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1.
Front Endocrinol (Lausanne) ; 13: 821113, 2022.
Article in English | MEDLINE | ID: mdl-35518937

ABSTRACT

One of the complications of chronic hyperglycemia and insulin resistance due to type 2 diabetes mellitus (T2DM) on the hypothalamic-pituitary-gonadal axis in men, is the high prevalence of hypogonadotropic hypogonadism, which has been recently defined as functional hypogonadism, characterized by low testosterone associated with inappropriately normal gonadotropin levels. Although the pathophysiology of this hormonal imbalance may be related to several factors, including glycemic control, concomitant sleep apnea, insulin resistance, the main role is determined by the degree of central or visceral obesity and the consequent inflammatory state. Several drugs have been developed to treat T2DM such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase 4 inhibitors, and sodium-glucose co-transporter 2 inhibitors. All appear to be effective in ameliorating blood glucose control, by lowering inflammation and body weight, and most seem to reduce the risk of micro- and macrovascular damage as a consequence of uncontrolled diabetes. A few studies have evaluated the impact of these drugs on gonadal function in T2DM patients with hypogonadism, with promising results. This review summarizes the main current knowledge of the effects of these new antidiabetic drugs on the hypothalamus-pituitary-gonadal axis, showing their potential future application in addition to glucose control in dysmetabolic male patients.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Hypogonadism , Insulin Resistance , Sodium-Glucose Transporter 2 Inhibitors , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Hypogonadism/complications , Hypogonadism/drug therapy , Male , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
2.
Sci Rep ; 12(1): 6708, 2022 Apr 25.
Article in English | MEDLINE | ID: mdl-35468904

ABSTRACT

Diabetes is a chronic disease leading to memory difficulties and deterioration of learning abilities. The previous studies showed that modulation of inflammatory pathways in the diabetic brain may reduce dysfunction or cell death in brain areas which are important for control of cognitive function. In the present study, we investigated the neuroprotective actions of newly synthesized adamantane derivatives on diabetes-induced cognitive impairment in mice. Our study relied on the fact that both vildagliptin and saxagliptin belong to DPP4 inhibitors and, contain adamantanyl group. Efficacy of tested compounds at reversing diabetes-induced different types of memory impairment was evaluated with the use of selected behavioural tests. The following neuroinflammatory indicators were also analyzed: neuroinflammatory indicators and the expression of genes involved in the inflammatory response of brain (Cav1, Bdnf). Our study demonstrated that new adamantane derivatives, similarly to DPP4 inhibitors, can restrict diabetes-induced cognitive deficits. We demonstrated that the overexpression of GLP-1-glucagon-like peptide as well as Bdnf, Cav1 genes translate into central blockade of pro-inflammatory synthesis of cytokines and significantly improvement on memory performance in diabetes mice. Newly synthesized adamantane derivatives might have important roles in prevention and treatment of cognitive impairment by inflammatory events in patients with diabetes or related diseases.


Subject(s)
Adamantane , Cognitive Dysfunction , Diabetes Mellitus , Dipeptidyl-Peptidase IV Inhibitors , Adamantane/pharmacology , Adamantane/therapeutic use , Animals , Brain-Derived Neurotrophic Factor/genetics , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/etiology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dopamine Agents , Humans , Inflammation/drug therapy , Inflammation Mediators , Mice , Neuronal Plasticity
3.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35443381

ABSTRACT

Diabetes mellitus implies a group of common metabolic disorders that share a phenotype of hyperglycemia. Peripheral insulin resistance and impaired insulin secretion forms two legs of this common, globally important non communicable disorder. Adiponectin is a hormone released by adipocytes which aids in enhancing insulin sensitivity, decreasing inflammatory mediators. Baseline adiponectin can predict diabetes and change in its value with change in metabolic parameters highlights the gravity of this molecule in more refined diagnosis and treatment of diabetes. AIMS: The objective was to ascertain change in adiponectin value in diabetics who were given either DPP-4 inhibitors or SU group drugs. Another objective was to find out correlation of serum adiponectin levels with various parameters involved in sugar and fat metabolism such as FBS, PPBS, HbA1c, LDL, HDL, VLDL, TG. MATERIAL: Total of 50 participants were taken, out of which 40 were diabetics and 10 were controls. They were selected using inclusion and exclusion criteria. Diabetics were divided into two arms with 20 participants each (a. dpp group b.su group). Clinical history, examination, sample collection was done. Serum adiponectin assay was performed using RayBio ELISA kit. OBSERVATION: Serum adiponectin levels in dpp group was higher at end of third month as compared to 0 month (45.9 +/- 5.9 vs. 39.8 +/- 4.1 mcg/dl; p<0.05). Likewise, adiponectin levels in su group was higher at end of third month as compared to 0 month (43.9 +/- 3.6 vs. 39.8 +/- 3.5 mcg/dl; p<0.05). CONCLUSION: Improvement in glycemic parameters (HbA1c, FBS, PPBS) is associated with rise in serum levels of adiponectin. General population possess higher levels of adiponectin as compared to diabetics. Adiponectin can serve as a marker for early diagnosis to diabetes. It can also aid in targeted therapy for metabolic disorders.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Insulin Resistance , Adiponectin , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/therapeutic use , Glycated Hemoglobin A/analysis , Humans , Sulfonylurea Compounds/therapeutic use
4.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35443346

