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Insulin Transdermal Delivery System for Diabetes Treatment Using a Biocompatible Ionic Liquid-Based Microemulsion

Islam MR, Uddin S, Chowdhury MR, Wakabayashi R, Moniruzzaman M, Goto M

ACS Appl Mater Interfaces, 2021 Sep 15;13(36):42461-42472.
PMID: 34460218 DOI: 10.1021/acsami.1c11533

Since injection administration for diabetes is invasive, it is important to develop an effective transdermal method for insulin. However, transdermal delivery remains challenging owing to the strong barrier function of the stratum corneum (SC) of the skin. Here, we developed ionic liquid (IL)-in-oil microemulsion formulations (MEFs) for transdermal insulin delivery using choline-fatty acids ([Chl][FAs])-comprising three different FAs (C18:0, C18:1, and C18:2)-as biocompatible surface-active ILs (SAILs). The MEFs were successfully developed using [Chl][FAs] as surfactants, sorbitan monolaurate (Span-20) as a cosurfactant, choline propionate IL as an internal polar phase, and isopropyl myristate as a continuous oil phase. Ternary phase behavior, dynamic light scattering, and transmission electron microscopy studies revealed that MEFs were thermodynamically stable with nanoparticle size. The MEFs significantly enhanced the transdermal permeation of insulin via the intercellular route by compromising the tight lamellar structure of SC lipids through a fluidity-enhancing mechanism. In vivo transdermal administration of low insulin doses (50 IU/kg) to diabetic mice showed that MEFs reduced blood glucose levels (BGLs) significantly compared with a commercial surfactant-based formulation by increasing the bioavailability of insulin in the systemic circulation and sustained the insulin level for a much longer period (half-life > 24 h) than subcutaneous injection (half-life 1.32 h). When [Chl][C18:2] SAIL-based MEF was transdermally administered, it reduced the BGL by 56% of its initial value. The MEFs were biocompatible and nontoxic (cell viability > 90%). They remained stable at room temperature for 3 months and their biological activity was retained for 4 months at 4 °C. We believe SAIL-based MEFs will alter current approaches to insulin therapy and may be a potential transdermal nanocarrier for protein and peptide delivery.

Matched MeSH terms: Diabetes Mellitus, Experimental/drug therapy*
Fulltext In vitro alpha-glucosidase and alpha-amylase enzyme inhibitory effects of Andrographis paniculata extract and andrographolide

Subramanian R, Asmawi MZ, Sadikun A

Acta Biochim. Pol., 2008;55(2):391-8.
PMID: 18511986

There has been an enormous interest in the development of alternative medicines for type 2 diabetes, specifically screening for phytochemicals with the ability to delay or prevent glucose absorption. The goal of the present study was to provide in vitro evidence for potential inhibition of alpha-glucosidase and alpha-amylase enzymes, followed by a confirmatory in vivo study on rats to generate a stronger biochemical rationale for further studies on the ethanolic extract of Andrographis paniculata and andrographolide. The extract showed appreciable alpha-glucosidase inhibitory effect in a concentration-dependent manner (IC(50)=17.2+/-0.15 mg/ml) and a weak alpha-amylase inhibitory activity (IC(50)=50.9+/-0.17 mg/ml). Andrographolide demonstrated a similar (IC(50)=11.0+/-0.28 mg/ml) alpha-glucosidase and alpha-amylase inhibitory activity (IC(50)=11.3+/-0.29 mg/ml). The positive in vitro enzyme inhibition tests paved way for confirmatory in vivo studies. The in vivo studies demonstrated that A. paniculata extract significantly (P<0.05) reduced peak blood glucose and area under curve in diabetic rats when challenged with oral administration of starch and sucrose. Further, andrographolide also caused a significant (P<0.05) reduction in peak blood glucose and area under the curve in diabetic rats. Hence alpha-glucosidase inhibition may possibly be one of the mechanisms for the A. paniculata extract to exert antidiabetic activity and indicates that AP extract can be considered as a potential candidate for the management of type 2 diabetes mellitus.

