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Objective To investigate the effect of liraglutide on glucagon release in obese type 2 diabetes (T2DM). Methods A multi-center, prospective, and self-comparison study was conducted in four hospitals in Qingdao. Twenty-four patients with T2DM were selected and treated with liraglutide for 12 weeks. Glucagon levels before and after treatment were detected before and 30 min, 60 min and 120 min after meals. Results After 12 weeks of treatment, the overall level of glucagon decreased, in which the differences in glucagon levels at 30 min [(220±79) ng/L vs. (203±77) ng/L, P<0.05] and 60 min [(248±119) ng/L vs. (203±82)ng/L, P<0.05] reached significance, respectively, comparing to those before treatment. The area under the curve of glucagon after treatment was significantly lower than that before treatment (438±190 vs. 389 ± 153, P<0.05). In contrast, after treatment, the overall level of C-peptide increased, especially the levels at 30 min [(1.53±1.02) nmol/L vs.(2.03±1.29) nmol/L ], 60 min [(1.93±1.19) nmol/L vs. (2.48±1.75) nmol/L] and 120 min [(2.36±1.47) nmol/L vs. (2.96±1.84) nmol/L], all P<0.05. The area under C-peptide curve increased significantly (3.6±2.2 vs. 4.6±2.9, P<0.05). Fasting plasma glucose, postprandial 2 h plasma glucose and glycosylated hemoglobin A1c were all lower than before, and the differences were statistically significant (P<0.05). Waist circumference and body mass index were significantly lower than before (P<0.05). The amount of insulin used for the treatment decreased by approximately 55.1% compared with that before liraglutide, and the difference was statistically significant (P<0.05). Conclusions Liraglutide inhibits glucagon secretion and lowers blood glucose. It can also reduce body weight, improve islet cell function and reduce insulin use in T2DM.
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Objective@#To elucidate the association between large conductance calcium-activated potassium channels (BKCa) in the paraventricular hypothalamic nucleus (PVN) and sympathetic outflow in rats with chronic heart failure (CHF) .@*Methods@#Male Wistar rats (6-7 weeks old) were randomized to sham operated group and CHF group (coronary artery ligation) . Two weeks after operation, BKCa inhibitor Iberiotoxin (IBTX) was infused into PVN by osmotic minipumps, rats were divided into following groups: sham+aCSF, CHF+aCSF, sham+low dose IBTX (0.125 nmol/nl) , CHF+low dose IBTX, sham+moderate dose IBTX (1.25 nmol/nl) , CHF+moderate dose IBTX, sham+ high dose IBTX (12.5 nmol/nl) , and CHF+high dose IBTX (n=6 each) . Additional rats were grouped as follows: sham+vehicle, sham+KCNMB4 knockdown (by rAAV2-KCNMB4 shRNA virus injection in PVN) , CHF+vehicle, CHF+ KCNMB4 knockdown group (n=6 each) . The cardiac function was determined by echocardiography, left ventricular hemodynamics were measured invasively, renal sympathetic nerve activity (RSNA) was recorded at 6 weeks after coronary artery ligation or sham operation. The contents of norepinephrine (NE) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in plasma were determined by enzyme-linked immunosorbent assay. The protein and mRNA expression of KCNMB4 in PVN were measured by immunofluorescence staining, Western blot, and real-time PCR, mRNA expression of BKCa in PVN was detected by real-time PCR.@*Results@#Compared with the sham operation group, the cardiac function of the heart failure group was significantly reduced (P<0.05) , and the plasma NE and the serum NT-proBNP were significantly elevated (P<0.05) . The protein and mRNA expression of KCNMB4 in PVN were obviously down-regulated in CHF rats (P<0.05) . After perfusion of IBTX or KCNMB4 knockdown by microinjection of rAAV2-KCNMB4 shRNA virus,right ventricular weight/body weight and lung weight/body weight ratio as well as left ventricular end-diastolic diameter were increased and left ventricular ejection fraction was decreased (all P<0.05) , the sympathetic driving indexes was increased in sham rats, changes of these parameters further aggravated in CHF rats (P<0.05) . KCNMB4 knockdown further downregulated protein expression in PVN of CHF rats.@*Conclusion@#Downregulation and blunted function of BKCa in PVN may contribute to sympathoexcitation and deterioration of cardiac function in rats with chronic heart failure.