ABSTRACT

Assessment of diabetes with daily blood glucose fluctuations including peaks and nadirs forms the crux of the modern management. Use of glycemic variability (GV) as a parameter to assess these fluctuations is emerging. It is important to determine the hyperglycemic and hypoglycemic episodes which are the culprits for increasing glycemic variation. Diabetes mellitus patients follow different clinical trajectories which can be traced by the ambulatory glucose profile (AGP) obtained from flash glucose monitoring system (FGMS). MATERIAL: This comparative observational study enrolled 106 adult (>18 years) type 2 diabetes patients with HbA1c<8%. Patients were divided into two groups (group A & group B) with 53 patients each. Group A included patients on OAD's (oral antidiabetic drug) with insulin and Group B included patients on OAD's without insulin. The patients were put on FGMS for 14 days and their AGP was analysed. Hyperglycemic episodes (level 1- >180 mg/dl, level 2- >250 mg/dl) and hypoglycemic episodes (level 1- 54-70 mg/dl, level 2- <54 mg/dl) were determined between the groups. OBSERVATION: Group A patients had significantly higher (29.99%) total number of hyperglycemic episodes (Level 1+ Level 2) as compared with group B (9.08%) (p <0.0001). Amongst group A, proportion of patients with total number of hyperglycemic episodes was significantly higher in insulin only subgroup (58.11%) followed by insulin +metformin+ 1 OAD (29.14%) & insulin+ metformin (26.82%) (p <0.0001). Amongst group B, total number of hyperglycemic episodes were found to be significantly higher with metformin only subgroup (10.19%) followed by metformin + 1 OAD (9.72%) & metformin + >1 OAD (8.1%) (p<0.0001). Amongst the add on OAD's, sulfonylurea contributed to 61.07% hyperglycemic episodes in group A & 11.63% in group B which was statistically more than DPP-4 inhibitors with 14.91% & 2.84% respectively (p <0.0001). Total number of hypoglycemic episodes seen in group A patients (8.66%) were significantly less as compared with group B (13.27%) (p<0.0001). Sulfonylurea contributed to 7.5% hypoglycemic episodes in group A & 13.2% in group B which was statistically more than DPP-4 inhibitors with 6.49% & 12.35% respectively when added to metformin (p<0.0001). CONCLUSION: Amongst the OAD's used in type 2 diabetes mellitus patients in this study, total number of hyperglycemic and hypoglycemic episodes were found to be more in patients taking sulfonylurea as compared with DPP4 inhibitors when used in combination with metformin with or without insulin.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Hypoglycemia , Metformin , Adult , Blood Glucose/analysis , Blood Glucose Self-Monitoring , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Therapy, Combination , Glucose , Glycated Hemoglobin A/analysis , Humans , Hypoglycemia/chemically induced , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Metformin/therapeutic use , Precision Medicine , Sulfonylurea Compounds/therapeutic use
5.
Int J Mol Sci ; 23(7)2022 Mar 27.
Article in English | MEDLINE | ID: mdl-35409028

