Jinlida for Diabetes Prevention in Impaired Glucose Tolerance and Multiple Metabolic Abnormalities: The FOCUS Randomized Clinical Trial.

Importance: Previous studies have shown that Jinlida (JLD) granules, an approved treatment for type 2 diabetes in China, can reduce blood glucose level, reduce glycated hemoglobin (HbA1c), and improve insulin resistance in people with type 2 diabetes. Objective: To evaluate the effect of long-term administration of JLD vs placebo on the incidence of diabetes in participants with impaired glucose tolerance (IGT) and multiple metabolic abnormalities. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial (FOCUS) was conducted across 35 centers in 21 cities in China from June 2019 to February 2023. Individuals aged 18 to 70 years with IGT and multiple metabolic abnormalities were enrolled. Intervention: Participants were randomly allocated 1:1 to receive JLD or placebo (9 g, 3 times per day, orally). They continued this regimen until they developed diabetes, withdrew from the study, were lost to follow-up, or died. Main Outcomes and Measures: The primary outcome was the occurrence of diabetes, which was determined by 2 consecutive oral glucose tolerance tests. Secondary outcomes included waist circumference; fasting and 2-hour postprandial plasma glucose levels; HbA1c; fasting insulin level; homeostatic model assessment for insulin resistance (HOMA-IR); total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels; ankle-brachial index; and carotid intima-media thickness. Results: A total of 889 participants were randomized, of whom 885 were in the full analysis set (442 in the JLD group; 443 in the placebo group; mean [SD] age, 52.57 [10.33] years; 463 [52.32%] female). Following a median observation period of 2.20 years (IQR, 1.27-2.64 years), participants in the JLD group had a lower risk of developing diabetes compared with those in the placebo group (hazard ratio, 0.59; 95% CI, 0.46-0.74; P < .001). During the follow-up period, the JLD group had a between-group difference of 0.95 cm (95% CI, 0.36-1.55 cm) in waist circumference, 9.2 mg/dL (95% CI, 5.4-13.0 mg/dL) in 2-hour postprandial blood glucose level, 3.8 mg/dL (95% CI, 2.2-5.6 mg/dL) in fasting blood glucose level, 0.20% (95% CI, 0.13%-0.27%) in HbA1c, 6.6 mg/dL (95% CI, 1.9-11.2) in total cholesterol level, 4.3 mg/dL (95% CI, 0.8-7.7 mg/dL) in low-density lipoprotein cholesterol level, 25.7 mg/dL (95% CI, 15.9-35.4 mg/dL) in triglyceride levels, and 0.47 (95% CI, 0.12-0.83) in HOMA-IR compared with the placebo group. After 24 months of follow-up, the JLD group had a significant improvement in ankle-brachial index and waist circumference compared with the placebo group. Conclusions and Relevance: The findings suggest that JLD can reduce the risk of diabetes in participants with IGT and multiple metabolic abnormalities. Trial Registration: Chinese Clinical Trial Register: ChiCTR1900023241.

Comparative effectiveness of acupuncture and pharmacological interventions in treating diabetic stroke: A protocol for a systematic review and network meta-analysis.

BACKGROUND: There is a close and causative correlation between stroke and diabetes, and the complication of the 2 diseases seriously harms human health and currently becomes a topic of clinical importance. To date, the common methods of treating diabetic stroke include acupuncture and pharmacological interventions. However, there is no high-quality or direct evidence of their comparative effectiveness. This review aims to provide a network meta-analysis to compare the efficacy of acupuncture and pharmacological interventions in treating diabetic stroke. METHODS: Databases such as PubMed, Cochrane Central Register of Controlled Trials, EMBASE, China National Knowledge Infrastructure, China Biology Medicine Disc will be searched for relevant randomized controlled trials to obtain literatures on the treatment of diabetic stroke, and clinical randomized controlled trials will be screened out from their inception to December 30, 2022. The participant intervention comparator outcomes of this study are as flowing: P, patients with diabetic stroke; I, acupuncture and pharmacological interventions; C, no treatment, pharmacological placebo, or sham acupuncture groups; O, primary outcome will be blood glucose levels, glycosylated hemoglobin levels, and the rate of stroke recurrence; secondary outcomes will include fasting and post-load blood glucose levels, cholesterol, triglycerides, and quality of life scale scores. Cochrane Risk of Bias Tool will be used in assessing literature's quality. Review Manager software 5.3 and Stata 15.1 will be used in data analysis. RESULT: This systematic review and network meta-analysis will provide evidence of the efficacy of different therapeutic methods in treating diabetic stroke, to show which forms of therapy are more commonly used with higher effectiveness. CONCLUSION: The results will systematically provide suggestions for medical practitioners to choose the effective, time-saving and economical therapeutic strategy for diabetic stroke.

