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Matsathit U, Komolkriengkrai M, Khimmaktong W. Glabridin and gymnemic acid alleviates choroid structural change and choriocapillaris impairment in diabetic rat's eyes. World J Diabetes 2025; 16:97336. [PMID: 40093291 PMCID: PMC11885962 DOI: 10.4239/wjd.v16.i3.97336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 11/11/2024] [Accepted: 12/25/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Small blood vessels in the eyes are more susceptible to injury, which can lead to complications. However, since diabetic retinopathy is often a serious clinical condition, most of this study focuses on the vascular system of the choroid. As part of this study, we looked at how gymnemic acid (from Gymnema sylvestre) and glabridin (from Glycyrrhiza glabra, or licorice) might help diabetic rats' choroid structural change and blood vessels. AIM To explore the effects of glabridin and gymnemic acid on the structural changes of the choroidal layer and choriocapillaris as well as the expression of vascular endothelial growth factor (VEGF) and cluster of differentiation (CD) 31 in diabetic rat's eye. METHODS The male Wistar rats were separated into five groups: The control group (control), the diabetic group (DM), the diabetic rats treated with glabridin 40 mg/kg body weight (DM + GB), the diabetic rats treated with gymnemic acid 400 mg/kg body weight (DM + GM), and the diabetic rats treated with glyburide 4 mg/kg body weight (DM + GR). RESULTS There was an increase in the thickness of both the choroid layer and the wall of the arteries in the DM. A decrease in vascularity and choroidal impairment was found in DM rats. After eight weeks of experimentation, the choroidal thickness increased, and the walls of choroid arteries. The choroidal thickness in the DM + GB was 15.69 ± 1.54 μm, DM + GM was 14.84 ± 1.31, and DM + GR groups was 16.45 ± 1.15 when compared with DM group (27.22 ± 2.05), the walls thickness of choroid arteries in the DM + GB was 10.23 ± 1.11, DM + GM was 10.41 ± 1.44, and DM + GR was 9.80 ± 1.78 when compared with DM group (16.35 ± 5.01), The expression of VEGF and CD31 was lower compared to the DM group. CONCLUSION In diabetic choroidopathy, hyperglycemia and inflammation cause damage to the neurovascular unit and blood-retinal barrier. Anti-VEGF treatments can slow or reverse the progression of the disease. According to current research findings, glabridin and gymnemic acid can reduce damage to the choroid, which is a factor that can sometimes result in vision loss.
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Affiliation(s)
- Udomlak Matsathit
- Department of Food Science and Nutrition, Faculty of Science and Technology, Prince of Songkla University, Pattani 94000, Thailand
| | - Manaras Komolkriengkrai
- Department of Anatomy, Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand
| | - Wipapan Khimmaktong
- Department of Anatomy, Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand
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Cordiner RLM, Bedair K, Mari A, Pearson E. Low-Dose Sulfonylurea Plus DPP4 Inhibitor Lower Blood Glucose and Enhance Beta-Cell Function Without Hypoglycemia. J Clin Endocrinol Metab 2024; 109:2106-2115. [PMID: 38267622 PMCID: PMC11244179 DOI: 10.1210/clinem/dgae033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/14/2023] [Accepted: 01/23/2024] [Indexed: 01/26/2024]
Abstract
CONTEXT Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. OBJECTIVE To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. METHODS Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. RESULTS SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2 mM-1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65). CONCLUSION Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU.
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Affiliation(s)
- Ruth L M Cordiner
- Division of Population, Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
| | - Khaled Bedair
- Division of Population, Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
| | - Andrea Mari
- National Research Council, Institute of Neuroscience, University of Padua, 35127 Padua, Italy
| | - Ewan Pearson
- Division of Population, Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
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Komolkriengkrai M, Nopparat J, Vongvatcharanon U, Anupunpisit V, Khimmaktong W. Effect of glabridin on collagen deposition in liver and amelioration of hepatocyte destruction in diabetes rats. Exp Ther Med 2019; 18:1164-1174. [PMID: 31316610 PMCID: PMC6601403 DOI: 10.3892/etm.2019.7664] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 10/12/2018] [Indexed: 12/11/2022] Open
Abstract
Abnormalities in insulin hormone levels leads to a hyperglycemic condition of diabetic mellitus. Hyperglycemia seriously induces organ and system destructions. The excessive accumulation of collagen fiber deposits occurs in inflammatory and reorganization processes of chronic liver diseases in type I insulin-dependent diabetes. Regarding the research objective, glabridin (GLB), an active compound of licorice, was used as a daily supplement (40 mg/kg) in order to decrease hepatocyte destruction and collagen deposition in liver tissue of diabetic animals induced by streptozotocin. A total of 40 were randomly allocated to five groups (each, n=10), control, control treated with GLB (GLB), diabetic rats (DM) injected with single dose of streptozotocin (60 mg/kg) to induce a diabetic condition, diabetic rats receiving GLB (DM+GLB; 40 mg/kg) and diabetic rats treated with glibenclamide (DM+GL; 4 mg/kg). Characteristic histopathological changes in liver cells and tissues of rats were determined by Masson's trichrome staining and transmission electron microscopy (TEM). Western blotting was used to detect the expression of the key markers, collagen type I and fibronectin proteins. The histological investigation of liver tissue of the DM group revealed that the collagen fiber deposition was increased in the periportal, pericentral and perisinusoidal spaces compared with controls. Hepatocytes appeared as small and fragmented cells in TEM examination. Collagenization of the perisinusoidal space was recently demonstrated to represent a new aspect of the microvascular abnormalities and liver fibrosis. Healthy hepatocytes with round nucleus were observed following supplementation of glabridin. In addition, collagen fiber deposition was reduced in the area adjacent to the perisinusoidal space. The expression of collagen type I and fibronectin decreased strongly following glabridin supplementation in DM+GLB rats compared with DM rats, indicating that the hepatic tissue reorganization regained its normal morphology. These findings suggest that it may be beneficial to examine the role of glabridin as a therapeutic agent in diabetes treatment in future research.
