Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition

The treatment of patients with diabetes mellitus, which is characterized by defective insulin secretion and/or the inability of tissues to respond to insulin, has been studied for decades. Many studies have focused on the use of incretin-based hypoglycemic agents in treating type 2 diabetes mellitus(T2DM). These drugs are classified as GLP-1 receptor agonists, which mimic the function of GLP-1,and DPP-4 inhibitors, which avoid GLP-1 degradation. Many incretin-based hypoglycemic agents have been approved and are widely used, and their physiological disposition and structural characteristics are crucial in the discovery of more effective drugs and provide guidance for clinical treatment of T2DM.Here, we summarize the functional mechanisms and other information of the drugs that are currently approved or under research for T2DM treatment. In addition, their physiological disposition, including metabolism, excretion, and potential drug drug interactions, is thoroughly reviewed. We also discuss similarities and differences in metabolism and excretion between GLP-1 receptor agonists and DPP-4 inhibitors. This review may facilitate clinical decision making based on patients' physical conditions and the avoidance of drug drug interactions. Moreover, the identification and development of novel drugs with appropriate physiological dispositions might be inspired.

Effect of Yanggyuksanhwa-Tang on Non-Insulin-Dependent Diabetes Mellitus Unresponsive to Oral Hypoglycemic Agents:A Case Report

Diabetes mellitus is the fourth leading cause of death worldwide, following cancer, cerebrovascular disease, and heart disease. It is triggered by hyperglycemia and other metabolic disorders. Diabetes is a complex endocrine disease that causes chronic vascular complications such as diabetic nephropathy, retinopathy, and polyneuropathy.

A Preliminary Investigation of the Possible Hypoglycemic Activity of Hibiscus rosa-sinensis

The hypoglycemic activity of an ethanol extract of Hibiscus rosa-sinsnsis was studied in glucose located rats. Afer a single dose of the extract, a slight but insignificant hypoglycemic effect was observed at 30 and 90 min. At 120 min it was mild but significant. After repeated administration of the extract (once a day for seven consecutive days) a statistically significant (P < 0 .001 ) reduction in blood glucose levels was observed at 30, 90 and 120 min after glucose loading. The average hypoglycemic activity, after repeated administration of 250 mg kg-1 leaf extract was 81 %, under similar conditions average activity of tolbutamide was 96%. At 250 mg·kg-1 the efficacy of the extract was found to be 84% of tolbutawhde (100mg·kg- 1 ). Repeated treatment of animals either with tolbutandde a sulphonylurea or H. rosa-sinensis caused a 2-3-fold improvement in glucose tolerance as compared to those receiving only once. These data suggest that the leaf extract acts like tolbutamide and the meehanism of action may be a stimulation of pancreatic hata cells to produce more insulin or an increase of the glycogen deposition in liver. It appeare that the active principle in the tested extract has the sulphonylurea Skeleton in which -SO2-NH-CO- group and the substituents (S1 and S2) may be the possible active sites responsible for its hypolycemic activity.

Hypoglycemic Therapy in Chronic Hepatic Disease Literature Review

Chronic liver disease (CLD) refers to a structural and functional change of the liver, which modifies the pharmacokinetics of multiple drugs, including hypoglycemic agents. This alteration depends on the severity degree of the liver disease, clinical characteristics of the patient, and comorbidities presence such as kidney disease and drug biochemistry. Insulin is considered a safe therapeutic strategy in patients with CLD, however, for many oral hypoglycemic agents, its use and dose adjustment will depend on the Child-Pugh score, based on the risk of hypoglycemia in this type of patient.

Alzheimer’s disease and type 2 diabetes mellitus:Pathophysiologic and pharmacotherapeutics links

At present,Alzheimer’s disease(AD)and type 2 diabetes mellitus(T2DM)are two highly prevalent disorders worldwide,especially among elderly individuals.T2DM appears to be associated with cognitive dysfunction,with a higher risk of developing neurocognitive disorders,including AD.These diseases have been observed to share various pathophysiological mechanisms,including alterations in insulin signaling,defects in glucose transporters(GLUTs),and mitochondrial dysfunctions in the brain.Therefore,the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives.In this context,the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain,increase in reactive oxygen species,and production of mitochondrial alterations that occur in T2DM.These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs,or,more recently,azeliragon,amylin,among others,which have shown possible beneficial effects in diabetic patients diagnosed with AD.

