Effect of Irisin on islet β cell function in type 2 diabetic rats by regulating autophagy through PI3K/AKT/mTOR pathway / 中国生物制品学杂志

@#Objective To investigate whether Irisin improves islet β cells function in rats with type 2 diabetes mellitus(T2DM)by enhancing autophagy through the phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)pathway,so as to provide new ideas for clinical treatment of chronic metabolic diseases such as T2DM and metabolic syndrome.Methods Thirty SD male rats were randomly divided into normal group(NC group),T2DM group,and Irisin intervention group(T2DM + Irisin group). High-fat and high-sugar diet for 5 weeks plus low-dose(35 mg/kg)streptozotocin(STZ)induced T2DM rat model. After 8 weeks of intraperitoneal injection of Irisin,rats were tested for fasting blood glucose(FBG),fasting insulin(FINS),triglyceride(TG),total cholesterol(TC),low density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C). The intraperitoneal glucose tolerance test(IPGTT),intraperitoneal insulin tolerance test(IPITT)and hyperglycemic clamp test were performed to assess the islet function and insulin resistance level of rats in each group. The expression levels of PI3K/AKT/mTOR pathway proteins and autophagyrelated proteins in the pancreas were subsequently detected by Western blot. The expression levels of insulin,microtubuleassociated protein 1 light chain 3(MAP1LC3),p62,and lysosomal associated membrane protein-2(LAMP-2)in rat pancreas were detected by immunohistochemistry(IHC).Results There was an interaction between FBG and intervention time in rats(F = 11. 751,P = 0. 000),and the FBG gradually decreased in the T2DM + Irisin group with the prolongation of the intervention time. From the 4th week of intervention,the FBG in the T2DM + Irisin group decreased significantly compared with that in the T2DM group(F = 1 008. 870,P = 0. 000). Compared with NC group,the serum concentrations of TC,TG,and LDL-C concentrations in the T2DM group significantly increased(each P = 0. 000),while the HDL-C concentrations significantly decreased(P = 0. 000). After Irisin intervention,the above indexes were all improved(P = 0. 010,0. 000,0. 000 and 0. 000,respectively). Western blot results showed that compared with NC group,p62 protein expression and LC3Ⅱ/LC3Ⅰincreased significantly(P = 0. 008 and 0. 048,respectively),and LAMP-2 protein expression decreased significantly(P = 0. 000)in T2DM group. LC3Ⅱ/LC3Ⅰexpression level further increased after Irisin intervention(P =0. 000),but p62 protein level significantly decreased(P = 0. 047)and LAMP-2 protein expression increased significantly(P = 0. 000),and the IHC results were consistent with the Western blot results. The levels of p-PI3K/PI3K,p-AKT/AKT and p-mTOR/mTOR decreased significantly in the T2DM group compared with NC group(P = 0. 006,0. 031 and0. 000,respectively),and the above indicators further decreased after Irisin intervention(P = 0. 033,0. 013 and 0. 000,respectively).Conclusion Irisin can enhance autophagy through PI3K/AKT/mTOR signaling pathway to improve islet βcells function,providing a new idea for the treatment of T2DM.

Interplay between non-coding RNA and insulin signaling pathway and its clinical application / 中国药科大学学报

@#Non-coding RNA (ncRNA) is a type of RNA that has no or limited protein-coding ability. It mainly includes microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), transfer RNA (tRNA), PIWI-interacting RNA (piRNA), and small nucleolar RNA (snoRNA).At present, research has found that ncRNA plays a central role in regulating the function of pancreatic β cells, and that defects of insulin signaling is an important cause of diabetes.This article reviews the relationship between ncRNA and insulin signaling pathway in recent years, and discusses the possibility of ncRNA as a potential therapeutic target and clinical diagnostic marker for diabetes, hoping to provide some reference for the treatment and diagnosis of diabetes.

Effect of Shenqi Compound on Islet β-cell Function in Type 2 Diabetic GK Rats / 中国实验方剂学杂志