Matched MeSH terms: Diabetes Mellitus, Experimental/blood; Diabetes Mellitus, Experimental/drug therapy
Immunolocalization of insulin-like growth factors and their receptors in the diabetic mouse oviduct and uterine tissues during the preimplantation period

Zakaria R, Rajikin MH, Yaacob NS, Nor NM

Acta Histochem, 2009;111(1):52-60.
PMID: 18676006 DOI: 10.1016/j.acthis.2008.04.002

The aim of the present study was to analyze the immunolocalization of insulin-like growth factor (IGF)-1 and IGF-2 and their receptors in the oviduct and uterus of control and diabetic mice. Sexually mature female ICR mice aged 6-8 weeks were rendered diabetic by streptozotocin (200 mg/kg, administered intraperitoneally). Oviductal and uterine tissues were obtained from the superovulated control and diabetic mice at 48, 72 and 96 h post-human chorionic gonadotropin (hCG) treatment. Localization of IGF-1, IGF-2, IGF-1R and IGF-2R was determined by immunohistochemistry and a semi-quantitative scoring of immunolabelling was performed using a standardized 5-point system. The immunohistochemical scorings for both IGF-1 and IGF-1R were significantly decreased in the oviducts of diabetic mice at 96 h post-hCG treatment. The scores for IGF-2 were significantly increased in the oviducts of diabetic mice at 48 and 72 h post-hCG treatment, and for IGF-2R at 72 h post-hCG treatment. However, there was no significant difference in the scores of IGFs and their receptors in the uterus of control and diabetic mice. In conclusion, the oviductal immunolabelling for IGFs and their receptors was significantly altered by maternal diabetes, which may be of importance in the pathogenesis of preimplantation diabetic embryopathy.

Matched MeSH terms: Diabetes Mellitus, Experimental/chemically induced; Diabetes Mellitus, Experimental/metabolism; Diabetes Mellitus, Experimental/pathology
Blunted endogenous GABA-mediated inhibition in the hypothalamic paraventricular nucleus of rats with streptozotocin-induced diabetes

Hassan Z, Sattar MZ, Suhaimi FW, Yusoff NH, Abdulla MH, Yusof AP, et al.

Acta Neurol Belg, 2013 Sep;113(3):319-25.
PMID: 23242937 DOI: 10.1007/s13760-012-0165-3

The hypothalamic paraventricular nucleus (PVN) is involved in the regulation of sympathetic outflow and particularly affects the heart. This study sets out to determine the role of GABA of the paraventricular nucleus (PVN) in cardiovascular regulation in streptozotocin-induced diabetic rats. Pharmacological stimulation of glutamatergic receptors with DL-Homocysteic acid (200 mM in 100 nL) in the PVN region showed a significant depression in both mean arterial pressure (MAP) and heart rate (HR) of diabetic rats (Diabetic vs. non-diabetic: MAP 15.0 ± 1.5 vs. 35.8 ± 2.8 mmHg; HR 3.0 ± 2.0 vs. 30.0 ± 6.0 bpm, P < 0.05). Microinjection of bicuculline methiodide (1 mM in 100 nL), a GABAA receptor antagonist, produced an increase in baseline MAP and HR in both non-diabetic and diabetic rats. In the diabetic rats, bicuculline injection into the PVN reduced the pressor and HR responses (Diabetic vs. non-diabetic: MAP 6.2 ± 0.8 vs. 25.1 ± 2.2 mmHg; HR 1.8 ± 1.1 vs. 25.4 ± 6.2 bpm, P < 0.05). A microinjection of muscimol (2 mM in 100 nL), which is a GABAA receptor agonist, in the PVN elicited decreases in MAP and HR in both groups. The diabetic group showed a significantly blunted reduction in HR, but not MAP (Diabetic vs. non-diabetic: MAP -15.7 ± 4.0 vs. -25.0 ± 3.8 mmHg; HR -5.2 ± 2.1 vs. -39.1 ± 7.9 bpm). The blunted vasopressor and tachycardic responses to bicuculline microinjection in the diabetic rats are likely to result from decreased GABAergic inputs, attenuated release of endogenous GABA or alterations in GABAA receptors within the PVN.

Matched MeSH terms: Diabetes Mellitus, Experimental/pathology*
Fulltext Functional subtypes of renal alpha1-adrenoceptor in diabetic and non-diabetic 2K1C Goldblatt renovascular hypertension

Armenia A, Sattar MA, Abdullah NA, Khan MA, Johns EJ

Acta Pharmacol Sin, 2008 May;29(5):564-72.
PMID: 18430364 DOI: 10.1111/j.1745-7254.2008.00788.x

This study investigates the subtypes of the alpha1-adrenoceptor mediating the adrenergically-induced renal vasoconstrictor responses in streptozotocin-induced diabetic and non-diabetic 2-kidney one clip (2K1C) Goldblatt hypertensive rats.