Jiedutongluotiaogan formula restores pancreatic function by suppressing excessive autophagy and endoplasmic reticulum stress.

CONTEXT: Jiedutongluotiaogan formula (JTTF), a traditional Chinese medicine (TCM), could promote islet function. However, the potential effect of JTTF on endoplasmic reticulum stress (ERS) and autophagy have not been reported. OBJECTIVE: This study explores the potential effect of JTTF on ERS and autophagy in the pancreas. MATERIALS AND METHODS: The Zucker diabetic fatty (ZDF) rats were randomised into five groups, control, model, JTTF (1, 3, 5 g/kg/day for 12 weeks). LPS induced pancreatic ß-cells were treated with JTTF (50, 100, 200 µg/mL). LPS was used to induce pancreatic ß-cell injury, with cell viability and insulin secretion evaluated using MTT, glucose-stimulated insulin secretion (GSIS) assays, and PCR. Intracellular Ca2+ concentration was measured using flow cytometry, while ERS and autophagy levels were monitored via Western blotting and/or immunostaining. RESULTS: Compared with the model group, body weight, FGB, HbA1c, IPGTT, FINs, and HOMA-IR in JTTF treatment groups were significantly reduced. In islets cells treated with JTTF, the pancreatic islet cells in the JTTF group were increased, lipid droplets were reduced, and there was a decrease in Ca2+ (16.67%). After JTTF intervention, PERK, p-PERK, IRE1α, p- IRE1α, ATF6, eIF2α, GRP78, p-ULK1, LC3 and p62 expression decreased, whereas Beclin1and p-mTOR expression increased. In addition, the expression of proteins related to apoptosis in the JTTF groups were lower than those in the control group. DISCUSSION AND CONCLUSIONS: JTTF may alleviate pancreatic ß-cell injury by inhibiting ER stress and excessive autophagy in diabetic rats. This provides a new direction for treating diabetes and restoring pancreatic dysfunction by TCM.

Efficacy and mechanism of Jiedu Tongluo Tiaogan Formula in treating type 2 diabetes mellitus combined with non-alcoholic fatty liver disease: Study protocol for a parallel-armed, randomized controlled trial.

Background: The incidence of Type 2 diabetes mellitus (T2DM) combined with non-alcoholic fatty liver disease (NAFLD) has risen over the years. This comorbid condition significantly increases the probability of cirrhosis, liver cancer, and mortality compared to the disease alone. The multi-targeted, holistic treatment efficacy of traditional Chinese medicine (TCM) plays a vital role in the treatment of T2DM and NAFLD. Jiedu Tongluo Tiaogan Formula (JTTF), based on TCM theory, is widely used in clinical treatment, and its effectiveness in lowering glucose, regulating lipids, improving insulin resistance, and its pathways of action have been demonstrated in previous studies. However, the mechanism of this formula has not been investigated from a metabolomics perspective. Moreover, high-quality clinical studies on T2DM combined with NAFLD are lacking. Therefore, we aim to conduct a clinical trial to investigate the clinical efficacy, safety, and possible pathways of JTTF in the treatment of T2DM combined with NAFLD using metabolomics techniques. Methods: A total of 98 participants will be recruited to this clinical trial and randomly assigned to either a treatment group (JTTF + conventional basic treatment) or control group (conventional basic treatment) in a 1:1 ratio. Both groups will have received the same lifestyle interventions in the preceding 12 weeks. The primary outcome will be change in visceral fat area and total score on the TCM syndromes efficacy score scale. The secondary outcome will include changes in ultrasound steatosis grade, fibrosis 4 score (FIB-4), metabolic parameters, anthropometric parameters, visceral fat area. In addition, serum and urine samples collected at baseline and at the end of 12 weeks of treatment will be sequentially tested for untargeted and targeted metabolomics. Discussion: This study will evaluate the efficacy and safety of JTTF, as well as investigate the differential metabolites and possible mechanisms of JTTF treatment in T2DM combined with NAFLD. We hypothesize that patients will benefit from JTTF, which may provide strong evidence for the clinical use of JTTF in the treatment of T2DM and NAFLD, leading to the possibility of further mechanistic exploration. Clinical Trial Registration: This clinical trial has been registered in China Clinical Trial Registry (ChiCTR 2100051174).