Objective:To explore the effect of Shenqi compound on islet β-cell function in type 2 diabetic GK rats. The whole genome expression profile chip technology is used to explore the molecular mechanism of Shenqi compound regulating pancreatic islet cell function and provide theoretical basis for the prevention and treatment of type 2 diabetes with traditional Chinese medicine. Method:GK rats were fed with high-fat diet daily for 4 weeks. Rats were randomly selected from GK rats to detect random blood glucose and verified the success of type 2 diabetes model. Rats were divided into 4 groups， Wistar group， model group， Shenqi compound（1.44 g∙kg-1） group and west glenn（16 mg∙kg-1） group. After 8 weeks of gavage， the serum insulin（INS） levels were detected by enzyme-linked immunosorbent assay（ELISA）. The apoptosis of islet β cells was detected by terminal-deoxynucleoitidyl transferase mediated nick end labeling（TUNEL）fluorescence method. Differential gene detection uses whole-genome expression profiling chip technology in each group of rat pancreatic tissues， the mRNA transcription level of key differential genes is detected by Real-time fluorescent quantitative polymerase chain reaction （Real-time PCR）. Result:Compared with blank group， before gavage， 4 weeks， 8 weeks， GK rats have higher blood sugar in each group （P<0.01）.Gavage for 4 weeks and gavage for 8 weeks， compared with model group， the blood sugar of rats in each drug intervention group was lower （P<0.01）. Gavage for 8 weeks， compared with blank group， the INS level of model group was lower （P<0.01）. Compared with model group， the Shenqi compound group had a higher INS level， and the sitagliptin group had a higher INS level （P<0.01）. After gavage for 8 weeks， compared with the blank group， the number of pancreatic islet β-cell apoptosis in the model group was higher （P<0.05）. Compared with model group， the number of pancreatic islet β cell apoptosis in the Shenqi compound group and sitagliptin group was lower （P<0.05，P<0.01）. Gene chip and Real-time PCR tests both showed that phosphatidylinositol 3-kinase receptor 1（PIK3R1） was up-regulated in the Shenqi compound group/model group， and down-regulated in the sitagliptin group/model group， model group/blank group. Protein kinase B1（Akt1） was expressed in the Shenqi compound group/model The expression was up-regulated in the group， sitagliptin group/model group， and down-regulated in the model group/blank group. Conclusion:Shenqi compound which has the function of supplenmenting Qi and Yin and promoting the blood circulation， can inhibit the islet β cell apoptosis， improve islet β cell function， regulate insulin secretion， and prevent T2DM by up-regulating the expression of genes PIK3R1 and Akt1.

Relationship between circular RNA and type 2 diabetes and its clinical application / 中国药科大学学报

@#Circular RNA (circRNA) is a novel type of non-coding RNA with covalently closed loops which plays an important role in the occurrence and development of type 2 diabetes. In this paper, the relationship between circRNA and type 2 diabetes in terms of the regulation of pancreatic β-cell function by circRNA and the metabolic activity of heart, kidney and other organs is reviewed, and the possibility of circRNA as a clinical diagnostic marker for type 2 diabetes and its complications is emphasized, hoping to provide reference and clues for the prevention, diagnosis and treatment of type 2 diabetes.

Effects of metformin on insulin sensitivity and islet beta cell secretion in obesity patients / 基础医学与临床

Objective To investigate the effects of metformin on insulin sensitivity and secretion in patients with obesity and insulin resistance. Methods This study enrolled 42 obesity patients with insulin resistance who were regularly followed-up in Peking Union Medical College Hospital from September 2012 to May 2016. They were divided into two groups according to their different status of glucose metabolism: normal glucose tolerance( NGT) and impaired glucose regulation( IGR) . Life style intervention and metformin were given to all these patients. The antropometric and metabolic data were collected before treatment, 3 and 6 months after treatment respectively. Results 42 patients, aged (23.6±6.5) years, including 11 males and 31 females were enrolled. 19 of them were NGT and 23 were IGR (8 of IGT and 15 of IFG) . Among all these patients, fasting insulin was significantly higher at 3 months after treatment(P＜0.05).The same results were shown in group-NGT(P＜0.05). Fasting insulin was significantly lower at 6 months after treatment than at baseline among all patients( P＜0.05) . HOMA-IR showed no significant difference between the baseline and 3 months after treatment, but significantly higher at baseline and 3 months after treatment than 6 months after therapy( P＜0.001) . HOMA-beta was significantly( P＜0.001) lower be-fore treatment and 6 months treatment the effect was more significant than 3 months after treatment among all pa-tients. HOMA-beta was significantly lower at baseline in group-IGR than at baseline in group-NGT ( P＜0.05) . Conclusions The effect of metformin on insulin secretion is earlier than that of improving the insulin sensitivity in patients with obesity and insulin resistance. Metformin is more likely to promote insulin secretion in patients with normal glucose tolerance than those with IGR within 3 months of intervention.

