Potential application of Nardostachyos Radix et Rhizoma-Rhubarb for the treatment of diabetic kidney disease based on network pharmacology and cell culture experimental verification

BACKGROUND Diabetic kidney disease(DKD)is one of the serious complications of diabetes mellitus,and the existing treatments cannot meet the needs of today's patients.Traditional Chinese medicine has been validated for its efficacy in DKD after many years of clinical application.However,the specific mechanism by which it works is still unclear.Elucidating the molecular mechanism of the Nardostachyos Radix et Rhizoma-rhubarb drug pair(NRDP)for the treatment of DKD will provide a new way of thinking for the research and development of new drugs.AIM To investigate the mechanism of the NRDP in DKD by network pharmacology combined with molecular docking,and then verify the initial findings by in vitro experiments.METHODS The Traditional Chinese Medicine Systems Pharmacology(TCMSP)database was used to screen active ingredient targets of NRDP.Targets for DKD were obtained based on the Genecards,OMIM,and TTD databases.The VENNY 2.1 database was used to obtain DKD and NRDP intersection targets and their Venn diagram,and Cytoscape 3.9.0 was used to build a"drug-component-target-disease"network.The String database was used to construct protein interaction networks.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis and Gene Ontology analysis were performed based on the DAVID database.After selecting the targets and the active ingredients,Autodock software was used to perform molecular docking.In experimental validation using renal tubular epithelial cells(TCMK-1),we used the Cell Counting Kit-8 assay to detect the effect of NRDP on cell viability,with glucose solution used to mimic a hyperglycemic environment.Flow cytometry was used to detect the cell cycle progression and apoptosis.Western blot was used to detect the protein expression of STAT3,p-STAT3,BAX,BCL-2,Caspase9,and Caspase3.RESULTS A total of 10 active ingredients and 85 targets with 111 disease-related signaling pathways were obtained for NRDP.Enrichment analysis of KEGG pathways was performed to determine advanced glycation end products(AGEs)-receptor for AGEs(RAGE)signaling as the core pathway.Molecular docking showed good binding between each active ingredient and its core targets.In vitro experiments showed that NRDP inhibited the viability of TCMK-1 cells,blocked cell cycle progression in the G0/G1 phase,and reduced apoptosis in a concentrationdependent manner.Based on the results of Western blot analysis,NRDP differentially downregulated p-STAT3,BAX,Caspase3,and Caspase9 protein levels(P<0.01 or P<0.05).In addition,BAX/BCL-2 and p-STAT3/STAT3 ratios were reduced,while BCL-2 and STAT3 protein expression was upregulated(P<0.01).CONCLUSION NRDP may upregulate BCL-2 and STAT3 protein expression,and downregulate BAX,Caspase3,and Caspase9 protein expression,thus activating the AGE-RAGE signaling pathway,inhibiting the vitality of TCMK-1 cells,reducing their apoptosis.and arresting them in the G0/G1 phase to protect them from damage by high glucose.

STUDY ON THE THERAPEUTIC EFFECT AND MECHANISMS OF AURICULAR ACUPUNCTURE FOR TREATMENT OF EXPERIMENTAL DIABETES MELLITUS IN THE RABBIT

In the present study, fasting blood glucose (FBG) concentration and serum insulin concentration and changes of the ultramicrostructure of the pancreatic islet cells are used as the indexes to evaluate the therapeutic effect of auricular acupuncture in the treatment of experimental diabetes mellitus (DM) and to analyze its mechanisms in the rabbit. Thirty-two rabbits are randomly divided into control, model, acupuncture and medication groups with 8 cases being in each group. DM model is established by intravenous injection of 4% Alloxan (150 mg/kg). Otopoints used are low-resistance points of Yidan (MA-SC 6), Neifenmi (MA-IC 3), Jiaogan (MA-AH 7), Fei (MA-IC 1), Wei (MA-IC), Shen (MA-SC), etc.. In medication group, the animals are fed with glybenzcyclamide, (1.25 mg/kg/day). The treatment of both groups is given once daily, 20 sessions altogether. Results display that after 2 courses of treatment (20 sessions), in comparison with pre-treatment and model group, FBG contents in acupuncture and medication groups decreased significantly (P<0.01), while insulin contents of acupuncture and medication groups increased remarkably (P<0.05). No significant differences between acupuncture and medication groups in FBG and insulin contents. Accordingly, electron microscopic observation shows some improvements in partial organells as lysosome being fewer, reduction of the nucleolar swelling, etc. in both acupuncture group and medication group. It shows that restoration of the structure of islet β-cells of the pancreas, increase of the synthesis and release of insulin as well as the activity of insulin may contribute to the effect of auricular acupuncture in lowering blood glucose level in DM rabbits.

