Publisher(s): China Academic Journals (CD Edition) Electronic Publishing House Co., Ltd.
ISBN: ISBN 978-7-499-00969-1 pdf
First Published: 2020.11.23
Discipline(s): Medicine & Public Health
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Diabetes (Western Medicine), as part of the China’s Medicine Progress Series, has 27 research articles regarding the application of western medical approaches in the treatment and care of diabetes. The included articles are recommended by the editorial boards of the journals in which they were first published, covering mechanism, clinical, and nursing studies and fully demonstrating the cutting-edge progress in the treatment of diabetes in China, with scientific methodological support and objective conclusions. The original papers were published in Chinese, and this book is a compilation of selections in English version.
JIANG Xiaoying, a second-tier professor and doctoral supervisor, was once the dean of School of Nursing, Fujian Medical University and is now the president of Chinese Journal of Nursing. He is granted the special government allowance by the State Council.
1. Alteration of Wnt/β-catenin signaling pathway in type 2 diabetic rats' aorta and regulation of SIRT1
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 32,No. 01
Aim To investigate the alteration of Wnt/β-catenin signaling and sirtuins 1 in type 2 diabetic rats' aorta and clarify its role in the development of diabetes aortic disease. Methods The type 2 diabetic rat model was established by injection of streptozocin after five-week of high fat diet. The rats were randomly divided into control group, DM model group of 2 weeks, 4 weeks, 8 weeks and 12 weeks. Fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C) and fasting insulin (FINS) levels were tested. HE staining was used to observe the pathological changes of aortal structures. The alteration of Wnt2, β-catenin, TCF4, SIRT1 and sFRP2 in aorta was determined by Western blot and RT-PCR. Results Compared with control group, TC, TG, LDL-C levels of type 2 diabetic rats were significantly increased, HDL-C levels were significantly reduced ( P < 0.01). Aortic histological analysis revealed that DM induced aortic endothelial cell vacuolar degeneration and necrosis. The expression of Wnt2 and β-catenin level increased significantly in the first 4 weeks of diabetic groups compared to control group, and that in model group of 8 weeks and 12 weeks kept in the high level and showed no significant alteration ( P > 0.05). But the expression of TCF4 and SIRT1 was enhanced continuously in DM compared with control group while sFRP2 decreased in the duration of DM development. Conclusions Wnt/β-catenin signaling pathway was activated in diabetic aorta injury by regulation of SIRT1 via sFRP2. Further researches on its mechanism of action in DM aorta injury may find a new therapeutic target for the disease.
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 32,No. 02
Aim To investigate the effect of ASIC1a (acid-sensing ion channel 1a) on the pathological change of diabetes complication liver fibrosis and the proliferation and activation of hepatic stellate cell (HSC-T6) stimulated by PDGF-BB under hyperglycemia. Methods Diabetes rats model was established by streptozotocin (STZ), and liver fibrosis rats model was induced by carbon tetrachloride (CCl 4). Then, the extent of liver damage and the expression of ASIC1a were observed in the diabetic rats, liver fibrosis rats and diabetes complication liver fibrosis rats. In vitro, after pretreated with amiloride, HSC-T6 was treated with high glucose for 24 h and then stimulated with PDGF-BB for another 24 h. The proliferation and activation of HSC-T6 were observed, and the expression of ASIC1a, α-SMA and collagen Ⅰ were detected by Western blot. Results Compared with the control group, rats from diabetic group induced by STZ, liver fibrosis group induced by CCl 4, and the diabetes complication liver fibrosis rats co-induced by STZ and CCl 4 were all observed with liver damage at different levels, and tissue injury of complication group was the most serious. However, the expression of ASIC1a in the three model groups was significantly increased compared to the control group. ASIC1a level was the most obvious in the diabetes complication liver fibrosis rats. Amiloride pretreatment significantly decreased ASIC1a expression and inhibited PDGF-BB mediated proliferation and the expression of α-SMA and collagen Ⅰ in HSC-T6 under high glucose environment. Conclusion High ambient glucose aggravates HSC activation and hepatic fibrosis, and this may be related with the increasing expression of ASIC1a.