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD), the most frequent liver disease in the Western world, is a common hepatic manifestation of metabolic syndrome (MetS). A specific cure has not yet been identified, and its treatment is currently based on risk factor therapy. Given that the initial accumulation of triglycerides in the liver parenchyma, in the presence of inflammatory processes, mitochondrial dysfunction, lipotoxicity, glucotoxicity, and oxidative stress, can evolve into non-alcoholic steatohepatitis (NASH). The main goal is to identify the factors contributing to this evolution because, once established, untreated NASH can progress through fibrosis to cirrhosis and, ultimately, be complicated by hepatocellular carcinoma (HCC). Several drugs have been tested in clinical trials for use as specific therapy for NAFLD; most of them are molecules used to cure type 2 diabetes mellitus (T2DM), which is one of the main risk factors for NAFLD. Among the most studied is pioglitazone, either alone or in combination with vitamin E, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors. Actually, the most promising category seems to be sodium-glucose cotransporter (SGLT2) inhibitors. Their action is carried out by inhibiting glucose reabsorption in the proximal renal tubule, leading to its increased excretion in urine and decreased levels in plasma. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD/NASH, and several trials in patients have proven their beneficial effects on liver enzymes, BMI, blood lipids, blood glucose, and insulin resistance in NAFLD patients, thus creating strong expectations for their possible use in preventing the evolution of liver damage in these patients. We will review the main pathogenetic mechanisms, diagnostic modalities, and recent therapies of NAFLD, with particular attention to the use of SGLT2 inhibitors.


Subject(s)
Carcinoma, Hepatocellular , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Sodium-Glucose Transporter 2 Inhibitors , Animals , Carcinoma, Hepatocellular/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucose/therapeutic use , Humans , Hypoglycemic Agents/adverse effects , Liver/metabolism , Liver Neoplasms/drug therapy , Non-alcoholic Fatty Liver Disease/complications , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
6.
Bioorg Chem ; 123: 105767, 2022 06.
Article in English | MEDLINE | ID: mdl-35381556

ABSTRACT

Type 2 diabetes mellitus (T2DM) is one of the most popular chronic diseases around the whole world. To improve the compliance of patients, long-acting antidiabetic drugs needed to be developed. Dipeptidyl peptidase-4 (DPP-4) inhibitors are becoming increasingly important in the T2DM treatment due to the favorable properties. In the present study, a series of new substituted dihydropyrido [4',3':3,4] pyrazolo [1,5-a] pyrimidin-9(10H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine were designed and synthesized as potent DPP-4 inhibitors. All compounds were characterized by 1H NMR, 13C NMR and HRMS and were evaluated in vitro. The inhibitory activity ranged from 0.43 to 12.70 µM while the inhibitory activity of positive control (omarigliptin) was 3.63 µM on DPP-4 in Caco-2 cells. Then pharmacokinetic studies were carried out in rats and compound 6c was finally selected for the further study because of its better pharmacokinetic profile. Additionally, preclinical pharmacological study of compound 6c exhibited extraordinary efficacy in vivo and good safety profile. In conclusion, compound 6c was considered as a promising DPP-4 inhibitor, which could be taken once a week or once every two weeks for the treatment of T2DM. More comprehensive researches will be carried out in the future for the further development of compound 6c.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Animals , Caco-2 Cells , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4 , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Rats
7.
Diabetes Metab Syndr ; 16(4): 102474, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35378386

ABSTRACT

BACKGROUND AND AIMS: Clinical trials indicate the efficacy of add-on therapy using incretin-related drugs to treat type 2 diabetes mellitus (DM) inadequately controlled by insulin. However, heterogeneity exists among these studies. Baseline body mass index (BMI) accounts for the heterogeneity of add-on therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors and the associated higher BMI with a lower efficacy. The efficacy of add-on therapy with glucagon-like peptide-1 (GLP-1) receptor agonists remains unclear. METHODS: We performed a meta-analysis of randomized controlled trials of ≥12 weeks reporting the endpoint of adjusted mean change in hemoglobin A1c levels (AMΔHbA1c) or hypoglycemia incidence. Patients with type 2 DM treated with insulin alone or with metformin for at least 8 weeks before the study treatment were included. The intervention group received liraglutide co-administered with insulin or a fixed-dose combination. The control group received a placebo or insulin. Covariates included five baseline parameters (HbA1c, fasting plasma glucose, BMI, type 2 DM duration, and treatment duration). RESULTS: Seven studies (2067 patients) were selected. AMΔHbA1c was -1.00% (95% confidence interval [CI]: -1.21 to -0.78, I2 = 74.7%). The odds ratio for hypoglycemia incidence was 0.97 (95% CI: 0.50-1.87, I2 = 81.9%). Covariates did not account for the heterogeneity in AMΔHbA1c or hypoglycemia incidence. CONCLUSIONS: Liraglutide add-on therapy reduced HbA1c levels without increasing hypoglycemia incidence, independent of BMI, in insulin non-responders with type 2 DM. GLP-1 receptor agonists may be more suitable than DPP-4 inhibitors for add-on therapy in patients with high BMI. REGISTRATION NUMBER: PROSPERO #CRD42021178888.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Hypoglycemia , Diabetes Mellitus, Type 2/complications , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Therapy, Combination , Glycated Hemoglobin A , Humans , Hypoglycemia/chemically induced , Hypoglycemia/epidemiology , Hypoglycemia/prevention & control , Hypoglycemic Agents , Insulin/therapeutic use , Liraglutide/therapeutic use , Treatment Outcome
8.
Life Sci ; 298: 120515, 2022 Jun 01.
Article in English | MEDLINE | ID: mdl-35367243

