Cinnamomi Cortex Regulates Incretin Effect in Diabetic Rats / 中国实验方剂学杂志

ObjectiveTo observe the pharmacodynamic effects of Cinnamomi Cortex on the incretin effect in the rat model of diabetes mellites （DM） induced by streptozotocin （STZ） and explore the underlying mechanism from glucagon-like peptide-1 （GLP-1） and dipeptidyl peptidase-4 （DPP-4）. MethodForty SD rats were randomly assigned into blank， model， sitagliptin （0.1 g·kg-1）， and low- and high-dose Cinnamomi Cortex （0.45 and 0.9 g·kg-1， respectively） groups. The DM rat model was established by a high-fat diet combined with intraperitoneal injection of 40 mg·kg-1 STZ in other groups except the blank group. The intervention lasted for 8 weeks. The status， body weight， water intake， food intake， and fasting blood glucose （FBG） of the rats were observed and determined. Hematoxylin-eosin staining was employed to reveal the pathological changes of the pancreas， and immunohistochemistry to detect the expression of glucagon in the pancreas. Biochemical assay was employed to measure the serum levels of lipid metabolism indexes such as total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein （LDL）， and high-density lipoprotein （HDL）. Enzyme-linked immunosorbent assay was employed to determine the levels of glycosylated hemoglobin， insulin， glucagon， GLP-1， and glucose-dependent insulinotropic polypeptide （GIP） in rat serum， and Western blot to determine the protein levels of GLP-1 and DPP-4 in the pancreas. ResultAfter 8 weeks of intervention， the model group showed higher body weight， FBG， TC， TG， LDL， glycosylated hemoglobin， glucagon， insulin， and insulin resistance index and lower HDL， GLP-1， and GIP than the blank group （P<0.05， P<0.01）. The Cinnamomi Cortex groups showed lower body weight， FBG， TC， TG， LDL， glycosylated hemoglobin， glucagon， insulin， and insulin resistance index and higher HDL， GLP-1， and GIP than the model group （P<0.05， P<0.01）. The Cinnamomi Cortex groups showed recovered morphology of islet cells and no nucleus aggregation. Compared with the model group， the Cinnamomi Cortex groups showed declined levels of glucagon in the center of islet cells. Compared with the blank group， the model group showed up-regulated protein level of DPP-4 and down-regulated protein level of GLP-1 （P<0.01）. Compared with the model group， the high-dose Cinnamomi Cortex groups showed down-regulated protein level of DPP-4 and up-regulated protein level of GLP-1 （P<0.05）. ConclusionCinnamomi Cortex may reduce blood glucose and improve incretin effect to lower the blood glucose level by regulating DPP-4 and GLP-1 in DM rats.

Effects of rhGLP-1 (7-36) on Akt/GSK3 signaling pathway in hepatocytes / 中华内分泌外科杂志

Objective:To observe the effect of rhGLP-1 (7-36) on Akt/GSK3 signaling pathway in hepatocytes.Methods:Human HL7702 cell line was cultured to the logarithmic growth stage and divided into experimental group and blank control group. The cultures were incubated with 100nM medium containing rhglp-1 (7-36) and without rhglp-1 (7-36) for 90min. The levels of Akt, Glycogen synthase Kinase 3 (GSK3) and Glycogen synthase (GS) in the two groups were detected by Western Blot.Results:Compared with blank control group, the protein expression of p-Akt (Thr308) in experimental group (1.81±0.28) was significantly increased ( P=0.01), but the protein expression of Akt and p-Akt (Ser473) was not significantly changed. The protein expression levels of p-GSK3α (Ser21) (1.27±0.09) and p-GSK3β (Ser9) (1.24±0.09) in the experimental group were significantly increased ( P=0.003, 0.002), while the protein expression levels of GSK3α and GSK3β were not significantly changed. The protein expression level of p-GS (Ser641) (0.70±0.16) was decreased in the experimental group ( P=0.03), but the protein expression level of GS did not change significantly. Conclusion:Glp-1 can inhibit GSK3/GS signaling pathway, activate GS activity and promote glycogen synthesis.