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Affiliation(s)
- Manaras Komolkriengkrai
- Department of Anatomy, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla 90110, Thailand
| | - Jongdee Nopparat
- Department of Anatomy, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla 90110, Thailand
| | - Uraporn Vongvatcharanon
- Department of Anatomy, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla 90110, Thailand
| | - Vipavee Anupunpisit
- Department of Anatomy, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| | - Wipapan Khimmaktong
- Department of Anatomy, Faculty of Science, Prince of Songkla University, Hatyai, Songkhla 90110, Thailand
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Hernández-Abad VJ, Sánchez-González EG, Espinosa-Contreras C, Marroquín-Segura R, Mora-Guevara JLA, Flores-Cabrera Y. Controlled release of glibenclamide from monolithic silica subdermal implants produced by the sol-gel process and its use for hyperglycaemia treatment in a murine model. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2019; 94:1009-1019. [DOI: 10.1016/j.msec.2018.10.050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 09/23/2018] [Accepted: 10/11/2018] [Indexed: 10/28/2022]
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Singh SVJ, Meetei UD, Akham SD, Sanjenbam RD. Effect of Ethyl Acetate Extract of Melothria Perpusilla on Oral Glucose Tolerance Test in Albino Rats. J Clin Diagn Res 2017; 11:FF04-FF06. [PMID: 28764193 DOI: 10.7860/jcdr/2017/26638.10001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Accepted: 03/16/2017] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Diabetes mellitus is a group of common metabolic disorders sharing the phenotype of hyperglycaemia. Certain disadvantages like side effects or less efficacy limit the optimal use of antidiabetic drugs. AIM To evaluate the effect of Ethyl Acetate Extract of MelothriaPerpusilla (EAEMP) on oral glucose tolerance test in albino rats. MATERIALS AND METHODS Six healthy albino rats weighing between 100-150 g were selected. The same set of six animals were used for the experiment throughout and successive tests were conducted after a drug wash out period of 10 days. Fasting blood glucose samples were measured using glucometer. A 2% gum acacia suspension {10 ml/kg per oral (p.o.)} was given in all six albino rats followed by the oral glucose load of 3g/kg. Glucose concentrations were estimated at one hour and two hour after the glucose load. Using the same set of animals, similar tests were repeated with the test dose of 250 mg/kg and 500 mg/kg of EAEMP and glibenclamide (0.5 mg/kg p.o.). In this experiment, glucose was given immediately at the dose of 3 g/kg p.o. after the treatments. Drug wash out period of 10 days was maintained in between the successive tests to avoid the interference of action of the drug with the other. The non parametric data were analysed by Kruskal Wallis test. RESULTS EAEMP produced a significant increase in the oral glucose tolerance test when compared with control and standard. CONCLUSION Treatment with Melothria perpusilla lowers the blood glucose level due to higher oral glucose tolerance possibly due to release of insulin from the pancreas.
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Affiliation(s)
| | - Usham Dharmaraja Meetei
- Assistant Professor, Department of Pharmacology, Regional Institute of Medical Sciences (R.I.M.S), Imphal, Manipur, India
| | - Subhalakshmi Devi Akham
- Professor, Department of Pharmacology, Regional Institute of Medical Sciences (R.I.M.S), Imphal, Manipur, India
| | - Rita Devi Sanjenbam
- Professor, Department of Pharmacology, Regional Institute of Medical Sciences (R.I.M.S), Imphal, Manipur, India
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Brown J, Martis R, Hughes B, Rowan J, Crowther CA, Cochrane Pregnancy and Childbirth Group. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. Cochrane Database Syst Rev 2017; 1:CD011967. [PMID: 28120427 PMCID: PMC6464763 DOI: 10.1002/14651858.cd011967.pub2] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a major public health issue with rates increasing globally. Gestational diabetes, glucose intolerance first recognised during pregnancy, usually resolves after birth and is associated with short- and long-term complications for the mother and her infant. Treatment options can include oral anti-diabetic pharmacological therapies. OBJECTIVES To evaluate the effects of oral anti-diabetic pharmacological therapies for treating women with GDM. SEARCH METHODS We searched Cochrane Pregnancy and Childbirth's Trials Register (14 May 2016), ClinicalTrials.gov, WHO ICTRP (14 May 2016) and reference lists of retrieved studies. SELECTION CRITERIA We included published and unpublished randomised controlled trials assessing the effects of oral anti-diabetic pharmacological therapies for treating pregnant women with GDM. We included studies comparing oral anti-diabetic pharmacological therapies with 1) placebo/standard care, 2) another oral anti-diabetic pharmacological therapy, 3) combined oral anti-diabetic pharmacological therapies. Trials using insulin as the comparator were excluded as they are the subject of a separate Cochrane systematic review.Women with pre-existing type 1 or type 2 diabetes were excluded. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and data were checked for accuracy. MAIN RESULTS We included 11 studies (19 publications) (1487 women and their babies). Eight studies had data that could be included in meta-analyses. Studies were conducted in Brazil, India, Israel, UK, South Africa and USA. The studies varied in diagnostic criteria and treatment targets for glycaemic control for GDM. The overall risk of bias was 'unclear' due to inadequate reporting of methodology. Using GRADE the quality of the evidence ranged from moderate to very low quality. Evidence was downgraded for risk of bias (reporting bias, lack of blinding), inconsistency, indirectness, imprecision and for oral anti-diabetic therapy versus placebo for generalisability. Oral anti-diabetic pharmacological therapies versus placebo/standard careThere was no evidence of a difference between glibenclamide and placebo groups for hypertensive disorders of pregnancy (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.81 to 1.90; one study, 375 women, very low-quality evidence), birth by caesarean section (RR 1.03, 95% CI 0.79 to 1.34; one study, 375 women, very low-quality evidence), perineal trauma (RR 0.98, 95% CI 0.06 to 15.62; one study, 375 women, very low-quality evidence) or induction of labour (RR 1.18, 95% CI 