ABSTRACT

AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been extensively used for the treatment of type 2 diabetes mellitus. Nevertheless, side effects like sore throat and diarrhea also occur in DPP-4 inhibitors treatment. The study aims to identify and develop novel DPP-4 inhibitors with better therapeutic profiles. MATERIALS AND METHODS: Here we synthesized a series of vildagliptin analogs, and among which, ZD-2 showed the moderate inhibition of DPP-4 activity compared with vildagliptin. High-fat-diet (HFD) mice were treated with ZD-2 (4.5 and 7.5 mg/kg) or vildagliptin (6 mg/kg) for 7 weeks following the examinations of metabolic index and pancreatic ß-cell function. Mouse pancreatic cell line MIN6 was used to evaluate ß-cell function, and intestinal enteroendocrine cell line STC-1 was used to evaluate the expression of gut hormones. KEY FINDINGS: The IC50 of ZD-2 was over 30-fold higher than vildagliptin. However, both ZD-2 and vildagliptin treatment showed comparable effects on improving glucose tolerance and reducing the steatosis of liver and fat mass in HFD mice. Moreover, ZD-2 exerted ß-cell-protective actions by preserving islet ß-cell mass and increasing the expression of functional ß-cell-related genes. Additionally, ZD-2 also stimulated the expression of gut hormones in STC-1 cells. SIGNIFICANCE: ZD-2 showed comparable anti-diabetic activities in HFD-fed mice although its lower potency on inhibition of DPP-4 compared with vildagliptin. Protection of ß-cell function might contribute to its anti-diabetic effects.


Subject(s)
Adamantane , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Animals , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diet, High-Fat/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glycemic Control , Hormones/therapeutic use , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Mice , Mice, Obese , Nitriles/pharmacology , Nitriles/therapeutic use , Pyrrolidines/pharmacology , Vildagliptin/pharmacology , Vildagliptin/therapeutic use
9.
Endocrinol Diabetes Nutr (Engl Ed) ; 69(3): 209-218, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35353681

ABSTRACT

BACKGROUND: This consensus aims to clarify the role of Dipeptidyl Peptidase-4 inhibitors (iDPP-4) in managing patients with diabetes during the COVID-19 pandemic. MATERIALS AND METHODS: A PubMed bibliographic search was carried out (December 2019-February 2021). Oxford methodology was used for the evaluation of evidence and possible recommendations were established by consensus. RESULTS: Diabetes appears to be an independent factor in COVID-19 disease (evidence 2b). No increased risk of contagion with iDPP-4 is demonstrated (evidence 2b), and its use has been shown to be safe (evidence 2b). The use of this drug may present a specific benefit in reducing mortality, particularly in in-hospital use (evidence 2a), reducing admission to intensive care units (evidence 2b) and the need for mechanical ventilation (evidence 2b). CONCLUSIONS: The use of iDPP-4 appears to be safe in patients with COVID-19, and quality studies are needed to clarify their possible advantages further.


Subject(s)
COVID-19 , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Consensus , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Pandemics
10.
BMC Res Notes ; 15(1): 120, 2022 Mar 29.
Article in English | MEDLINE | ID: mdl-35351190