Progress in experimental models to investigate the in vivo and in vitro antidiabetic activity of drugs

Diabetes mellitus is one of the world's most prevalent and complex metabolic disorders,and it is a rapidly growing global public health issue.It is characterized by hyperglycemia,a condition involving a high blood glucose level brought on by deficiencies in insulin secretion,decreased activity of insulin,or both.Prolonged effects of diabetes include cardiovascular problems,retinopathy,neuropathy,nephropathy,and vascular alterations in both macro-and micro-blood vessels.In vivo and in vitro models have always been important for investigating and characterizing disease pathogenesis,identifying targets,and reviewing novel treatment options and medications.Fully understanding these models is crucial for the researchers so this review summarizes the different experimental in vivo and in vitro model options used to study diabetes and its consequences.The most popular in vivo studies involves the small animal models,such as rodent models,chemically induced diabetogens like streptozotocin and alloxan,and the possibility of deleting or overexpressing a specific gene by knockout and transgenic technologies on these animals.Other models include virally induced models,diet/nutrition induced diabetic animals,surgically induced models or pancreatectomy models,and non-obese models.Large animals or non-rodent models like porcine(pig),canine(dog),nonhuman primate,and Zebrafish models are also outlined.The in vitro models discussed are murine and human beta-cell lines and pancreatic islets,human stem cells,and organoid cultures.The other enzymatic in vitro tests to assess diabetes include assay of amylase inhibition and inhibition ofα-glucosidase activity.

Effects of Diabetes Education on Emotional Distress in Patients with Type 2 Diabetes—An Experimental Study

Objective: It was to evaluate the effect of diabetes education on emotional distress in type 2 diabetes patients treated with oral medications. Methods: The experimental study took place in Albania and overall, 200 type 2 diabetes patients were enrolled (in both groups, intervention, and control) treated with oral medications, having levels of Glycated hemoglobin HbA1c > 6.5% as well the absence of associated diseases such as dementia and psychiatric disorders. Patients were randomly selected from the medical registry of family physicians in the Tirana region. Patients were screened for the emotional distress before and after the intervention with the self-administered questionnaire Problem Areas in Diabetes PAID 5. In addition, the levels of HbA1c in % were evaluated before and after intervention in both groups. Only intervention group underwent four diabetes education sessions offered by trained nursing staff while the control group continued the previous regime. The questionnaire reliability analysis was estimated by the Cronbach alpha coefficient. To compare the groups the t-test was used and the value of p Results: Mean age of patients in intervention and control group was respectively 54.03 ±9.57 and 55.82 ± 7.86. Before and after health education PAID 5 scores for the intervention group were respectively 11.3 vs. 8.75 while for the control group 11.9 vs. 11.35, p = 0.018. Levels of HbA1c% before and after education for the intervention group were 7.02 vs. 6.2 while for the control group 6.9 vs. 6.8, p = 0.001. Positive and significant correlation (r = 0.321, p = 0.001) was between level of emotional distress and the age of the patients. Conclusions: The study found that besides better control of diabetes, additional education of diabetic patients seemed to significantly improve the level of emotional distress due to diabetes in diabetic patients.

Comparison of the effect of intravitreal bevacizumab and intravitreal fasudil on retinal VEGF,TNFα,and caspase 3 levels in an experimental diabetes model

AIM: To evaluate the influence of an intravitreal injection of bevacizumab and fasudil on the retinal vascular endothelial growth factor(VEGF),tumor necrosis factor alpha(TNFα),and caspase 3 levels in a diabetic rabbit model. · METHODS: The study included 6 healthy rabbits(Group 1),6 rabbits with experimentally induced diabetes mellitus(DM)(Group 2),7 rabbits with experimentally induced DM to which intravitreal bevacizumab was administered(Group 3),and 7 rabbits with experimentally induced DM to which intravitreal fasudil was administered(Group 4). An intravitreal injection of 1.25mg/50μL bevacizumab in the right eye of rabbits in Group 3 and an intravitreal injection of 0.0064mg/50μL fasudil in the right eye of rabbits in Group 4 were administered on day 21 after the induction of DM. The studied eyes of the rabbits were enucleated three days after the intravitreal injection. The TNFα,VEGF,and caspase 3 levels were determined using the ELISA method. · RESULTS: There was a statistically significant difference in the VEGF and caspase 3 levels between groups(P =0.005 and P =0.013,respectively),but the TNF α level did not differ significantly between groups(P = 0.792). It was found that VEGF levels were significantly lower in Group 1 and Group 3 than in Group 2 using the Mann-Whitney U test with the Bonferroni correction(P = 0.004 for both comparison). There was no statistically significant difference between other groups with regard to VEGF levels(the P value ranged between 0.015 and 0.886). Although the P values of the caspase 3 levels were 0.015 for Group 1 and Group 4,0.038 for Group 2and Group 3,and 0.018 for Group 3 and Group 4,these P values remained above the threshold P value of 0.0083,which was the statistically significant level for post hoc tests. ·CONCLUSION: An intravitreal injection of bevacizumab decreased both the VEGF level,which plays a role in angiogenesis,and the caspase 3 level,which plays a role in apoptosis. Although not as effective as bevacizumab,fasudil had a beneficial effect on the VEGF levels but significantly increased the caspase 3 levels.