0.79 to 1.76; one study, 375 women; very low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant, there was no evidence of a difference in the risk of being born large-for-gestational age (LGA) between infants whose mothers had been treated with glibenclamide and those in the placebo group (RR 0.89, 95% CI 0.51 to 1.58; one study, 375, low-quality evidence). No data were reported for other infant primary or GRADE outcomes (perinatal mortality, death or serious morbidity composite, neurosensory disability in later childhood, neonatal hypoglycaemia, adiposity, diabetes). Metformin versus glibenclamideThere was no evidence of a difference between metformin- and glibenclamide-treated groups for the risk of hypertensive disorders of pregnancy (RR 0.70, 95% CI 0.38 to 1.30; three studies, 508 women, moderate-quality evidence), birth by caesarean section (average RR 1.20, 95% CI 1.20; 95% CI 0.83 to 1.72, four studies, 554 women, I2 = 61%, Tau2 = 0.07 low-quality evidence), induction of labour (0.81, 95% CI 0.61 to 1.07; one study, 159 women; low-quality evidence) or perineal trauma (RR 1.67, 95% CI 0.22 to 12.52; two studies, 158 women; low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant there was no evidence of a difference between the metformin- and glibenclamide-exposed groups for the risk of being born LGA (average RR 0.67, 95% CI 0.24 to 1.83; two studies, 246 infants, I2 = 54%, Tau2 = 0.30 low-quality evidence). Metformin was associated with a decrease in a death or serious morbidity composite (RR 0.54, 95% CI 0.31 to 0.94; one study, 159 infants, low-quality evidence). There was no clear difference between groups for neonatal hypoglycaemia (RR 0.86, 95% CI 0.42 to 1.77; four studies, 554 infants, low-quality evidence) or perinatal mortality (RR 0.92, 95% CI 0.06 to 14.55, two studies, 359 infants). No data were reported for neurosensory disability in later childhood or for adiposity or diabetes. Glibenclamide versus acarboseThere was no evidence of a difference between glibenclamide and acarbose from one study (43 women) for any of their maternal or infant primary outcomes (caesarean section, RR 0.95, 95% CI 0.53 to 1.70; low-quality evidence; perinatal mortality - no events; low-quality evidence; LGA , RR 2.38, 95% CI 0.54 to 10.46; low-quality evidence). There was no evidence of a difference between glibenclamide and acarbose for neonatal hypoglycaemia (RR 6.33, 95% CI 0.87 to 46.32; low-quality evidence). There were no data reported for other pre-specified GRADE or primary maternal outcomes (hypertensive disorders of pregnancy, development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour) or neonatal outcomes (death or serious morbidity composite, adiposity or diabetes). AUTHORS' CONCLUSIONS There were insufficient data comparing oral anti-diabetic pharmacological therapies with placebo/standard care (lifestyle advice) to inform clinical practice. There was insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral anti-diabetic pharmacological therapy over another due to limited reporting of data for the primary and secondary outcomes in this review. Short- and long-term clinical outcomes for this review were inadequately reported or not reported. Current choice of oral anti-diabetic pharmacological therapy appears to be based on clinical preference, availability and national clinical practice guidelines.The benefits and potential harms of one oral anti-diabetic pharmacological therapy compared with another, or compared with placebo/standard care remains unclear and requires further research. Future trials should attempt to report on the core outcomes suggested in this review, in particular long-term outcomes for the woman and the infant that have been poorly reported to date, women's experiences and cost benefit.
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Affiliation(s)
- Julie Brown
- The University of AucklandLiggins InstitutePark RdGraftonAucklandNew Zealand1142
| | - Ruth Martis
- The University of AucklandLiggins InstitutePark RdGraftonAucklandNew Zealand1142
| | | | - Janet Rowan
- National Women's HealthPrivate Bag 92024AucklandNew Zealand1003
| | - Caroline A Crowther
- The University of AucklandLiggins InstitutePark RdGraftonAucklandNew Zealand1142
- The University of AdelaideARCH: Australian Research Centre for Health of Women and Babies, Robinson Research Institute, Discipline of Obstetrics and GynaecologyWomen's and Children's Hospital72 King William RoadAdelaideSouth AustraliaAustralia5006
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Foster SR, Omoruyi FO, Bustamante J, Lindo RLA, Dilworth LL. The effect of combined inositol hexakisphosphate and inositol supplement in streptozotocin-induced type 2 diabetic rats. Int J Exp Pathol 2016; 97:397-407. [PMID: 27921351 DOI: 10.1111/iep.12210] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 09/08/2016] [Indexed: 12/28/2022] Open
Abstract
Inositol hexakisphosphate (IP6) and inositol both regulate insulin secretion, but their combined use in the management of diabetes deserves investigation. The combined effects of IP6 and inositol supplementation were investigated in streptozotocin-induced type 2 diabetic rats. The following groups of rats were studied for 8 weeks: non-diabetic control, non-diabetic high-fat diet control, diabetic untreated, diabetic rats treated with the combination of IP6 and inositol (650 mg/kg bw) and diabetic rats treated with glibenclamide (10 mg/kg bw). High-fat diet and streptozotocin were used to induce type 2 diabetes mellitus in Sprague-Dawley rats. Body weight, blood glucose, glycated haemoglobin, insulin, serum leptin, HOMA-insulin resistance scores, intestinal amylase activity, serum and faecal lipids and food and fluid consumption were measured. Treatment with the combination significantly reduced blood glucose (306 ± 53 mg/dl) and insulin resistance score (1.93 ± 0.45) compared with diabetic controls (522 ± 24 mg/dl and 5.1 ± 0.69 respectively). Serum leptin (2.8 ± 0.6 ng/dl) and faecal triglycerides (108 ± 8 mg/dl) were significantly increased in rats treated with the combination compared with the diabetic control (1.8 ± 0.06 ng/dl and 86 ± 4 mg/dl). Serum triglyceride (47 ± 5.1 mg/dl), total cholesterol (98 ± 3.2 mg/dl) and food intake (26 ± 0.3 g) were significantly reduced by 45%, 25% and 25%, respectively, in rats treated with the combination compared with the diabetic control. Inositol and IP6 combined supplementation may be effective in the management of type 2 diabetes mellitus and related metabolic disorders by regulating some aspects of lipid and carbohydrate metabolism.