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AIM:To investigate the expression of fatty-acid amide hydrolase(FAAH)in paraventricular nu-cleus(PVN)and its contribution to renal sympathetic nerve activity in rats with chronic heart failure(CHF).METH-ODS:A rat model of CHF was established by ligation of the left coronary artery to induce acute myocardial infarction. Eight weeks after ischemia,the rat model of CHF was identified by echocardiogram and histopathological observation.The plasma level of norepinephrine(NE)was detected by ELISA.The protein expression levels of FAAH in the PVN were de-termined by Western blot.The N-arachidonoylethanolamide(AEA)generation in PVN was analyzed by high-performance liquid chromatography.After microinjection of AEA,PF3845(an FAAH inhibitor)or rAAV2-FAAH shRNA virus in PVN, the sympathetic drive indexes were recorded in different experiment groups.RESULTS: Compared with the rats in sham group,the cardiac function and AEA concentration in PVN were significantly reduced, while the plasma NE level and FAAH expression in PVN were obviously increased in the CHF rats(P<0.05).After microinjecion of PF3845, AEA or rAAV2-FAAH shRNA virus in PVN, the sympathetic drive indexes were decreased significantly and the cardiac function were improved in the CHF rats.CONCLUSION:Upregulated FAAH expression in PVN may result in sympathoexcitation in the rat with CHF.
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Cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent chloride channel, plays key roles in fluid secretion in serous epithelial cells. Previously, we identified two polymethoxylated flavonoids, 3',4',5,5',6,7-hexamethoxyflavone (HMF) and 5-hydroxy-6,7,3',4'-tetramethoxyflavone (HTF) which could potentiate CFTR chloride channel activities. The present study was aimed to investigate the potentiation effects of HMF and HTF on CFTR Cl(-) channel activities by using a cell-based fluorescence assay and the short circuit Ussing chamber assay. The results of cell-based fluorescence assay showed that both HMF and HTF could dose-dependently potentiate CFTR Cl(-) channel activities in rapid and reversible ways, and the activations could be reversed by the CFTR blocker CFTRinh-172. Notably, HMF showed the highest affinity (EC50 = 2 μmol/L) to CFTR protein among the flavonoid CFTR activators identified so far. The activation of CFTR by HMF or HTF was forskolin (FSK) dependent. Both compounds showed additive effect with FSK and 3-Isobutyl-1-methylx (IBMX) in the activation of CFTR, while had no additive effect with genistein (GEN). In ex vivo studies, HMF and HTF could stimulate transepithelial Cl(-) secretion in rat colonic mucosa and enhance fluid secretion in mouse trachea submucosal glands. These results suggest that HMF and HTF may potentiate CFTR Cl(-) channel activities through both elevation of cAMP level and binding to CFTR protein pathways. The results provide new clues in elucidating structure and activity relationship of flavonoid CFTR activators. HMF might be developed as a new drug in the therapy of CFTR-related diseases such as bronchiectasis and habitual constipation.
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Animals , Mice , Rats , Colforsin , Colon , Metabolism , Cystic Fibrosis Transmembrane Conductance Regulator , Flavones , Physiology , Flavonoids , Pharmacology , Genistein , Intestinal Mucosa , MetabolismABSTRACT
Objective To study the assosiation of angiopoietin-like protein 2 (ANGPTL2) to lower extremity arterial disease in type 2 diabetes mellitus.Methods A total of 360 type 2 diabetic patients were divided into three groups:without (group A),with mild to moderate (group B),and severe (group C) lower extremity arterial disease according to the ankle brachial index.And,120 healthy subjects serveed as control group.The levels of ANGPTL2,high sensitivity C-reactive protein (hsCRP),free fatty acid,biochemical index,and fasting insulin were detected.And,waist-to-hip ratio (WHR),body mass index (BMI),insulin resistance index were calculated.Results The level of ANGPTL2 was getting higher and higher as lower extremity arterial disease progressing.The level of ANGPTL2 in group B was higher than that in group A [1.27 (1.09,1.51) vs 0.88 (0.66,1.07) μg/L,P＜0.05],and the level of ANGPTL2 in group C was higher than that in group B [1.70 (1.45,1.91) vs 1.27 (1.09,1.51)μg/L,P＜0.05].Pearson correlation analysis showed that the ANGPTL2 level in serum positively correlated with hsCRP,BMI,WHR,cholesterol,low-density lipoprotein-cholesterol,fasting insulin,and insulin resistance index.Logistic regression analysis showed that the levels of ANGPTL2,hsCRP,and glycosylated hemoglobin were significantly associated with lower extremity arterial disease in type 2 diabetes mellitus.Conclusion It is possible that ANGPTL2 is one of the risk factors of lower extremity arterial disease in type 2 diabetes mellitus,and which is likely to be of great significance in the early prediction,disease assessment,and prognosis evaluation for lower extremity arterial disease in type 2 diabetes mellitus.