Dual therapy of rosiglitazone/pioglitazone with glimepiride on diabetic nephropathy in experimentally induced type 2 diabetes rats

Diabetic nephropathy is a major cause of end-stage renal disease （ESRD） in the general population. It is estimated that diabetic nephropathy will eventually develop in about 40% of all patients with diabetes; therefore, prevention is critical for delaying the development and progression of diabetic kidney disease. Despite extensive efforts, medical advances are still not successful enough to prevent the progression of the disease. In the present study, we focused on the comparison of combination therapies and whether they offered additional renoprotection. Type 2 diabetes mellitus was induced by intraperitoneally administering streptozotocin （90 mg/kg） in neonatal rats and then these rats were treated with rosiglitazone （1.0 mg/kg） in combination with glimepiride （0.5 mg/kg） or with pioglitazone （2.5 mg/kg） in combination with glimepiride （0.5 mg/kg）. Diabetic nephropathy markers were evaluated by biochemical and ELISA kits and renal structural changes were examined by light microscopy and transmission electron microscopy. Results show that the combination of pioglitazone with glimepiride is more effective in amelioration of diabetic nephropathy than rosiglitazone with glimepiride drug therapy due to glycemic control, suppressing albumin excretion rate, total protein excretion rate and augmented TNF-α signaling during the development of streptozotocin induced type 2 diabetic nephropathy.

Feasibility of large experimental animal models in testing novel therapeutic strategies for diabetes

Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017.The incidence and prevalence of diabetes is predicted to increase.To alleviate this potentially severe situation,safer and more effective therapeutics are urgently required.Mice have long been the mainstay as preclinical models for basic research on diabetes,although they are not ideally suited for translating basic knowledge into clinical applications.To validate and optimize novel therapeutics for safe application in humans,an appropriate large animal model is needed.Large animals,especially pigs, are well suited for biomedical research and share many similarities with humans,including body size,anatomical features,physiology,and pathophysiology.Moreover,pigs already play an important role in translational studies,including clinical trials for xenotransplantation.Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals,including porcine models of diabetes.This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.

Exacerbated VEGF up-regulation accompanies diabetes-aggravated hemorrhage in mice after experimental cerebral ischemia and delayed reperfusion

Reperfusion therapy is the preferred treatment for ischemic stroke,but is hindered by its short treatment window,especially in patients with diabetes whose reperfusion after prolonged ischemia is often accompanied by exacerbated hemorrhage.The mechanisms underlying exacerbated hemorrhage are not fully understood.This study aimed to identify this mechanism by inducing prolonged 2-hour transient intraluminal middle cerebral artery occlusion in diabetic Ins2Akita/+mice to mimic patients with diabetes undergoing delayed mechanical thrombectomy.The results showed that at as early as 2 hours after reperfusion,Ins2Akita/+mice exhibited rapid development of neurological deficits,increased infarct and hemorrhagic transformation,together with exacerbated down-regulation of tight-junction protein ZO-1 and upregulation of blood-brain barrier-disrupting matrix metallopeptidase 2 and matrix metallopeptidase 9 when compared with normoglycemic Ins2+/+mice.This indicated that diabetes led to the rapid compromise of vessel integrity immediately after reperfusion,and consequently earlier death and further aggravation of hemorrhagic transformation 22 hours after reperfusion.This observation was associated with earlier and stronger up-regulation of pro-angiogenic vascular endothelial growth factor(VEGF)and its downstream phospho-Erk1/2 at 2 hours after reperfusion,which was suggestive of premature angiogenesis induced by early VEGF up-regulation,resulting in rapid vessel disintegration in diabetic stroke.Endoplasmic reticulum stress-related pro-apoptotic C/EBP homologous protein was overexpressed in challenged Ins2Akita/+mice,which suggests that the exacerbated VEGF up-regulation may be caused by overwhelming endoplasmic reticulum stress under diabetic conditions.In conclusion,the results mimicked complications in patients with diabetes undergoing delayed mechanical thrombectomy,and diabetes-induced accelerated VEGF up-regulation is likely to underlie exacerbated hemorrhagic transformation.Thus,suppression of the VEGF pathway could be a potential approach to allow reperfusion therapy in patients with diabetic stroke beyond the current treatment window.Experiments were approved by the Committee on the Use of Live Animals in Teaching and Research of the University of Hong Kong[CULATR 3834-15(approval date January 5,2016);3977-16(approval date April 13,2016);and 4666-18(approval date March 29,2018)].