Polydatin prevents lipotoxicity-induced dysfunction in pancreatic ß-cells by inhibiting endoplasmic reticulum stress and excessive autophagy.

BACKGROUND: Chronically elevated free fatty acid levels can adversely affect pancreatic ß-cells, leading to insulin resistance and eventually type 2 diabetes mellitus (T2DM). Polydatin (PD) from Polygonum cuspidatum has been shown to regulate blood lipid content and lower cholesterol levels. However, there have been no reports on the potential therapeutic effects and actions of PD on lipotoxicity in ß-cells. PURPOSE: This study aimed to investigate the protective effects of PD on palmitate (PA)-treated INS-1 insulinoma cells and diabetic mice. METHODS: Cells were incubated with PA and varying concentrations of PD for 24 h. Viability assays, morphological observations, flow cytometric analysis, western blotting, and reverse transcription-quantitative polymerase chain reaction were used to assess the effects of PD on PA-induced lipotoxicity. Western blotting was used to measure the endoplasmic reticulum stress (ERS) and the levels of autophagy-related factors after incubation with inducers and inhibitors of ERS and autophagy. Diabetic mice were treated with intragastric PD for 6 weeks followed by the measurement of their physiological and blood lipid indices and assessment of the results of histological and immunofluorescence analyses. RESULTS: Treatment with PD after PA exposure enhanced insulin secretion and the expression of diabetes-associated genes. PD promoted ß-cell function by reducing the levels of proteins associated with ERS and autophagy while also attenuating ERS triggered by tunicamycin. PD also reduced tunicamycin-induced autophagy, indicating that it regulated ERS-mediated autophagy and reduced PA-induced cellular dysfunction. In addition, treatment of db/db mice with PD substantially reduced body weight gain, alleviated dyslipidemia, improved ß-cell function, and reduced insulin resistance. CONCLUSION: These results suggest that PD protects ß-cells from lipotoxicity-induced dysfunction and apoptosis by inhibiting ERS and preventing excessive autophagy. Our study provides a new basis for exploring the potential of PD against ß-cell lipotoxicity and T2DM.

Pharmacological effects of polydatin in the treatment of metabolic diseases: A review.

BACKGROUND: Metabolic diseases (MDs), a series of chronic disorders, severely decreases the quality of life for patients but also cause a heavy economic burden. Emerging evidence suggests that Polydatin (PD), an important glucoside of resveratrol, is widely distributed in many plants and has shown good therapeutic potential in metabolic diseases. PURPOSE: To review the PD discovered before 2021 and their potential to treat metabolic diseases. The activities against diabetes, Obesity, atherosclerosis, NAFLD, NASH, hyperlipidemia, and gout with special emphasis on pharmacology, pharmacokinetics, mechanisms of action, possible roles in current medicine, and future perspectives are discussed. METHODS: A comprehensive search of published literature was conducted to locate original publications pertaining to polydatin and MDs through the end of 2021 using MEDLINE, Elsevier, Springer, PubMed, Scholar, and CNKI databases. The main inquiry used was for the presence of the following keywords in various combinations in the abstracts: 'Polydatin', 'Metabolic diseases', 'Pharmacology', 'Toxicology', 'Pharmacokinetics', 'Diabetes', 'Obesity', 'Atherosclerosis', 'Non-alcoholic fatty liver disease', 'Non-alcoholic steatohepatitis', 'Hyperlipidemia', and 'Gout'. RESULTS: The search yielded 987 articles, of which 33 articles were included in this review. Studies have revealed that PD can promote insulin secretion, alleviate insulin resistance, regulate glucose and lipid metabolism, reduce liver lipid deposition, inhibit inflammation, oxidative stress, and decrease uric acid deposition in preclinical experiments. The underlying mechanisms of PD in treatment MDs may be attributed to the regulation of multiple signaling pathways, including. NF-κB, AGEs/RAGE, MAPK/ERK, AMPK/LDLR, IRS1/PI3K/AKT, LKB1/AMPK, PPARß-NO, SIRT1-PGC-1α-SOD2, PKC, etc., The pharmacokinetic profiles of PD provide valuable information on therapeutic efficacy in treating metabolic diseases. CONCLUSION: This review summarizes the available reports and evidence which support the use of PD as a potential candidate in the treatment of MDs and provides an overview of the modulatory effects of PD in metabolic diseases and cell signaling pathways, which may have important implications in its future clinical use.