The protective effects of saxagliptin onβ-cell proliferation by inhibiting the degradation of SDF-1 in type 2 diabetes rats / 天津医药

Objective To investigate the mechanism of a dipeptidyl-peptidase-4 (DPP-4) inhibitor, saxagliptin, pro?moting the regeneration of islet beta cells in diabetic rats. Methods The male SD rats were randomly divided into three groups including control group (NC, n=10), diabetes group (DM, n=10) and diabetes treated with saxagliptin group (DM-S, n=10). DM-S group was treated with saxagliptin 1 mg/(kg·d) for twelve weeks. The pancreaticβcell function was analysed by hyperglycemic clamps. Immunohistochemistry with anti-PCNA was performed to observe the proliferation rate of pancreaticβcells. Immunofluorescence double staining with anti-insulin, anti-glucagon, anti-DPP-4 and anti-SDF-1 were performed to observe the expression of insulin, glucagon, DPP-4 and SDF-1 in pancreatic tissue. Western blot assay was performed to test the expression of Akt, p-Akt,β-catenin and free-β-catenin protein, and RT-PCR was performed to test the expressionlevels of c-myc and cyclinD1 mRNA in pancreatic tissue. Results Compared with NC group, there were significantly in?creased blood glucose, decreased islet function andβcell mass in DM group. Compared with DM rats, saxagliptin treatment significantly inhibited the expression of DPP-4, decreased the degradation of SDF-1, stimulated the proliferation ofβcells, and ultimately improved the islet function and histopathological changes of pancreas. Conclusion DPP-4 inhibitor saxa?gliptin can significantly improve islet function, which involved in the inhibition of the expression of DPP-4, the decreased degradation of SDF-1 and the stimulation of the proliferation ofβcells.

Relationship between serum 25-hydroxy vitamin D3 level and function of islet beta cell in newly diagnosed type 2 diabetes / 中国基层医药

Objective To evaluate the serum 25-hydroxy vitamin D 3 level in newly diagnosed type 2 diabe-tes,and its relationship with function of islet beta cell .Methods 60 newly diagnosed type 2 diabetes patients and 48 normal glucose tolerance healthy control cases were selected .The level of serum 25-hydroxy vitamin D3 of two groups were measured using the way of high performance liquid chromatograph .The difference was compared between two groups.Insulin resistance index(HOMA-IR) and islet beta cell secrete index(HOMA-β) was used to respectively es-timate insulin sensitivity and islet beta cell function in type 2 diabetes group .The correlation was analyzed between 25-hydroxy vitamin D 3 and fasting blood glucose ,HOMA-IR,HOMA-β.Results The level of serum 25-hydroxy vita-min D3 (28.68 ±1.61) ng/mL in type 2 diabetes group was significantly lower than that of control group (41.30 ± 1.12)ng/mL(t=3.47,P0.05).Conclusion The level of 25-hydroxy vitamin D 3 was significantly low in newly diagnosed type 2 diabetes patients .Low serum 25-hydroxyl vitamin D 3 level affects islet beta secretion cell function ,the supplementation of vitamin D 3 may be a simple and effective method to reduce the ocurrence of type 2 diabetes .

Influence of combination therapy of epalrestat and insulin on islet beta cell function in newly diagnosed type 2 diabetic patients / 中国基层医药

Objective To observe the influence of epalrestat combined with insulin therapy on islet beta cell function in newly diagnosed type 2 diabetic patients.Methods 45 newly diagnosed type 2 diabetic patients were randomly treated with 4 times of subcutaneous insulin therapy(RI group) or epalrestat plus 4 times of subcutaneous insulin therapy(RI + EP group).Patients were followed up for 3 months.The fasting blood-glucose (FPG),the 2 hour postprandial blood glucose (2 h PG),fasting insulin (FINS),the 2 hour postprandial blood insulin (2 h INS),glycated hemoglobin (HbA1 C),superoxide dismutase (SOD),malondialdehyde (MDA),insulin resistance index (HOMA-IR) and insulin release index(HOMA-β) were observed at 3th month after the initiation of therapy.Results Follow-up evaluation of 22 cases in RI group,23 cases in group RI + EP were completed 3 months of treatment.After treatment,FPG,2 h PG,HbA1 C,MDA and HOMA-IR in the two groups were decreased than those before treatment,the serum FINS,2 h INS,SOD and HOMA-β were higher than those before treatment,the differences were statistically significant (all P ＜0.05).After treatment,FINS,2 h INS,SOD and HOMA-β of RI + EP group were higher than those in RI group,MDA was lower than that of RI group,the differences were statistically significant (t =3.228,2.536,3.021,2.343,2.122,all P ＜ 0.05).FPG,2 h PG,HbA1 C,HOMA-IR between the two groups had no significant differences (all P ＞ 0.05).Linear regression analysis showed that HOMA-β was positively correlated with SOD level (r =0.888,r2 =0.783,all P ＜ 0.01).Conclusion The results suggest that epalrestat combined with insulin therapy can inhibit oxidative stress,and improve islet beta cell function in newly diagnosed type 2 diabetic patients,and its clinical effect is better than monotherapy with insulin.

