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Antioxidant, anti-inflammatory and synergistic anti-hyperglycemic effects of Malaysian propolis and metformin in streptozotocin-induced diabetic rats

Nna VU, Abu Bakar AB, Md Lazin MRML, Mohamed M

Food Chem Toxicol, 2018 Oct;120:305-320.
PMID: 30026088 DOI: 10.1016/j.fct.2018.07.028

Diabetes mellitus is characterized by hyperglycemia which causes oxidative stress. Propolis has been reported to have antihyperglycemic and antioxidant potentials. The present study therefore examined the anti-hyperglycemic, antioxidant and anti-inflammatory activities of Malaysian propolis (MP) using streptozotocin-induced diabetic rats. Ethanol extract of MP showed in vitro antioxidant (DPPH, FRAP and H2O2 radical scavenging) and α-glucosidase inhibition activities. Male Sprague Dawley rats were either treated with distilled water (normal control and diabetic control), MP (300 mg/kg b. w.), metformin (Met) (300 mg/kg b. w.) or both. After four weeks, fasting blood glucose decreased, while body weight change and serum insulin level increased significantly in MP, Met and MP + Met treated diabetic groups compared to diabetic control (DC) group. Furthermore, pancreatic antioxidant enzymes, total antioxidant capacity, interleukin (IL)-10 and proliferating cell nuclear antigen increased, while malondialdehyde, nuclear factor-kappa B (p65), tumor necrosis factor alpha, IL-1β and cleaved caspase-3 decreased significantly in the treated diabetic groups compared to DC group. Histopathology of the pancreas showed increased islet area and number of beta cells in the treated groups, compared to DC group, with D + MP + Met group comparable to normal control. We conclude that MP has anti-hyperglycemic, antioxidant, anti-inflammatory and antiapoptotic potentials, and exhibits synergistic effect with metformin.

Matched MeSH terms: Metformin
Fulltext Observational study investigating the prevalence of asymptomatic stage B heart failure in patients with type 2 diabetes who are not known to have coronary artery disease

Oo MM, Tan Chung Zhen I, Ng KS, Tan KL, Tan ATB, Vethakkan SR, et al.

BMJ Open, 2021 01 21;11(1):e039869.
PMID: 33478961 DOI: 10.1136/bmjopen-2020-039869

OBJECTIVE: To identify the prevalence of stage B heart failure (SBHF) in patients with type 2 diabetes mellitus (T2DM) with no history of cardiovascular disease (CVD).
DESIGN: Observational study.
SETTING: A single-centre study in which eligible patients were recruited from T2DM clinic. Following consent, patients completed a questionnaire and underwent physical examinations. Patients had blood drawn for laboratory investigations and had a transthoracic echocardiography.
PARTICIPANTS: A total of 305 patients who were not known to have CVD were recruited. Patients with deranged liver function tests and end stage renal failure were excluded.
MAIN OUTCOME MEASURES: Echocardiographic parameters such as left ventricular ejection fraction, left ventricular mass index (LVMI), left ventricular hypertrophy, left atrial enlargement and diastolic function were examined.
RESULTS: A total of 305 patients predominantly females (65%), with mean body mass index of 27.5 kg/m2 participated in this study. None of them had either a history or signs and symptoms of CVD. Seventy-seven percent of patients had a history of hypertension and 83% of this study population had T2DM for more than 10 years. Mean HbA1c of 8.3% was recorded. Almost all patients were taking metformin. Approximately, 40% of patients were on newer anti-T2DM agents such as sodium-glucose cotransporter-2 and dipeptidyl peptidase 4 inhibitors. Fifty-seven percent (n=174) of the study population had SBHF at the time of study: diastolic dysfunction, increased LVMI and increased left atrial volume index (LAVI) were noted in 51 patients (17%), 128 patients (42%) and 98 patients (32%), respectively. Thirty-seven patients (12%) had both increase LVMI and LAVI.
CONCLUSION: Our study has revealed a high prevalence of SBHF in T2DM patients without overt cardiac disease in Malaysia that has one of the highest prevalence of TDM in the world.