Decoding the chemical composition and pharmacological mechanisms of Jiedu Tongluo Tiaogan Formula using high-performance liquid chromatography coupled with network pharmacology-based investigation.

Type 2 diabetes mellitus (T2DM), a chronic low-grade inflammatory disease with high morbidity and mortality, is a serious threat to public health. Previously we demonstrated that a traditional Chinese medicine formulation, Jiedu Tongluo Tiaogan Formula (JDTL), exerted a favorable hypoglycemic effect due to unknown molecular mechanisms involving interactions among JDTL compounds and various cellular components. This study aimed to explore JDTL mechanisms for alleviating hyperglycemia using an integrated strategy incorporating system pharmacology, bioinformatics analysis, and experimental verification. This strategy entailed initial elucidation of JDTL chemical composition using fingerprint analysis via high performance liquid chromatography (HPLC). Next, functions of putative shared target genes and associated pathways were deduced using GO and KEGG pathway enrichment and molecular docking analyses. Ultimately, targets associated with JTDL anti-T2DM effects were found to be functionally associated with biological functions related to lipopolysaccharide and cytokine receptor binding. These results implicated PI3K-Akt signaling pathway involvement in JDTL anti-T2DM effects, as this pathway had been previously shown to play significant roles in glucose and lipid metabolism-related diseases. Furthermore, addition of JDTL to INS-1 and HepG2 cell cultures stimulated cellular mRNA-level and protein-level expression leading to enhanced production of IRS1, Akt, and PI3K. In summary, here JDTL bioactive ingredients, potential targets, and molecular mechanisms underlying JDTL anti-T2DM effects were identified using a multi-component, multi-target, and multi-channel analytical approach, thus providing an important scientific foundation to facilitate development of new drugs mechanistic strategies for preventing and treating T2DM.

A Study on the Mechanism of Milkvetch Root in the Treatment of Diabetic Nephropathy Based on Network Pharmacology.

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. Owing to its complicated pathogenesis, no satisfactory treatment strategies for DN are available. Milkvetch Root is a common traditional Chinese medicine (TCM) and has been extensively used to treat DN in clinical practice in China for many years. However, due to the complexity of botanical ingredients, the exact pharmacological mechanism of Milkvetch Root in treating DN has not been completely elucidated. The aim of this study was to explore the active components and potential mechanism of Milkvetch Root by using a systems pharmacology approach. First, the components and targets of Milkvetch Root were analyzed by using the Traditional Chinese Medicine Systems Pharmacology database. We found the common targets of Milkvetch Root and DN constructed a protein-protein interaction (PPI) network using STRING and screened the key targets via topological analysis. Enrichment of Gene Ontology (GO) pathways and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed. Subsequently, major hubs were identified and imported to the Database for Annotation, Visualization and Integrated Discovery for pathway enrichment analysis. The binding activity and targets of the active components of Milkvetch Root were verified by using the molecular docking software SYBYL. Finally, we found 20 active components in Milkvetch Root. Moreover, the enrichment analysis of GO and KEGG pathways suggested that AGE-RAGE signaling pathway, HIF-1 signaling pathway, PI3K-Akt signaling pathway, and TNF signaling pathway might be the key pathways for the treatment of DN; more importantly, 10 putative targets of Milkvetch Root (AKT1, VEGFA, IL-6, PPARG, CCL2, NOS3, SERPINE1, CRP, ICAM1, and SLC2A) were identified to be of great significance in regulating these biological processes and pathways. This study provides an important scientific basis for further elucidating the mechanism of Milkvetch Root in treating DN.

Corrigendum: Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Jinlida Granules on Metabolic Syndrome in Patients With Abnormal Glucose Metabolism.

[This corrects the article DOI: 10.3389/fendo.2020.00415.].

Effectiveness comparisons of catgut implantation at acupoint for obese type 2 diabetes: A protocol for systematic review and meta analysis.

