In Silico Characterization of a Novel Bioactive Compound derived from Psidium guajava 4-[5-(Pyridin-4-yl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine: A Potential Inhibitor for Targeting Signaling Proteins involved in Diabetes Development

Pharmacological interventions for diabetes predominantly involve chemically synthesized compounds, often causing undesirable side effects. This has led to a growing interest in plant-based therapeutic alternatives. Technological advancements have facilitated the discovery of bioactive phytochemicals with medicinal properties. This study employs molecular docking analysis to assess the anti-diabetic potential of a naturally derived compound, 4-[5-(Pyridin-4-yl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine (POA), obtained from Psidium guajava leaf extract. The evaluation focuses on its inhibitory action against four human proteins 11 ? -HSD1 (PDB: 4K1L), GFAT (PDB ID: 2ZJ4), SIRT6 (PDB ID: 3K35) and Aldose reductase (PDB ID: 3G5E) associated with diabetes. Physicochemical, pharmacokinetic, and ADMET profiles were computed using online web servers Molinspiration, ADMETLAB 2.0, and SWISSADME. POA demonstrated superior binding affinity (in Kcal/mol) -8.0, -7.5, -8.9 and -9.5, respectively) compared to the widely used diabetic drug Metformin -5.4, -6.0, -5.4 and -7.2 with these receptor proteins. Based on molecular docking studies and pharmacokinetics/ADMET profiles, POA may act as a multi-targeted, less harmful, and more efficacious medication for Type 2 Diabetes Mellitus (T2DM) compared to Metformin.

Effect of Bushen Jianpi Recipe in Treating Patients with Type 2 Diabetes Mellitus Complicated with Dyslipidemia and Its Effect on Adiponectin / 广州中医药大学学报

Objective To investigate the clinical efficacy of Bushen Jianpi Recipe(mainly composed of Astragali Radix,Epimedii Folium,Dioscoreae Rhizoma,Salviae Miltiorrhizae Radix et Rhizoma,Cervi Cornus Colla,Astragali Complanati Semen,Polygoni Multiflori Radix Preparata,Polygonati Rhizoma,Puerariae Lobatae Radix,and Rhei Radix et Rhizoma)on patients with type 2 diabetes mellitus(T2DM)complicated with dyslipidemia and differentiated as spleen-kidney deficiency type,and to observe its effect on the level of adiponectin(ADP).Methods Ninety patients with T2DM complicated with dyslipidemia and differentiated as spleen-kidney deficiency type were randomly divided into western medicine group,Chinese medicine(CM)group,and combination of CM and western medicine group(hereinafter referred to as combination group),and each group had 30 patients.All of the 3 groups were given conventional hypoglycemic treatment.Moreover,the western medicine group was given oral use of Atorvastatin Calcium Tablets,CM group was given Bushen Jianpi Recipe,and the combination group was given Atorvastatin Calcium Tablets together with Bushen Jianpi Recipe orally.The course of treatment lasted for 8 weeks.The changes of traditional Chinese medicine(TCM)syndrome scores,glucose and lipid metabolism indexes,fasting insulin(FINS),insulin resistance index(HOMA-IR)and serum ADP levels of the three groups were observed before and after the treatment.After treatment,the efficacy of TCM syndrome of the three groups was evaluated.Results(1)After 8 weeks of treatment,the total effective rates for TCM syndrome efficacy in the western medicine group,CM group,and combination group were 66.67%(20/30),90.00%(27/30),and 93.33%(28/30),respectively.The intergroup comparison showed that the TCM syndrome efficacy of the CM group and the combination group was significantly superior to that of the western medicine group(P＜0.05).(2)After treatment,the TCM syndrome scores in all of the three groups were decreased compared with those before treatment(P＜0.01),and the decreases of the scores in both CM group and combination group was superior to that in the western medicine group(P＜0.05 or P＜0.01).(3)After treatment,the levels of lipid metabolism parameters of total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C),and low-density lipoprotein cholesterol(LDL-C)in the three groups were improved to various degrees compared with the pre-treatment levels,of which the levels of TC,TG,and LDL-C were significantly decreased,and the level of HDL-C was significantly increased in comparison with that before treatment,and the differences were statistically significant(P＜0.05 or P＜0.01).The intergroup comparison showed that the decrease of TC and LDL-C and the increase of HDL-C in the CM group were inferior to those in the western medicine group and the combination group(P＜0.05 or P＜0.01).(4)After treatment,the levels of glucose metabolism parameters of fasting plasma glucose(FPG),2-hour postprandial glucose(2hPG),glycated hemoglobin(HbA1c),FINS,and HOMA-IR in the CM group and the combination group were significantly decreased compared with those before treatment(P＜0.05 or P＜0.01),while only the levels of FPG,2hPG,and HOMA-IR in the western medicine group were decreased compared with those before treatment(P＜0.05 or P＜0.01).The intergroup comparison showed that the patients in the decrease of FPG,2hPG,HbA1c,FINS,and HOMA-IR levels in the CM group and the combination group was significantly superior to that in the western medicine group(P＜0.05 or P＜0.01).(5)In terms of adipokines,the serum ADP level in the three groups after treatment was significantly increased compared with that before treatment(P＜0.05 or P＜0.01),and the increase of serum ADP level in both CM group and combination group was significantly superior to that in the western medicine group(P＜0.05).Conclusion Bushen Jianpi Recipe has certain effect on regulating lipid metabolism,and has obvious advantages in improving clinical symptoms and insulin resistance,lowering blood glucose,and increasing ADP level in patients with T2DM complicated with dyslipidemia and differentiated as spleen-kidney deficiency type.