Matched MeSH terms: Diabetes Mellitus, Experimental/metabolism*; Diabetes Mellitus, Experimental/physiopathology
Fulltext Self-nanoemulsifying Delivery of Andrographolide: Ameliorating Islet Beta Cells and Inhibiting Adipocyte Differentiation

Syukri Y, Taher M, Martien R, Lukitaningsih E, Nugroho AE, Zakaria ZA

Adv Pharm Bull, 2021 Jan;11(1):171-180.
PMID: 33747864 DOI: 10.34172/apb.2021.018

Purpose:
Insulin resistance is a characteristic of non-insulin-dependent diabetes mellitus associated with obesity and caused by the failure of pancreatic beta cells to secrete sufficient amount of insulin. Andrographolide (AND) improves beta-cell reconstruction and inhibits fat-cell formation. This research aimed to improve the delivery of water-insoluble AND in self-nanoemulsifying (ASNE) formulation, tested in streptozotocin (STZ)-induced diabetic rats and 3T3-L1 preadipocyte cells.
Methods:
A conventional formulation of AND in suspension was used as a control. The experimental rats were orally administered with self-nanoemulsifying (SNE) and suspension of AND for 8 days. Measurements were performed to evaluate blood glucose levels in preprandial and postprandial conditions. Immunohistochemistry was used to assess the process of islet beta cell reconstruction. In vitro study was performed using cell viability and adipocyte differentiation assay to determine the delivery of AND in the formulation.
Results:
ASNE lowered blood glucose levels (day 4) faster than AND suspension (day 6). The histological testing showed that ASNE could regenerate pancreatic beta cells. Therefore, ASNE ameliorated pancreatic beta cells. The in vitro evaluation indicated the inhibition of adipocyte differentiation by both AND and ASNE, which occurred in a time-dependent manner. ASNE formulation had better delivery than AND.
Conclusion:
ASNE could improve the antidiabetic activity by lowering blood glucose levels, enhancing pancreatic beta cells, and inhibiting lipid formation in adipocyte cells.

Matched MeSH terms: Diabetes Mellitus, Experimental
Modulation of oxidative stress by Chlorella vulgaris in streptozotocin (STZ) induced diabetic Sprague-Dawley rats

Aizzat O, Yap SW, Sopiah H, Madiha MM, Hazreen M, Shailah A, et al.

Adv Med Sci, 2010;55(2):281-8.
PMID: 21147697 DOI: 10.2478/v10039-010-0046-z

Chlorella vulgaris (CV), a fresh water alga has been reported to have hypoglycemic effects. However, antioxidant and anti-inflammatory effects of CV in diabetic animals have not been investigated to date. The aim of the present study was to investigate the role of CV in inflammation and oxidative damage in STZ-induced diabetic rats.

Matched MeSH terms: Diabetes Mellitus, Experimental/diet therapy*
Fulltext Histological changes in the heart and the proximal aorta in experimental diabetic rats fed with Piper sarmentsoum

Thent ZC, Lin TS, Das S, Zakaria Z

Afr J Tradit Complement Altern Med, 2012;9(3):396-404.
PMID: 23983373

Cardiovascular complications are one of the major causes of death in diabetes mellitus. Piper sarmentosum (P.s) is an herb that possesses antihyperglycaemic effects. The main aim of the study was to observe the histological changes in the heart and the proximal aorta of streptozotocin-induced diabetic rats following P.s administration. Twenty-four male Sprague-Dawley rats (n=24) were equally randomized into four groups: control group supplemented with normal saline (C); control group supplemented with P.s (CTx) ; diabetic group supplemented with normal saline (D) and, diabetic group supplemented with P.s (DTx). Diabetes was induced by STZ (50mg/kg body weight) intramuscularly. P.s extract (0.125g/kg) was administered orally for 28 days, following four weeks of STZ induction. The cardiac and aortic tissues were collected and processed under different stains: Haematoxylin and Eosin (H & E), Verhoeff-Van Gieson (VVG), Masson's Trichome (MT) and Periodic Acid- Schiff (PAS). There were abnormal cardiomyocytes nuclei, disarray of myofibres and increase in connective tissue deposits in cardiac tissues of the diabetic untreated group. The thickness of tunica media and ratio of tunica intima to media were found to be significantly increased in the aorta of diabetic untreated group (P < 0.05) compared to the control group. There were degenerative changes in the proximal aorta in diabetic untreated groups. All the histological damages of cardiac and aortic tissues were found to be lesser in the diabetic treated groups. Supplementation with P.s extract prevented the oxidative damage arising from diabetes mellitus, and reduced its complications.

Matched MeSH terms: Diabetes Mellitus, Experimental/drug therapy*; Diabetes Mellitus, Experimental/pathology
Fulltext No effect of NOS inhibition on skeletal muscle glucose uptake during in situ hindlimb contraction in healthy and diabetic Sprague-Dawley rats

Hong YH, Betik AC, Premilovac D, Dwyer RM, Keske MA, Rattigan S, et al.