The protection of islet β-cells in db/db mice by combination pioglitazone and glucagon like peptide-1 treatment / 中华内科杂志

ObjectivesTo evaluate the effect of combination of liraglutide,a glucagon-like peptide-1 analogue and pioglitazone,an insulin sensitizer,on diabetic db/db mice.MethodsThirty-five 8-week old male db/db mice were divided into control group (n = 8 ),pioglitazone group (n =9 ),liraglutide group (n =9) and combined therapeutic group (n =9),which was given normal saline 0.1 ml,2/d,pioglitazone 24 mg· kg-1 · d-1 (feed contained 0.02％ pioglitazone) + normal saline 0.1 ml,2/d,liraglutide 300 mg/kg,2/d,and pioglitazone 20 mg · kg-1 · d -1 ( feed contained 0.02％ pioglitazone) +liraglutide 300 mg/kg,2/d,respectively.Liraglutide were given at 8:00 and 16:00 via subcutaneous injection after having been diluted with sterilized normal saline.Effect on glucose,lipid metabolism and islet β-cell preservation were assessed after 4 weeks.Oneway ANOVA was adopted for statistical analysis.Results Combination therapy displayed promising anti-hyperglycemic[glycosylated hemoglobin Alc: (4.5 ± 0.6)％vs.(7.3 ±0.4)％,P ＜ 0.001].Glucose tolerance were improved assessed by area under curve(AUC) of glucose by intraperitoneal glucose tolerance test (IPGTT)[(1814 ±91 ) mmol · min · L-1 vs.(4042 ±183) mmol · min · L-1,P ＜0.001];insulin release response to glucose were also preserved as AUC of insulin by IPGTT was higher[( 1639 ±372) μg · min · L-1 vs.(834 ±201 )μg · min · L-1].Combination therapy also reduced circulated free fatty acids and TG[( 202.0 ± 20.4 ) μmol/L vs.( 272.5 ± 21.7 )μmol/L,(0.81 ± 0.28) mmol/L vs.( 1.35 ± 0.21 ) mmol/L],and increased plasma adiponectin [(16.7±2.0)mg/L vs.(10.2±1.8)mg/L].All P value ＜0.05.Islet immunohistochemistry showed that combination therapy significantly increased insulin positive area were[( 59.5 ± 1.5 ) ％ vs.( 22.4 ±1.5) ％]and ratio of Brdu positive β-cells was three folds than vehicle-treated mice[( 2.4 ± 0.5 ) ％ vs.(0.8 ±0.3)％],both greater than each single treatment.Combined therapy significantly improved islet β cell/α cell distribution,which led to islet recovery.ConclusionsCombined therapy improves glucose and lipid metabolism,preserves islet β-cell function and stimulates β-cell proliferation,greater than either liraglutide or pioglitazone treatment alone.

Fuel-Stimulated Insulin Secretion Depends upon Mitochondria Activation and the Integration of Mitochondrial and Cytosolic Substrate Cycles

The pancreatic islet beta-cell is uniquely specialized to couple its metabolism and rates of insulin secretion with the levels of circulating nutrient fuels, with the mitochondrial playing a central regulatory role in this process. In the beta-cell, mitochondrial activation generates an integrated signal reflecting rates of oxidativephosphorylation, Kreb's cycle flux, and anaplerosis that ultimately determines the rate of insulin exocytosis. Mitochondrial activation can be regulated by proton leak and mediated by UCP2, and by alkalinization to utilize the pH gradient to drive substrate and ion transport. Converging lines of evidence support the hypothesis that substrate cycles driven by rates of Kreb's cycle flux and by anaplerosis play an integral role in coupling responsive changes in mitochondrial metabolism with insulin secretion. The components and mechanisms that account for the integrated signal of ATP production, substrate cycling, the regulation of cellular redox state, and the production of other secondary signaling intermediates are operative in both rodent and human islet beta-cells.

Factors related to the apoptosis of Islets beta-cells in type 2 diabetes / 医学研究生学报

Insulin deficiency is a key factor involved in the pathogenesis of diabetes. Apoptosis is one of the reasons for the lose of islets. The whole process of apoptosis is quite complex. This article summarizes the role of several factors such as glucose, free fatty acid, GLP-1, and in the islets apoptosis.