ABSTRACT

OBJECTIVES: Due to the increase of type 2 diabetes (T2D), the number of patients in treatment with multiple anti-diabetic agents is increased. According to the recent recommendation of treatment guidelines, sodium-glucose cotransporter 2 (SGLT2) inhibitors would be used as additional treatment to the currently administered anti-diabetic drugs for poorly controlled T2D patients. Here, we assessed the efficacy of SGLT2 inhibitors added to the current treatment with metformin, dipeptidyl peptidase-4 (DPP4) inhibitors, or both in Japanese T2D patients. RESULTS: Japanese T2D subjects with poor glucose control, who were treated with metformin (n = 10), DPP4 inhibitors (n = 11), or both (n = 28) and who were in need of additional treatment, were recruited. HbA1c levels before and 6 months after addition of SGLT2 inhibitor treatment were used to compare the effectiveness. The HbA1c levels after addition of SGLT2 inhibitors significantly decreased in all groups. The change in HbA1c levels (delta HbA1c) showed no significant difference between the three groups. The present data indicated that addition of SGLT2 inhibitors to metformin and/or DPP4 inhibitors is equally effective in the treatment of Japanese T2D patients.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Sodium-Glucose Transporter 2 Inhibitors , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/therapeutic use , Japan , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
11.
Front Endocrinol (Lausanne) ; 13: 836365, 2022.
Article in English | MEDLINE | ID: mdl-35330915

ABSTRACT

Objective: We assessed the effects of sodium glucose cotransporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) in a large real-world Asian cohort with type 2 diabetes (T2D) and performed a systematic review with integrating the present study findings to provide up-to-date evidence from the Asian perspective. Methods: New users of SGLT2is or DPP4is were identified from the Taiwan's National Health Insurance Research Database and followed until 2018. Primary outcomes were hospitalization for heart failure (HHF) and three-point major adverse cardiovascular event (3P-MACE; namely, myocardial infarction [MI], stroke, or cardiovascular death). Other outcomes included all-cause death, chronic kidney disease (CKD), amputation, and hospitalized hypoglycemia. Subdistribution hazard models were employed to assess treatment-associated clinical outcomes. Results: A total of 21,329 SGLT2i and DPP4i propensity-score-matched pairs were analyzed. SGLT2is versus DPP4is showed lower risks of HHF (hazard ratio [95% CI]: 0.52 [0.45-0.59]), 3P-MACE (0.62 [0.55-0.70]), MI (0.63 [0.50-0.79]), stroke (0.60 [0.51-0.70]), all-cause death (0.57 [0.49-0.67]), CKD (0.46 [0.43-0.50]), amputation (0.64 [0.42-0.98]), and hospitalized hypoglycemia (0.54 [0.45-0.64]). Our results were consistent with findings from a systematic review. Conclusion: Among Asian patients with T2D, SGLT2is versus DPP4is showed benefits for several clinical outcomes. More research is warranted to explore the heterogeneous treatment effects of SGLT2is and DPP4is by race/ethnicity.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Heart Failure , Hypoglycemia , Myocardial Infarction , Renal Insufficiency, Chronic , Sodium-Glucose Transporter 2 Inhibitors , Stroke , Amputation , Cohort Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Female , Heart Failure/drug therapy , Humans , Hypoglycemia/chemically induced , Hypoglycemic Agents/therapeutic use , Male , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/epidemiology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use
12.
Int J Mol Sci ; 23(6)2022 Mar 12.
Article in English | MEDLINE | ID: mdl-35328486

ABSTRACT

The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-α treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-α-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1ß (IL-1ß) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-κB (NF-κB)-dependent pathway. Linagliptin attenuated tissue factor expression via the Akt/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Sepsis , Thrombosis , Animals , Dipeptidyl Peptidase 4 , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases , Disease Models, Animal , Human Umbilical Vein Endothelial Cells , Humans , Hypoglycemic Agents/pharmacology , Inflammation/drug therapy , Linagliptin/pharmacology , Linagliptin/therapeutic use , Lipopolysaccharides/pharmacology , Mice , Microcirculation , Sepsis/complications , Sepsis/drug therapy , Thrombosis/drug therapy , Thrombosis/etiology , Tumor Necrosis Factor-alpha/pharmacology
13.
Sci Rep ; 12(1): 5129, 2022 03 24.
Article in English | MEDLINE | ID: mdl-35332212