Am J Physiol Regul Integr Comp Physiol, 2015 May 15;308(10):R862-71.
PMID: 25786487 DOI: 10.1152/ajpregu.00412.2014

Nitric oxide (NO) has been shown to be involved in skeletal muscle glucose uptake during contraction/exercise, especially in individuals with Type 2 diabetes (T2D). To examine the potential mechanisms, we examined the effect of local NO synthase (NOS) inhibition on muscle glucose uptake and muscle capillary blood flow during contraction in healthy and T2D rats. T2D was induced in Sprague-Dawley rats using a combined high-fat diet (23% fat wt/wt for 4 wk) and low-dose streptozotocin injections (35 mg/kg). Anesthetized animals had one hindlimb stimulated to contract in situ for 30 min (2 Hz, 0.1 ms, 35 V) with the contralateral hindlimb rested. After 10 min, the NOS inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME; 5 μM) or saline was continuously infused into the femoral artery of the contracting hindlimb until the end of contraction. Surprisingly, there was no increase in skeletal muscle NOS activity during contraction in either group. Local NOS inhibition had no effect on systemic blood pressure or muscle contraction force, but it did cause a significant attenuation of the increase in femoral artery blood flow in control and T2D rats. However, NOS inhibition did not attenuate the increase in muscle capillary recruitment during contraction in these rats. Muscle glucose uptake during contraction was significantly higher in T2D rats compared with controls but, unlike our previous findings in hooded Wistar rats, NOS inhibition had no effect on glucose uptake during contraction. In conclusion, NOS inhibition did not affect muscle glucose uptake during contraction in control or T2D Sprague-Dawley rats, and this may have been because there was no increase in NOS activity during contraction.

Matched MeSH terms: Diabetes Mellitus, Experimental/metabolism*; Diabetes Mellitus, Experimental/physiopathology
Fulltext Malaysian propolis and metformin mitigate subfertility in streptozotocin-induced diabetic male rats by targeting steroidogenesis, testicular lactate transport, spermatogenesis and mating behaviour

Nna VU, Bakar ABA, Ahmad A, Umar UZ, Suleiman JB, Zakaria Z, et al.

Andrology, 2020 05;8(3):731-746.
PMID: 31816190 DOI: 10.1111/andr.12739

BACKGROUND: Diabetes mellitus is one of the risk factors for male subfertility/infertility. Malaysian propolis is reported to decrease hyperglycaemia in diabetic state.
OBJECTIVES: The present study investigated the protective effect of Malaysian propolis on diabetes-induced subfertility/infertility. Additionally, its combined beneficial effects with metformin were investigated.
MATERIALS AND METHODS: Forty adult male Sprague Dawley rats were randomly assigned into five groups, namely normal control, diabetic control, diabetic + Malaysian propolis (300 mg/k.g. b.w.), diabetic + metformin (300 mg/kg b.w.) and diabetic + Malaysian propolis + metformin. Diabetes was induced using a single intraperitoneal injection of streptozotocin (60 mg/kg b.w.) and treatment lasted for 4 weeks. During the 4th week, mating behavioural experiments were performed using sexually receptive female rats. Thereafter, fertility parameters were assessed in the female rats.
RESULTS: Malaysian propolis increased serum and intratesticular free testosterone levels, up-regulated the mRNA levels of AR and luteinizing hormone receptor, up-regulated the mRNA and protein levels of StAR, CYP11A1, CYP17A1, 3β-HSD and 17β-HSD in the testes of diabetic rats. Furthermore, Malaysian propolis up-regulated testicular MCT2, MCT4 and lactate dehydrogenase type C mRNA levels, in addition to improving sperm parameters (count, motility, viability and normal morphology) and decreasing sperm nDNA fragmentation in diabetic rats. Malaysian propolis improved mating behaviour by increasing penile guanosine monophosphate levels. Malaysian propolis also improved fertility outcome as seen with decreases in pre- and post-implantation losses, increases in gravid uterine weight, litter size per dam and foetal weight. Malaysian propolis's effects were comparable to metformin. However, their combination yielded better results relative to the monotherapeutic interventions.
CONCLUSION: Malaysian propolis improves fertility potential in diabetic state by targeting steroidogenesis, testicular lactate metabolism, spermatogenesis and mating behaviour, with better effects when co-administered with metformin. Therefore, Malaysian propolis shows a promising complementary effect with metformin in mitigating Diabetes mellitus-induced subfertility/infertility.