Effect of Prosopis ruscifolia on incretin and insulin secretion in alloxan-induced hyperglycemic rats / Efecto de Prosopis ruscifolia sobre la secreción de incretina e insulina de ratas hiperglicémicas por aloxano

Background: Diabetes mellitus treatment is based on oral hypoglycemic agents or insulin. Medicinal plants constitute an option, and the leaves of Prosopis ruscifolia (Pr) were shown to be effective in reducing glycemia in hyperglycemic animals. Objective: In this paper, we report the effect of P. rusciofolia (Pr) on insulin and incretin secretion in alloxan-induced hyperglycemic rats. Methodology: The effective dose was selected, and four groups (n=10) of Wistar rats were used. Two groups with normal glycemia received water or Pr (75 mg/Kg, per os, p.o.), and two groups with hyperglycemia induced by alloxan (intraperitoneal, ip), received water or Pr (75 mg/Kg, p.o.) for 2 weeks. Oral glucose tolerance test, and incretin and insulin levels were measured at the end of the experimental period. Results: The results showed that extract promotes better tolerance to oral glucose overload, in addition to a statistically significant (p<0.001) increase in blood levels of incretin and insulin, compared to the hyperglycemic rats. Conclusion: It is concluded that the ethanolic extract of P. ruscifolialeaves has a hypoglycemic effect in hyperglycemic animals by a mechanism that involves the incretin-insulin system

Antecedentes: la diabetes mellitus es una enfermedad metabólica cuyo tratamiento se basa en el uso de agentes hipoglicemiantes orales o insulina. Una opción al tratamiento son las plantas medicinales y en ese sentido, estudios previos en animales con hojas de Prosopis ruscifolia (Pr) han demostrado efecto hipoglicemiante. Objetivo: en este trabajo se reporta el efecto de P. rusciofolia (Pr) en la secreción de insulina e incretina, en ratas hiperglicémicas por aloxano. Metodología: se emplearon cuatro grupos de ratas Wistar (n=10). Dos grupos con glicemia normal que fueron tratadas con agua Pr (75 mg/Kg, per os, p.o.) y dos grupos con hiperglicemia inducida por la inyección intraperitoneal de aloxano recibieron agua Pr (75 mg/Kg, per os, p.o.) durante dos semanas. Se midieron la tolerancia oral a la glucosa, y los niveles de incretina e insulina al final del periodo de experimentación. Resultados: se encontró que el extracto promueve una mayor tolerancia a la sobrecarga de glucosa, y además un incremento significativo (p<0.001) de los niveles de incretina e insulina en sangre, comparados al grupo de ratas hiperglicémicas. Conclusión: se concluye que e l estracto etanólico de las hojas de P. ruscifolia tienen efecto hipoglicemiante en animales hiperglicémicos por un mecanismo que incluye al sistema incretina-insulina

Effects of Incretin - based Therapy on High - sensitivity C - reactive Protein in Patients with Type 2 Diabetes: A Systematic Review and Meta - Analysis

ABSTRACT Background: Recently, studies had shown that incretin-based therapies could reduce the levels of pro-inflammatory markers. The data on the effects of incretin-based therapies on serum high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetes (T2DM) were inconsistent. Objective: The objective of the study was to assess the effects of incretin-based therapies on hs-CRP in patients with T2DM by meta-analysis. Methods: We searched PubMed, EMBASE, the Cochrane Collaboration Library, and Web of Science to identify the eligible randomized clinical trials until August 2019. The pooled standard mean differences (SMD) were calculated by random-effects model using STATA 11.0. Results: Twenty-five studies with 28 randomized controlled trials were finally included into the meta-analysis. Meta-analysis revealed a significant reduction in hs-CRP following treatment with incretin-based regimens compared to controls (SMD = −0.452, p < 0.001). Subgroup analysis of different class of incretin-based drugs showed that therapy with both dipeptidyl peptidase 4 inhibitors (DPP-4Is, SMD = −0.338, p = 0.026) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs, SMD = −0.544, p = 0.003) caused significant reductions in hs-CRP. Besides, there was a significant reduction in hs-CRP with an intervention duration more than 24 weeks (SMD = −0.465, p = 0.001), while no significant difference with <24 weeks. Meta-regression analyses showed that better glycemic control and more body mass index (BMI) decline were associated with hs-CRP reduction after incretin-based therapies. Conclusions: This meta-analysis suggests that incretin-based therapies, both GLP-1 RAs and DPP-4Is, can cause a significant reduction in hs-CRP in patients with T2DM, which is related to long intervention duration, better glycemic control, and more BMI decline.

Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect - a narrative review

ABSTRACT Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.

Are dipeptidyl peptidase-4 inhibitors effective and safe in long term when added to ongoing therapies of diabetics? a real-life study in tertiary referral center

Background: The aim of this study was to determine how HbA1c, lipid, renal functions and such parameters were affected in the long term by adding dipeptidyl peptidase-4 inhibitors to the ongoing treatment regimens of patients with Type 2 diabetes mellitus.Methods: The study was conducted in diabetes mellitus outpatient clinic of Kayseri Training and Research Hospital between February 2012 and May 2017, with patients who did not achieve the sufficient success in diabetes their controls at the time of admission. From these patients, those who added (dipeptidyl peptidase-4 inhibitors) to their treatments were selected. Patients were followed up as long as they continued to these new treatments and the parameters at the baseline were compared with final values.Results: A total of 80 diabetic patients were followed in the study. The median age of the patients was 56.08±9.71 years. During this follow-up, an average decrease of 1.03% was noted when patients were compared with 9.53±1.87% of the initial hemoglobin A1c, and 8.50±1.48% of the Hemoglobin A1c values at the end of follow-up. This decrease was statistically significant (p <0.001). However, differences in the initial and final values of the lipid parameters of the patients were not statistically significant.Conclusions: Addition of dipeptidyl peptidase-4 inhibitors to patients' treatments causes significant decreases in Hemoglobin A1c mean values. This decline is long lasting. However, there are no positive or negative effects on biochemical parameters such as lipids, kidney and liver functions.

Factors Related to Blood Intact Incretin Levels in Patients with Type 2 Diabetes Mellitus

BACKGROUND: We performed this study to identify factors related to intact incretin levels in patients with type 2 diabetes mellitus (T2DM). METHODS: We cross-sectionally analyzed 336 patients with T2DM. Intact glucagon-like peptide 1 (iGLP-1) and intact glucose-dependent insulinotropic polypeptide (iGIP) levels were measured in a fasted state and 30 minutes after ingestion of a standard mixed meal. The differences between 30 and 0 minute iGLP-1 and iGIP levels were indicated as ΔiGLP-1 and ΔiGIP. RESULTS: In simple correlation analyses, fasting iGLP-1 was positively correlated with glucose, C-peptide, creatinine, and triglyceride levels, and negatively correlated with estimated glomerular filtration rate. ΔiGLP-1 was positively correlated only with ΔC-peptide levels. Fasting iGIP showed positive correlations with glycosylated hemoglobin (HbA1c) and fasting glucose levels, and negative correlations with ΔC-peptide levels. ΔiGIP was negatively correlated with diabetes duration and HbA1c levels, and positively correlated with Δglucose and ΔC-peptide levels. In multivariate analyses adjusting for age, sex, and covariates, fasting iGLP-1 levels were significantly related to fasting glucose levels, ΔiGLP-1 levels were positively related to ΔC-peptide levels, fasting iGIP levels were related to fasting C-peptide levels, and ΔiGIP levels were positively related to ΔC-peptide and Δglucose levels. CONCLUSION: Taken together, intact incretin levels are primarily related to C-peptide and glucose levels. This result suggests that glycemia and insulin secretion are the main factors associated with intact incretin levels in T2DM patients.