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.

Relationship between serum lncRNA XIST and SIRT1 levels with diabetic retinopathy and their diagnostic value / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To detect the expression levels of long non-coding RNA(lncRNA)X-inactive specific transcript(XIST)and silencing information regulatory factor 2 associated enzyme 1(SIRT1)in serum of patients with type 2 diabetes mellitus(T2DM), and to explore their correlation with diabetic retinopathy(DR)and their diagnostic value. METHODS: Prospective study. A total of 214 patients with T2DM admitted to our hospital from January 2022 to February 2023 were selected as the research subjects. Based on whether retinopathy occurred, they were divided into 126 cases(126 eyes)in the non-DR group and 88 cases(88 eyes)in the DR group. An additional 130 healthy individuals who underwent a physical examination during the same period were selected as the control group. The serum levels of lncRNA XIST and SIRT1 in the three groups were measured and compared. The relationship between lncRNA XIST and SIRT1 expression with DR was analyzed using Pearson's method. The receiver operating characteristic(ROC)curve was used to evaluate the predictive value of serum lncRNA XIST, SIRT1, and their combination for DR. Multivariate Logistic regression analysis was performed to investigate the factors affecting the occurrence of DR in T2DM patients.RESULTS: Compared with the control group, the levels of serum lncRNA XIST and SIRT1 in the non-DR group and DR group were successively decreased(all P<0.05). The levels of serum lncRNA XIST and SIRT1 were positively correlated in DR patients(r=0.639, P<0.05). ROC analysis showed that the area under the curve(AUC)for predicting DR by combining serum lncRNA XIST and SIRT1 was 0.940, which was higher than the AUC by serum lncRNA XIST and SIRT1 alone(0.855, 0.875). Logistic regression analysis showed that lncRNA XIST(OR=0.752)and SIRT1(OR=0.694)were influencing factors for the occurrence of DR(both P<0.01).CONCLUSION: The serum levels of lncRNA XIST and SIRT1 are both lower in DR patients, and the combination of lncRNA XIST and SIRT1 has a better assessment capacity for the occurrence of DR.

Metabolic basis of solute carrier transporters in treatment of type 2 diabetes mellitus

Solute carriers (SLCs) constitute the largest superfamily of membrane transporter proteins. These transporters, present in various SLC families, play a vital role in energy metabolism by facilitating the transport of diverse substances, including glucose, fatty acids, amino acids, nucleotides, and ions. They actively participate in the regulation of glucose metabolism at various steps, such as glucose uptake (e.g., SLC2A4/GLUT4), glucose reabsorption (e.g., SLC5A2/SGLT2), thermogenesis (e.g., SLC25A7/UCP-1), and ATP production (e.g., SLC25A4/ANT1 and SLC25A5/ANT2). The activities of these transporters contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). Notably, SLC5A2 has emerged as a valid drug target for T2DM due to its role in renal glucose reabsorption, leading to groundbreaking advancements in diabetes drug discovery. Alongside SLC5A2, multiple families of SLC transporters involved in the regulation of glucose homeostasis hold potential applications for T2DM therapy. SLCs also impact drug metabolism of diabetic medicines through gene polymorphisms, such as rosiglitazone (SLCO1B1/OATP1B1) and metformin (SLC22A1-3/OCT1-3 and SLC47A1, 2/MATE1, 2). By consolidating insights into the biological activities and clinical relevance of SLC transporters in T2DM, this review offers a comprehensive update on their roles in controlling glucose metabolism as potential drug targets.

Mechanism of Natural Plant Essential Oil in Intervention in Type 2 Diabetes Mellitus： A Review / 中国实验方剂学杂志

Type 2 diabetes mellitus （T2DM） is a heterogeneous disease with insulin deficiency and insulin resistance （IR） as the main etiology and is often accompanied by complications. Volatile oil is a volatile oily liquid extracted from natural plants， which has many pharmacological effects such as regulating Qi， relieving pain， inhibiting bacteria， and reducing inflammation. In recent years， there have been numerous reports on the treatment of T2DM by natural plant volatile oil and its effective components， which has become one of the new directions in the treatment of T2DM. With natural plant essential oil and its active components as the starting point， this paper comprehensively analyzed and summarized the material basis， mechanism， and signaling pathways of essential oil in the treatment of T2DM and its complications in China and abroad in recent years， and focused on the inhibitory effect of essential oil and its active components， such as carvacrol， paeonol， and β-caryophylene， on IR to improve T2DM by protecting pancreatic β-cells， inhibiting α-glucosidase activity， regulating the abundance and diversity of intestinal microbiota， and regulating glucose transporter protein type4 （GLUT4）， adenylate 5′-monophosphate-activated protein kinase （AMPK）， phosphatidylinositol-3 kinase （PI3K）/protein kinase B （Akt） signaling pathways to provide some references for the volatile oil intervention in T2DM and the development of new green antidiabetic drugs.