Matched MeSH terms: Diabetes Mellitus, Experimental/complications*
Fulltext Down-regulation of steroidogenesis-related genes and its accompanying fertility decline in streptozotocin-induced diabetic male rats: ameliorative effect of metformin

Nna VU, Bakar ABA, Ahmad A, Mohamed M

Andrology, 2019 01;7(1):110-123.
PMID: 30515996 DOI: 10.1111/andr.12567

BACKGROUND: Metformin has long been used for glycemic control in diabetic state. Recently, other benefits of metformin beyond blood glucose regulation have emerged.
OBJECTIVES: To investigate the effect of metformin on the expression of testicular steroidogenesis-related genes, spermatogenesis, and fertility of male diabetic rats.
MATERIALS AND METHODS: Eighteen adult male Sprague Dawley rats were divided into three groups, namely normal control (NC), diabetic control (DC), and metformin-treated (300 mg/kg body weight/day) diabetic rats (D+Met). Diabetes was induced using a single intraperitoneal injection of streptozotocin (60 mg/kg b.w.), followed by oral treatment with metformin for four weeks.
RESULTS: Diabetes decreased serum and intratesticular testosterone levels and increased serum but not intratesticular levels of luteinizing hormone. Sperm count, motility, viability, and normal morphology were decreased, while sperm nuclear DNA fragmentation was increased in DC group, relative to NC group. Testicular mRNA levels of androgen receptor, luteinizing hormone receptor, cytochrome P450 enzyme (CYP11A1), steroidogenic acute regulatory (StAR) protein, 3β-hydroxysteroid dehydrogenase (HSD), and 17β-HSD, as well as the level of StAR protein and activities of CYP11A1, 3β-HSD, and 17β-HSD, were decreased in DC group. Similarly, decreased activities of epididymal antioxidant enzymes and increased lipid peroxidation were observed in DC group. Consequently, decreased litter size, fetal weight, mating and fertility indices, and increased pre- and post-implantation losses were recorded in DC group. Following intervention with metformin, we observed increases in serum and intratesticular testosterone levels, Leydig cell count, improved sperm parameters, and decreased sperm nuclear DNA fragmentation. Furthermore, mRNA levels and activities of steroidogenesis-related enzymes were increased, with improved fertility outcome.
DISCUSSION AND CONCLUSION: Diabetes mellitus is associated with dysregulation of steroidogenesis, abnormal spermatogenesis, and fertility decline. Controlling hyperglycemia is therefore crucial in preserving male reproductive function. Metformin not only regulates blood glucose level, but also preserves male fertility in diabetic state.

Matched MeSH terms: Diabetes Mellitus, Experimental/chemically induced; Diabetes Mellitus, Experimental/genetics*; Diabetes Mellitus, Experimental/pathology*
Antioxidant protection of Malaysian tualang honey in pancreas of normal and streptozotocin-induced diabetic rats

Erejuwa OO, Sulaiman SA, Wahab MS, Sirajudeen KN, Salleh MS, Gurtu S

Ann Endocrinol (Paris), 2010 Sep;71(4):291-6.
PMID: 20398890 DOI: 10.1016/j.ando.2010.03.003

Glucotoxicity contributes to beta-cell dysfunction through oxidative stress. Our previous study demonstrated that tualang honey ameliorated renal oxidative stress and produced hypoglycemic effect in streptozotocin (STZ)-induced diabetic rats. This present study investigated the hypothesis that hypoglycemic effect of tualang honey might partly be due to protection of pancreas against oxidative stress. Diabetes was induced by a single dose of STZ (60 mg/kg; ip). Diabetic rats were randomly divided into two groups and administered distilled water (0.5 ml/d) and tualang honey (1.0 g/kg/d). Similarly, two groups of non-diabetic rats received distilled water (0.5 ml/d) and tualang honey (1.0 g/kg/d). The animals were treated orally for 28 days. At the end of the treatment period, the honey-treated diabetic rats had significantly (p<0.05) reduced blood glucose levels [8.8 (5.8)mmol/L; median (interquartile range)] compared with the diabetic control rats [17.9 (2.6)mmol/L]. The pancreas of diabetic control rats showed significantly increased levels of malondialdehyde (MDA) and up-regulation of superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Catalase (CAT) activity was significantly reduced while glutathione-S-transferase (GST) and glutathione reductase (GR) activities remained unchanged in the pancreas of diabetic rats. Tualang honey significantly (p<0.05) reduced elevated MDA levels. Honey treatment also restored SOD and CAT activities. These results suggest that hypoglycemic effect of tualang honey might be attributed to its antioxidative effect on the pancreas.