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 32,No. 03
Aims To investigate the influences of metformin (MET) on the expression of renal tissue advanced glyclation end-products (AGEs) protein and its receptor mRNA (RAGE mRNA) in renal tissue in type 2 diabetes mellitus (T2DM) rat model, and to discuss the mechanism of MET in the treatment of diabetic nephropathy (DN). Methods The rat model of T2DM was established by treatment of high-fat diet and intraperitoneal injection of low-dose strptozotocin (STZ). All rats were randomly divided into metformin group (MET, 300 mg·kg ?1), glyburide group (GLY, 5 mg·kg ?1·d ?1), T2DM model group (T2DM) and normal control group (NC). After 8 weeks’ observation, blood glucose (BG), glycated hemoglobin (HbA1c), blood urea nitrogen (BUN), urinary albumin, urinary AGE2 and urine creatinine were detected. The expression of renal tissue AGEs was detected by immunohistochemistry assay, and the expression of RAGE mRNA was measured by real-time PCR. Results The levels of BG, HbA1c, urinary albumin/rine creatinine (UACR), glomerular basement membrane thickness (GBMT) in MET group and GLY group were significantly lower than those of T2DM group, while higher than those of NC group ( P < 0.05). The levels of BG, FINS and HbA1c were not statistically significant between MET and GLY groups ( P > 0.05). The urinary AGEs/urine creatinine (UGCR), the expression levels of renal tissue AGEs and RAGE mRNA in MET group and GLY group were significantly decreased compared with those of T2DM group ( P < 0.05), but higher than those of NC group ( P < 0.05). The UGCR, the expression levels of AGEs and RAGE mRNA in MET group were lower than those of GLY group ( P < 0.05). Conclusion MET can reduce the accumulation of AGEs in the renal tissue, and down-regulate the over-expression of RAGW mRNA in T2DM rats.
The Chinese Journal of Clinical Pharmacology,Part 1: Mechanism Study,Vol 32,No. 04
Objective To explore the effect of calcium dobesilate on the apoptosis of retinal cells in diabetic rats. Methods A total of 36 Wistar rats were randomly into three groups: normal group ( n = 12), model group ( n = 12), test group ( n = 12). The rats in model and test groups of diabetes were given high sucrose diet for 8 weeks, and then was subjected to intraperitoneal injection of streptozotocin (STZ). After diatetes animal model was successfully established, the rats in test group were lavaged with 150 mg·kg ?1·d ?1 calcium dobesilate for 8 consecutive weeks, and the rats in normal and model groups were given same amount of normal saline. Neuronal apoptosis in retina was detected by TdT-mediated dUTP nick end labeling (TUNEL). The expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-assaciated X protein (Bax), p53 protein and mRNA was assayed by Western blot and reverse transcription-polymerase chain reaction. The activity of cysteinyl aspartate specific proteinase 3 (Caspase 3) was measured by spectrophotometry. Results Compared with normal group, apoptosis index of retina, the expression of Bax, p53 protein and mRNA, and the activity of Caspase 3 were increased ( P < 0.01), and the expression of Bcl-2 protein and mRNA was decreased in model group ( P < 0.01). The expression of Bax, Bcl-2 and p53 mRNA was (0.20 ± 0.03) vs. (1.00 ± 0.09), (1.39 ± 0.10) vs. (0.21 ± 0.02) and (0.28 ± 0.05) vs. (0.88 ± 0.08) in normal group and model group, respectively. Compared with model group, apoptosis index of retina (12.40 ± 1.24), the expression of Bax (0.57 ± 0.05) and p53 (0.35 ± 0.03) protein, the expression of Bax (0.56 ± 0.05) and p53 (0.36 ± 0.04) mRNA, the activity of Caspase 3 (1.72 ± 0.17) in test group were all decreased. However, the expression of Bcl-2 protein (0.63 ± 0.06) and mRNA (0.74 ± 0.04) were increased in test group (all P < 0.01). Conclusion The calcium dobesilate inhibit neuronal apoptosis by regulating the expression of cell apoptosis-related protein.