Experimental Study of Excitability and Autorhthmicity in Urinary Bladder Detrusor of Diabetes Rats

Summary： The changes in excitability and autorhthmicity of bladder detrusor in experimental non- insulin dependent diabetes mellitus （NIDDM） rats were observed. Sixty-nine NIDDM rats as NIDDM group and 69 normal rats as control group were enrolled into this experimental study. At 6th, 10th, 14th, 18th, 22nd and 26th week after the rats were iniected last time, the changes in the excitability and autorhthmicity of detrusor strips in vitro were observed. The results showed that the threshold of the tension which made the detrusor strips contract was significantly higher in NIDDM group （0.716±0.325 g） than in control group （0.323±0. 177 g）（F=59.63, P〈0.001）. At different stages, the threshold of the tension resulting the contract of the detrusor strips in NIDDM group was also higher than in control group. At 18th week after STZ iniection, the frequency of spontaneous contract of the detrusor strips in NIDDM was significantly higher than in control group （P〈0.05）, whereas at 22nd week, that in NIDDM group was significantly lower than in control group （P〈0. 05）. It was concluded that the decreased excitability of the bladder detrusor was the earliest and most obvious changes in bladder function in diabetes rats and the autorhthmicity had also changed at the early stage of diabetic bladder.

Integration of network pharmacology with experimental verification reveals the hypoglycemic mechanism of coptisine in Jinqi Jiangtang tablets:inhibition of the FoxO1 signaling pathway and hepatic gluconeogenesis

Background:Jinqi Jiangtang tablets(JQJT)have been approved for the treatment of type 2 diabetes mellitus(T2DM)in China for many years.Exploring the effective substances and mechanisms of JQJT is important for its clinical application and further drug research and development.This study aimed to explore the chemical basis and mechanisms of JQJT in the treatment of T2DM.Methods:With network pharmacology,we screened substances in JQJT and their possible targets,then constructed the action network and enriched the biological functions and pathways associated with the active components,and identified the potential targets and mechanisms of JQJT in the treatment of T2DM.Based on the network pharmacology data,we explored the hypoglycemic mechanisms of coptisine in JQJT through western blot and quantitative real-time polymerase chain reaction.Results:Forty-three compounds with good pharmacokinetic properties were identified in JQJT,together with 146 potential biological targets.Among these potential targets,74 were associated with treatment of T2DM.A compound-target network of the 43 compounds against T2DM was constructed.Biological process and signal pathway enrichment analysis of the network highlighted the FoxO signaling pathway.Western blot and quantitative real-time polymerase chain reaction results showed that coptisine,but not epiberberine,significantly inhibited expression of key genes involved in hepatocyte gluconeogenesis by regulating the FoxO1 signaling pathway.Conclusion:Network pharmacology analysis and cell experiments showed that coptisine regulated glucose homeostasis by inhibiting the FoxO1 signaling pathway and hepatic gluconeogenesis,which may be one of the mechanisms of JQJT in the treatment of T2DM.

Prevalence and risk factors of diabetes mellitus among elderly patients in the Lugu community

BACKGROUND Age is a significant risk factor of diabetes mellitus(DM).With the develop of population aging,the incidence of DM remains increasing.Understanding the epidemiology of DM among elderly individuals in a certain area contributes to the DM interventions for the local elderly individuals with high risk of DM.AIM To explore the prevalence of DM among elderly individuals in the Lugu community and analyze the related risk factors to provide a valid scientific basis for the health management of elderly individuals.METHODS A total of 4816 elderly people who came to the community for physical examination were retrospectively analyzed.The prevalence of DM among the elderly was calculated.The individuals were divided into a DM group and a non-DM group according to the diagnosis of DM to compare the differences in diastolic blood pressure(DBP)and systolic blood pressure(SBP),fasting blood glucose,body mass index(BMI),waist-to-hip ratio(WHR)and incidence of hypertension(HT),coronary heart disease(CHD),and chronic kidney disease(CKD).RESULTS DM was diagnosed in 32.70%of the 4816 elderly people.The BMI of the DM group(25.16±3.35)was greater than that of the non-DM group(24.61±3.78).The WHR was 0.90±0.04 in the non-DM group and 0.90±0.03 in the DM group,with no significant difference.The left SBP and SBP in the DM group were 137.9 mmHg±11.92 mmHg and 69.95 mmHg±7.75 mmHg,respectively,while they were 126.6 mmHg±12.44 mmHg and 71.15 mmHg±12.55 mmHg,respectively,in the non-DM group.These findings indicate higher SBP and lower DBP in DM patients than in those without DM.In the DM group,1274 patients were diagnosed with HT,accounting for 80.89%.Among the 3241 non-DM patients,1743(53.78%)were hypertensive and 1498(46.22%)were nonhypertensive.The DM group had more cases of HT than did the non-DM group.There were more patients with CHD or CKD in the DM group than in the non-DM group.There were more patients who drank alcohol more frequently(≥3 times)in the DM group than in the non-DM group.CONCLUSION Older adults in the Lugu community are at a greater risk of DM.In elderly individuals,DM is closely related to high BMI and HT,CHD,and CKD.Physical examinations should be actively carried out for elderly people to determine their BMI,SBP,DBP,and other signs,and sufficient attention should be given to abnormalities in the above signs before further diagnosis.