Matched MeSH terms: Diabetes Mellitus, Experimental/prevention & control*
Urinary Metabolomics and Biochemical Analysis of Antihyperglycemic Effect of Ficus deltoidea Jack Varieties in Streptozotocin-Nicotinamide-Induced Diabetic Rats

Mohammad Noor HS, Ismail NH, Kasim N, Mediani A, Mohd Zohdi R, Ali AM, et al.

Appl Biochem Biotechnol, 2020 Sep;192(1):1-21.
PMID: 32215848 DOI: 10.1007/s12010-020-03304-y

Patients are turning into herbs for the management of diabetes, which cause increasing in the demand of plant-based alternative medicines. Ficus deltoidea or locally known as "Mas Cotek" in Malaysia is a famous herbal plant. However, many varieties of F. deltoidea existed with varied antidiabetic activities inspire us to evaluate in vivo antidiabetic activity of the most available varieties of F. deltoidea. Therefore, antihyperglycemic effect of different varieties of F. deltoidea at dose 250 mg/kg was evaluated on streptozotocin-nicotinamide-induced diabetic rats and further assessed their urinary metabolites using proton nuclear magnetic resonance (1H-NMR). The hyperglycemic blood level improved towards normoglycemic state after 30 days of treatment with standardized extracts of F. deltoidea var. trengganuensis, var. kunstleri, and var. intermedia. The extracts also significantly managed the biochemical parameters in diabetic rats. Metabolomics results showed these varieties were able to manage the altered metabolites of diabetic rats by shifting some of the metabolites back to their normal state. This knowledge might be very important in suggesting the use of these herbs in long-term treatment for diabetes. The most potential variety can be recommended, which may be useful for further pharmacological studies and herbal authentication processes.

Matched MeSH terms: Diabetes Mellitus, Experimental/drug therapy*; Diabetes Mellitus, Experimental/urine*
Metabolite Variation in Lean and Obese Streptozotocin (STZ)-Induced Diabetic Rats via (1)H NMR-Based Metabolomics Approach

Abu Bakar Sajak A, Mediani A, Maulidiani, Ismail A, Abas F

Appl Biochem Biotechnol, 2017 Jun;182(2):653-668.
PMID: 27995574 DOI: 10.1007/s12010-016-2352-9

Diabetes mellitus (DM) is considered as a complex metabolic disease because it affects the metabolism of glucose and other metabolites. Although many diabetes studies have been conducted in animal models throughout the years, the pathogenesis of this disease, especially between lean diabetes (ND + STZ) and obese diabetes (OB + STZ), is still not fully understood. In this study, the urine from ND + STZ, OB + STZ, lean/control (ND), and OB + STZ rats were collected and compared by using (1)H NMR metabolomics. The results from multivariate data analysis (MVDA) showed that the diabetic groups (ND + STZ and OB + STZ) have similarities and dissimilarities for a certain level of metabolites. Differences between ND + STZ and OB + STZ were particularly noticeable in the synthesis of ketone bodies, branched-chain amino acid (BCAA), and sensitivity towards the oral T2DM diabetes drug metformin. This finding suggests that the ND + STZ group was more similar to the T1DM model and OB + STZ to the T2DM model. In addition, we also managed to identify several pathways and metabolism aspects shared by obese (OB) and OB + STZ. The results from this study are useful in developing drug target-based research as they can increase understanding regarding the cause and effect of DM.

Matched MeSH terms: Diabetes Mellitus, Experimental/metabolism*
Hibiscus sabdariffa (roselle) polyphenol-rich extract averts cardiac functional and structural abnormalities in type 1 diabetic rats

Mohammed Yusof NL, Zainalabidin S, Mohd Fauzi N, Budin SB

Appl Physiol Nutr Metab, 2018 Dec;43(12):1224-1232.
PMID: 29726706 DOI: 10.1139/apnm-2018-0084