Research progress in correlation between insulin-like growth factor 2 mRNA binding protein 2 gene and type 2 diabetes mellitus / 中国生物制品学杂志

@#Type 2 diabetes mellitus(T2DM)was a chronic,non-communicable disease with a combination of multiple genetic and environmental factors,of which the main characteristics included insufficient insulin secretion and insulin resistance.Insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2/IMP2),an important insulin secretion-related protein in human body,is mainly expressed in tissues and cells such as pancreas,fat and intestine.It has been confirmed that IGF2BP2 can down-regulate the expression of IGF2 and the function damage of the related islet β cell is an important cause of T2DM and vascular complications.Therefore,IGF2BP2 gene can be used as an important predictor for diabetes mellitus risk.This paper reviews the correlation between IGF2BP2 gene and T2DM.

Hypoglycemic effect of electroacupuncture at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus based on AMPK / 中国针灸

OBJECTIVE@#To observe the hypoglycemic effect of electroacupuncture (EA) at "Tianshu" (ST 25) combined with metformin on rats with type 2 diabetes mellitus (T2DM) as well as its effect on expression of adenosine monophosphate activated protein kinase (AMPK) in liver and pancreas.@*METHODS@#Thirty-six male SD rats were randomly divided into a blank group (6 rats) and a model establishing group (30 rats). The rats in the model establishing group were fed with high-fat diet and treated with intraperitoneal injection of low-dose streptozotocin (STZ) to establish T2DM model. The rats with successful model establishment were randomly divided into a model group, a control group, a metformin group, an EA group and a combination group, 6 rats in each group. The rats in the EA group were treated with EA at "Tianshu" (ST 25), dense-disperse wave, 2 Hz/15 Hz in frequency and 2 mA in current intensity, 20 min each time. The rats in the metformin group were treated with intragastric administration of metformin (190 mg/kg) dissolved in 0.9% sodium chloride solution (2 mL/kg). The rats in the combination group were treated with EA at "Tianshu" (ST 25) and intragastric administration of metformin. The rats in the control group were treated with intragastric administration of 0.9% sodium chloride solution with the same dose. All the treatments were given once a day for 5 weeks. After the intervention, the body mass and random blood glucose were detected; the serum insulin level was detected by ELISA; the expression of AMPK and phosphorylated adenosine monophosphate activated protein kinase (p-AMPK) in liver and pancreas was detected by Western blot method; the expression of protein gene product 9.5 (PGP9.5) was detected by immunofluorescence.@*RESULTS@#①Compared with the blank group, the body mass in the model group was decreased (P<0.05); compared with the model group, the body mass in the EA group and the combination group was decreased (P<0.05); the body mass in the EA group and the combination group was lower than the metformin group (P<0.05). Compared with the blank group, the random blood glucose in the model group was increased (P<0.01); compared with the model group, the random blood glucose in the metformin group, the EA group and the combination group was decreased (P<0.01). The random blood glucose in the combination group was lower than the metformin group and the EA group (P<0.05). ②Compared with the blank group, the insulin level in the model group was decreased (P<0.05); compared with the model group, the insulin level in the metformin group, the EA group and the combination group was all increased (P<0.05). The insulin level in the combination group was higher than the metformin group and the EA group (P<0.05). ③Compared with the blank group, the protein expression of AMPK and p-AMPK in liver tissue was decreased (P<0.05), and the protein expression of AMPK and p-AMPK in pancreatic tissue was increased (P<0.05) in the model group. Compared with the model group, the protein expression of AMPK and p-AMPK in liver tissue in the metformin group, the EA group and the combination group was increased (P<0.05, P<0.01); the protein expression of AMPK in pancreatic tissue in the metformin group was increased (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was decreased (P<0.05); the protein expression of p-AMPK in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05). The protein expression of AMPK and p-AMPK in liver tissue in the combination group was higher than that in the metformin group and the EA group (P<0.05); the protein expression of AMPK in pancreatic tissue in the EA group and the combination group was less than that in the metformin group (P<0.05), and the expression of p-AMPK protein in pancreatic tissue in the combination group was less than that in the metformin group and the EA group (P<0.05). ④Compared with the blank group, the expression of PGP9.5 in pancreatic tissue in the model group was increased (P<0.01); compared with the model group, the expression of PGP9.5 in pancreatic tissue in the metformin group, the EA group and the combination group was decreased (P<0.05, P<0.01). The expression of PGP9.5 in pancreatic tissue in the EA group was lower than the metformin group and the combination group (P<0.05).@*CONCLUSION@#Electroacupuncture at "Tianshu" (ST 25) could promote the effect of metformin on activating AMPK in liver tissue of T2DM rats, improve the negative effect of metformin on AMPK in pancreatic tissue, and enhance the hypoglycemic effect of metformin. The mechanism may be related to the inhibition of pancreatic intrinsic nervous system.