Clinical effects of antidiabetic drugs on psoriasis:The perspective of evidence-based medicine

Psoriasis and diabetes shared common underlying pathophysiological mechanisms.Emerging data suggested that antidiabetic medications may improve the psoriasis severity in patients with diabetes mellitus.Several hypoglycemic agents including thiazolidinediones,glucagon-like peptide-1 receptor agonists,dipeptidyl peptidase-4 inhibitors,and biguanides have been reported to make a remarkable reduction in the Psoriasis Area and Severity Index score from baseline.This antipsoriatic effect could be mediated not only by the glucoselowering action of these agents but also via inhibition of keratinocyte over proliferation,increase expression of differentiation markers,suppression the immune inflammatory pathway,and blocking the calcium channels and mitogen-activated protein kinase signaling pathways.On the other hand,there was no significant increase in adverse reactions associated with the treatment of pioglitazone or metformin.However,previous studies often had the relatively short duration of the trials,and did not have enough power to assess recurrence of psoriasis.Potential bias in the study and missing data could undermine the reliability of the results.Therefore,the appropriately randomized controlled studies with large sample sizes and long-term durations in various psoriasis patients are warranted for further support.

Effectiveness and safety of human umbilical cord-mesenchymal stem cells for treating type 2 diabetes mellitus

BACKGROUND Progressive pancreaticβ-cell dysfunction is a fundamental part of the pathology of type 2 diabetes mellitus(T2DM).Cellular therapies offer novel opportunities for the treatment of T2DM to improve the function of isletβ-cells.AIM To evaluate the effectiveness and safety of human umbilical cord-mesenchymal stem cell(hUC-MSC)infusion in T2DM treatment.METHODS Sixteen patients were enrolled and received 1×10^(6) cells/kg per week for 3 wk as intravenous hUC-MSC infusion.The effectiveness was evaluated by assessing fasting blood glucose,C-peptide,normal glycosylated hemoglobin A1c(HbA1c),insulin resistance index(homeostatic model assessment for insulin resistance),and isletβ-cell function(homeostasis model assessment ofβ-cell function).The dosage of hypoglycemic agents and safety were evaluated by monitoring the occurrence of any adverse events(AEs).RESULTS During the entire intervention period,the fasting plasma glucose level was significantly reduced[baseline:9.3400(8.3575,11.7725),day 14±3:6.5200(5.2200,8.6900);P<0.01].The HbA1c level was significantly reduced on day 84±3[baseline:7.8000(7.5250,8.6750),day 84±3:7.150(6.600,7.925);P<0.01].The patients’isletβ-cell function was significantly improved on day 28±3 of intervention[baseline:29.90(16.43,37.40),day 28±3:40.97(19.27,56.36);P<0.01].The dosage of hypoglycemic agents was reduced in all patients,of whom 6(50%)had a decrement of more than 50%and 1(6.25%)discontinued the hypoglycemic agents.Four patients had transient fever,which occurred within 24 h after the second or third infusion.One patient(2.08%)had asymptomatic nocturnal hypoglycemia after infusion on day 28±3.No liver damage or other side effects were reported.CONCLUSION The results of this study suggest that hUC-MSC infusion can improve glycemia,restore isletβ-cell function,and reduce the dosage of hypoglycemic agents without serious AEs.Thus,hUC-MSC infusion may be a novel option for the treatment of T2DM.

Hypoglycemic and hypolipidemic effects of rutin on hyperglycemic rats

OBJECTIVE:To study the effects of rutin on serum glucose and lipid levels in hyperglycemic rats.METHODS:Male Wistar rats were subjected to intraperitoneal streptozotocin injections and a high-sugar,high-fat diet to establish a hyperglycemic and hyperlipidemic model.The model was considered to be successfully established in rats with fasting blood sugar(FBS)≥11.1 mmol/L.The study included 6 groups with 10 rats each:a blank control group,a model group,a metformin group,and groups on large,medium and small doses of rutin.The groups received intraperitoneal streptozotocin or normal saline for 21 d.FBS,serum lipids,serum insulin,insulin sensitivity index(ISI),and levels of catalase(CAT),glutathione peroxidase(GSH-Px),superoxide dismutase(SOD)and malondialdehyde(MDA)levels were evaluated in all rats.Pancreatic tissue samples were harvested to observe structural changes in islet cells.RESULTS:Large,medium,and small doses of rutin were associated with significantly reduced FBS(P<0.05),and increased levels of ISI,CAT,GSH-Px and SOD,as well as decreased MDA(P<0.05).Rutin administration was also related with reduced total cholesterol,triglycerides and low density lipoprotein chesterol,as well as increased high density lipoprotein chesterol(P<0.05).Histologic evaluation revealed rutin induced repair of damaged islet cells.CONCLUSION:In diabetic rat models,rutin can significantly reduce FBS and blood lipids,improve anti-oxidant activity,increase insulin sensitivity,and induce repair of damaged islet cells.