Diabetes mellitus is often associated with cardiac functional and structural alteration, an initial event leading to cardiovascular complications. Roselle (Hibiscus sabdariffa) has been widely proven as an antioxidant and recently has incited research interest for its potential in treating cardiovascular disease. Therefore, this study aimed to determine the cardioprotective effects of H. sabdariffa (roselle) polyphenol-rich extract (HPE) in type-1-induced diabetic rats. Twenty-four male Sprague-Dawley rats were randomized into 4 groups (n = 6/group): nondiabetic, diabetic alone (DM), diabetic supplemented with HPE (DM+HPE), and diabetic supplemented with metformin. Type-1 diabetes was induced with streptozotocin (55 mg/kg intraperitoneally). Rats were forced-fed with HPE (100 mg/kg) and metformin (150 mg/kg) daily for 8 weeks. Results showed that HPE supplementation improved hyperglycemia and dyslipidemia significantly (p < 0.05) in the DM+HPE compared with the DM group. HPE supplementation attenuated cardiac oxidative damage in the DM group, indicated by low malondialdehyde and advanced oxidation protein product. As for the antioxidant status, HPE significantly (p < 0.05) increased glutathione level, as well as catalase and superoxide dismutase 1 and 2 activities. These findings correlate with cardiac function, whereby left ventricle developed pressure in DM+HPE (79.13 ± 3.08 mm Hg) was higher significantly compared with DM (45.84 ± 1.65 mm Hg). Coronary flow of DM+HPE (17.43 ± 0.62 mL/min) was also greater compared with DM (13.02 ± 0.6 mL/min), showing that HPE supplementation improved cardiac contractility and relaxation rate significantly (p < 0.05). Histological analysis showed a marked decrease in cardiomyocyte hypertrophy and fibrosis in DM+HPE compared with the DM group. Ultrastructural changes and impairment of mitochondria induced by diabetes were minimized by HPE supplementation. Collectively, these findings suggest that HPE is a potential cardioprotective agent in a diabetic setting through its hypoglycemic, anti-hyperlipidemia, and antioxidant properties.

Matched MeSH terms: Diabetes Mellitus, Experimental/metabolism*
Aqueous calyxes extract of Roselle or Hibiscus sabdariffa Linn supplementation improves liver morphology in streptozotocin induced diabetic rats

Nazratun Nafizah AH, Budin SB, Zaryantey AH, Mariati AR, Santhana RL, Osman M, et al.

Arab J Gastroenterol, 2017 Mar;18(1):13-20.
PMID: 28336227 DOI: 10.1016/j.ajg.2017.02.001

BACKGROUND AND STUDY AIMS: The complex series of deleterious events among diabetes patients leads to multiple organ failure. Therefore, a holistic approach of treatment is urgently required to prevent worsening of complications. The present investigation was carried out to study the possible protective effects of Roselle or Hibiscus sabdariffa Linn (HSL) calyxes aqueous extract, as an antidiabetic and antioxidant agent against oxidative liver injury in streptozotocin-induced diabetic rats.
MATERIAL AND METHODS: A single dose of streptozotocin (45mg/kg body weight, iv) was used to induced diabetes in male Sprague Dawley rats which were then divided into two groups: Diabetic control (DC) and HSL-treated diabetic (DR) group. Normal rats were divided into normal control (NC), HSL-treated control (NR). Aqueous calyxes extract of HSL (100mg/kg/day, orally) was given for 28 consecutive days in the treated group. Weight, biochemical and histopathological (light and electron microscopic) parameters were compared in all groups.
RESULTS: Supplementation of HSL significantly lowered the level of fasting blood glucose and increased plasma insulin level in DR group compared to DC group (p<0.05). Alanine aminotransaminases and aspartate aminotransferase enzymes level were found to be significantly reduced in DR compared to DC. Microscopic examination demonstrated destruction of the liver architecture, cytoplasmic vacuolation of the hepatocytes and signs of necrosis in diabetic rats. Moreover, dilatation and congestion of blood vessels with leucocytes adherence were detected. Ultrastructural study using electron microscope showed homogeneous substance accumulation in nuclear chromatin, a decrease of organelles and mitochondrial degeneration in the diabetic rats.
CONCLUSION: Administration of HSL in diabetic rats causes significant decrease in hepatocyte destruction and prevented the changes associated with the diabetic condition. Thus, our findings provide a scientific rationale for the use of HSL as promising agent in preventing liver injury in diabetes.

Matched MeSH terms: Diabetes Mellitus, Experimental*
Metformin mitigates impaired testicular lactate transport/utilisation and improves sexual behaviour in streptozotocin-induced diabetic rats

Nna VU, Abu Bakar AB, Ahmad A, Mohamed M

Arch Physiol Biochem, 2021 Feb;127(1):51-60.
PMID: 31072137 DOI: 10.1080/13813455.2019.1610778