Icariin accelerates bone regeneration by inducing osteogenesisangiogenesis coupling in rats with type 1 diabetes mellitus

BACKGROUND Icariin(ICA),a natural flavonoid compound monomer,has multiple pharmacological activities.However,its effect on bone defect in the context of type 1 diabetes mellitus(T1DM)has not yet been examined.AIM To explore the role and potential mechanism of ICA on bone defect in the context of T1DM.METHODS The effects of ICA on osteogenesis and angiogenesis were evaluated by alkaline phosphatase staining,alizarin red S staining,quantitative real-time polymerase chain reaction,Western blot,and immunofluorescence.Angiogenesis-related assays were conducted to investigate the relationship between osteogenesis and angiogenesis.A bone defect model was established in T1DM rats.The model rats were then treated with ICA or placebo and micron-scale computed tomography,histomorphometry,histology,and sequential fluorescent labeling were used to evaluate the effect of ICA on bone formation in the defect area.RESULTS ICA promoted bone marrow mesenchymal stem cell(BMSC)proliferation and osteogenic differentiation.The ICA treated-BMSCs showed higher expression levels of osteogenesis-related markers(alkaline phosphatase and osteocalcin)and angiogenesis-related markers(vascular endothelial growth factor A and platelet endothelial cell adhesion molecule 1)compared to the untreated group.ICA was also found to induce osteogenesis-angiogenesis coupling of BMSCs.In the bone defect model T1DM rats,ICA facilitated bone formation and CD31hiEMCNhi type H-positive capillary formation.Lastly,ICA effectively accelerated the rate of bone formation in the defect area.CONCLUSION ICA was able to accelerate bone regeneration in a T1DM rat model by inducing osteogenesis-angiogenesis coupling of BMSCs.

Vitamin D,selenium,and antidiabetic drugs in the treatment of type 2 diabetes mellitus with Hashimoto's thyroiditis

BACKGROUND Diabetes and thyroiditis are closely related.They occur in combination and cause significant damage to the body.There is no clear treatment for type-2 diabetes mellitus(T2DM)with Hashimoto's thyroiditis(HT).While single symptomatic drug treatment of the two diseases is less effective,combined drug treatment may improve efficacy.AIM To investigate the effect of a combination of vitamin D,selenium,and hypoglycemic agents in T2DM with HT.METHODS This retrospective study included 150 patients with T2DM and HT treated at The Central Hospital of Shaoyang from March 2020 to February 2023.Fifty patients were assigned to the control group,test group A,and test group B according to different treatment methods.The control group received low-iodine diet guidance and hypoglycemic drug treatment.Test group A received the control treatment plus vitamin D treatment.Test group B received the group A treatment plus selenium.Blood levels of markers of thyroid function[free T3(FT3),thyroid stimulating hormone(TSH),free T4(FT4)],autoantibodies[thyroid peroxidase antibody(TPOAB)and thyroid globulin antibody(TGAB)],blood lipid index[low-density lipoprotein cholesterol(LDL-C),total cholesterol(TC),triacylglycerol(TG)],blood glucose index[fasting blood glucose(FBG),and hemoglobin A1c(HbA1c)]were measured pre-treatment and 3 and 6 months after treatment.The relationships between serum 25-hydroxyvitamin D3[25(OH)D3]level and each of these indices were analyzed.RESULTS The levels of 25(OH)D3,FT3,FT4,and LDL-C increased in the order of the control group,test group A,and test group B(all P<0.05).The TPOAB,TGAB,TC,TG,FBG,HbA1c,and TSH levels increased in the order of test groups B,A,and the control group(all P<0.05).All the above indices were compared after 3 and 6 months of treatment.Pre-treatment,there was no divergence in serum 25(OH)D3 level,thyroid function-related indexes,autoantibodies level,blood glucose,and blood lipid index between the control group,test groups A and B(all P>0.05).The 25(OH)D3 levels in test groups A and B were negatively correlated with FT4 and TGAB(all P<0.05).CONCLUSION The combination drug treatment for T2DM with HT significantly improved thyroid function,autoantibody,and blood glucose and lipid levels.