ABSTRACT

Dipeptidyl-peptidase-4 inhibitors (DPP4i) have been the most used antidiabetic medications worldwide due to their good safety profiles and tolerability with a low risk of hypoglycemia, however, large cardiovascular outcome trials (CVOTs) have not shown any significant the prognostic superiority. On the contrary, since observational studies have suggested the effects of DPP4i are enhanced some populations, such as Asians and those who without overweight, their prognostic benefit is still under debate. The aim of this study was thus to assess the prognostic impact of DPP4i in patients with both diabetes and coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI) through the insulin-like growth factor-1 (IGF-1) axis, a substrate of DPP4. This single-center analysis involved consecutive Japanese diabetic patients who underwent PCI for the first time between 2008 and 2018 (n = 885). Primary and secondary endpoints were set as cardiovascular (CV) death and the composite of CV death, non-fatal myocardial infarction and ischemic stroke (3P-MACE). Serum levels of IGF-1 and its main binding protein (insulin-like growth factor binding protein-3: IGFBP-3) were measured. In consequences, unadjusted Kaplan-Meier analyses revealed reduced incidences of CV-death and 3P-MACE by DPP4i, which was particularly enhanced in patients who were not overweight (BMI ≤ 25). Multivariate Cox hazard analyses consistently indicated reduced risks of CV death by DPP4i at PCI (hazard ratio (HR) 0.39, 95% confidence interval (CI) 0.16-0.82, p = 0.01) and 3P-MACE (HR 0.47, 95% CI 0.25-0.84, p = 0.01), respectively. Moreover, elevated IGF-1 activity indicated by the IGF-1/IGFBP-3 ratio was associated with decreased risks of both endpoints and it was significantly higher in patients with DPP4i (p < 0.0001). In conclusion, the findings of the present study indicate beneficial effects of DPP4i to improve outcomes in Japanese diabetic patients following PCI, which might be mediated by DPP4-IGF-1 axis.


Subject(s)
Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Diabetes Mellitus , Dipeptidyl-Peptidase IV Inhibitors , Percutaneous Coronary Intervention , Cardiovascular Diseases/epidemiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Dipeptidyl Peptidase 4 , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Heart Disease Risk Factors , Humans , Insulin-Like Growth Factor Binding Protein 3 , Insulin-Like Growth Factor I , Percutaneous Coronary Intervention/adverse effects , Risk Factors , Treatment Outcome
14.
BMC Nephrol ; 23(1): 117, 2022 03 24.
Article in English | MEDLINE | ID: mdl-35331159

ABSTRACT

BACKGROUND: Host factors such as angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine-subtype-2 (TMPRSS2) are important factors for SARS-CoV-2 infection. Clinical and pre-clinical studies demonstrated that RAAS-blocking agents can be safely used during a SARS-CoV-2 infection but it is unknown if DPP-4 inhibitors or SGLT2-blockers may promote COVID-19 by increasing the host viral entry enzymes ACE2 and TMPRSS2. METHODS: We investigated telmisartan, linagliptin and empagliflozin induced effects on renal and cardiac expression of ACE2, TMPRSS2 and key enzymes involved in RAAS (REN, AGTR2, AGT) under high-salt conditions in a non-diabetic experimental 5/6 nephrectomy (5/6 Nx) model. In the present study, the gene expression of Ace2, Tmprss2, Ren, Agtr2 and Agt was assessed with qRT-PCR and the protein expression of ACE2 and TMPRSS2 with immunohistochemistry in the following experimental groups: Sham + normal diet (ND) + placebo (PBO); 5/6Nx + ND + PBO; 5/6Nx + high salt-diet (HSD) + PBO; 5/6Nx + HSD + telmisartan; 5/6Nx + HSD + linagliptin; 5/6Nx + HSD + empagliflozin. RESULTS: In the kidney, the expression of Ace2 was not altered on mRNA level under disease and treatment conditions. The renal TMPRSS2 levels (mRNA and protein) were not affected, whereas the cardiac level was significantly increased in 5/6Nx rats. Intriguingly, the elevated TMPRSS2 protein expression in the heart was significantly normalized after treatment with telmisartan, linagliptin and empagliflozin. CONCLUSIONS: Our study indicated that there is no upregulation regarding host factors potentially promoting SARS-CoV-2 virus entry into host cells when the SGLT2-blocker empagliflozin, telmisartan and the DPP4-inhibitor blocker linagliptin are used. The results obtained in a preclinical, experimental non-diabetic kidney failure model need confirmation in ongoing interventional clinical trials.


Subject(s)
COVID-19 , Dipeptidyl-Peptidase IV Inhibitors , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Animals , COVID-19/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Kidney/metabolism , Nephrectomy , Rats , SARS-CoV-2 , Sodium-Glucose Transporter 2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
15.
J Am Heart Assoc ; 11(7): e023489, 2022 Apr 05.
Article in English | MEDLINE | ID: mdl-35322676