Effect of Dendrobii Caulis Mixture on Cell Inflammatory Response and Apoptosis in Diabetic Rats with Nonalcoholic Fatty Liver Disease Based on NF-κB/NLRP3/IL-1β Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect of Dendrobii Caulis mixture on cell inflammatory response and apoptosis in diabetic rat with non-alcoholic fatty liver disease（NAFLD） and its possible mechanism. MethodForty male SD rats were randomly divided into blank group and model group of type 2 diabetes mellitus（T2DM） with NAFLD according to body weight. The model was established by high-sugar and high-fat diet combined with intraperitoneal injection of streptozotocin（STZ）， which was randomly divided into the model group， Dendrobii Caulis mixture group（16.67 g·kg-1·d-1） and metformin group（100 mg·kg-1·d-1） according to blood glucose and body weight， and 10 rats in each group. Rats in each group were administered by continuous gavage for 4 weeks， the blank and model groups were given saline by gavage at 10 mL·kg-1·d-1. Fasting blood glucose（FBG）， serum insulin（INS）， glycosylated serum protein（GSP）， triglyceride（TG）， total cholesterol（TC）， high density lipoprotein（HDL-C）， low density lipoprotein（LDL-C）， alanine aminotransferase（ALT） and aspartate aminotransferase（AST） were detected in each group of rats. The liver tissues of rats in each group were stained with hematoxylin-eosin（HE） to observe the pathological changes， and the positive expressions of nuclear transcription factor（NF）-κB， NOD-like receptor heat protein structural domain-related protein 3（NLRP3）， interleukin（IL）-1β and tumor necrosis factor（TNF）-α were observed by immunohistochemistry. Western blot and fluorescence quantitative polymerase chain reaction（Real-time PCR） were used to detect the protein and mRNA expression of B-cell lymphoma-2（Bcl-2）， Bcl-2 associated X protein（Bax）， Caspase-3 and NF-κB p65， NLRP3， IL-1β， TNF-α in liver tissue of rats in each group. ResultCompared with the blank group， FBG， GSP， TC， TG， LDL-C， AST and ALT levels were increased， INS and HDL-C levels were decreased， Bax， Caspase-3， NLRP3， IL-1β， TNF-α protein and mRNA expression were increased in model group， the ratio of p-NF-κB/NF-κB protein increased， the expression of Bcl-2 protein and mRNA decreased， and the positive immunohistochemical expression of NF-κB， NLRP3， IL-1β and TNF-α increased， and the differences were statistically significant（P<0.01）. The morphological structure of the liver was disrupted， and obvious fat vacuoles were seen. Compared with the model group， FBG， GSP， TC， TG， LDL-C， AST and ALT levels of Dendrobii Caulis mixture group and metformin group were decreased， INS and HDL-C levels were increased， and protein and mRNA expressions of Bax， Caspase-3， NLRP3， IL-1β and TNF-α were decreased， the protein ratio of p-NF-κB/NF-κB decreased， the expression of Bcl-2 protein and mRNA increased， and the positive immunohistochemical expressions of NF-κB， NLRP3， IL-1β and TNF-α decreased， and the differences were statistically significant（P<0.01）. The liver morphology and structure were relatively complete， and the fat vacuoles were reduced. ConclusionDendrobii Caulis mixture can inhibit cell apoptosis， reduce inflammatory response and alleviate liver injury in rats with T2DM and NAFLD， the mechanism may be related to inhibiting the activation of NF-κB pathway， blocking the activation of NLRP3 inflammatory vesicles， reducing IL-1β secretion， attenuating Caspase-3 activity and reducing the ratio of Bcl-2/Bax.

Cardioprotective of Saffron (Crocus sativus L.) treatment in patients with type 2 diabetes mellitus: a systematic review and meta-analysis / 数字中医药（英文）

Objective@#To investigate the cardioprotective effect of Saffron (Crocus sativus L.) treatment as a potential supplement on patients with type 2 diabetes mellitus (T2DM).@*Methods@#Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied to analyze articles retrieved from PubMed, ScienceDirect, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), and China Biology Medicine (CBM) with a publication time span from January 15, 2015 to March 20, 2023. The articles were published in English only, including randomized controlled trials (RCTs) on adult patients who were diagnosed with T2DM, and received either Saffron or placebo treatment. Meta-analysis was performed using Review Manager 5.4 software. The present study was registered on the International Prospective Register of Systematic Reviews (PROSPERO) with a registration number as CRD42023443180.@*Results@#Seven RCTs with 455 patients were included in the study. The data revealed that Saffron treatment significantly reduced tumor necrosis factor (TNF)-α (P = 0.008) and fasting blood glucose (FBG) (P = 0.04) levels compared with what placebo did in T2DM patients. No significant differences were shown in the levels of interleukin (IL)-6, malondialdehyde (MDA), high serum C-reactive protein (hs-CRP), lipid profile, blood pressure, and body mass index (BMI) between Saffron and placebo ( P > 0.05) .@*Conclusion@#Saffron treatment has a cardioprotective effect in T2DM patients by reducing TNF-α and FBG levels. However, the potential anti-oxidant, anti-hypertensive, and anti-dyslipidaemia effects of the phytochemical need to be further investigated.

Mori Folium Improves Glucose and Lipid Metabolism Disorders in Rats with Type 2 Diabetes Mellitus by Regulating PI3K/Akt/PPARα/CPT-1 Pathway / 中国实验方剂学杂志