Matched MeSH terms: Metformin
Fulltext Swietenine potentiates the antihyperglycemic and antioxidant activity of Metformin in Streptozotocin induced diabetic rats

Shiming Z, Mak KK, Balijepalli MK, Chakravarthi S, Pichika MR

Biomed Pharmacother, 2021 Jul;139:111576.
PMID: 33862494 DOI: 10.1016/j.biopha.2021.111576

Diabetes mellitus or type-2 diabetes, commonly referred as diabetes, is a metabolic disorder that results in high blood sugar level. Despite the availability of several antidiabetic drugs in the market, they still do not adequately regulate blood sugar levels. Thus, in general people prefer to use herbal supplements/medicines along with antidiabetic drugs to control blood sugar levels. One of such herbal medicine is Swietenia macrophylla seeds. It is widely used in Asia for controlling blood sugar levels. One of the major bioactive compounds, Swietenine, is reported to be responsible for controlling blood glucose levels. However, there were no studies on its efficacy in controlling the blood glucose in diabetic rats. In this study, we evaluated the antihyperglycemic activity of Swietenine and its pharmacodynamic interaction with Metformin in Streptozotocin induced diabetes in rats. The activity of Swietenine was investigated at three different doses: 10, 20 and 40 mg/kg body weight (bw). Metformin (50 mg/kg bw) was used as a standard drug. Swietenine (20 and 40 mg/kg bw) and Metformin (50 mg/kg bw) showed significant effect in reducing the glucose, cholesterol, triglycerides, low-density lipoprotein, urea, creatinine, alanine transaminase, alkaline phosphatase, aspartate transaminase, alanine transaminase, and malondialdehyde level in serum while it had increased the high-density lipoprotein, glutathione, and total antioxidant capacity level. In addition, Swietenine (20 and 40 mg/kg) had shown significant synergistic effect with Metformin. Administration of Swietenine at 10 mg/kg bw neither showed activity nor influenced Metformin's activity. The results from this study confirmed the beneficial effects of Swietenine and its synergistic action with Metformin in controlling the dysregulated serum parameters in Streptozotocin induced diabetes in rats.

Matched MeSH terms: Metformin
Fulltext Antidiabetic, Antihyperlipidemic, Antioxidant, Anti-inflammatory Activities of Ethanolic Seed Extract of Annona reticulata L. in Streptozotocin Induced Diabetic Rats

Wen W, Lin Y, Ti Z

Front Endocrinol (Lausanne), 2019;10:716.
PMID: 31708869 DOI: 10.3389/fendo.2019.00716

Annona reticulata L. (Bullock's heart) is a pantropic tree commonly known as custard apple, which is used therapeutically for a variety of maladies. The present research was carried out to evaluate the possible protective effects of Annona reticulata L. (A. reticulata) ethanolic seed extract on an experimentally induced type 2 diabetes rat model. Male Albino Wistar rats were randomly divided into five groups with six animals in each group viz., control rats in group I, diabetic rats in group II, diabetic rats with 50 and 100 mg/kg/bw of ethanolic seed extract of A. reticulata in groups III and IV, respectively, and diabetic rats with metformin in group V. Treatment was given for 42 consecutive days through oral route by oro-gastric gavage. Administration of A. reticulata seed extract to diabetes rats significantly restored the alterations in the levels of body weight, food and water intake, fasting blood glucose (FBG), insulin levels, insulin sensitivity, HbA1c, HOMA-IR, islet area and insulin positive cells. Furthermore, A. reticulata significantly decreased the levels of triglycerides, cholesterol, LDL, and significantly increased the HDL in diabetic rats. A. reticulata effectively ameliorated the enzymatic (ALT, AST, ALP, GGT) and modification of histopathological changes in diabetic rats. The serum levels of the BUN, creatinine levels, uric acid, urine volume, and urinary protein were significantly declined with a significant elevation in CCr in diabetic rats treated with A. reticulata. MDA and NO levels were significantly reduced with an enhancement in SOD, CAT, and GPx antioxidant enzyme activities in the kidney, liver, and pancreas of diabetic rats treated with A. reticulata. Diabetic rats treated with A. reticulata have shown up-regulation in mRNA expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (NQO1), Heme oxygenase-1 (HO-1) and protein expression level of Nrf2 with diminution in Keap1 mRNA expression level in pancreas, kidney, and liver. From the outcome of the current results, it can be inferred that seed extract of A. reticulata exhibits a protective effect in diabetic rats through its anti-diabetic, anti-hyperlipidemic, antioxidant and anti-inflammatory effects and could be considered as a promising treatment therapy in the treatment of diabetes mellitus.