BACKGROUND: With the change of people's life style, many more people are suffering from obese type 2 diabetes mellitus (T2DM). Acupoint catgut embedding is one of the acupuncture treatment principles in traditional Chinese medicine, which is widely used in the treatment of obese T2DM. However, there is no systematic review of the therapeutic effect of acupoint catgut embedding on obesity T2DM. Therefore, this article aims at the meta-analysis of acupoint catgut embedding in the treatment of obese T2DM, to clarify its curative effect. METHODS: A structured and systemic literature search was conducted in the following databases up to December 1, 2019: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, EMBASE, CNKI, Wanfang Database. We will use the Review Manager 5.3 software provided by Cochrane collaborative network for statistical analysis. Then we assessed the quality and risk of the included studies and observed the outcome measures. RESULTS: This meta-analysis will further determine the beneficial efficacy of acupoint catgut embedding on obesity T2DM. CONCLUSION: The purpose of this meta-analysis is to explore the effect of acupoint catgut embedding intervention on obese T2DM patients, and provide more options for clinicians and patients to treat obese T2DM. ETHICS AND DISSEMINATION: This systemic review will evaluate the efficacy and safety of acupoint catgut embedding in the treatment of obesity T2DM. Since all the data included are published, the systematic review does not need ethical approval. REGISTRATION NUMBER: CRD42020160801.

International traditional Chinese medicine guideline for diagnostic and treatment principles of diabetes.

Diabetes mellitus (DM) was one of the most severe public health problems that affected nearly 463 million adults around the world. In addition to insulin and oral hypoglycemic agents, traditional Chinese medicine (TCM) was an effective alternative therapy for diabetes and its complications, and it had been widely used in the Pan-Pacific region, especially in Southeast Asia, however, TCM lacked specialized standards of care for DM in the past, which limited the TCM clinical efficacy of diabetes. Since March 2017, the Endocrinology Committee of World Federation of Chinese Medicine Societies (WFCMS) had invited experts in diabetes, TCM, and international standard setting to work with TCM endocrinologists from the Guideline Development Committee to review the TCM clinical research evidence related to the prevention and treatment of diabetes over the previous 14 years. Over an 8-months careful revision, the international TCM guideline was finally developed under the guidance of review experts, physicians and surveyed patients, to provide standardized diagnosis and treatment advice of diabetes for global TCM doctors. This guideline clarified the TCM classification, staging, and syndromes of diabetes, gave the instructions that how to identified different stages and syndromes clearly, and accordingly recommended different TCM therapies based on the level of evidence. It's worth noting that when the guideline was being made, fewer high-quality clinical research evidence could be found, and very few researches were so outdated that need to be updated. More high-quality research evidence would be included in the updated version of guideline to continuously improve the overall level of global TCM in preventing and treating diabetes, and long-term clinical researches were advocated.

Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Jinlida Granules on Metabolic Syndrome in Patients With Abnormal Glucose Metabolism.

Background: Metabolic syndrome (MS) is a powerful risk factor for cardiovascular and cerebrovascular diseases. Although lifestyle intervention reduces several of the symptoms of the syndrome and cardiovascular risks, the lifestyle intervention that yields the benefits is restrictive. Jinlida is a Chinese patent medicine that has shown activity in type 2 diabetes, which has been approved in China. Preclinical studies in Jinlida granules support an improved role of abnormal glucose and lipids metabolism as well as reducing weight. Here, we describe the protocol of an ongoing clinical trial investigating a new therapy for metabolic syndrome in patients with abnormal glucose metabolism. Methods: This study will enroll 880 subjects (aged 18-70 years) who have metabolic syndromes with abnormal glucose metabolism. All the participants in a double-blind, parallel, randomized, placebo-controlled trial, will receive Jinlida or placebo, orally, 9 g/time, three times daily for 2-4 years period on the basis of lifestyle intervention. The primary outcome measure (Incidence of type 2 diabetes) will be assessed during intervention cycles. Adverse events were monitored. All statistical tests will be performed using a two-sided test, and a p ≤ 0.05 (two-sided test) will be considered to be statistically significant results. Discussion: Results from this study will provide evidence on whether incorporating oral Jinlida granules treatment into lifestyle intervention can delay or inhibit the development of diabetes mellitus in metabolic syndrome subjects with abnormal glucose metabolism. Clinical trial registration: Registered at http://www.chictr.org.cn/enIndex.aspx. Trial registration number: ChiCTR1900023241.