CONTEXT: Lactate is the preferred energy substrate for developing testicular germ cells. Diabetes is associated with impaired testicular lactate transport/utilisation, and poor sexual behaviour.
OBJECTIVE: To examine the effects of metformin on parameters involved in testicular lactate production, transport/utilisation, and sexual behaviour in diabetic state.
METHODS: Male Sprague-Dawley rats were assigned into normal control (NC), diabetic control (DC), and metformin-treated diabetic group (n = 6/group). Metformin (300 mg/kg b.w./day) was administrated orally for 4 weeks.
RESULTS: Intra-testicular glucose and lactate levels, and lactate dehydrogenase (LDH) activity increased, while the mRNA transcript levels of genes responsible for testicular glucose and lactate transport/utilisation (glucose transporter 3, monocarboxylate transporter 4 (MCT4), MCT2, and LDH type C) decreased in DC group. Furthermore, penile nitric oxide increased, while cyclic guanosine monophosphate decreased, with impaired sexual behaviour in DC group. Treatment with metformin improved these parameters.
CONCLUSIONS: Metformin increases testicular lactate transport/utilisation and improves sexual behaviour in diabetic state.

Matched MeSH terms: Diabetes Mellitus, Experimental/drug therapy*
Diabetes-induced testicular oxidative stress, inflammation, and caspase-dependent apoptosis: the protective role of metformin

Nna VU, Bakar ABA, Ahmad A, Mohamed M

Arch Physiol Biochem, 2020 Dec;126(5):377-388.
PMID: 30513216 DOI: 10.1080/13813455.2018.1543329

Context: Metformin's effect on glycaemic control is well documented, but its effect on diabetes-induced testicular impairment has been scarcely reported.Objective: To investigate the effects of metformin on testicular oxidative stress, inflammation, and apoptosis, which largely contribute to fertility decline in diabetic state.Methods: Male Sprague-Dawley rats were divided into 3 groups (n = 6/group) namely: normal control (NC), diabetic control (DC), and metformin (300 mg/kg b.w./d)-treated diabetic groups. Metformin was administrated for 4 weeks.Results: Decreased mRNA expressions and activities of antioxidant enzymes were seen in the testes of DC group. mRNA and protein expressions of pro-inflammatory and pro-apoptotic markers increased, while interleukin-10 and proliferating cell nuclear antigen (PCNA) decreased in the testes of DC group. Treatment with metformin up-regulated antioxidant enzymes, down-regulated inflammation, and apoptosis and increased PCNA immunoexpression in the testes.Conclusions: Metformin protects the testes from diabetes-induced impairment and may improve male reproductive health in diabetic state.

Matched MeSH terms: Diabetes Mellitus, Experimental/complications*
Effect of vitamin E on plasma malondialdehyde, antioxidant enzyme levels and the rates of wound closures during wound healing in normal and diabetic rats

Musalmah M, Fairuz AH, Gapor MT, Ngah WZ

Asia Pac J Clin Nutr, 2002;11 Suppl 7:S448-51.
PMID: 12492633

Vitamin E is composed of various subfamilies that include tocopherols and tocotrienols. These compounds have antioxidant properties but differ in structure, dietary source and potency. In this study we evaluated the efficacy of alpha-tocopherol as an antioxidant and its role in wound closure in normal and streptozotocin-induced diabetic rats. The healing of 6 cm linear incisions created on the back of each male Sprague-Dawley rat (250-300 g) was monitored by measuring the length of the wounds daily. The rats were divided into two categories; normal and streptozotocin-induced diabetic rats. For each category, the animals were further divided into two groups; those untreated and those receiving 200 mg/kg bodyweight alpha-tocopherols daily by oral gavage. All rats were fed standard food and water ad libitum. Blood samples were taken at 0, 5 and 10 days after the wounds were created for the determination of malondialdehyde levels and red cell superoxide dismutase, catalase and glutathione peroxidase activities. The results showed that alpha-tocopherol reduced plasma malondialdehyde levels, increased glutathione peroxidase activity and accelerated the rate of wound closure in treated rats.

Matched MeSH terms: Diabetes Mellitus, Experimental/blood; Diabetes Mellitus, Experimental/enzymology; Diabetes Mellitus, Experimental/metabolism*
Fulltext Hypoglycemic and anti-hyperglycemic study of Gynura procumbens leaf extracts

Algariri K, Meng KY, Atangwho IJ, Asmawi MZ, Sadikun A, Murugaiyah V, et al.

Asian Pac J Trop Biomed, 2013 May;3(5):358-66.
PMID: 23646298 DOI: 10.1016/S2221-1691(13)60077-5

To study the antidiabetic activity of Gynura procumbens (G. procumbens) used in the traditional management of diabetes in Southern Asia.

Matched MeSH terms: Diabetes Mellitus, Experimental/chemically induced; Diabetes Mellitus, Experimental/drug therapy

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