Matched MeSH terms: Metformin
Fulltext Efficacy and safety of fixed-dose combination therapy, alogliptin plus metformin, in Asian patients with type 2 diabetes: A phase 3 trial

Ji L, Li L, Kuang J, Yang T, Kim DJ, Kadir AA, et al.

Diabetes Obes Metab, 2017 05;19(5):754-758.
PMID: 28075066 DOI: 10.1111/dom.12875

This study evaluated the efficacy and safety of 26 weeks of twice-daily (BID) alogliptin + metformin fixed-dose combination (FDC) therapy in Asian patients with type 2 diabetes. Patients aged 18 to 75 years with hemoglobin A1c (HbA1c) of 7.5% to 10.0% after ≥2 months of diet and exercise and a 4-week placebo run-in were enrolled. Eligible patients were randomized (1:1:1:1) to placebo, alogliptin 12.5 mg BID, metformin 500 mg BID or alogliptin 12.5 mg plus metformin 500 mg FDC BID. The primary endpoint was change in HbA1c from baseline to end of treatment (Week 26). In total, 647 patients were randomized. The least-squares mean change in HbA1c from baseline to Week 26 was -0.19% with placebo, -0.86% with alogliptin, -1.04% with metformin and -1.53% with alogliptin + metformin FDC. Alogliptin + metformin FDC was significantly more effective ( P metformin alone. The safety profile of alogliptin + metformin FDC was similar to that of the individual components alogliptin and metformin. The study demonstrated that treatment with alogliptin + metformin FDC BID resulted in better glycaemic control than either monotherapy and was well tolerated in Asian patients with type 2 diabetes.

Matched MeSH terms: Metformin/adverse effects; Metformin/therapeutic use*
The effect of Metformin on endometrial tumor-regulatory genes and systemic metabolic parameters in polycystic ovarian syndrome--a proof-of-concept study

Shafiee MN, Malik DA, Yunos RI, Atiomo W, Omar MH, Ghani NA, et al.

Gynecol Endocrinol, 2015 Apr;31(4):286-90.
PMID: 25495168 DOI: 10.3109/09513590.2014.989982

The aim of this proof-of-concept study was to determine the effects of three-month Metformin therapy on the expression of tumor-regulatory genes (p53, cyclin D2 and BCL-2) in the endometrium of women with polycystic ovary syndrome (PCOS). A total of 40 women, aged between 21 and 45 years with PCOS (Rotterdam criteria) were recruited. The participants were assessed at pre- and 3-month-post-Metformin therapy for the menstrual regularities, weight reduction, Ferriman Galway scores, fasting blood glucose (FBG), total cholesterol, LDL, HDL and p53, BCL-2 and cyclin D2 gene expression. Five participants conceived spontaneously after the initial recruitment. Majority (68%) resumed regular menstrual cycles after Metformin. There were significant reduction in BMI (p = 0.001), weight (p = 0.001) and Ferriman Galway scores (p = 0.001). A significant improvement was seen in mean FBG (p = 0.002), total cholesterol (p = 0.001), LDL (p = 0.003) and HDL cholesterol levels (p = 0.015). Tumor suppressor gene (p53) was significantly up-regulated after Metformin (10 out of 14 women), with p value 0.016. BCL-2 and cyclin D2 (oncogenes) were slightly up-regulated without significant difference (p = 0.119 and 0.155, respectively). In conclusion, Metformin therapy improved clinical and metabolic parameters in women with PCOS and up-regulated p53 tumor suppressor gene significantly. Further studies are however required to independently validate our findings.

Matched MeSH terms: Metformin/adverse effects; Metformin/therapeutic use*
Sargassum polycystum reduces hyperglycaemia, dyslipidaemia and oxidative stress via increasing insulin sensitivity in a rat model of type 2 diabetes