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Affiliation(s)
- Shadae R Foster
- Biochemistry Section, Department of Basic Medical Sciences, The University of the West Indies, Mona, Jamaica
| | - Felix O Omoruyi
- Department of Life Sciences, Texas A&M University, Corpus Christi, TX, USA
| | - Juan Bustamante
- Rangel College of Pharmacy, Texas A&M University, Kingsville, TX, USA
| | - Ruby L A Lindo
- Biochemistry Section, Department of Basic Medical Sciences, The University of the West Indies, Mona, Jamaica
| | - Lowell L Dilworth
- Department of Pathology, the University of the West Indies, Mona, Jamaica
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Urbano F, Filippello A, Di Pino A, Barbagallo D, Di Mauro S, Pappalardo A, Rabuazzo AM, Purrello M, Purrello F, Piro S. Altered expression of uncoupling protein 2 in GLP-1-producing cells after chronic high glucose exposure: implications for the pathogenesis of diabetes mellitus. Am J Physiol Cell Physiol 2016; 310:C558-67. [DOI: 10.1152/ajpcell.00148.2015] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 01/06/2016] [Indexed: 01/11/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is a gut L-cell hormone that enhances glucose-stimulated insulin secretion. Several approaches that prevent GLP-1 degradation or activate the GLP-1 receptor are being used to treat type 2 diabetes mellitus (T2DM) patients. In T2DM, GLP-1 secretion has been suggested to be impaired, and this defect appears to be a consequence rather than a cause of impaired glucose homeostasis. However, although defective GLP-1 secretion has been correlated with insulin resistance, little is known about the direct effects of chronic high glucose concentrations, which are typical in diabetes patients, on GLP-1-secreting cell function. In the present study, we demonstrate that glucotoxicity directly affects GLP-1 secretion in GLUTag cells chronically exposed to high glucose. Our results indicate that this abnormality is associated with a decrease in ATP production due to the elevated expression of mitochondrial uncoupling protein 2 (UCP2). Furthermore, UCP2 inhibition using small interfering RNA (siRNA) and the application of glibenclamide, an ATP-sensitive potassium (KATP+) channel blocker, reverse the GLP-1 secretion defect induced by chronic high-glucose treatment. These results show that glucotoxicity diminishes the secretory responsiveness of GLP-1-secreting cells to acute glucose stimulation. We conclude that the loss of the incretin effect, as observed in T2DM patients, could at least partially depend on hyperglycemia, which is typical in diabetes patients. Such an understanding may not only provide new insight into diabetes complications but also ultimately contribute to the identification of novel molecular targets within intestinal L-cells for controlling and improving endogenous GLP-1 secretion.
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Affiliation(s)
- Francesca Urbano
- Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and
| | - Agnese Filippello
- Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and
| | - Antonino Di Pino
- Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and
| | - Davide Barbagallo
- Department of BioMedical Sciences and BioTechnology, section of Biology and Genetics Giovanni Sichel, Unit of Molecular, Genome and Complex Systems BioMedicine, University of Catania, Catania, Italy
| | - Stefania Di Mauro
- Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and
| | - Alessandro Pappalardo
- Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and
| | - Agata Maria Rabuazzo
- Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and
| | - Michele Purrello
- Department of BioMedical Sciences and BioTechnology, section of Biology and Genetics Giovanni Sichel, Unit of Molecular, Genome and Complex Systems BioMedicine, University of Catania, Catania, Italy
| | - Francesco Purrello
- Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and
| | - Salvatore Piro
- Department of Clinical and Experimental Medicine, Garibaldi-Nesima Hospital, University of Catania, Catania, Italy; and
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Brown J, Martis R, Hughes B, Rowan J, Crowther CA. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2015. [DOI: 10.1002/14651858.cd011967] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Investigation of the Blood Glucose Lowering Potential of the Jamaican Momordica charantia (Cerasee) Fruit in Sprague-Dawley Rats. W INDIAN MED J 2015; 64:315-9. [PMID: 26624580 DOI: 10.7727/wimj.2014.093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 04/23/2014] [Indexed: 11/18/2022]
Abstract
The Momordica charantia (MC) fruit has been documented to possess antidiabetic properties. However, these studies were not without controversy surrounding the blood glucose-lowering ability and the mechanism of action in diabetes therapy. In an effort to evaluate such claims in the Jamaican MC species known as cerasee, aqueous extracts of the unripe fruit were studied in normal and diabetic rats. Normal male Sprague-Dawley rats were divided into groups (n = 6) orally administered distilled water, 10% dimethyl sulfoxide (DMSO) solution, the aqueous extract (400 mg/kg body weight) and glibenclamide (15 mg/kg body weight), respectively prior to assessment of fasting blood glucose (FBG) concentration. The oral glucose tolerance test (OGTT) was conducted in normoglycaemic rats orally administered distilled water, 10% DMSO solution, glibenclamide (15 mg/kg body weight) or aqueous extracts of the fruit (200 and 400 mg/kg body weight). Blood glucose concentration was also monitored in streptozotocin-induced diabetic rats administered the aqueous extract (250 mg/kg body weight) or water vehicle after an overnight fast. The aqueous extracts showed no hypoglycaemic or antidiabetic activity. However, the administration of the aqueous extracts (200 and 400 mg/kg body weight) resulted in significant improvement in glucose tolerance of glucose-primed normoglycaemic rats during the OGTT. These data suggest that the glucose-lowering mechanism of the Jamaican MC fruit species likely involves altered glucose absorption across the gastrointestinal tract.