ObjectiveTo investigate the effect and mechanism of Mori Folium extract on the glucose and lipid metabolism disorders in the liver of rats with type 2 diabetes mellitus （T2DM） through the phosphatidylinositol 3-kinase/protein kinase B/peroxisome proliferation-activated receptor α/carnitine palmitoyl transferase-1 （PI3K/Akt/PPARα/CPT-1） signaling pathway. MethodThe T2DM model was induced by the high-fat diet combined with the intraperitoneal injection of streptozotocin （STZ）. The model rats were randomly divided into a model group， a metformin （0.2 g·kg-1） group， and a Mori Folium water extract （4.0 g·kg-1） group according to blood glucose and body weight. In the 8-week administration， fasting blood glucose was measured at the same time every week. The histomorphological and fat changes in the rat liver were observed by hematoxylin-eosin （HE） staining and oil red O staining. The levels of total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， alanine aminotransferase （ALT）， and aspartate aminotransferase （AST） in the serum were measured by biochemical methods. Western blot （WB） was used to quantitatively detect the protein expression of p-PI3K，PI3K，p-Akt，Akt，PPARα，and CPT-1 in the rat liver. ResultAfter 8-week administration， the blood glucose of rats was higher in the model group than that in the control group （P<0.01）， and lower in the Mori Folium water extract group than that in the model group （P<0.01）. The results of HE staining showed that the liver tissue structure of the control group was complete， and the hepatocytes were arranged radially around the central vein， while the hepatocyte injury in the model group was obvious. Compared with the model group， the Mori Folium water extract group showed improved vacuolar degeneration and no lesions such as small bile duct hyperplasia. Oil red O staining showed that there was no obvious steatosis and necrosis in the hepatocytes of rats in the control group， and no lipid droplets in the hepatocytes were observed， while the model group showed increased lipid droplets. Mori Folium significantly reduced the lipid droplets in the liver. Biochemical analysis showed that the levels of TC， TG， LDL-C， AST， and ALT in the model group were significantly higher than those in control group （P<0.01）. The levels of TC， TG， LDL-C， AST， and ALT in the Mori Folium water extract group were significantly lower than those in the model group （P<0.05，P<0.01）. WB showed that the protein expression of p-PI3K/PI3K， p-Akt/Akt， PPARα， and CPT-1 in the model group were lower than those in the control group （P<0.01）. Mori Folium water extract could increase the protein expression of p-PI3K/PI3K， p-Akt/Akt， PPARα， and CPT-1 （P<0.05 or P<0.01）. ConclusionThe hypoglycemic mechanism of Mori Folium water extract may be related to the regulation of the PI3K/Akt/PPARα/CPT-1 signaling pathway.

Regulatory Effect of Herbal Pair Astragali Radix-Puerariae Lobatae Radix on PI3K/Akt/FoxO1 Signaling Pathway in Rats with T2DM Based on Network Pharmacology / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of herbal pair Astragali Radix-Puerariae Lobatae Radix （AR-PLR） against type 2 diabetes mellitus （T2DM） based on network pharmacology and experimental verification. MethodThe active ingredients and targets of AR and PLR were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）. The related targets of T2DM were retrieved from disease databases and the common targets of drugs and diseases were extracted. The protein-protein interaction （PPI） network was analyzed and constructed by STRING and the network topology of key targets was analyzed by Cytoscape 3.7.1. Then gene ontology（GO） and Kyoto encyclopedia of genes and genomes（KEGG） enrichment analyses of core targets were carried out by DAVID to explore its possible molecular mechanism. The T2DM model was induced in rats by the high-fat diet combined with tail intravenous injection of streptozocin. The rats were divided into a normal group，a model group，a metformin group，and high-，medium- and low-dose AR-PLR groups. After four weeks of intragastric administration，the serum levels of fasting blood sugar （FBS），fasting insulin（FINS），aspartate aminotransferase（AST），alanine aminotransferase（ALT），triglyceride（TG），total cholesterol（TC），low-density lipoprotein cholesterin（LDL-C），high-density lipoprotein cholesterin （HDL-C），interleukin-6（IL-6）， and tumor necrosis factor-α（TNF-α） of rats in each group were measured. The protein expression of insulin receptor substrate-2（IRS-2），phosphatidylinositol 3-kinase（PI3K），protein kinase B（Akt）， and forkhead box transcription factor O1（FoxO1） in rat liver was detected by Western blot. ResultA total of 131 core targets of AR-PLR in the treatment of T2DM were screened out by network pharmacology， where Akt1，mitogen-activated protein kinase 1 （MAPK1），TNF-α，and IL-6 were critical. As revealed by KEGG enrichment analysis， AR-PLR exerted the hypoglycemic effect mainly through the PI3K/Akt，TNF， and FoxO signaling pathways. Compared with the model group，the high- and medium-dose AR-PLR groups showed reduced FBS and FINS levels and increased glycogen level （P<0.05，P<0.01），all the AR-PLR groups showed decreased levels of AST，ALT，TG， and LDL-C （P<0.05，P<0.01）， the high- and low-dose AR-PLR groups showed decreased TC levels （P<0.05）. Compared with the model group， the high- and medium-dose AR-PLR groups showed reduced levels of IL-6 and TNF-α（P<0.05，P<0.01）， and the high-dose AR-PLR group showed increased expression of IRS-2， Akt， p-Akt， PI3K， and p-PI3K， and decreased expression of FoxO1 protein（P<0.05）. ConclusionAR-PLR has the characteristics of multi-component，Multi-target and multi-pathway in the treatment of T2DM. This herbal pair may regulate the PI3K/Akt/FoxO1 signaling pathway through IL-6， TNF-α， and other targets to affect insulin resistance， glycogen synthesis， gluconeogenesis， glucose transport， inflammation， immune response， and other processes， thereby treating T2DM.