Treatment of Type 2 diabetes with Tianqi Jiangtang Capsule: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Tianqi Jiangtang Capsule is a commonly used Chinese patent medicine for the treatment of type 2 diabetes mellitus (T2DM) in China. The purpose of this study is to systematically evaluate the clinical efficacy and safety of Tianqi Jiangtang Capsule in the treatment of type 2 diabetes mellitus. METHODS: Randomized controlled trials (RCTs) of Tianqi Jiangtang Capsule in the treatment of type 2 diabetes mellitus were retrieved. According to the requirements of Cochrane Manual, the included literature was assessed and meta-analyzed with RevMan 5.3 software. RESULTS: (1) Meta-analysis included 8 RCTs and 1029 participants.(2) There were two studies on adverse reactions.(3) Meta-analysis showed that Tianqi Jiangtang Capsule could significantly reduce HbA1c (n = 1029; MD, -0.31; 95% CI, [-0.43 to -0.19]; P < .00001; I = 0%). FBG (Z = 4.28 (P < .0001), MD = 0.78, 95%CI[-1.14 to -0.43]). 2hPG [OR = -1.25, 95% CI [-1.25 to -0.65], Z = 6.26 (P < .00001)] compared with the control group. CONCLUSIONS: According to the results of this study, Tianqi Jiangtang Capsule combined with antidiabetic agents may have a better therapeutic effect on diabetes mellitus than antidiabetic agents alone, but due to the low methodological quality and limited number of studies, more high-quality studies are needed to verify it.

Network Pharmacology-based Investigation of the Underlying Mechanism of Panax notoginseng Treatment of Diabetic Retinopathy.

BACKGROUND: Panax notoginseng, a Chinese herbal medicine, has been widely used to treat vascular diseases. Diabetic retinopathy (DR) is one of the complications of diabetic microangiopathy. According to recent studies, the application of Panax notoginseng extract and related Chinese patent medicine preparations can significantly improve DR. However, the pharmacological mechanisms remain unclear. Therefore, the purpose of this study was to decipher the potential mechanism of Panax notoginseng treatment of DR using network pharmacology. METHODS: We evaluated and screened the active compounds of Panax notoginseng using the Traditional Chinese Medicine Systems Pharmacology database and collected potential targets of the compounds by target fishing. A multi-source database was also used to organize targets of DR. The potential targets as the treatment of DR with Panax notoginseng were then obtained by matching the compound targets with the DR targets. Using protein-protein interaction networks and topological analysis, interactions between potential targets were identified. In addition, we also performed gene ontology-biological process and pathway enrichment analysis for the potential targets by using the Biological Information Annotation Database. RESULTS: Eight active ingredients of Panax notoginseng and 31 potential targets for the treatment of DR were identified. The screening and enrichment analysis revealed that the treatment of DR using Panax notoginseng primarily involved 28 biological processes and 10 related pathways. Further analyses indicated that angiogenesis, inflammatory reactions, and apoptosis may be the main processes involved in the treatment of DR with Panax notoginseng. In addition, we determined that the mechanism of intervention of Panax notoginseng in treating DR may involve five core targets, VEGFA, MMP-9, MMP-2, FGF2, and COX-2. CONCLUSION: Panax notoginseng may treat diabetic retinopathy through the mechanism of network pharmacological analysis. The underlying molecular mechanisms were closely related to the intervention of angiogenesis, inflammation, and apoptosis with VEGFA, MMP-9, MMP-2, FGF2, and COX-2 being possible targets.

Utilizing network pharmacology to explore the underlying mechanism of Radix Salviae in diabetic retinopathy.

INTRODUCTION: Radix Salviae (Dan-shen in pinyin), a classic Chinese herb, has been extensively used to treat diabetic retinopathy in clinical practice in China for many years. However, the pharmacological mechanisms of Radix Salviae remain vague. The aim of this study was to decrypt the underlying mechanisms of Radix Salviae in the treatment of diabetic retinopathy using a systems pharmacology approach. METHODS: A network pharmacology-based strategy was proposed to elucidate the underlying multi-component, multi-target, and multi-pathway mode of action of Radix Salviae against diabetic retinopathy. First, we collected putative targets of Radix Salviae based on the Traditional Chinese Medicine System Pharmacology database and a network of the interactions among the putative targets of Radix Salviae and known therapeutic targets of diabetic retinopathy was built. Then, two topological parameters, "degree" and "closeness certainty" were calculated to identify the major targets in the network. Furthermore, the major hubs were imported to the Database for Annotation, Visualization and Integrated Discovery to perform a pathway enrichment analysis. RESULTS: A total of 130 nodes, including 18 putative targets of Radix Salviae, were observed to be major hubs in terms of topological importance. The results of pathway enrichment analysis indicated that putative targets of Radix Salviae mostly participated in various pathways associated with angiogenesis, protein metabolism, inflammatory response, apoptosis, and cell proliferation. The putative targets of Radix Salviae (vascular endothelial growth factor, matrix metalloproteinases, plasminogen, insulin-like growth factor-1, and cyclooxygenase-2) were recognized as active factors involved in the main biological functions of treatment, which implied that these were involved in the underlying mechanisms of Radix Salviae on diabetic retinopathy. CONCLUSIONS: Radix Salviae could alleviate diabetic retinopathy via the molecular mechanisms predicted by network pharmacology. This research demonstrates that the network pharmacology approach can be an effective tool to reveal the mechanisms of traditional Chinese medicine from a holistic perspective.