Efficacy and Safety of Berberine in Patients with Type 2 Diabetes Mellitus: A Meta-Analysis

Objective To assess the efficacy and safety of berberine（BBR） in patients with type 2 diabetes mellitus（T2DM） by performing a systematic review. Methods PubM ed, Cochrane Library, Embase, CNKI, and CBM were searched until May 2014. The randomized controlled trials（RCTs） of the effects of BBR on blood glucose in patients with T2 DM were included. The quality of RCTs was assessed by the Jadad scale, and the Review Manager 5.1 software was used for data syntheses and analyses. Results Seventeen RCTs involving 1198 patients were included. The methodological quality of these RCTs was generally low. Compared with the control groups（placebo or no intervention with medicine）, BBR suggested the statistically significant benefits in improving fasting blood glucose（FBG）, postprandial blood glucose（PBG）, glycosylated hemoglobin, and homeostasis model assessment of insulin resistance. Subgroups analysis of BBR compared with metformin（MET） showed that 1.5g/d MET was significantly better than BBR（0.9-1.5 g/d） in lowering FBG and PBG. However, there was no significant difference between 1.5g/d BBR and 0.75g/d MET groups in blood glucose profiles. In comparison with rosiglitazone, BBR suggested the statistically significant benefits in lowering FBG. And there was no significant difference between BBR and glipizide groups in blood glucose profiles. In addition, the combination therapy of BBR and oral hypoglycemic agents had the advantages over oral hypoglycemic agents alone. No serious adverse effects of BBR have been reported. Conclusion BBR may have the beneficial effects in the control of blood glucose levels, though the efficacy of BBR is not superior to MET. BBR appeares to have advantages over rosiglitazone in improving FBG levels. In addition, the combination therapy of BBR and oral hypoglycemic agents may be a new attempt. However, the efficacy of BBR in patients with T2 DM should be further evaluated by more RCTs in a larger population of patients.

Ethnobotanical survey of medicinal plants used in the management of cancer and diabetes

OBJECTIVE:To conduct an ethnobotanical survey and document the traditional anticancer and antidiabetic plants used by the local tribes of Mizoram,Northeast India.METHODS:A systematic survey was conducted in rural and urban areas of Mizoram by interviewing traditional practitioners,and cancer and diabetes patients.A detailed literature search was carried out using MEDLINE and SCOPUS and available literatures were selected and included in the study.The use value(UV)of the selected plants was calculated based on the number of citations per species given by informants.RESULTS:Data was obtained for 201 traditional medicinal plants from Mizoram,Northeast India.These plants were from 72 different families and belonged to 140 genera.Of these,103 plants were reported for the first time as possessing either anticancer or antidiabetic potential,and 105 plants were identified that were used for the treatment of both diseases.Three plants(Phlogacanthus thysiformis,Solanum gilo and Lobelia angulata)with antidiabetic potential,and six plants(Dillenia scabrella,Circium sinesis,Eupatorium nodiflorum,Pratia begonifolia,Vernonia teres and Plantago erosa)with both as anticancer and antidiabetic potential were documented for the first time.CONCLUSION:In this study,we documented several explored and unexplored medicinal plants that may be useful for the management of cancer and diabetes.This study suggests that there is a broad scope fordeveloping potent anticancer and antidiabetic agent from the flora of Mizoram,Northeast India.