Role of DPP-4 inhibitors in the management of type 2 diabetes

Among various insulinotropic agents used in treatment of Type 2 DM, inclusion of DPP4 inhibitors are considered as major breakthrough as far as new drug development is concerned. In this review article we have discussed in detail about the pathogenesis of diabetes mellitus especially the role of incretin, DPP4 enzyme and implication of its inhibitors in treatment of DM. Also, various clinical studies regarding use of DPP4 inhibitors as monotherapy and as combination therapy with other antidiabetic agents were discussed. DPP-4 inhibitors control glucose in fasting as well as in postprandial state both in monotherapy and in combination with other oral antidiabetic agents. Significant reduction in HbA1c observed with DPP4 inhibitors as monotherapy. On combining DPP 4 inhibitor as add-on therapy to metformin, glitazone or sulphonylurea therapy in patients with type 2 diabetes not reaching therapeutic goals, DPP-4 inhibitors reduce HbA1c, fasting plasma glucose and 2-h postprandial plasma glucose up to the desired level. Various DPP-4 inhibitors have been proven to be as safe and tolerable both as monotherapy and combination with other antidiabetic agents. Inhibition of DPP-4 enzyme has been proven as a promising aspect in the treatment of type 2 diabetes and various drugs inhibiting DPP4 enzymes have been developed now. They are highly recommended in the treatment of Type 2 DM both as monotherapy as well as combination therapy.

History and development of incretin effect:the evidence and promise of incretin-based therapies in the clinical practice / 中华内分泌代谢杂志

The discovery and development of incretin effect has changed the landscape of diabetes treatment over past decades. Nowadays, incretin-based agents, such as glucagon-like peptide-1 ( GLP-1) receptor agonists and dipeptidyl peptidase-4 ( DPP-4) inhibitors have been wildly used in the therapy of type 2 diabetes. These agents show the beneficial effects on the multiple pathophysiological defects of type 2 diabetes, and provide a safe approach for achieving glycemic control with low risk of hypoglycemia and weight gain. Moreover, incretin-based therapies are still in development. Novel incretin-related therapies, such as fixed-dose combinations of GLP-1 receptor agonists and basal insulins, oral GLP-1 receptor agonists, and GLP-1 secretagogues, will be available in clinical practice in the near future.

Effects of incretin class of antidiabetic drugs on lipid metabolism in patients with type 2 diabetes and its mechanism / 中华内分泌代谢杂志

Chronic hyperglycemia is often accompanied by abnormal lipid metabolism, hypertension, low-grade systemic inflammation and oxidative stress.These factors increase the risk of cardiovascular disease(CVD)in type 2 diabetes mellitus(T2DM)patients.Comprehensive treatment of T2DM should emphasize the improvement of abnormal lipid metabolism, prevention of weight gain and reduction of the CVD risk in addition to proper glycemic control.Incretin, as a new hypoglycemic drug, has more advantages in improving glucose and lipid metabolism, finally to reduce cardiovascular risk.Through possible mechanisms including direct influence on liver lipid metabolism, change of fat mobilization and delay of gastric emptying, incretin shows positive influence on the lipid metabolic markers such as low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, triglycerides, and total cholesterol, while it improves glucose control.Thus, incretin plays an important role in the comprehensive management of type 2 diabetes mellitus.

The Validity of the Assessment Criteria and Data Extraction in Meta-Analysis Articles / 医薬品情報学