Diabetes mellitus in patients with type 1 autoimmune pancreatitis at diagnosis and after corticosteroid therapy

Background:A high prevalence of diabetes mellitus(DM)coexisting with autoimmune pancreatitis(AIP)is observed.However,evidence on the circumstances under which corticosteroid therapy(CST)for AIP improves or worsens DM is scarce.This study aimed to demonstrate and identify predictors of DM control under the influence of CST.Methods:Patients diagnosed with type 1 AIP were enrolled from a prospectively maintained cohort and were classified into three groups according to the chronology in which AIP and DM were diagnosed:pre-existing DM(pDM),concurrent DM(cDM),and non-DM(nDM).The responses of DM to CST were assessed when corticosteroid was ceased or tapered to a maintenance dose and classified as‘improvement’and‘non-improvement’(including‘no change’and‘exacerbation’).Results:Among 101 patients with type 1 AIP,52(51.5%)patients were complicated with DM at the time of AIP diagnosis,with 36 patients in the cDM group and 16 patients in the pDM group.The incidences of diffuse pancreatic swelling(72.2%)and pancreatic body/tail involvement(91.7%)were significantly higher in the cDM group than in both the pDM and nDM groups.Of the 52 patients with DM,CST was administered in 48 cases.Multivariate logistic analysis identified that elevated serum gamma-glutamyl transferase(GGT)level at AIP diagnosis[odds ratio(OR)=0.032,95%confidence interval(CI):0.003-0.412,P=0.008]and pancreatic atrophy after CST(OR=0.027,95%CI:0.003-0.295,P=0.003)were negatively associated with DM control improvement.Conclusions:Patients with diffuse pancreatic swelling and pancreatic body/tail involvement in pancreatitis tended to be complicated with cDM at AIP diagnosis.CST exerted a beneficial effect on the clinical course of DM in nearly half of the AIP patients complicated with DM at diagnosis,particularly in those without elevated serum GGT levels at diagnosis and who did not experience pancreatic atrophy after CST.

Clinical study of different prediction models in predicting diabetic nephropathy in patients with type 2 diabetes mellitus

BACKGROUND Among older adults,type 2 diabetes mellitus(T2DM)is widely recognized as one of the most prevalent diseases.Diabetic nephropathy(DN)is a frequent com-plication of DM,mainly characterized by renal microvascular damage.Early detection,aggressive prevention,and cure of DN are key to improving prognosis.Establishing a diagnostic and predictive model for DN is crucial in auxiliary diagnosis.AIM To investigate the factors that impact T2DM complicated with DN and utilize this information to develop a predictive model.METHODS The clinical data of 210 patients diagnosed with T2DM and admitted to the First People’s Hospital of Wenling between August 2019 and August 2022 were retrospectively analyzed.According to whether the patients had DN,they were divided into the DN group(complicated with DN)and the non-DN group(without DN).Multivariate logistic regression analysis was used to explore factors affecting DN in patients with T2DM.The data were randomly split into a training set(n=147)and a test set(n=63)in a 7:3 ratio using a random function.The training set was used to construct the nomogram,decision tree,and random forest models,and the test set was used to evaluate the prediction performance of the model by comparing the sensitivity,specificity,accuracy,recall,precision,and area under the receiver operating characteristic curve.RESULTS Among the 210 patients with T2DM,74(35.34%)had DN.The validation dataset showed that the accuracies of the nomogram,decision tree,and random forest models in predicting DN in patients with T2DM were 0.746,0.714,and 0.730,respectively.The sensitivities were 0.710,0.710,and 0.806,respectively;the specificities were 0.844,0.875,and 0.844,respectively;the area under the receiver operating characteristic curve(AUC)of the patients were 0.811,0.735,and 0.850,respectively.The Delong test results revealed that the AUC values of the decision tree model were lower than those of the random forest and nomogram models(P<0.05),whereas the difference in AUC values of the random forest and column-line graph models was not statistically significant(P>0.05).CONCLUSION Among the three prediction models,random forest performs best and can help identify patients with T2DM at high risk of DN.