Detailed approach toward the anti-hyperglycemic potential of Sterculia diversifolia G.Don against alloxan-induced in vivo hyperglycemia model

OBJECTIVE:To investigate Sterculia diversifolia G.Don for potential anti-diabetic activity in the in vivo mouse model of alloxan-induced hyperglycemia.METHODS:Sterculia diversifolia(S.diversifolia)was subjected to extraction and isolation techniques and structural characterization of the isolated compounds were performed using spectroscopic methods.The acute toxicity test was performed by orally administering S.diversifolia in doses of 500-2000 mg/kg.For the assessment of anti-hyperglycemic activity,S.diversifolia bark and leaves extracts were administered orally in doses of 50,100,and 200 mg/kg,along with metformin(150 mg/kg,i.p)as positive control,after confirmation of alloxan(150 mg/kg,i.p.)induced hyperglycemia in BALB/c mice.Serum biochemical parameters were monitored for the period of study.RESULTS:The phytochemical studies showed the presence of quercetin and kaempferol in S.diversifolia.The IC50 values in the in vivo acute toxicity study revealed the safety margin of S.diversifolia bark(1166.66 mg/kg)and leaves(683.34 mg/kg)extracts.A significant attenuation of alloxan induced hyperglycemia was produced by S.diversifolia extracts at 50 mg/kg(P<0.05),100 mg/kg(P<0.05,<0.01),and 150 mg/kg(P<0.05,<0.01,<0.001)during 1-4 h,which was comparable to metformin(P<0.001).Significant(P<0.001)improvement appeared in blood hemoglobin,protein,cholesterol,triglycerides,urea,creatinine,HDL,and LDL of the stem bark and leaves extracts treated diabetic mice.CONCLUSION:These findings connote the usefulness of S.diversifolia as an anti-diabetic in traditional medicine and this might be attributed to the presence of quercetin and kaempferol,among other phytochemicals.

In-vitro and in-vivo pharmacological screening of Iris albicans

OBJECTIVE:To evaluate the anti-oxidant,enzyme inhibition,anti-pyretic,anti-inflammatory and anti-diabetic activities of Iris albicans.METHODS:Anti-oxidant assay was evaluated using DPPH(2,2-diphenyl-1-picrylhydrazyl)radical scavenging and ABTS(2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid)inhibitory protocol while enzyme inhibitory assay was evaluated by lipoxygenase and cyclooxygenase-2 inhibitory protocol respectively.Antipyretic,anti-inflammatory and anti-diabetic potential was evaluated using brewer's yeast induced pyrexia,carrageenan induced paw edema and streptozocin induced diabetes protocols respectively.Serum biochemical parameters were monitored for the period of study.RESULTS:The anti-oxidant activity of chloroform fraction of Iris albicans showed the highest scavenging potential against DPPH and ABTS while the maximum inhibitory action recorded against lipo-oxygenase and cyclooxygenase-2 enzymes was shown by n-hexane and chloroform fractions respectively.The anti-pyretic potential of the crude methanolic extract showed dose dependent activity in reducing pyrexia,thereby when the dose was increased the anti-pyretic effect was also enhanced.The anti-inflammatory action of the crude methanolic extract administered at the dose of 300 mg/kg was significant at 1 h after its administration,which was found maintained up to 5 h.Similarly the anti-diabetic effect of the crude methanolic extract administered at the dose of 200 and 300 mg/kg was noted highly significant at day 6 and was found well maintained throughout the study time period up to 10 days.Significant(P<0.001)improvement appeared in hemoglobin,protein,cholesterol,triglycerides,urea,creatinine,HDL and LDL of extract treated diabetic mice.CONCLUSION:From this data it could be concluded that Iris albicans have significant anti-oxidant,enzyme inhibition,ant-pyretic,anti-inflammatory and anti-diabetic potential.

Clinical and experimental studies on polyherbal formulations for diabetes: current status and future prospective

Diabetes is a leading cause of morbidity an active search for antidiabetic drugs with greater and mortality in the world. There is currently effectiveness with fewer and less adverse side effects. Although numerous individual herbs have been experimentally or clinically reported to possess antidiabetic effects, considerably less research has been conducted on polyherbal compounds. It is believed that herbal compounds containing multiple plant products have synergistic antidiabetic effects and could enhance the desired actions. Several polyherbal formulations have been studied as therapeutic agents in diabetes management. To describe the current state of research on polyherbal compounds in the treatment of diabetes, an extensive review of literature was undertaken on several major databases. This paper presents what is known about the efficacy of these polyherbal formulations and compare their antidiabetic effects with those of current oral hypoglycemic drugs as reference. The percent decrease in blood glucose, lipids and other biochemical parameters achieved by each product in diabetic animals and patients is reported. Also, the possible mechanisms responsible for hypoglycemic action of polyherbal formulations are discussed.