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The insulin secretory action of novel polycyclic guanidines: Discovery through open innovation phenotypic screening, and exploration of structure–activity relationships. Bioorg Med Chem Lett 2014; 24:1031-6. [DOI: 10.1016/j.bmcl.2014.01.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2013] [Revised: 01/06/2014] [Accepted: 01/08/2014] [Indexed: 11/18/2022]
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Yimam M, Zhao J, Corneliusen B, Pantier M, Brownell L, Jia Q. Blood glucose lowering activity of aloe based composition, UP780, in alloxan induced insulin dependent mouse diabetes model. Diabetol Metab Syndr 2014; 6:61. [PMID: 24891878 PMCID: PMC4041641 DOI: 10.1186/1758-5996-6-61] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 05/18/2014] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND There are a few nutritional approaches to address the increased needs of managing diabetic conditions. Previously it has been reported that UP780, a standardized composition of aloe chromone formulated with an aloe polysaccharide, has a significant impact in reducing HbA1C, fasting blood glucose, fructosamine and plasma insulin level in humans and improved impaired glucose and insulin resistance in high-fat diet-induced and db/db non-insulin dependent diabetic mouse models. Here we describe activity of UP780 and its constituents to improve insulin sensitivity in alloxan induced insulin dependent diabetic mouse model. MATERIALS AND METHOD Insulin dependent diabetes was induced by administering a single intraperitoneal injection of alloxan monohydrate at a dose of 150 mg/kg to CD-1 mice. Aloesin (UP394) was formulated with an Aloe vera inner leaf gel powder polysaccharide (Qmatrix) to yield a composition designated UP780. Efficacy of oral administration of UP780 at 2000 mg/kg and its constituents (aloesin at 80 mg/kg and Qmatrix at 1920 mg/kg) were evaluated in this model. Glyburide, a sulfonylurea drug used in the treatment of type 2 diabetes, was used at 5 mg/kg as a positive control. Effect of UP780 on non-diabetic normal mice was also addressed. RESULTS Mice administered intraperitoneal alloxan monohydrate developed progressive type-1 diabetes like symptom. After 4 weeks of daily oral administration, reductions of 35.9%, 17.2% and 11.6% in fasting blood glucose levels were observed for UP780, the UP780 Aloe vera inner leaf gel polysaccharide preparation without chromone (Qmatrix), and Aloesin (UP394), treated animals respectively, compared to vehicle treated animals. UP780 has no impact on blood glucose level of non-diabetic healthy mice. UP780 showed statistically significant improvement for blood glucose clearance in oral glucose tolerance tests. Similarly, enhanced improvement in plasma insulin level and statistically significant reduction in triglyceride level was also observed for animals treated with the composition. CONCLUSION These findings suggest that UP780, a chromone standardized Aloe based composition, could possibly be used as a natural supplement alternative to facilitate maintenance of healthy blood glucose levels.
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Affiliation(s)
- Mesfin Yimam
- Unigen, Inc, 3005 1st Ave, Seattle, WA, 98121, USA
| | - Jifu Zhao
- Unigen, Inc, 3005 1st Ave, Seattle, WA, 98121, USA
| | | | | | | | - Qi Jia
- Unigen, Inc, 3005 1st Ave, Seattle, WA, 98121, USA
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Piro S, Rabuazzo AM, Renis M, Purrello F. Effects of metformin on oxidative stress, adenine nucleotides balance, and glucose-induced insulin release impaired by chronic free fatty acids exposure in rat pancreatic islets. J Endocrinol Invest 2012; 35:504-10. [PMID: 21750398 DOI: 10.3275/7866] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
BACKGROUND In rat pancreatic islets, chronic exposure to high free fatty acid (FFA) levels impairs insulin secretion and β cell mass. The mechanisms underlying this defect are not completely understood. Since islets have intrinsically low anti-oxidant enzyme defense, oxidative stress might be responsible for β cell damage. AIM In this study, we investigated if FFA could induce oxidative stress in rat pancreatic islets and if metformin might reverse adverse effects. MATERIAL AND METHODS We cultured rat pancreatic islets in the presence or absence of FFA (oleate/palmitate 2:1, 2 mM) for 72 h. In some experiments, we used metformin (2.5 μg/ml) during the last 24 h. RESULTS In our model, glucosestimu lated insulin release was markedly reduced (p<0.005) after chronic FFA exposure, and the ATP/ADP ratio was altered (p<0.05). We observed a significant increase of reactive oxygen species (ROS) (p<0.001), malondialdehyde a lipid peroxidation product (p<0.01) and nitric oxide (NO) levels in the culture media (p<0.001). Inducible NO synthase (iNOS) and heat shock protein-70 (HSP-70) protein expression were also increased (p<0.001 and p<0.01, respectively). When metformin was present during the last 24 h of culture, insulin secretion was restored, and the ATP/ADP ratio was normalized. ROS production, NO production, lipid peroxidation, iNOS and HSP-70 protein expression levels had decreased. CONCLUSIONS These data indicate that, in rat pancreatic islets, chronic exposure to high FFA induces oxidative stress and that metformin, by reducing this effect, may have a direct beneficial effect on insulin secretion impaired by lipotoxicity.
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Affiliation(s)
- S Piro
- Department of Clinical and Molecular Biomedicine, Laboratory of Molecular Medicine, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636-95122, Catania, Italy
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Wang ZQ, Lu FE, Leng SH, Fang XS, Chen G, Wang ZS, Dong LP, Yan ZQ. Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity. World J Gastroenterol 2008; 14:6004-11. [PMID: 18932278 PMCID: PMC2760199 DOI: 10.3748/wjg.14.6004] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the effect of berberine on insulin secretion in rat pancreatic islets and to explore its possible molecular mechanism.