ABSTRACT

Background Evidence is limited in comparing treatment modification by substitution or add-on of glucose-lowering medications in patients with type 2 diabetes. This observational study aims to compare switching versus add-on of incretin-based drugs among patients with type 2 diabetes on background sodium-glucose cotransporter-2 inhibitors (SGLT2i). Methods and Results This population-based, retrospective cohort study was conducted using the IQVIA Medical Research Data, including adults with type 2 diabetes on background SGLT2i from 2005 to 2020. New users of incretin-based drugs were allocated into the "Switch" group if they had discontinued SGLT2i treatment, or the "Add-on" group if their background SGLT2i was continued. Baseline characteristics of patients were balanced between groups. Study outcomes were all-cause mortality, cardiovascular diseases, kidney diseases, hypoglycemia, and ketoacidosis. Patients were observed from the index date of initiating incretin-based drugs until the earliest of an outcome event, death, or data cut-off date. Changes in anthropometric and metabolic parameters were also compared between groups from baseline to 12-month follow-up. A total of 2888 patients were included, classified into "Switch" (n=1461) or "Add-on" group (n=1427). Median follow-up was 18 months with 5183 person-years. Overall, no significant differences in the risks of study outcomes were observed between groups; however, patients in the "Add-on" group achieved significantly greater reductions in glycated hemoglobin, weight, percentage weight loss, and systolic blood pressure than their "Switch" counterparts. Conclusions Initiating incretin-based drugs as add-on among patients with type 2 diabetes on background SGLT2i was associated with risks of clinical end points comparable to switching treatments, in addition to better glycemic and weight control observed with the combination approach.


Subject(s)
Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Sodium-Glucose Transporter 2 Inhibitors , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Glucose , Humans , Hypoglycemic Agents/adverse effects , Incretins/adverse effects , Retrospective Studies , Sodium , Sodium-Glucose Transporter 2 Inhibitors/adverse effects
17.
Front Immunol ; 13: 830863, 2022.
Article in English | MEDLINE | ID: mdl-35309368

ABSTRACT

Dipeptidyl-peptidase IV (DPP4), originally identified as an aminopeptidase in 1960s, is an ubiquitously expressed protease presented as either a membrane-bound or soluble form. DPP4 cleaves dipeptide off from the N-terminal of its substrates, altering the bioactivity of its substrates. Subsequent studies reveal that DPP4 is also involved in various cellular processes by directly binding to a number of ligands, including adenosine deaminase, CD45, fibronectin, plasminogen, and caveolin-1. In recent years, many novel functions of DPP4, such as promoting fibrosis and mediating virus entry, have been discovered. Due to its implication in fibrotic response and immunoregulation, increasing studies are focusing on the potential role of DPP4 in inflammatory disorders. As a moonlighting protein, DPP4 possesses multiple functions in different types of cells, including both enzymatic and non-enzymatic functions. However, most of the review articles on the role of DPP4 in autoimmune disease were focused on the association between DPP4 enzymatic inhibitors and the risk of autoimmune disease. An updated comprehensive summary of DPP4's immunoregulatory actions including both enzymatic dependent and independent functions is needed. In this article, we will review the recent advances of DPP4 in immune regulation and autoimmune rheumatic disease.


Subject(s)
Autoimmune Diseases , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Immunity
18.
J Ethnopharmacol ; 292: 115203, 2022 Jun 28.
Article in English | MEDLINE | ID: mdl-35304277

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Gynura divaricata (L.) DC. (GD), a herbal medicine, has been used for the prevention and treatment of hyperglycemia in China. However, hypoglycemic ingredients within GD have not yet been well studied. AIM OF THE STUDY: The aim of this study was to explore undiscovered compounds with dipeptidyl peptidase IV (DPP-IV) inhibitory activity within GD. MATERIALS AND METHODS: A four-step strategy was developed to explore undiscovered DPP-IV inhibitors within GD. First, the components were preliminarily characterized using UHPLC-HRMS combined with a library search. Second, preliminarily characterized compounds were searched for potential bioactivity. Third, a mixture of these preliminarily characterized compounds was isolated and thoroughly characterized based on fragmentation patterns associated with molecular networking. Fourth, the activities of these compounds were verified using DPP-IV inhibitory assay and molecular docking. RESULTS: Diprotin A, a tripeptide inhibitor against DPP-IV, was identified. Thereafter, a mixture of twenty-five diprotin A analogs was isolated and characterized, which exhibited IC50 of 0.40 mg/mL for DPP-IV. Molecular docking results also confirmed the interactions between the tripeptide analogs and DPP-IV mainly via H-bonds and hydrophobic interactions. CONCLUSIONS: This is the first report of DPP-IV inhibitors within GD. These findings demonstrate that the extract of GD might be beneficial for the treatment of type 2 diabetes mellitus, and is expected to promote further development and utilization of GD in herbal medicine.