The Efficacy and Safety of the Chinese Herbal Formula, JTTZ, for the Treatment of Type 2 Diabetes with Obesity and Hyperlipidemia: A Multicenter Randomized, Positive-Controlled, Open-Label Clinical Trial.

BACKGROUND AND AIM: Studies have shown an increasing number of type 2 diabetes (T2D) patients with concomitant obesity and hyperlipidemia syndromes, resulting from relevant metabolic disorders. However, there are few medications and therapies, which can thoroughly address these issues. Therefore, the current study evaluated the efficacy and safety of using JTTZ, a Chinese herbal formula, to treat T2D with obesity and hyperlipidemia. METHODS: A total of 450 participants with T2D (HbA1c ≥ 7.0%; waist circumference ≥ 90 cm and 80 cm in males and females, resp.; and triglycerides (TG) ≥ 1.7 mmol/L) were randomly assigned, in equal proportions, to two groups in this multicenter randomized, positive-controlled, open-label trial. One group received JTTZ formula, and the other received metformin (MET) for 12 consecutive weeks. The primary efficacy outcomes were changes in HbA1c, TG, weight, and waist circumference. Adverse reactions and hypoglycemia were monitored. RESULTS: HbA1c decreased by 0.75 ± 1.32% and 0.71 ± 1.2% in the JTTZ and MET groups, respectively, after 12 weeks of treatment. TG levels in the JTTZ and MET groups were reduced by 0.64 ± 2.37 mmol/L and 0.37 ± 2.18 mmol/L, respectively. Weight was decreased by 2.47 ± 2.71 kg in the JTTZ group and by 2.03 ± 2.36 kg in the MET group. JTTZ also appeared to alleviate insulin resistance and increase HOMA-ß. In addition, symptoms were significantly relieved in participants in the JTTZ group compared to those in the MET group. One case of hypoglycemia was reported in the MET group. No severe adverse events were reported in either group. CONCLUSIONS: The JTTZ formula led to safe and significant improvements in the blood glucose, blood lipids, and weight levels; relieved symptoms; and enhanced ß cell function for T2D patients with obesity and hyperlipidemia. The JTTZ formula has shown that it could potentially be developed as an alternative medicine for patients with T2D, particularly those who cannot tolerate metformin or other hypoglycemic drugs. This trial was registered with Clinicaltrials.gov NCT01471275.

Ginsenoside Rg1 inhibits dietary-induced obesity and improves obesity-related glucose metabolic disorders.

Obesity and its consequent type 2 diabetes are significant threats to global health. Emerging evidence indicates that ginsenosides from ginseng (Panax ginseng) have anti-diabetic activity. We hypothesized that ginsenosides Rg1 could suppress dietary-induced obesity and improve obesity-related glucose metabolic disorders. Our results showed that ginsenoside Rg1 attenuated dietary-induced body weight gain and fat accumulation in white adipocyte tissue of mice fed a high-fat diet. Furthermore, we found that ginsenosides Rg1 not only decreased fasting glucose concentration and the 2-h postprandial glucose concentration, but also improved insulin resistance and glucose intolerance in those mice. Ginsenoside Rg1 also activated the AMPK pathway in vitro and in vivo and increased plasma membrane translocation of GLUT4 in C2C12 skeletal muscle cells. In conclusion, our observations suggested that ginsenoside Rg1 inhibited dietary-induced obesity and improved obesity-related insulin resistance and glucose intolerance by activation of the AMPK pathway.