METHODS: Primary rat islets were isolated from male Sprague-Dawley rats by collagenase digestion and treated with different concentrations (1, 3, 10 and 30 μmol/L) of berberine or 1 μmol/L Glibenclamide (GB) for 24 h. Glucose-stimulated insulin secretion (GSIS) assay was conducted and insulin was determined by radioimmunoassay. 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to evaluate cytotoxicity. The mRNA level of hepatic nuclear factor 4 alpha (HNF4α) was determined by reverse transcription polymerase chain reaction (RT-PCR). Indirect immunofluorescence staining and Western blot analysis were employed to detect protein expression of HNF4α in the islets. Glucokinase (GK) activity was measured by spectrophotometric method.
RESULTS: Berberine enhanced GSIS rather than basal insulin secretion dose-dependently in rat islets and showed no significant cytotoxicity on islet cells at the concentration of 10 μmol/L. Both mRNA and protein expressions of HNF4α were up-regulated by berberine in a dose-dependent manner, and GK activity was also increased accordingly. However, GB demonstrated no regulatory effects on HNF4α expression or GK activity.
CONCLUSION: Berberine can enhance GSIS in rat islets, and probably exerts the insulinotropic effect via a pathway involving HNF4α and GK, which is distinct from sulphonylureas (SUs).
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Murugan P, Pari L, Rao CA. Effect of tetrahydrocurcumin on insulin receptor status in type 2 diabetic rats: studies on insulin binding to erythrocytes. J Biosci 2008; 33:63-72. [PMID: 18376071 DOI: 10.1007/s12038-008-0022-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Curcumin is the most active component of turmeric. It is believed that curcumin is a potent antioxidant and anti-inflammatory agent. Tetrahydrocurcumin (THC) is one of the major metabolites of curcumin, and exhibits many of the same physiological and pharmacological activities as curcumin and, in some systems, may exert greater antioxidant activity than curcumin. Using circulating erythrocytes as the cellular mode, the insulin-binding effect of THC and curcumin was investigated. Streptozotocin (STZ)-nicotinamide-induced male Wistar rats were used as the experimental models. THC (80 mg/kg body weight) was administered orally for 45 days. The effect of THC on blood glucose, plasma insulin and insulin binding to its receptor on the cell membrane of erythrocytes were studied. Mean specific binding of insulin was significantly lowered in diabetic rats with a decrease in plasma insulin. This was due to a significant decrease in mean insulin receptors. Erythrocytes from diabetic rats showed a decreased ability for insulin-receptor binding when compared with THC-treated diabetic rats. Scatchard analysis demonstrated that the decrease in insulin binding was accounted for by a decrease in insulin receptor sites per cell, with erythrocytes of diabetic rats having less insulin receptor sites per cell than THC-treated rats. High affinity (K d1), low affinity (K d2) and kinetic analyses revealed an increase in the average receptor affinity of erythrocytes from THC-treated rats compared with those of diabetic rats. These results suggest that acute alteration of the insulin receptor on the membranes of erythrocytes occurred in diabetic rats. Treatment with THC significantly improved specific insulin binding to the receptors, with receptor numbers and affinity binding reaching near-normal levels. Our study suggests the mechanism by which THC increases the number of total cellular insulin binding sites resulting in a significant increase in plasma insulin. The effect of THC is more prominent than that of curcumin.
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Affiliation(s)
- Pidaran Murugan
- Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar 608 002, India
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Badole SL, Patel NM, Thakurdesai PA, Bodhankar SL. Interaction of Aqueous Extract of Pleurotus pulmonarius (Fr.) Quel-Champ. with Glyburide in Alloxan Induced Diabetic Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2008; 5:159-64. [PMID: 18604261 PMCID: PMC2396481 DOI: 10.1093/ecam/nem010] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2006] [Accepted: 01/16/2007] [Indexed: 01/10/2023]
Abstract
Mushrooms are low calorie food with very little fat and are highly suitable for obese persons. With no starch and very low sugars, they are the 'delight of the diabetics'. Combination of herbal drugs (or isolated phytochemicals) is found to be beneficial in certain diseases when given along with conventional drugs. The aim of the present study was to evaluate the effects of aqueous extract of Pleurotus pulmonarius (Lentinaceae) (called as PP-aqu) and its interaction with glyburide in alloxan induced diabetic mice. The diabetic mice treated were with PP-aqu (500 mg/kg, p.o.) alone or combination with glyburide (10 mg/kg, p.o.) for 28 days. Blood samples were collected by orbital sinus puncture using heparinized capillary glass tubes and were analyzed for serum glucose on 0, 7th, 14th, 21st and 28th days. Body weights and mortality were noted during the study period. In oral glucose tolerance test (OGTT), glucose (2.5 g/kg, p.o.) was administered with either vehicle, PP-aqu alone or in combination with glyburide and serum glucose level analyzed at 0, 30, 60 and 120 min after drug administration. Administration of PP-aqu (500 mg/kg) and its combination with glyburide (10 mg/kg) significantly (P < 0.001) decreased serum glucose level in diabetic mice. In OGTT, glyburide or PP-aqu treatment alone or their combination produced significant (P < 0.001) increase in glucose threshold. Thus we suggest that P. pulmonarius showed potent and synergistic antihyperglycemic effect in combination with glyburide.