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Objective To observe the effect of irbesartan on the expression of angiopoietinlike protein 2 (ANGPTL2) in the diabetic rats kidney and explore the underlying mechanism.Methods A total of sixty male SD rats were divided into normal control group (NC group,n=15) and experimental group (n=45) randomly.The experimental group was fed with high sugar-fat diet and given a low dose streptozocin (STZ 30 mg/kg)to establish type 2 diabetic model.Rats successfully induced diabetes were randomly divided into 2 groups:diabetes group (DM) and irbesartan group (DI).Weight,blood pressure,blood glucose,serum creatinine (Scr),blood urea nitrogen(BUN),24 hour urinary albumin(UAL) and renal histomorphology were observed after drug intervention at the 4th,8th and 12thweeks.The expression of ANGPTL2 in renal tissue were detected by immunohistochemistry,real-time PCR and Western blotting.Results The levels of Scr,BUN,TG,TC and UAL in group DM were higher than in group NC at the 4th,8th and 12th week (all P ＜ 0.05).Compared with that in group DM,above indexes were lower in group DI at the 4th,8th and 12th week (all P ＜ 0.05).The pathological changes of the kidney in group DM were more serious than that in group DI.The expression of ANGPTL2 in group DM was much higher than that in group NC at the 4th,8th and 12th week (all P ＜0.05),and irbesartan treatment inhibited the up-regulation of ANGPTL2 in group DI(all P ＜ 0.05).Conclusion The expression of ANGPTL2 increases in T2DM rats kidney tissue with time and irbesartan can inhibit the up-regulation of ANGPTL2 in T2DM rats.
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OBJECTIVE: To systematically evaluate the application of microcapsuled cell or encystation materials for treating diabetes mellitus at hone or abroad in recent years.METHODS: A computer-based online search of PubMed database was undertaken to identify related articles about the microcapsulated cell or encystation material for treating diabetes mellitus published from 1980 to 2009 by using the key words of "microcapsulation, islet, transplantation" in English. Meanwhile, we search CNKI for relevant articles published between 1999 and 2009 with the same key words in Chinese. The related randomized, controlled, and clinical studies were collected according to conclusion and exclusion criteria.RESULTS: Among 25 articles, there were 46 patients with type I diabetes mellitus, 106 rats, 20 pigs, and 25 monkeys. The experimental results showed that both the microcapsulated islets and non-microcapsulated islets could secrete insulin and decrease blood glucose level. The normal blood glucose level with microcapulated islets could be maintained for a long time.Thus, microcapsule had a great immune isolation reaction.CONCLUSION: After transplantation, microencapsulated islet cells could improve and adjust abnormal glycometabolism of patients with diabetes mellitus; furthermore, the immunoisolation effect of microcapsule could eliminate or relieve the immunological rejection of receptors to allograft or xenograft, while it could also relieve or eliminate dependence on immunosuppressive drugs. Appropriate material of microcapsule, reasonable process, advanced equipment, advanced separation and purification technologies of islet, and suitable site for transplantation could improve the function of artificial islet cell, enhance the anti-machinery and chemical strength of microencapsuiated islet, improve biocompatibility, and prolong survival time.
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Objective To study the relationship between serum C-reactive protein(CRP)levels and insulin resistance(IR)in patients with hyperglycemia and obesity.Methods Fasting plasma glucose(FPG),2h plasma glucose(2hPG),fasting insulin(INS),patient height and weight were measured.Body mass index(BMI)and Homa insulin resistance index(Homa-IR)were calculated.Based on BMI and PG,the participants were divided into 4 groups:normal control group(30 cases),simple obesity group(30 cases),impaired glucose regulation(IGR)obesity group(30 cases)and type 2 diabetic obese group(30 cases).Serum C-reactive protein levels were measured with immunoturbimetric assay.Results(1)CRP and the Homa-IR in other groups were significantly increased comparing with normal control group,with statistical difference observed(P