<b>Objective: </b>Clinical articles are important for individualization of drug therapy.  Especially, meta-analysis is positioned at the highest evidence level.  Therefore, we assessed the Quality Score of Meta-Analysis (QSMA) which provides simple assessments of both the quality and the format of meta-analyses, by applying them to incretin-related drugs as a model.  Furthermore, we attempted to extract clinical data from the literature employing a certain minimum standard.<br><b>Method: </b>We searched for meta-analyses of incretin-related drugs for diabetes in PubMed and the Cochrane Library, scoring the extracted articles for format using PRISMA statements, and for quality using QSMA.  Additionally, we classified these articles into two groups with a QSMA score of 70% as the basis, and verified the analysis sets (ITT, FAS, PP or APT) and sensitivity analysis.  Furthermore, we looked into those articles that scored 70% or higher to extract data that were deemed to have significant statistical differences.<br><b>Results: </b>Scoring of the 66 articles studied yielded 69.9±19.4% (mean ± SD) for format and 62.1±17.8% for quality.  These two variables produced a regression line of <i>y</i>=0.777<i>x</i>+7.834.  Comparison of the two groups classified on the basis of a 70% score on QSMA yielded a significant difference in sensitivity analysis only (<i>p</i><0.05).  Seven effects and five side effects were extracted from articles with a QSMA score of 70% or higher.<br><b>Conclusion: </b>Although QSMA can provide simple assessment of quality and structure using eight items, analysis sets needs to be verified individually.  As the articles assessed provided statistically endorsed data, the clinical application of QSMA will be an issue in the future.

Research progress of the relationship between glucagon and Type 1 diabetes / 医学研究生学报

The impact of glucagon on diabetes mellitus has become a hot area at present .Researchers hold that both the lack of isletβcells and islet αcells dysfunction exist in Type 1 diabetes mellitus (T1DM).Glucagon plays an important role in the occur-rence and development of T1DM, such as regulating the blood glucose and βcell function.Currently, a new therapy model represented by incretin is emerging , aiming at adjusting islet αcells function.And it has the prospect of becoming a new treatment of T 1DM be-sides insulin.Here we summarize the effect of glucagon on blood glucose and βcell function in T1DM, as well as the progress of T1DM treatment with glucagon as the therapeutic target .

The impact of three combinations vildagliptin/metformin, vildagliptin/pioglitazone, and metformin/pioglitazone on glycemic control and atherogenic dyslipidemia in patients with Type 2 diabetes mellitus.

Background: There are limitations of currently recommended stepwise treatment for Type 2 diabetes, especially failure with monotherapies to achieve the strict glycemic control. This has prompted the intensification of therapy with such combinations which have additive efficacy and complimentary mechanisms of action. Vildagliptin is one such agent with the above potential which does not increase the risk of hypoglycemia and does not promote weight gain. Methods: It was a prospective, open-label, randomized, and parallel group study involving 90 patients, divided into three Groups A, B, and C. Group A given vildagliptin/metformin (50/500 mg), Group B vildagliptin/pioglitazone (50/15 mg)and Group C metformin/pioglitazone (500/15 mg) combinations twice daily for 12 weeks. Fasting blood glucose (FBG) was estimated biweekly while hemoglobin A1c (HbA1c), lipid profile, insulin, and C-peptide levels at 0 and 12th week. Statistical analysis was done using ANOVA and Student’s t-test. Results: At the end, mean percentage of age fall in HbA1c and FBG from baseline was maximum in Group B, which was found out to be more efficacious than Group A and C (p<0.001) on glycemic parameters. Mean percentage of age decrease in triglyceride from baseline was maximum in Group C, which was found out to be more efficacious than Group A and B (p<0.001) on lipid parameters. The adverse effects were low in all the groups. However, the incidence of peripheral edema and weight gain was more with the use of Group C while nausea, vomiting, and nasopharyngitis was more with the use of Group A. Conclusion: Vildagliptin/pioglitazone combination is of choice in patients with uncontrolled hyperglycemia but normal lipid profile while metformin/pioglitazone combination in diabetic patients with dyslipidemia.

Clinical studies of incretin-based therapy in type 1 diabetes: a new approach of antidiabetic drugs? / 中华内分泌代谢杂志

Incretin-based therapies are now being widely used in type 2 diabetes as a new type of antidiabetic drugs,with their efficacy and safety having been confirmed.However,there are relatively few researches carried out in type 1 diabetes.A variety of clinical studies (mainly in type 2 diabetes) have shown that incretin-based therapy could effectively improve glucose control.In this article,the clinieal application of incretin-based therapy in type 1 diabetes will be reviewed and commented from the prospective of clinical studies,combined with animal experiments.