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 33,No. 05
Aim To investigate the changes of cerebral blood flow in rats with diabetic cognitive impairment by two-channel laser Doppler flowmeter, and to explore the changes of cerebral blood flow in diabetic rats with cognitive impairment and to investigate the changes of cerebral blood flow lesions and the central nervous system function changes in the study to provide pre-foundation. Methods Thirty-four male Wistar rats were randomly divided into two groups: blank control group and diabetic model group. The rats in the model group were treated with streptozocin (STZ) 60 mg·kg ?1, and the glucose oxidase method was used to determine fasting blood glucose ≥ 16.7 mmol·L ?1 as the standard of the model. The Water maze was used to observe the behavioral changes of diabetic rats. Dual-channel laser doppler flowmeter was used to measure cerebral blood flow in diabetic rats with cognitive impairment. Another 34 male Wistar rats were randomly divided into two groups: control group and diabetic model group. Dual-channel laser doppler flowmeter was used to dynamically monitor cerebral blood flow on 0 d, 7 d, 14 d, 21 d, 28 d, 35 d, 42 d, 56 d and 75 d. ELISA was applied to detect the concentration of iNOS, cNOS and ET-1 in cerebrospinal fluid. Results Morris water maze test showed that the time of the platform (latency) was significantly longer than that of the blank control group ( P < 0.05). The cerebral blood flow/100 g of diabetic rats with cognitive impairment was significantly lower than that of the control group ( P < 0.05), and the blood flow in the model group was significantly lower than that in the model group ( P < 0.05). Compared with control group, iNOS and cNOS concentrations were markedly elevated, while ET-1 concentration obviously decreased. Conclusions The decrease of blood flow in the frontal cortex of diabetic rats with cognitive impairment suggests that it may be one of the factors leading to cognitive impairment in diabetes mellitus. Cerebral blood flow reduction occurs in the early stages of diabetes, followed by no significant deterioration. Cerebral blood flow may not be related to the changes of NO and ET-1, but the trend of cerebral blood flow may be related to the change of the two.
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 34,No. 06
Aim To observe the influence of meisoindigo on the alteration of Wnt/β-catenin signaling in type 1 diabetic rats’ myocardium and clarify its role in the development of diabetic cardiomyopathy. Methods The type 1 diabetes rat model was established by injection of streptozocin after one-week adaptive feeding. The successful modeling rats were randomly divided into DM model group of 4 weeks and 8 weeks, meisoindigo group of 4 weeks and 8 weeks. Fasting blood glucose (FBG) levels were tested. HE staining was used to observe the pathological changes of myocardial structures. The alteration of GSK-3β, p-GSK-3β, Wnt2, β-catenin, NF-κB-p65, and p-NF-κB-p65 in myocardium was determined by Western blot and immunohistochemistry. Results Compared with control group, FBG levels of type 1 diabetic rats significantly increased ( P < 0.01), while body weight levels significantly decreased ( P < 0.01); compared with DM group, FBG levels of 8 weeks meisoindigo group significantly decreased ( P < 0.01). Myocardial histological analysis revealed that DM induced myocardial focal myocyte hypertrophy, solubility, necrosis, fiber tissue hyperplasia; compared with DM group, these symptoms were eased in meisoindigo group of 4 weeks and 8 weeks. Compared with control group, the expression of p-GSK-3β, Wnt2, β-catenin, p-NF-κB-p65 level increased, especially with DM group of 8 weeks ( P < 0.01). The expression of p-GSK-3β, Wnt2, β-catenin, p-NF-κB-p65 level in meisoindigo group of 4 weeks and 8 weeks decreased significantly ( P < 0.01). Conclusions The repair effect of meisoindigo on myocardial damage in type 1 diabetic rats may be caused by lowering the expression of proteins in Wnt/β-catenin signaling and inhibiting the activation of Wnt/β-catenin signaling pathway, participating in the repair of myocardial damage and inflammatory in diabetic rats. Further researches on its mechanism in repairing diabetic myocardial damage may find new therapeutic targets for diabetic cardiomyopathy.