Ameliorative Effect of miR-31 on Liver Injury in Type 2 Diabetic Mice / 中国生物化学与分子生物学报

Type 2 diabetes mellitus (T2DM) is a metabolic disease with an increasing incidence worldwide, which leads to damage to various tissues and organs including the liver. MiR-31 is conserved across species and closely associated with metabolic diseases, but its role in type 2 diabetic liver injury has not been elucidated. This study aimed to investigate the effect of miR-31 on liver injury in type 2 diabetes and its underlying mechanism. Four to six weeks old male FVB mice and miR-31-positive transgenic mice were randomly divided into FVB mice control group (C), FVB mice induced diabetes group (DM) and miR-31-overexpression transgenic mice induced diabetes group (31DM). After 1 week of adaptive feeding, the T2DM mouse model was induced by high-fat feeding combined with intraperitoneal injection of streptozotocin (STZ) for 6 weeks. The general condition of mice and related metabolic indicators showed that the increased food and water intake, weight loss and glucose and lipid metabolism disorders could be reversed by miR-31 in T2DM mice. HE staining and liver histological activity index (HAI) scoring results showed that miR-31 improved the inflammatory status in the liver tissue of T2DM mice and decreased the HAI score. RT-qPCR results showed that the high expression of miR-31 was accompanied by a decrease in the expression of activating transcription factor 6 (ATF6) mRNA in the liver of T2DM mice. Furthermore, Western blotting results showed that miR-31 inhibited the expression of endoplasmic reticulum stress-related proteins such as ATF6, glucoregulatory protein 78 (GRP78) and C/EBP homologous protein (CHOP) in the liver of T2DM mice. In conclusion, miR-31 may ameliorate liver injury in T2DM mice by regulating glucose and lipid metabolism disorders and insulin resistance, and inhibiting endoplasmic reticulum stress factors such as ATF6, GRP78, and CHOP.

Profile of pharmaceutical interventions of a pharmacotherapeutic follow-up model for diabetic patients in a community pharmacy

Abstract The insertion of Pharmaceutical Care in Primary Health Care (PHC) improves patients' clinical outcomes and quality of life. Pharmacotherapeutic follow-up can contribute to the management of chronic diseases such as diabetes, promoting better glycemic control and adherence to therapy. This study aimed to assess the Drug-therapy Problems (DTPs) and Pharmacist Interventions (PIs) on the pharmacotherapeutic management in patients with type 2 diabetes mellitus (T2DM) in a community pharmacy. A quantitative, retrospective, and cross-sectional study was conducted in a Pharmaceutical Care Program within the PHC in Juiz de Fora (Minas Gerais, Brazil). Inclusion criteria were patients with T2DM above 18, who attended at least three pharmaceutical consultations between July 2016 and October 2018 and presented two or more glycated hemoglobin tests. The study group (n = 17) was largely composed of women (65%), elderly (76%), sedentary (72%), and obese people (52%). The resolution was achieved in 79% of the DTPs identified (n = 115). Most of DTPs were related to administration and adherence to pharmacotherapy (46%). 60% of the 437 PIs involved the provision of information and counseling. In other words, accessible interventions lead to high resolvability. Therefore, clinical actuation of pharmacists could improve the prognosis in diabetes treatment

Effect of Yinchenhao Tang on Type 2 Diabetes Mellitus Complicated with Non-alcoholic Fatty Liver Disease in MKR Mice / 中国实验方剂学杂志

Objective:To investigate the action mechanism of Yinchenhao Tang against type 2 diabetes mellitus （T2DM） complicated with non-alcoholic fatty liver disease （NAFLD） in MKR mice. Method:Forty eight-week-old MKR mice were fed a high-fat diet for eight weeks and then divided into the model group，original Yinchenhao Tang （17.16 g·kg^-1） group，Yinchenhao Tang group at a specified dose （4.68 g·kg^-1） in teaching materials，and positive drug ［metformin + simvastatin， （65+2.6）×10^-3 g·kg^-1］ group. Another 10 MKR mice of the same age were classified into the blank group and 10 FVB mice into the normal group. After eight weeks of intragastric administration in each group，the liver wet weight，oral glucose tolerance test （OGTT），serum inflammatory factors interleukin-6 （IL-6） and tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>），and changes in blood lipid and liver function were determined. Hematoxylin-eosin （HE） staining was conducted for observing the morphological changes in liver tissue under a transmission electron microscope，followed by the detection of Toll-like receptor 4 （TLR4），myeloid differentiation factor 88 （MyD88），and nuclear transcription factor-<italic>κ</italic>B （NF-<italic>κ</italic>B） protein expression by Western blot. Result:Compared with the model group，the medication groups exhibited significantly reduced liver wet weight index （<italic>P</italic><0.01），improved OGTT result （<italic>P</italic><0.05），and down-regulated serum IL-6 and TNF-<italic>α</italic> levels （<italic>P</italic><0.01）. In terms of morphological changes，Yinchenhao Tang protected the hepatocyte structure and alleviated hepatocyte steatosis. Moreover， Yinchenhao Tang obviously down-regulated the protein expression levels of TLR4，MyD88，and NF-<italic>κ</italic>B in liver tissue of MKR mice with T2DM combined with NAFLD （<italic>P</italic><0.05），and the down-regulation of TLR4 and NF-<italic>κ</italic>B in the original Yinchenhao Tang group was better than that in the Yinchenhao Tang group at a specified dose in teaching materials （<italic>P</italic><0.05）. Conclusion:Yinchenhao Tang is able to reduce inflammatory factor levels and down-regulate TLR4，MyD88，and NF-<italic>κ</italic>B expression in liver tissue to relieve the pathological liver injury and interfere with T2DM combined with NAFLD of MKR mice. It exerts a certain liver-protective effect by lowering the blood lipids and delaying the hepatic inflammation.