The new choice for the treatment of type 2 diabetes-DPP-4 inhibitors / 中国药学杂志

OBJECTIVE: To review the epidemiological status of type 2 diabetes (T2DM) and therapeutic applications of incre-tin-based novel oral hypoglycemic agents. METHODS: Based on the literatures in recent years, the mechanism and clinical evidence of DPP-4 inhibitors, particularly sitagliptin, in diabetes management were reviewed and introduced, especially sitagliptin. RESULTS AND CONCLUSION: DPP-4 inhibitors have many advantages and a good future in diabetes care, as either monotherapy or combination therapy. DPP-4 inhibitors have good safety profile and are recommend by some academic organizations.

A meta-analysis of GI adverse events of GLP-1 receptor agonists and DPP-4 inhibitors / 中国药学杂志

OBJECTIVE: To compare the gastrointestional (GI) adverse events of glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors by systematic review and meta-analysis to provide reference for clinicians. METHODS: The following databases were searched: Pubmed, Embase, Cochrane, ClinicalTrials, and CNKI. And the following terms were used to search head to head studies comparing the GI adverse events of GLP-1 receptor agonists and DPP-4 inhibitors: "GLP-1 receptor agonist", "DPP-4 inhibitor", "incretin-based therapy", "adverse events", and "safety". Meta-analysis was performed by Revman 5.0 software, with results expressed as odds ratio (OR) and 95% confidence interval (CI) for GI adverse events. RESULTS: A total of 1 231 articles were obtained, among which six randomized clinical trials (RCTs) which include 884 GLP-1 receptor agonists users and 798 DPP-4 inhibitors users (total number=1 682), were included for the meta-analysis. The result showed that GLP-1 receptor agonists were associated with a higher incidence of GI adverse events, the ORs of high dose GLP-1 receptor agonists versus DPP-4 inhibitors for nausea, vomiting, diarrhea, and constipation were 4.68(3.36, 6.52), 4.66(2.51, 8.65), 2.17(1.54, 3.06) and 2.39(1.35, 4.24), respectively; the ORs of low dose GLP-1 receptor agonists versus DPP-4 inhibitors for nausea, vomiting, diarrhea, and constipation were 4.09(3.06, 5.48), 3.80(2.22, 6.50), 2.06(1.46, 2.93) and 2.39(1.35, 4.24), respectively. CONCLUSION: Compared to DPP-4 inhibitors, GLP-1 receptor agonists are associated with a higher incidence of GI side effects including nausea, vomiting, diarrhea, and constipation.

Expression of Glucagon-Like Peptide-1 Receptor in Papillary Thyroid Carcinoma and Its Clinicopathologic Significance

BACKGROUND: Incretin-based therapies are rapidly becoming one of the main glycemic control strategies in diabetes. Considering the large numbers of papillary thyroid carcinomas (PTCs) and possible effects of glucagon-like peptide-1 (GLP-1) on cell proliferation, the expression of GLP-1 receptor (GLP-1R) in PTC is likely to have clinical significance. We performed this study to evaluate the expression of GLP-1R in PTC and the clinical meaning of GLP-1R expression in PTC. METHODS: Fifty-six cases of PTC, four cases of medullary thyroid cancer (MTC), seven cases of nodular hyperplasia and 56 normal thyroid tissue samples were selected for immunostaining for GLP-1R. Clinical parameters were obtained by retrospective review of medical records. RESULTS: Immunohistochemical staining for GLP-1R showed immunoreactivity in 18 of 56 cases of PTC (32.1%). All four cases of MTC exhibited cytoplasmic GLP-1R expression. Nodular hyperplasia exhibited immunoreactivity in two of seven cases (28.6%). All normal thyroid follicular cells showed negative immunoreactivity. In univariable and multivariable analyses, tumor multifocality was negatively correlated with GLP-1R expression. Extrathyroidal extension showed positive association with GLP-1R expression that was almost significant. Sex, age, tumor size, and lymph node metastasis were not significantly associated with GLP-1R expression. CONCLUSION: Some parts of PTC tissues express GLP-1R, and GLP-1R expression in PTC was negatively correlated with tumor multifocality. The long-term influence of pharmacologically increased GLP-1 on thyroid follicular cells and development and progression of tumors originating from thyroid follicular cells should be investigated.