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Affiliation(s)
- Sachin L Badole
- Pharmacology Division, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Paud Road, Pune 411-038, India
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Ashokkumar N, Pari L, Rao CA. Effect of N-benzoyl-D-phenylalanine and metformin on insulin receptors in neonatal streptozotocin-induced diabetic rats: studies on insulin binding to erythrocytes. Arch Physiol Biochem 2006; 112:174-81. [PMID: 17132543 DOI: 10.1080/13813450600935339] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
In the present study, we focused on the insulin-receptor binding in circulating erythrocytes of N-benzoyl-D-phenylalanine (NBDP) and metformin in neonatal streptozotocin (nSTZ)-induced male Wistar rats. We measured blood levels of glucose and plasma insulin and the binding of insulin to cell-membrane ER receptors in NBDP and metformin-treated diabetic rats. The mean specific binding of insulin to ER was significantly lower in diabetic control rats (DC) (53.0 +/- 3.1%) than in NBDP (62.0 +/- 3.1%), metformin (66.0 +/- 3.3%) and NBDP and metformin combination-treated (72.0 +/- 4.2%) diabetic rats, resulting in a significant decrease in plasma insulin. Scatchard plot analysis demonstrated that the decrease in insulin binding was accounted for by a lower number of insulin receptor sites per cell in DC rats when compared with NBDP and metformin-treated rats. High-affinity (Kd1), low-affinity (Kd2), and kinetic analysis revealed an increase in the average receptor affinity in ER from NBDP and metformin-treated diabetic rats having NBDP 2.0 +/- 0.10 x 10(-10) M(-1) (Kd1); 12.0 +/- 0.85 x 10(-8) M(-1) (Kd2), Metformin 2.1 +/- 0.15 x 10(-10) M(-1) (Kd1); 15.0 +/- 0.80 x 10(-8) M(-1) (Kd2), NBDP and metformin 2.7 +/- 0.10 x 10(-10) M(-1) (Kd1); 20.0 +/- 1.2 x 10(-8) M(-1) (Kd2) compared with 0.9 +/- 0.06 x 10(-10) M(-1) (Kd1); 6.0 +/- 0.30 x 10(-8) M(-1) (Kd2) in DC rats. The results suggest an acute alteration in the number of insulin receptors on ER membranes in nSTZ induced diabetic control rats. Treatment with NBDP along with metformin significantly improved specific insulin binding, with receptor number and affinity binding reaching almost normal non-diabetic levels. The data presented here show that NBDP along with metformin increase total ER membrane insulin binding sites with a concomitant significant increase in plasma insulin.
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Affiliation(s)
- N Ashokkumar
- Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar, 608 002, Tamil Nadu, India
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Chen J, Jeppesen PB, Abudula R, Dyrskog SEU, Colombo M, Hermansen K. Stevioside does not cause increased basal insulin secretion or β-cell desensitization as does the sulphonylurea, glibenclamide: Studies in vitro. Life Sci 2006; 78:1748-53. [PMID: 16260001 DOI: 10.1016/j.lfs.2005.08.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2005] [Accepted: 08/10/2005] [Indexed: 10/25/2022]
Abstract
We have shown that stevioside (SVS) enhances insulin secretion and thus may have a potential role as antihyperglycemic agent in the treatment of type 2 diabetes mellitus. However, whether SVS stimulates basal insulin secretion (BIS) and/or cause desensitization of beta cells like sulphonylureas (SU), e.g. glibenclamide (GB), is not known. To explore and compare the effects of SVS pretreatment with those of GB and glucagon-like peptide-1 (GLP-1), we exposed isolated mouse islets to low or high glucose for 1 h after short-term (2 h) or long-term (24 h) pretreatment with SVS, GB or GLP-1, respectively. BIS at 3.3 or 5.5 mM glucose were not changed after short-term pretreatment with SVS (10(-7) M), while it increased about three folds after pretreatment with GB (10(-7) M). Glucose stimulated insulin secretion (GSIS) (16.7 mM) increased dose-dependently after long-term pretreatment with SVS at concentrations from 10(-7) to 10(-5) M. Pretreatment for 24 h with GB (10(-7) M) increased the subsequent BIS (3.3 mM glucose) (p < 0.001), but decreased GSIS (16.7 mM glucose) (p < 0.001). In contrast SVS (10(-7) M) and GLP-1 (10(-7) M) did not stimulate BIS but both enhanced the subsequent GSIS (16.7 mM glucose) (p < 0.05 and p < 0.05, respectively). While SVS pretreatment increased the intracellular insulin content, GB pretreatment decreased the insulin content. Our study suggests that SVS pretreatment does not cause a stimulation of BIS and does not desensitize beta-cells, i.e. SVS seems to have advantageous characteristics to GB as a potential treatment of type 2 diabetes.
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Affiliation(s)
- Jianguo Chen
- Department of Endocrinology and Metabolism, Aarhus Sygehus THG, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark.
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Pari L, Latha M, Rao CA. Effect of Scoparia dulcis extract on insulin receptors in streptozotocin induced diabetic rats: studies on insulin binding to erythrocytes. J Basic Clin Physiol Pharmacol 2005; 15:223-40. [PMID: 15803960 DOI: 10.1515/jbcpp.2004.15.3-4.223] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
We investigated the insulin-receptor-binding effect of Scoparia dulcis plant extract in streptozotocin (STZ)-induced male Wistar rats, using circulating erythrocytes (ER) as a model system. An aqueous extract of S dulcis plant (SPEt) (200 mg/kg body weight) was administered orally. We measured blood levels of glucose and plasma insulin and the binding of insulin to cell-membrane ER receptors. Glibenclamide was used as standard reference drug. The mean specific binding of insulin to ER was significantly lower in diabetic control rats (DC) (55.0 +/- 2.8%) than in SPEt-treated (70.0 +/- 3.5%)- and glibenclamide-treated (65.0 +/- 3.3%) diabetic rats, resulting in a significant decrease in plasma insulin. Scatchard plot analysis demonstrated that the decrease in insulin binding was accounted for by a lower number of insulin receptor sites per cell in DC rats when compared with SPEt- and glibenclamide-treated rats. High-affinity (Kd1), low-affinity (Kd2), and kinetic analysis revealed an increase in the average receptor affinity in ER from SPEt and glibenclamide treated diabetic rats having 2.5 +/- 0.15 x 10(10) M(-1) (Kd1); 17.0 +/- 1.0 x 10(-8) M(-1) (Kd2), and 2.0 +/- 0.1 x 10(-10) M(-1) (Kd1); 12.3 +/- 0.9 x 10(-8) M(-1) (Kd2) compared with 1.0 +/- 0.08 x 10(-10) M(-1) (Kd1); 2.7 +/- 0.25 x 10(-8) M(-1) (Kd2) in DC rats. The results suggest an acute alteration in the number of insulin receptors on ER membranes in STZ-induced diabetic rats. Treatment with SPEt and glibenclamide significantly improved specific insulin binding, with receptor number and affinity binding (p < 0.001) reaching almost normal non-diabetic levels. The data presented here show that SPEt and glibenclamide increase total ER membrane insulin binding sites with a concomitant significant increase in plasma insulin.