Subject(s)
Asteraceae , Diabetes Mellitus, Type 2 , Dipeptidyl-Peptidase IV Inhibitors , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Molecular Docking Simulation
19.
Biomed J ; 44(6S2): S210-S217, 2021 Dec.
Article in English | MEDLINE | ID: mdl-35300943

ABSTRACT

BACKGROUND: Previous studies showed inconsistent Results of the effects of dipeptidyl peptidase (DPP)-IV inhibitors on syngeneic mouse islet transplantation. We hypothesized that the implanted islet numbers are critical for the effects of DPP-IV inhibitors on the outcomes of transplantation. METHODS: One hundred and fifty or three hundred islets were syngeneically transplanted under the renal capsule of each streptozocin-diabetic C57BL/6 mouse and recipients were then treated without or with LAF237 (10 mg/kg/day, po) for 6 weeks. After transplantation, recipients' blood glucose, body weight and intraperitoneal glucose tolerance test (IPGTT) were followed-up periodically. The graft was removed for the measurement of ß-cell mass at 6 weeks. RESULTS: In recipients with 150 islets, it was not significantly different between the LAF237- treated group (n = 14) and control group (n = 14) in terms of the blood glucose, body weight, glucose tolerance at 2, 4 and 6 weeks or the graft ß-cell mass at 6 weeks. In contrast, in recipients with 300 islets, the LAF237-treated group (n = 24) did have a lower area under the curve of the IPGTT at 4 weeks (p = 0.0237) and 6 weeks (p = 0.0113) as well as more graft ß-cell mass at 6 weeks (0.655 ± 0.008 mg vs. 0.435 ± 0.006 mg, p = 0.0463) than controls (n = 24). CONCLUSIONS: Our findings revealed 6-week treatment of LAF237 improves glucose tolerance and increases graft ß-cell mass in diabetic mice transplanted with a sufficient number but not a marginal number of islets. These indicate that the effects of DPP-IV inhibitors are influenced by the implanted islet mass.


Subject(s)
Diabetes Mellitus, Experimental , Dipeptidyl-Peptidase IV Inhibitors , Adamantane/analogs & derivatives , Animals , Blood Glucose , Body Weight , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/surgery , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases , Humans , Hypoglycemic Agents/pharmacology , Mice , Mice, Inbred C57BL , Pyrrolidines
20.
J Mol Endocrinol ; 68(4): 225-241, 2022 Apr 29.
Article in English | MEDLINE | ID: mdl-35302950

ABSTRACT

Obesity causes white and brown adipocyte dysfunction, reducing browning and stimulating whitening. Drugs that tackle adipocyte dysfunction through thermogenesis stimulation could be used to treat obesity. This study sought to address whether a combination of the PPAR-alpha agonist (WY14643) and DPP4i (linagliptin) potentiates browning and mitigates adipose tissue dysfunction, emphasizing the pathways related to browning induction and the underlying thermogenesis in high-fat-fed mice. Adult male C57BL/6 mice were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for 12 weeks. Experiment 1 aimed to evaluate whether 5 weeks of combined therapy was able to potentiate browning using a five-group design: C, HF, HFW (monotherapy with WY14643, 2.5 mg/kg body mass), HFL (monotherapy with linagliptin, 15 mg/kg body mass), and HFC (a combination of both drugs). Experiment 2 further addressed the pathways involved in browning maximization using a four-group study design: C, CC (C diet plus the drug combination), HF, and HFC (HF diet plus the drug combination). The HF group showed overweight, oral glucose intolerance, sWAT adipocyte hypertrophy, and reduced numerical density of nuclei per area of BAT confirming whitening. Only the combined treatment normalized these parameters in addition to body temperature increase, browning induction, and whitening rescue. The high expression of thermogenic marker genes parallel to reduced expression of inflammatory and endoplasmic reticulum stress genes mediated the beneficial findings. Hence, the PPAR-alpha agonist and DPP-4i combination is a promising target for obesity control by inducing functional brown adipocytes, browning of sWAT, and enhanced adaptive thermogenesis.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Adipocytes, Brown/metabolism , Adipose Tissue, Brown/metabolism , Adipose Tissue, White/metabolism , Animals , Diet, High-Fat/adverse effects , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Linagliptin/metabolism , Linagliptin/therapeutic use , Lipids , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/drug therapy , Obesity/etiology , Obesity/metabolism , Peroxisome Proliferator-Activated Receptors/metabolism , Thermogenesis
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