Emerging global interest:Unraveling the link between diabetes mellitus and depression

BACKGROUND Studies have shown a strong bidirectional association between diabetes and depression,with diabetes increasing the risk of developing depression and vice versa.Depression among patients with diabetes is associated with poor glycemic control,complications,and poor self-care.AIM To explore the present state of research globally concerning diabetes and depression,to aid understanding the current research landscape and identify potential future areas of research.METHODS A bibliometric approach was used,utilizing the Scopus database to gather pertinent research articles released from 2004 to 2023.Analyses encompassed publication patterns,significant contributors,research focal points,prevalent themes,and the most influential articles,aimed at discerning emerging research subjects.RESULTS A total of 3229 publications that met the search criteria were identified.A significant increase in the number of publications related to diabetes and depression has been observed in the past two decades.The most productive nation was the USA(n=1015;31.43%),followed by China(n=325;10.07%),the UK(n=236;7.31%),and Germany(n=218;6.75%).Three principal themes in research on depression and diabetes were delineated by the analysis.First,the exploration of the elevated prevalence and etiology of this comorbidity;second,the focus on interventions,particularly randomized controlled trials,aimed at enhancing diabetes management among individuals with depression;and finally,the investigation of the involved risk factors and biological mechanisms under-lying this bidirectional relationship.CONCLUSION There has been a recent surge of interest in the relationship between diabetes and depression.This could aid researchers to identify areas lacking in the literature and shape future research.

Insulin is necessary for the hypertrophic effect of cholecystokinin-octapeptide following acute necrotizing experimental pancreatitis

AIM:In previous experiments we have demonstrated that by administering low doses of cholecystokinin-octapeptide (CCK-8),the process of regeneration following L-arginine (Arg)-induced pancreatitis is accelerated.In rats that were also diabetic(induced by streptozotocin,STZ),pancreatic regeneration was not observed.The aim of this study was to deduce whether the administration of exogenous insulin could in fact restore the hypertrophic effect of CCK-8 in diabetic-pancreatitic rats. METHODS:Male Wistar rats were used for the experiments. Diabetes mellitus was induced by administering 60mg/kg body mass of STZ intraperitoneally(i.p.),then,on d 8, pancreatitis was induced by 200mg/100 g body mass Arg i.p.twice at an interval of 1 h.The animals were injected subcutaneously twice daily(at 7 a.m.and 7 p.m.)with 1 μg/kg of CCK-8 and/or 2 IU mixed insulin(300g/L short- action and 700g/L intermediate-action insulin) for 14 d after pancreatitis induction.Following this the animals were killed and the serum amylase,glucose and insulin levels as well as the plasma glucagon levels,the pancreatic mass/body mass ratio(pm/bm),the pancreatic contents of DNA,protein,amylase,lipase and trypsinogen were measured.Pancreatic tissue samples were examined by light microscopy on paraffin-embedded sections. RESULTS:In the diabetic-pancreatitic rats treatment with insulin and CCK-8 significantly elevated pw/bm and the pancreatic contents of protein,amylase and lipase vs the rats receiving only CCK-8 treatment.CCK-8 administered in combination with insulin also elevated the number of acinar cells with mitotic activities,whereas CCK-8 alone had no effect on laboratory parameters or the mitotic activities in diabetic-pancreatitic rats. CONCLUSION:Despite the hypertrophic effect of CCK-8 being absent following acute pancreatitis in diabetic-rats, the simultaneous administration of exogenous insulin restored this effect.Our results clearly demonstrate that insulin is necessary for the hypertrophic effect of low-doses of CCK-8 following acute pancreatitis.

KCNQ1 rs2237895 gene polymorphism increases susceptibility to type 2 diabetes mellitus in Asian populations