Dipeptidyl Peptidase-4 Inhibitor / 대한내과학회지

Recent advances in incretin biology have led to the development of a new class of oral anti-diabetic drugs. To date, there are two known incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), of which the former is a more important therapeutic target for type 2 diabetes. GLP-1 is secreted by intestinal L-cells in response to oral nutrient intake, and it stimulates insulin secretion and suppresses glucagon secretion in a glucose-dependent manner. However, both GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase-4 (DPP-4), a multifunctional type II transmembrane glycoprotein. Thus, several DPP-4 inhibitors with different pharmacologic features are now available and can be used either as monotherapy or in combination with other anti-diabetic agents for the treatment of type 2 diabetes. In both therapeutic regimens, DPP-4 inhibitors have been shown to reduce hemoglobin A1c levels by approximately 0.5-0.8%. In clinical trials, DPP-4 inhibitors were generally well-tolerated, posed a low risk of hypoglycemia, and did not increase body weight. Despite some reports of a possible increased risk of pancreatitis with GLP-1 receptor agonists and DPP-4 inhibitors, no causal associations have been found. Recent randomized controlled clinical trials have shown that DPP-4 inhibitors did not increase or decrease the rates of major adverse cardiovascular events in patients with type 2 diabetes at high risk of cardiovascular disease, even though this class of anti-diabetic agents had various salutary effects in many studies involving animals or healthy and diabetic humans. Additional studies will be required to resolve these disparate conclusions.

Glucagon-Like Peptide-1 (GLP-1) Agonist / 대한내과학회지

The prevalence of diabetes is increasing worldwide. Glycemic control has been shown to prevent microvascular complications. Many oral hyperglycemic drugs and insulin are being used in the treatment of diabetes, but the effects of those treatments are suboptimal. The two incretin hormones GLP-1 and GIP are released from L- and K-cells, respectively, in response to nutrient intake. GLP-1 stimulates glucose-dependent insulin release. Recently, incretin hormone-based therapies, including GLP-1 agonists and DPP-4 inhibitors, have been used as new treatment options to control glucose levels in patients with type 2 diabetes mellitus. The purpose of this article is to review the efficacy and safety of GLP-1 agonists in the treatment of type 2 diabetes.

Effect of Sitagliptin in Type 1 or Type 2 Diabetic Patients with Absolute Insulin Deficiency: A 48 Weeks Observational Study.

Aims: The aim of this study is to investigate the long-term efficacy of sitagliptin added to insulin in type 1 or type 2 diabetic patients with absolute insulin deficiency. Study Design: 48 weeks open-label, observational study. Place and Duration of Study: Department of Internal Medicine, Gyoda General Hospital, between June 2010 and December 2012. Methodology: Sitagliptin 25-100 mg/day was added to the ongoing insulin therapy in those without any detectable post-meal C-peptide levels. HbA1c and other parameters were followed for 48 weeks. Results: Effective reductions of HbA1c levels were already observed at 12 weeks and sustainable throughout the study period. However, 2 subjects had severe hypoglycemic evens. Post-meal C-peptide remained undetectable with all the subjects. Interestingly, significant increases of body weight were observed. Conclusion: Sitagliptin as an adjunct to insulin in patients with absolute insulin deficiency may be effective and sustainable for at least 48 weeks, allowing for less intense therapy. However, it should be noted that some patients may have severe hypoglycemic events. In spite of the significant glycemic effects of sitagliptin in the setting of this study, endogenous insulin secretory capacity remained absent, suggesting that the glucose lowering effect of this drug may be mediated through GLP-1 independent pathway as well.