Ginsenoside Rg1 inhibits dietary-induced obesity and improves obesity-related glucose metabolic disorders

Obesity and its consequent type 2 diabetes are significant threats to global health. Emerging evidence indicates that ginsenosides from ginseng (Panax ginseng) have anti-diabetic activity. We hypothesized that ginsenosides Rg1 could suppress dietary-induced obesity and improve obesity-related glucose metabolic disorders. Our results showed that ginsenoside Rg1 attenuated dietary-induced body weight gain and fat accumulation in white adipocyte tissue of mice fed a high-fat diet. Furthermore, we found that ginsenosides Rg1 not only decreased fasting glucose concentration and the 2-h postprandial glucose concentration, but also improved insulin resistance and glucose intolerance in those mice. Ginsenoside Rg1 also activated the AMPK pathway in vitro and in vivo and increased plasma membrane translocation of GLUT4 in C2C12 skeletal muscle cells. In conclusion, our observations suggested that ginsenoside Rg1 inhibited dietary-induced obesity and improved obesity-related insulin resistance and glucose intolerance by activation of the AMPK pathway.

Polyethylene glycol loxenatide injections added to metformin effectively improve glycemic control and exhibit favorable safety in type 2 diabetic patients.

BACKGROUND: The aim of the present study was to evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) injections in Chinese type 2 diabetic (T2D) patients. METHODS: The present multicenter randomized double-blind parallel placebo-controlled clinical trial enrolled patients who had been treated with a stable dose of metformin (≥1500 mg/day) for ≥12 weeks and had an HbA1c level between 7% and 11%. Subjects were randomly divided into three groups (1: 1: 1) and were treated with once weekly subcutaneous injections of either placebo or 100 or 200 µg PEX168 for 12 weeks. All subjects continued to receive metformin daily. RESULTS: After 12 weeks treatment, the adjusted least-squares mean of HbA1c reductions from baseline values in the 100 and 200 µg PEX168 groups were significantly higher than in the placebo group (-1.02% [95% confidence interval {CI} -1.33, -0.71), -1.36% [95% CI -1.68, -1.04], and 0.13% [95% CI -0.20, 0.45], respectively; P < 0.05). After treatment, 50% and 60.5% of subjects in the 100 and 200 µg PEX168 groups, respectively, achieved HbA1c levels <7% (P < 0.01 for both vs placebo [HbA1c 11.1%]). The most frequent adverse reactions in the PEX168 groups were mild to moderate dose-dependent gastrointestinal reactions. There were no reports of hypoglycemia or pancreatitis in any of the groups. CONCLUSIONS: Continuous 12 week treatment with PEX168 showed excellent safety and efficacy in T2D patients whose glucose was not well controlled with metformin alone.

Efficacy and safety of saxagliptin monotherapy or added to metformin in Chinese patients with type 2 diabetes mellitus: results from the 24-week, post-marketing SUNSHINE study.

BACKGROUND: The aim of the present study was to explore the efficacy and safety of saxagliptin in a large Chinese population with type 2 diabetes mellitus (T2DM). METHODS: In all, 1423 T2DM patients from 92 research centers, either drug naïve or uncontrolled by metformin, were enrolled in this single-arm cohort study; patients were treated with saxagliptin 5 mg once daily for 24 weeks. The primary efficacy endpoint was the change from baseline in HbA1c at 24 weeks in the per-protocol analysis set. Secondary endpoints included the proportion of patients achieving HbA1c <7% and changes from baseline in fasting plasma glucose (FPG) and 2-h postprandial plasma glucose (PPG) concentrations at 24 weeks. Safety endpoints included adverse events (AEs) and the incidence of hypoglycemia. RESULTS: Among 1210 patients in the per-protocol analysis set, mean HbA1c, FPG and 2-h PPG decreased by 1.61 ± 0.04%, 0.55 ± 0.07 mmol/L, and 2.83 ± 0.27 mmol/L, respectively, at week 24. The proportion of patients achieving HbA1c <7% was 44.1%. No new (previously unreported) AEs occurred. The incidence of serious AEs and hypoglycemia was low (1.8% and 1.2%, respectively). There were no significant differences in efficacy endpoints in subgroup analyses by age, creatinine clearance, body mass index, or treatment background. In elderly patients (≥65 years) and those with mild renal impairment (50 < CCr ≤ 80 mL/min), the incidence of AEs was similar to that of the entire study population. CONCLUSIONS: Saxagliptin significantly improved glycemic control and was well tolerated in Chinese T2DM patients, including the elderly and patients with mild renal impairment.