the utilization of glucose by the PI3K/AKT pathway. These results suggested that KMPS may be a potential component for targeting inflammation in the treatment of type 2 diabetes.

Evaluation of the hypoglycaemic and antioxidant effects of submerged Ganoderma lucidum cultures in type 2 diabetic rats.

We aim to investigate the hypoglycaemic and antioxidant effects of submerged Ganoderma lucidum cultures and elucidate the potential mechanisms behind these effects using a type 2 diabetic rat model. Diabetic rats were daily fed with a high-fat diet supplemented with 1% or 3% freeze-dried whole submerged cultures of G. lucidum or mycelia for 5 weeks. We observed significantly decreased fasting plasma glucose levels, homoeostasis model assessment equation-insulin resistance, and plasma glucose in oral glucose tolerance test. Furthermore, we observed increased levels of glycogen, hepatic hexokinase, glucose-6-phosphate dehydrogenase, and intestinal disaccharidase activities. G. lucidum supplement downregulated the plasma levels of aspartate aminotransferase, alanine aminotransferase, creatinine, and urea nitrogen as well as liver and kidney levels of thiobarbituric acid reactive substances. Based on the hypoglycaemic and antioxidant effects of G. lucidum submerged cultures, we recommend the potential application of these products as functional foods or additives for controlling type 2 diabetes. Abbreviations ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; BW: Body weight; CREA: Creatinine; FPG: Fasting plasma glucose; G6Pase: Glucose-6-phosphatase; G6PD: Glucose-6-phosphate dehydrogenase; HOMA-IR: Homoeostasis model assessment of insulin resistance; OGTT: Oral glucose tolerance test; PTP: Protein tyrosine phosphatase; STZ: Streptozotocin; TBARS: Thiobarbituric acid reactive substances.

Cell-penetrating peptide enhanced insulin buccal absorption.

Non-injectable delivery of peptides and proteins is not feasible due to the limitations of large molecular mass, high hydrophilic properties, and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue. The objective of this study was to propose a novel protein delivery strategy to overcome the poor efficacy and irritation of buccal insulin delivery. In this study, we applied a conjugate of cell-penetrating peptides (LMWP) and insulin (INS-PEG-LMWP) for buccal delivery. INS-PEG-LMWP was prepared using insulin solution and mixture as references. The transport behaviour, in vivo bioactivity, hypoglycaemic effect, and safety of INS-PEG-LMWP were systematically characterised. An in vitro study demonstrated that the uptake and transportation of INS-PEG-LMWP across buccal mucosal multilayers significantly increased. By comparing the effects of different endocytic inhibitors on INS-PEG-LMWP uptake, the conjugate might be delivered via an energy independent, electrostatically adsorbed pathway. INS-PEG-LMWP's relative pharmacological bioavailability was high and its relative bioavailability was up to 26.86%, demonstrating no visible mucosal irritation. Cell-penetrating peptides are likely to become a reliable and safe tool for overcoming insulin's low permeability through the epithelial multilayers, the major barrier to buccal delivery.

Comparison of PEGylated FGF-21 with insulin glargine for long-lasting hypoglycaemic effect in db/db mice.

AIM: This study investigated the long-acting antidiabetic efficacy of PEGylated fibroblast growth factor (FGF)-21 in type 2 diabetic db/db mice. METHODS: PEGylated FGF-21 was prepared by modifying the N-terminus of human FGF-21 (hFGF-21) using mPEG-ALD. To compare the long-lasting hypoglycaemic effects of PEGylated FGF-21 and insulin glargine in diabetic db/db mice, their pharmacological efficacy was evaluated by changes in blood glucose levels, body weight, insulin levels, glycosylated haemoglobin levels, lipid profile and liver function parameters, and by oral glucose tolerance tests (OGTTs). RESULTS: Both PEGylated FGF-21 and insulin glargine decreased plasma glucose in db/db mice. However, compared with insulin glargine treatment, PEGylated FGF-21 therapy had more significant effects in lowering blood glucose and glycosylated haemoglobin levels, improving lipid profile and liver function parameters, alleviating insulin resistance and reducing the glucose area under the curve in OGTTs. CONCLUSION: Our results suggest that PEGylated FGF-21 is an ideal candidate as a long-acting antidiabetes drug, and holds significant promise as an effective therapeutic agent in the treatment of type 2 diabetes patients.

In vivo hypoglycemic effect of methanolic fruit extract of Momordica charantia L.

BACKGROUND: Momordica charantia L. is a medicinal plant commonly used in the management of diabetes mellitus. OBJECTIVES: We investigated the blood glucose lowering effect of the methanolic fruit extract of the Ugandan variety of M. charantia L. in alloxan-induced diabetic albino rats. METHODS: 500g of M. charantia powder were macerated in methanol and the extract administered to two groups of alloxan-induced diabetic rats. The first group received 125mg/kg, the second 375mg/kg and a third group 7mg/kg of metformin. A fourth group received 1ml normal saline. Fasting blood glucose (FBG) levels were measured at 0.5,1,2,3,5,8 and 12 hours and compared using one-way ANOVA. RESULTS: There was an initial rise in FBG for 1 hour after administration of extracts followed by steep reductions. Significant reduction in FBG occurred at 2 hours for 125mg/kg of extract (-3.2%, 313±25.9 to 303±25.0mg/dL, p = 0.049), 375mg/kg of extract (-3.9%, 356±19.7 to 342±20.3mg/dL, p = 0.001), and metformin (-2.6%, 344±21.7 to 335±21.1mg/dL, p = 0.003) when compared to normal saline. The maximum percentage reduction in FBG by both extracts occurred between 3 and 12 hours post dose. CONCLUSIONS: The methanolic fruit extract of M. charantia exhibits dose dependent hypoglycaemic activity in vivo.

Hypoglycaemic effect of Berberis vulgaris L. in normal and streptozotocin-induced diabetic rats.

OBJECTIVE: To achieve a primary pharmacological screening contained in the aqueous extract of Berberis vulgaris (B. vulgaris) and to examine the hypoglycaemic effect and biochemical parameters of aqueous and saponins extract on groups of rats rendered diabetic by injection of streptozotocin. METHODS: The phytochemical tests to detect the presence of different compounds were based on the visual observation of color change or formation of precipitate after the addition of specific reagents. Diabetes was induced in rats by intraperitoneal (i.p.) injection of streptozotocin (STZ) at a dose of 65 mg/kg bw. The fasting blood glucose levels were estimated by glucose oxidase-peroxidase reactive strips (Dextrostix, Bayer Diagnostics). Blood samples were taken by cutting the tip of the tail. Serum cholesterol and serum triglycerides were estimated by enzymatic DHBS colorimetric method. RESULTS: Administration of 62.5 and 25.0 mg/kg of saponins and aqueous extract respectively in normal rats group shows a significant hypoglycemic activity (32.33% and 40.17% respectively) during the first week. However, diabetic group treated with saponin extract produced a maximum fall of 73.1% and 76.03% at day 1 and day 21 compared to the diabetics control. Also, blood glucose levels of the diabetic rats treated with aqueous extract showed decrease of 78.79% on the first day and the effect remains roughly constant during 3 week. Both extracts also declined significantly biochemical parameters (20.77%-49.00%). The control in the loss of body weight was observed in treated diabetic rats as compared to diabetic controls. CONCLUSIONS: These results demonstrated significant antidiabetic effects and showed that serum cholesterol and serum triglycerides levels were decreased, significantly, consequently this plant might be of value in diabetes treatment.