Motshakeri M, Ebrahimi M, Goh YM, Matanjun P, Mohamed S

J Sci Food Agric, 2013 May;93(7):1772-8.
PMID: 23208488 DOI: 10.1002/jsfa.5971

BACKGROUND: Sargassum polycystum, a brown seaweed, contains various nutrients and bioactive compounds that have antioxidant and healing properties. The research hypothesises that antioxidants and pigments in dietary S. polycystum extracts can improve insulin sensitivity, blood sugar levels and blood lipid levels in a rat model of type 2 diabetes. The diabetes was induced by a high-sugar, high-fat diet for 16 weeks to enhance insulin resistance, followed by a low-dose intraperitoneal injection of streptozotocin (35 mg kg(-1) body weight). The doses of S. polycystum tested on diabetic rats were 150 and 300 mg kg(-1) body weight for the ethanolic extract or 150 and 300 mg kg(-1) for the water extract. Normal rats, untreated diabetic and metformin-treated diabetic rats (n = 6) were used as control.
RESULTS: Both doses of the alcohol extract of S. polycystum and the 300 mg kg(-1) water extract, significantly reduced blood glucose and glycosylated haemoglobin (HbA1C ) levels. Serum total cholesterol, triglyceride levels and plasma atherogenic index were significantly decreased after 22 days treatment in all seaweed groups. Unlike metformin, S. polycystum did not significantly change plasma insulin in the rats, but increased the response to insulin.
CONCLUSION: The consumption of either ethanolic or water extracts of S. polycystum dose dependently reduced dyslipidaemia in type 2 diabetic rats. S. polycystum is a potential insulin sensitiser, for a comestible complementary therapy in the management of type 2 diabetes which can help reduce atherogenic risk.

Matched MeSH terms: Metformin/pharmacology; Metformin/therapeutic use
Fulltext Formononetin: A Review of Its Anticancer Potentials and Mechanisms

Tay KC, Tan LT, Chan CK, Hong SL, Chan KG, Yap WH, et al.

Front Pharmacol, 2019;10:820.
PMID: 31402861 DOI: 10.3389/fphar.2019.00820

Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.

Matched MeSH terms: Metformin
Fulltext Catalpol Ameliorates Insulin Sensitivity and Mitochondrial Respiration in Skeletal Muscle of Type-2 Diabetic Mice Through Insulin Signaling Pathway and AMPK/SIRT1/PGC-1α/PPAR-γ Activation

Yap KH, Yee GS, Candasamy M, Tan SC, Md S, Abdul Majeed AB, et al.

Biomolecules, 2020 09 24;10(10).
PMID: 32987623 DOI: 10.3390/biom10101360

Catalpol was tested for various disorders including diabetes mellitus. Numerous molecular mechanisms have emerged supporting its biological effects but with little information towards its insulin sensitizing effect. In this study, we have investigated its effect on skeletal muscle mitochondrial respiration and insulin signaling pathway. Type-2 diabetes (T2DM) was induced in male C57BL/6 by a high fat diet (60% Kcal) and streptozotocin (50 mg/kg, i.p.). Diabetic mice were orally administered with catalpol (100 and 200 mg/kg), metformin (200 mg/kg), and saline for four weeks. Fasting blood glucose (FBG), HbA1c, plasma insulin, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), oxygen consumption rate, gene (IRS-1, Akt, PI3k, AMPK, GLUT4, and PGC-1α) and protein (AMPK, GLUT4, and PPAR-γ) expression in muscle were measured. Catalpol (200 mg/kg) significantly (p < 0.05) reduced the FBG, HbA1C, HOMA_IR index, and AUC of OGTT whereas, improved the ITT slope. Gene (IRS-1, Akt, PI3k, GLUT4, AMPK, and PGC-1α) and protein (AMPK, p-AMPK, PPAR-γ and GLUT4) expressions, as well as augmented state-3 respiration, oxygen consumption rate, and citrate synthase activity in muscle was observed in catalpol treated mice. The antidiabetic activity of catalpol is credited with a marked improvement in insulin sensitivity and mitochondrial respiration through the insulin signaling pathway and AMPK/SIRT1/PGC-1α/PPAR-γ activation in the skeletal muscle of T2DM mice.

Matched MeSH terms: Metformin
Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea

Ji L, Han P, Liu Y, Yang G, Dieu Van NK, Vijapurkar U, et al.

Diabetes Obes Metab, 2015 Jan;17(1):23-31.
PMID: 25175734 DOI: 10.1111/dom.12385

To evaluate the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin or metformin in combination with sulphonylurea.

Matched MeSH terms: Metformin/therapeutic use*
Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells

Soo JS, Ng CH, Tan SH, Malik RA, Teh YC, Tan BS, et al.

Apoptosis, 2015 Oct;20(10):1373-87.
PMID: 26276035 DOI: 10.1007/s10495-015-1158-5

Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

Matched MeSH terms: Metformin/pharmacology*

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