Effect of Zhenzhu Tiaozhi Capsule on HbA1c in Patient with Type 2 Diabetes Mellitus： A Real-world Study / 中国实验方剂学杂志

Objective:To explore the long-term effect of Zhenzhu Tiaozhi capsule（FTZ） on hemoglobin A1c（HbA1c）in patients with type 2 diabetes mellitus （T2DM） based on real-world data. Method:T2DM patients who were provided with FTZ （FTZ group） and those receiving conventional hypoglycemic drugs （control group） were extracted from the hospital information system （HIS） of the First Affiliated Hospital of Guangdong Pharmaceutical University， followed by propensity score matching （PSM） for balancing the confounding factors between groups. With HbA1c as the efficacy evaluation index， the difference in efficacy between the two groups was compared using <italic>t</italic>-test and <italic>χ</italic>² test. For repeated measurement data of the same patient， the difference in efficacy and the stability of FTZ against HbA1c were analyzed by generalized estimating equation （GEE）. The factors that might affect the efficacy of FTZ against HbA1c were subjected to multivariate linear regression analysis （MLRA）， and the subgroup analyses were then conducted after the stratification of relevant factors. Result:There were 46 patients included in the FTZ group and 1 208 patients in the control group. PSM yielded 42 pairs of samples with balanced covariates between groups. As revealed by one-year observation， ① HbA1c in the FTZ group after treatment was 6.51%±1.09%. No significant difference was observed either in pre- and post-treatment comparison in the FTZ group or in its comparison with the control group. At the same time， the HbA1c compliance rate in the FTZ group was 73.8% after treatment. No significant difference was observed either in pre- and post-treatment comparison in the FTZ group or in its comparison with the control group. ② The GEE results showed that the post-treatment HbA1c levels in the two groups were not significantly different from each other. Moreover， the HbA1c level remained stable over treatment time. ③ MLRA and subgroup analyses results demonstrated that FTZ was more effective in patients with high baseline HbA1c ［<italic>β</italic>=-0.530，95% confidence interval（CI） -0.850～-0.209，<italic>P</italic><0.01］ or those who were complicated with hypertension （<italic>β</italic>=-0.918，95%CI -1.614～-0.222，<italic>P</italic><0.05）. Conclusion:In the real world， FTZ is able to control the blood sugar， and its effect is similar to those of conventional hypoglycemic drugs. Besides， it is capable of stabilizing the blood sugar for a long time.

Effect of Compatibility of Anemarrhenae Rhizoma-Phellodendri Chinensis Cortex Couplet Medicines on Glucolipid Metabolism in Type 2 Diabetic Rats Before and After Salt-processing / 中国实验方剂学杂志

Objective:To investigate the effect of compatibility of Anemarrhenae Rhizoma-Phellodendri Chinensis Cortex couplet medicines on glucolipid metabolism in type 2 diabetic rats before and after salt-processing. Method:The type 2 diabetic rat model was induced by high-fat and high-glucose diet combined with low dose streptozotocin （STZ）， the model rats were randomly divided into six groups， including the model group， metformin group （200 mg·kg^-1）， and different compatibility groups of raw and salt-processed of Anemarrhenae Rhizoma and Phellodendri Chinensis Cortex （6.48 g·kg^-1）. In addition， The same week old rats fed with normal diet were set as the blank group. After 30 d of continuous intragastric administration， changes of fasting blood glucose （FBG）， fasting serum insulin （FINS）， glycosylated serum protein （GSP）， hepatic glycogen， blood lipid ［total cholesterol （TC）， triglyceride （TG）， low density lipoprotein cholesterol （LDL-C）， high density lipoprotein cholesterol （HDL-C）］， nonesterified fatty acid （NEFA）， adipocytokines ［adiponectin （ADP） and leptin）］， kidney function ［blood urea nitrogen （BUN） and creatinine （CRE）］ and other indicators of rats from different groups were detected， and the insulin sensitivity index （ISI） and insulin resistance index （HOMA-IR） were calculated， hematoxylin-eosin （HE） staining was used to observe the morphological changes of pancreas， liver and kidney of rats from different groups. Result:Compared with the model group， compatibility of Anemarrhenae Rhizoma-Phellodendri Chinensis Cortex couplet medicines before and after salt-processing all could decrease the levels of FBG， GSP， TC， TG， LDL-C， NEFA， leptin， BUN， CRE and HOMA-IR， and increase the contents of FINS， HDL-C， ADP， hepatic glycogen and ISI， among which the compatibility of salt-processed Anemarrhenae Rhizoma and salt-processed Phellodendri Chinensis Cortex had the most significant effect on regulating glucolipid metabolism in type 2 diabetic rats. The compatibility of all couplet medicines could improve the histopathological changes of pancreas， liver and kidney in type 2 diabetic rats， among which the compatibility of salt-processed Anemarrhenae Rhizoma and salt-processed Phellodendri Chinensis Cortex had the most prominent effect on repairing pathological damage. Conclusion:The compatibility of Anemarrhenae Rhizoma and Phellodendri Chinensis Cortex before and after salt-processing can improve glucolipid metabolism in type 2 diabetic rats， while the comprehensive effect of salt-processed Anemarrhenae Rhizoma and salt-processed Phellodendri Chinensis Cortex<italic> </italic>on lowering glucose and regulating lipid is the best.