BACKGROUND The association of single nucleotide polymorphism of KCNQ1 gene rs2237895 with type 2 diabetes mellitus(T2DM)is currently controversial.It is unknown whether this association can be gene realized across different populations.AIM To determine the association of KCNQ1 rs2237895 with T2DM and provide reliable evidence for genetic susceptibility to T2DM.METHODS We searched PubMed,Embase,Web of Science,Cochrane Library,Medline,Baidu Academic,China National Knowledge Infrastructure,China Biomedical Literature Database,and Wanfang to investigate the association between KCNQ1 gene rs2237895 and the risk of T2DM up to January 12,2022.Review Manager 5.4 was used to analyze the association of the KCNQ1 gene rs2237895 polymorphism with T2DM and to evaluate the publication bias of the selected literature.RESULTS Twelve case–control studies(including 11273 cases and 11654 controls)met our inclusion criteria.In the full population,allelic model[odds ratio(OR):1.19;95%confidence interval(95%CI):1.09–1.29;P<0.0001],recessive model(OR:1.20;95%CI:1.11–1.29;P<0.0001),dominant model(OR:1.27.95%CI:1.14–1.42;P<0.0001),and codominant model(OR:1.36;95%CI:1.15–1.60;P=0.0003)(OR:1.22;95%CI:1.10–1.36;P=0.0002)indicated that the KCNQ1 gene rs2237895 polymorphism was significantly correlated with susceptibility to T2DM.In stratified analysis,this association was confirmed in Asian populations:allelic model(OR:1.25;95%CI:1.13–1.37;P<0.0001),recessive model(OR:1.29;95%CI:1.11–1.49;P=0.0007),dominant model(OR:1.35;95%CI:1.20–1.52;P<0.0001),codominant model(OR:1.49;95%CI:1.22–1.81;P<0.0001)(OR:1.26;95%CI:1.16–1.36;P<0.0001).In non-Asian populations,this association was not significant:Allelic model(OR:1.06,95%CI:0.98–1.14;P=0.12),recessive model(OR:1.04;95%CI:0.75–1.42;P=0.83),dominant model(OR:1.06;95%CI:0.98–1.15;P=0.15),codominant model(OR:1.08;95%CI:0.82–1.42;P=0.60.OR:1.15;95%CI:0.95–1.39;P=0.14).CONCLUSION KCNQ1 gene rs2237895 was significantly associated with susceptibility to T2DM in an Asian population.Carriers of the C allele had a higher risk of T2DM.This association was not significant in non-Asian populations.

Identification of hub genes associated with Helicobacter pylori infection and type 2 diabetes mellitus:A pilot bioinformatics study

BACKGROUND Helicobacter pylori(H.pylori)infection is related to various extragastric diseases including type 2 diabetes mellitus(T2DM).However,the possible mechanisms connecting H.pylori infection and T2DM remain unknown.AIM To explore potential molecular connections between H.pylori infection and T2DM.METHODS We extracted gene expression arrays from three online datasets(GSE60427,GSE27411 and GSE115601).Differentially expressed genes(DEGs)commonly present in patients with H.pylori infection and T2DM were identified.Hub genes were validated using human gastric biopsy samples.Correlations between hub genes and immune cell infiltration,miRNAs,and transcription factors(TFs)were further analyzed.RESULTS A total of 67 DEGs were commonly presented in patients with H.pylori infection and T2DM.Five significantly upregulated hub genes,including TLR4,ITGAM,C5AR1,FCER1G,and FCGR2A,were finally identified,all of which are closely related to immune cell infiltration.The gene-miRNA analysis detected 13 miRNAs with at least two gene cross-links.TF-gene interaction networks showed that TLR4 was coregulated by 26 TFs,the largest number of TFs among the 5 hub genes.CONCLUSION We identified five hub genes that may have molecular connections between H.pylori infection and T2DM.This study provides new insights into the pathogenesis of H.pylori-induced onset of T2DM.

Serum tumor markers expression(CA199,CA242,and CEA)and its clinical implications in type 2 diabetes mellitus

BACKGROUND Glucose and lipid metabolic disorder in patients with type 2 diabetes mellitus(T2DM)is associated with the levels of serum tumor markers of the digestive tract,such as cancer antigen(CA)199.Therefore,tumor markers in T2DM are important.AIM To evaluate the expression of serum tumor markers[CA199,CA242,and carcinoembryonic antigen(CEA)]and the clinical implications of the expression in T2DM.METHODS For this observational study conducted at Hefei BOE Hospital,China,we enrolled 82 patients with first-onset T2DM and 51 controls between April 2019 and December 2020.Levels of fasting blood glucose(FBG),tumor markers(CA199,CEA,and CA242),glycosylated hemoglobin(HbA1c),etc.were measured and group index levels were compared.Moreover,FBG and HbA1c levels were correlated with tumor marker levels.Tumor markers were tested for diagnostic accuracy in patients with>9%HbA1c using the receiver operating curve(ROC)curve.RESULTS The T2DM group had high serum FBG,HbA1c,CA199,and CEA levels(P<0.05).A comparative analysis of the two groups based on HbA1c levels(Group A:HbA1c≤9%;Group B:HbA1c>9%)revealed significant differences in CEA and CA199 levels(P<0.05).The areas under the ROC curve for CEA and CA199 were 0.853 and 0.809,respectively.CA199,CEA,and CA242 levels positively correlated with HbA1c(r=0.308,0.426,and 0.551,respectively)and FBG levels(r=0.236,0.231,and 0.298,respectively).CONCLUSION As compared to controls,serum CEA and CA199 levels were higher in patients with T2DM.HbA1c and FBG levels correlated with CA199,CEA,and CA242 levels.Patients with poorly controlled blood sugar must be screened for tumor markers.