7. The therapeutic effect of rh-aFGF carbomer 940 gel on wound healing in type Ⅰ diabetic SD rat models
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 34,No. 07
Aim To study the therapeutic effect of recombinant human acidic fibroblast growth factor (rh-aFGF) carbomer 940 gel in the treatment of skin wound healing in type I diabetic rats. Methods Two types of skin trauma models, namely, full-thickness wound and scalded wound, were established in a model of type I diabetes mellitus using STZ-induced SD rats. The rats were divided into control group, vehicle group, 90 AU rh-aFGF gel group and 270 AU rh-aFGF gel group in each skin wound models. The wound area and wound healing rate were used to evaluate the therapeutic effect. The growth of fibroblasts, fibrocytes, collagen fibers and vessel capillaries in the wound was observed using HE staining and analyzed by semiquantitative score. Results The rh-aFGF carbomer gel significantly reduced the traumatic area as well as promoted the wound healing rate of the skin trauma model of SD rats of type I diabetes mellitus ( P < 0.05). HE staining showed that rh-aFGF carbomer gel significantly promoted the pathological score of fibroblasts and collagen fibers ( P < 0.05). Conclusions rh-aFGF carbomer gel might play a protective role in micro-environment of wound and rh-aFGF, which could benefit for proliferation of fibroblasts and collagen, therefore promoting the healing process of skin wound in SD rats with type I diabetes mellitus, and it might be expected to be a new preparation for the treatment of chronic trauma in diabetes mellitus.
8. Research of mechanisms of liraglutide inducing expression of fibroblast growth factor 21 in white adipose tissues of obese type 2 diabetic rats
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 34,No. 08
Aim To investigate the effect of liraglutide on expression of fibroblast growth factor 21 in white adipose tissues and its mechanisms. Methods Male SD rats were subjected to a standard control diet or high-fat diet (HFD) for 12 weeks, then the HFD group was injected introperitoneally with 30 mg·kg ?1 streptozotocin to induce type 2 diabetes mellitus model. Half number of rats of type 2 diabetes mellitus were injected with liraglutide (DM + LRG, 0.4 mg·kg ?1·d ?1, two times one day) for another 6 weeks. Serum biochemical indices and FGF21 levels were detected. The pathological changes in epididymal adipose tissues were detected by HE staining. The mRNA and protein expression and phosphorylation of FGF21, peroxisome proliferator-activated receptor γ (PPARγ), fibroblast growth factor receptor 3 (FGFR3), β-Klotho, liver kinase B1 (LKB1), AMP-activated kinase (AMPK), acetyl-CoA carboxylase (ACC) and phosphorylation of signaling molecules in MAPK pathway were assessed by RT-PCR, immunohistochemistry and Western blot respectively. Results Body mass and serum lipid, ALT and AST levels increased in DM group, while FGF21level decreased, and the volume of adipose cells in epididymal adipose tissues was expanded. Expressions of FGF21, PPARγ, p-FGFR3, β-Klotho, p-LKB1, pAMPK, p-ACC were down-regulated, while p-ERK, p-JNK and p-p38 expression were all increased. These indices were reverted by liraglutide treatment. Conclusion Liraglutide has significant lipid-lowering effect, which maybe related with increased FGF21 expression, activating AMPK pathway and inhibiting MAPK pathway.
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 34,No. 09
Aim To observe the effects of vaspin on myocardial fibrosis and cardiac function in diabetic cardiomyopathy (DCM) rats. Methods Male SD rats were divided randomly into three groups: control group, DCM group, and vaspin group. Rats in control group were simply treated with normal saline (0.5 mL·kg ?1·d ?1) and those in vaspin group were injected intraperitoneally with vaspin (320 ng·kg ?1·d ?1) solution daily for 12 weeks after diabetes was developed. Then the following experiments were performed: Echocardiography to assess left ventricular ejection fraction (LVEF), fractional shortening (FS), left ventricular end-diastole diameter (LVIDd), left ventricular end-systolic diameter (LVIDs) and Em/Am; ELISA to measure serum TNF-α concentration; Masson’s trichrome method to assess cardiac fibrosis and analyze collagen volume fraction (CVF); Western blot to examine the expressions of LC3, Beclin-1, P62, Bax, Bcl-2, TGF-β1 and collagen I in the myocardium. Results As for TNF-α levels, there was no statistically significant difference between DCM group and vaspin group, or statistically significant difference between DCM and control group. Echocardiography performed to assess the effect of vaspin on cardiac function showed that LVEF and FS levels were decreased in DCM group while increased in vaspin group. The ratio of Em/Am was decreased in DCM group but was not improved in vaspin group. Western blot showed that LC3-II/LC3-I ratio and Beclin-1 expression decreased and P62 expression increased in DCM group, which were reversed by vaspin treatment. Compared with DCM group, collagen deposition in vaspin group decreased. Western blot suggested that vaspin could reduce the expression of collagen I, but had no significant effect on the expression of TGF-β1. Conclusion Vaspin increases the level of autophagy and could ameliorate myocardial fibrosis and cardiac function in rats with diabetic cardiomyopathy.