Research on related factors for hypoglycemic episodes in patients with type 2 diabetes mellitus based on continuous glucose monitoring system / 复旦学报（医学版）

Objective To identify related factors for hypoglycemic episodes in patients with type 2 diabetes mellitus(T2DM)through continuous glucose monitoring(CGM). Methods The included 147 patients with T2DM were those who had undergone CGM for 5 days in our ward of Department of Endocrinology and Metabolism,Huashan Hospital from Dec 2018 to Oct 2019. The general information, laboratory parameters and CGM parameters of the patients were collected. According to whether there wasan episode of hypoglycemia during the monitoring period,the patients were divided into non-hypoglycemia group and hypoglycemic group. A single hypoglycemia episode was defined as a sensor monitoring blood glucose of less than 3.9 mmol/L and lasting for more than 15 minutes.CGM parameters included the mean blood glucose(MBG),standard deviation(SD),coefficient of variation(CV),the differences between maximum and minimum blood glucose (BG) levels (ΔBG),mean amplitude of glycemic excursions (MAGE)and the percentage of time in range(％TIR)of BG at <3.9 mmol/L,3.9-7.8 mmol/L,>7.8 mmol/L,3.9-10.0 mmol/L,and >10.0 mmol/L. Results Logistic regression analysis showed that lower estimated glomerular filtration rate(eGFR)levels,increased use of insulin and its analogs and lower MBG levels were associated with hypoglycemic episodes. Spearman correlation analysis showed that the MBG level and the ％TIR of BG>7.8 mmol/L and BG>10.0 mmol/L were negatively associated while glycemic variability(GV)levels(SD,CV,ΔBG,MAGE)and ％ TIR of BG at 3.9-7.8 mmol/L were positively associated with hypoglycemic episodes. Pearson correlation analysis showed that the duration of hypoglycemic episodes was positively correlated with the use of sulfonylureas and CV levels. Conclusion Lower eGFR levels,increased treatment with insulin and its analogs and lower MBG levels were related factors for hypoglycemic episodes in patients with T2DM.

Diabetic Knowledge of T2DM Patients in Hospital Pakar Sultanah Fatimah, Muar, Johor, Malaysia

@#Introduction: Diabetic knowledge is one of the limiting factors in optimizing treatment for diabetic patients. Despite educational programs carried out by healthcare practitioners, most diabetic patients are not managing their diabetes well. Thus, this study aimed to determine the level of patients’ diabetic knowledge in Hospital Pakar Sultanah Fatimah and factors affecting it. Methods: A cross-sectional study was conducted among Type 2 Diabetic Mellitus (T2DM) patients in Hospital Pakar Sultanah Fatimah using the 14-item Michigan Diabetes Knowledge Test (MDKT) validated questionnaire. The questionnaires were self-administered by patients during their scheduled appointments at outpatient pharmacy and Medical Outpatient Clinic (MOPC). Descriptive statistics were used to summarize patients’ demographics, socioeconomic status and knowledge scores; while non-parametric tests were used to analyze the relationship between diabetic knowledge with patient demography and socioeconomic status. Results: There were a total of 262 respondents with median (IQR) age of 59(13.5) years. Majority of the patients were Malay, retiree/ unemployed and have household income less than RM3000. 66.4% of patients scored ≥7 points in MDKT-14. Race, household income and educational levels were significantly associated with knowledge scores (p=0.003, p=0.027 and p<0.001 respectively). A multivariate analysis was conducted and found that race and education level were significantly predictive of knowledge score with adjusted R2 =0.28. Conclusion: The respondents’ diabetic knowledge was moderate. By identifying the income, race and educational level as the contributing factors of patient’s poor diabetic knowledge score, we may target these areas to improve patients’ medication adherence and hence treatment outcome.

Serum mir-195-5p exhibits clinical significance in the diagnosis of essential hypertension with type 2 diabetes

OBJECTIVES: Diagnosis and management of essential hypertension (EH) or type 2 diabetes mellitus (T2DM) by combining comprehensive treatment and classificatory diagnosis have been continuously improved. However, understanding the pathogenesis of EH patients with concomitant T2DM and subsequent treatment remain the major challenges owing to the lack of non-invasive biomarkers and information regarding the underlying mechanisms. METHODS: Herein, we collected 200 serum samples from EH and/or T2DM patients and healthy donors (N). Gene-expression profiling was conducted to identify candidate microRNAs with clinical significance. Then, a larger cohort of the aforementioned patients and 50 N were used to identify the correlation between the tumor suppressor miR-195-5p and EH and/or T2DM. The dual-luciferase reporter assay was used to explore the target genes of miR-195-5p. The suppressive effects of miR-195-5p on the 3′-UTR of the dopamine receptor D1 (DRD1) transcript in EH patients with concomitant T2DM were verified as well. RESULTS: Compared with that in other groups, serum miR-195-5p was highly downregulated in EH patients with concomitant T2DM. miR-195-5p overexpression efficiently suppressed DRD1 expression by binding to the two 3′-UTRs. Additionally, two single nucleotide polymorphisms, including 231T-A and 233C-G, in the miR-195-5p binding sites of the DRD1 3′-UTR were further identified. Collectively, we identified the potential clinical significance of DRD1 regulation by miR-195-5p in EH patients with concomitant T2DM. CONCLUSIONS: Our data suggested that miR-195-5p circulating in the peripheral blood served as a novel biomarker and therapeutic target for EH and T2DM, which could eventually help address major challenges during the diagnosis and treatment of EH and T2DM.