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Affiliation(s)
- Leelavinothan Pari
- Department of Biochemistry, Faculty of Science, Annamalai University, Annamalainagar - 608 002, Tamil Nadu, India.
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Patanè G, Anello M, Piro S, Vigneri R, Purrello F, Rabuazzo AM. Role of ATP production and uncoupling protein-2 in the insulin secretory defect induced by chronic exposure to high glucose or free fatty acids and effects of peroxisome proliferator-activated receptor-gamma inhibition. Diabetes 2002; 51:2749-56. [PMID: 12196468 DOI: 10.2337/diabetes.51.9.2749] [Citation(s) in RCA: 133] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
In rat pancreatic islets chronically exposed to high glucose or high free fatty acid (FFA) levels, glucose-induced insulin release and mitochondrial glucose oxidation are impaired. These abnormalities are associated with high basal ATP levels but a decreased glucose-induced ATP production (Delta of increment over baseline 0.7 +/- 0.5 or 0.5 +/- 0.3 pmol/islet in islets exposed to glucose or FFA vs. 12.0 +/- 0.6 in control islets, n = 3; P < 0.01) and, as a consequence, with an altered ATP/ADP ratio. To investigate further the mechanism of the impaired ATP formation, we measured in rat pancreatic islets glucose-stimulated pyruvate dehydrogenase (PDH) activity, a key enzyme for pyruvate metabolism and for the subsequent glucose oxidation through the Krebs cycle, and also the uncoupling protein-2 (UCP-2) content by Western blot. In islets exposed to high glucose or FFA, glucose-stimulated PDH activity was impaired and UCP-2 was overexpressed. Because UCP-2 expression is modulated by a peroxisome proliferator- activated receptor (PPAR)-dependent pathway, we measured PPAR-gamma contents by Western blot and the effects of a PPAR-gamma antagonist. PPAR-gamma levels were overexpressed in islets cultured with high FFA levels but unaffected in islets exposed to high glucose. In islets exposed to high FFA concentration, a PPAR-gamma antagonist was able to prevent UCP-2 overexpression and to restore insulin secretion and the ATP/ADP ratio. These data indicate that in rat pancreatic islets chronically exposed to high glucose or FFA, glucose-induced impairment of insulin secretion is associated with (and might be due to) altered mitochondrial function, which results in impaired glucose oxidation, overexpression of the UCP-2 protein, and a consequent decrease of ATP production. This alteration in FFA cultured islets is mediated by the PPAR-gamma pathway.
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Affiliation(s)
- Giovanni Patanè
- Institute of Internal Medicine, Endocrinology and Metabolism, "Signorelli" Diabetes Center, University of Catania, Ospedale Garibaldi and Ospedale Cannizzaro, Catania, Italy
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Chan SL, Mourtada M, Morgan NG. Characterization of a KATP channel-independent pathway involved in potentiation of insulin secretion by efaroxan. Diabetes 2001; 50:340-7. [PMID: 11272145 DOI: 10.2337/diabetes.50.2.340] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Efaroxan, like several other imidazoline reagents, elicits a glucose-dependent increase in insulin secretion from pancreatic beta-cells. This response has been attributed to efaroxan-mediated blockade of KATP channels, with the subsequent gating of voltage-sensitive calcium channels. However, increasing evidence suggests that, at best, this mechanism can account for only part of the secretory response to the imidazoline. In support of this, we now show that efaroxan can induce functional changes in the secretory pathway of pancreatic beta-cells that are independent of KATP channel blockade. In particular, efaroxan was found to promote a sustained sensitization of glucose-induced insulin release that persisted after removal of the drug and to potentiate Ca2+-induced insulin secretion from electropermeabilized islets. To investigate the mechanisms involved, we studied the effects of the efaroxan antagonist KU14R. This agent is known to selectively inhibit insulin secretion induced by efaroxan, without altering the secretory response to glucose or KCl. Surprisingly, however, KU14R markedly impaired the potentiation of insulin secretion mediated by agents that raise cAMP, including the adenylate cyclase activator, forskolin, and the phosphodiesterase inhibitor isobutylmethyl xanthine (IBMX). These effects were not accompanied by any reduction in cAMP levels, suggesting an antagonistic action of KU14R at a more distal point in the pathway of potentiation. In accord with our previous work, islets that were exposed to efaroxan for 24 h became selectively desensitized to this agent, but they still responded normally to glucose. Unexpectedly, however, the ability of either forskolin or IBMX to potentiate glucose-induced insulin secretion was severely impaired in these islets. By contrast, the elevation of cAMP was unaffected by culture of islets with efaroxan. Taken together, the data suggest that, in addition to effects on the KATP channel, imidazolines also interact with a more distal component that is crucial to the potentiation of insulin secretion. This component is not required for Ca2+-dependent secretion per se but is essential to the mechanism by which cAMP potentiates insulin release. Overall, the results indicate that the actions of efaroxan at this distal site may be more important for control of insulin secretion than its effects on the KATP channel.
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Affiliation(s)
- S L Chan
- Institute of Cell Signalling, University of Nottingham, UK
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