10. Role of Glu-mGluR2/3-ERK signaling pathway in apoptosis of neurons in the prefrontal cortex of diabetic rats with depression
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 34,No. 10
Aim To investigate the key role of Glu-mGluR2/3-ERK signaling pathway in the apoptosis of prefrontal cortex neurons in diabetic rats with depression (DD). Methods Animal experiments were divided into two parts. The first part was divided into four groups: control, diabetes, depression and DD group. The second part was divided into three groups: control, DD, mGluR2/3 blocker + DD group (LY341495 group). Hormonal and Morris water maze tests were used to evaluate the depression-like behavior of rats. HE staining was used to observe the pathological damage in the prefrontal cortex. HPLC was applied to determine glutamate (Glu) content, and immunohistochemistry was employed to assess the positive expression of mGluR2/3, ERK, and caspase-3. Results Compared with control group, the depression-like behavior of the rats in DD model group was obvious. The prefrontal cortex neurons had pathological lesions such as swelling of the cell body, nuclear condensation, disordered arrangement, and reduced number, and the positive expression of caspase-3 was increased significantly. Meanwhile, Glu content was increased abnormally, its receptor mGluR2/3 expression was increased, and the downstream molecules ERK expression was decreased, indicating that neuronal apoptosis might be related to Glu-mGluR2/3-ERK pathway. Further study revealed that after the administration of mGluR2/3 blocker LY341495, the expression levels of mGluR2/3, ERK and caspase-3 in the prefrontal cortex of rats in DD group were reversed, and the pathological damage was alleviated to some extent. Conclusion The Glu-mGluR2/3-ERK signaling pathway is involved in the apoptosis of prefrontal cortex neurons in DD rats.
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 35,No. 11
Aim To observe the effect of uc.48 + small interference RNA (siRNA) on liver glycogen abnormality in type 2 diabetic rats and its possible mechanism. Methods The diabetes model was established by feeding high glucose and high fat diet combined with streptozotocin (STZ). After the success of the model, the long noncoding RNA uc.48 + siRNA was injected into the rat body via tail vein. The changes of blood glucose and the content of liver glycogen were detected dynamically, and the liver glycogen was detected one week after injection. Glucokinase (GK) mRNA and protein expression in liver tissues of each group were detected by qPCR and Western blot. Results It was observed that postprandial blood glucose and fasting blood glucose decreased in diabetic model rats after treated with uc.48 + siRNA compared with those in model rats. The level of liver glycogen in diabetic model rats was significantly lower than that in control group. The synthesis of liver glycogen in diabetic model rats with uc.48 + siRNA treatment increased compared with that in diabetic model group. The expressions of GK mRNA and protein in the diabetic model group were significantly lower than those in control group. The expression of GK mRNA and protein markedly increased after uc.48 + siRNA treatment. Conclusions uc.48 + siRNA reduced blood glucose and increased glycogen synthesis in type 2 diabetic rats, and its mechanism may involve in increasing GK expression and Akt1 phosphorylation.
12. Alpha lipoic acid provides protection on renal tissue fibrosis of diabetic rats by inhibiting activation of TLR4 and NLRP3 inflammatory signal
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 35,No. 12
Aim To investigate the effects of alpha lipoic acid (ALA) on Notch2, TLR4, NLRP3 and inflammatory factor expression in renal tissues of diabetes mellitus (DM) rats, and to explore its possible mechanism of anti-inflammatory and anti-fibrosis by Alpha lipoic acid. Methods The diabetic rat model was established by streptozotocin. The rats were divided into two groups: the DM group and ALA group. Meanwhile, and another eight rats were used as normal control (NC group). After eight weeks, the rats were sacrificed to detect the relevant biochemical parameters and oxidative stress indexes. In addition, immunohistochemical staining was employed to detect the protein expression localization sites of Notch2, TLR4 and NLRP3. Western blot analysis was used to detect the expression of Notch2, TLR4, NLRP3 and collagen Ⅳ proteins in renal tissues. ELISA was utilized to detect the inflammatory factor expression of IL-6 and TNF-α. Results Compared with NC group, the levels of blood glucose, 24 h urine protein, total cholesterol and triglyceride all increased in DM group, and the activity of T-AOC was reduced whereas the MDA content was up-regulated in DM group, all items but blood glucose were significantly reduced in ALA group, and the activity of T-AOC remarkably increased, while the MDA content was reduced in ALA group. Compared with NC group, the protein levels of Notch2, TLR4, NLRP3 and collagen Ⅳ in kidneys were raised, and the inflammatory factor expression of IL-6 and TNF-α significantly increased in DM group. Conclusions ALA may down-regulate the inflammatory signal of TLR4 and NLRP3 in kidney of diabetic rats, and reduce the expression of inflammatory factor and the accumulation of extracellular matrix via inhibiting the expression of Notch2 at protein level.
13. Cardioprotective effect of recombinant adeno-associated virus mediated nerve growth factor gene transfection in diabetic rats
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 35,No. 13
Aim To investigate the feasibility of recombinant adeno-associated virus serotype9 (rAAV9) mediated nerve growth factor (NGF) transfection in diabetic rats by intramyocardial injection, and to confirm the protective effect of this method on diabetic cardiac autonomic neuropathy. Methods At the 4th week after the establishment of diabetic model, the recombinant adeno-associated virus (rAAV9-NGF) carrying NGF gene was injected into the heart of rats. Five weeks later, the distributions of NGF, calcitonin gene-related peptide (calcitonin gene-related peptide, CGRP) and nerve fibers were detected by immunofluorescence. Hemodynamic parameters were used to evaluate cardiac function, and ELISA method was used to detect the expression of NGF, CGRP in myocardium. Results The exogenous gene NGF mediated by rAAV9 could be stably transfected and over-expressed in the myocardium of diabetic rats. The left ventricular systolic pressure, heart rate, and maximal rate of increase of left ventricular pressure significantly decreased, the left ventricular end-diastolic pressure and the maximal decrease rate of left ventricular pressure significantly increased, and the cardiac function was improved. The NGF, CGRP proteins in myocardial tissues were up-regulated, and the immunofluorescence showed that the decrease of NGF, CGRP and nerve fibers in myocardial tissues could be partially reversed after transfection. Conclusions Intramyocardial injection of NGF gene can effectively enhance the expression of NGF and promote the growth of nerve fiber, exerting a protective effect in diabetic rat heart.
Acta Pharmaceutica Sinica,Part 1: Mechanism Study,Vol 54,No. 14
Sangzhi alkaloids (SZ-A) are derived from traditional Chinese medicine Ramulus Mori, serving well as an innovative antidiabetic drug, due to α-glucosidase inhibition. To evaluate the potency of glucosidase inhibitory effect of SZ-A, the enzyme-based screening platforms, including sucrase, maltase and amylase were established, and IC 50 was calculated. The effects of SZ-A on postprandial blood glucose at a single dose, oral sucrose, starch and glucose loading were determined in normal ICR mice and alloxan-induced hyperglycemic mice. To confirm the anti-diabetic effects of SZ-A on glucose and lipid metabolism after long-term administration, the postprandial and fasting blood glucose, serum insulin, urinary glucose levels, glycosylated serum proteins and blood lipid levels were determined in high-fat fed C57 obese mice (pre-diabetic HFC57 mice) and diabetic rats induced by streptozotocin (STZ). The Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College approved all of the protocols for this research. We found that SZ-A exhibited a significant inhibitory effect on the sucrase and maltase. SZ-A showed no effect on amylase. In normal ICR mice and alloxan-induced hyperglycemic mice, SZ-A at a single dose significantly delayed and reduced the peak of blood glucose after sucrose or starch loading, but showed no effect on the increase of blood glucose after glucose loading. In STZ diabetic rats, SZ-A significantly reduced the postprandial or fasting blood glucose levels, glycosylated serum proteins and urinary glucose. SZ-A also reduced serum triglyceride (TG) and cholesterol (TC) levels after three weeks of treatment. SZ-A ameliorated the postprandial blood glucose or the fasting blood glucose elevation, and reduced the incidence of hyperglycemia in HFC57 mice. SZ-A decreased the basal insulin level, improved insulin sensitivity, and ameliorated glucose intolerance in pre-diabetic HFC57 mice. Our results indicated that SZ-A had a novel inhibitory activity on α-glucosidase, especially on disaccharidases. SZ-A at a single dose significantly reduced the peak of blood glucose elevation and delayed the increase of blood glucose in normal and diabetic mice after disaccharide and polysaccharide loading. Long-term treatment with SZ-A improved the glucose and lipid metabolic profiles by delaying carbohydrate absorption from the intestine and reduced the postprandial blood glucose levels in both pre-diabetic and diabetic animal models. Therefore, SZ-A application may display a beneficial role in preventing the occurrence and development of diabetes and its complications.
15. Effect of activated canonical Wnt/β-catenin/TCF7L2 signaling pathway in type 1 diabetic cardiomyopathy
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 35,No. 15
Aim To determine the role of Wnt/β-catenin/TCF7L2 pathway in diabetic cardiomyopathy. Methods A model of type 1 diabetes mellitus was established by intraperitoneal injection of streptozotocin (STZ) into 7 or 8-week old C57BL/6 mice. After four weeks, the diabetic animals were divided into three groups with seven to eight in each: diabetes mellitus (DM), diabetes injected with β-catenin inhibitor iCRT14 (2.5 and 5 mg·kg ?1). After continuous intraperitoneal administration for 8 weeks, heart samples were stained with HE and examined under light microscopy. The expression and distributions of β-catenin and TCF7L2 in myocardium were detected by immunohistochemistry. The protein levels of β-catenin, TCF7L2 were detected by Western blot. The mRNA levels of β-catenin, TCF7L2, Nppa and c-Myc were detected by qPCR. Results The myocardial cells in DM were relatively disordered and the size of the nucleus was irregular. The Western blot and immunohistochemistry data showed that the expression of β-catenin and TCF7L2 in heart with DM increased, while that in nucleus of the cardiomyocytes significantly increased. qPCR showed that the mRNA expression of β-catenin downstream target c-Myc and cardiac hypertrophy marker Nppa was upregulated. After injection of eight weeks with different iCRT14 doses, the cardiomyocytes were relatively regular; the protein levels of β-catenin and TCF7L2 decreased, and their expression in nucleus decreased as well; the mRNA levels of Nppa and c-Myc markedly decreased. Conclusions Activation of canonical Wnt/β-catenin/TCF7L2 signaling pathway plays a pivotal role in diabetic cardiomyopathy; iCRT14 significantly improves the phenotype of cardiomyopathy in type 1 diabetic mice.
Chinese Pharmacological Bulletin,Part 1: Mechanism Study,Vol 35,No. 16
Aim To study the mechanism of metformin in the treatment of type 2 diabetic mellitus (T2DM) rats. Methods Rats were randomly divided into normal group, model group and metformin group with 10 rats in each group. Four weeks after induction with HFSD, 35 mg·kg ?1 STZ was injected intramuscularly, and the experiment was completed after eight weeks of administration. UPLC/ESI-TOF-MS was used to study the effects of metformin on metabolites in serum of T2DM rats, and qPCR was used to find its target. Results Compared with normal group, the body weight, pancreatic index and insulin level in model group decreased significantly ( P < 0.05), the liver index, GLU, TC, TG and FFA levels increased significantly ( P < 0.01), OGTT was significantly impaired, while metformin could significantly increase the body weight, pancreatic index and insulin level ( P < 0.05), reduce the liver index, GLU, TC, TG and FFA levels ( P < 0.05), and improve OGTT. After metabonomics, 17 biomarkers were obtained. After verification, metformin was found to regulate the synthesis and metabolism of cholesterol, fatty acids, bile acids and phospholipids. Conclusions Metformin can improve the lipid metabolism disorder of T2 DM by regulating the synthesis and metabolism of cholesterol, fatty acids, bile acids and phospholipids.