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1.
Sci Rep ; 10(1): 3373, 2020 02 25.
Article in English | MEDLINE | ID: mdl-32099009

ABSTRACT

Dipeptidyl peptidase 4 inhibitors and angiotensin II receptor blockers attenuate chronic kidney disease progression in experimental diabetic and non-diabetic nephropathy in a blood pressure and glucose independent manner, but the exact molecular mechanisms remain unclear. MicroRNAs (miRNAs) are short, non-coding RNA species that are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of nephropathy. miRNAs are present in urine in a remarkably stable form, packaged in extracellular vesicles. Here, we investigated linagliptin and telmisartan induced effects on renal and urinary exosomal miRNA expression in 5/6 nephrectomized rats. In the present study, renal miRNA profiling was conducted using the Nanostring nCounter technology and mRNA profiling using RNA sequencing from the following groups of rats: sham operated plus placebo; 5/6 nephrectomy plus placebo; 5/6 nephrectomy plus telmisartan; and 5/6 nephrectomy plus linagliptin. TaqMan Array miRNA Cards were used to evaluate which of the deregulated miRNAs in the kidney are present in urinary exosomes. In kidneys from 5/6 nephrectomized rats, the expression of 13 miRNAs was significantly increased (>1.5-fold, P < 0.05), whereas the expression of 7 miRNAs was significantly decreased (>1.5-fold, P < 0.05). Most of the deregulated miRNA species are implicated in endothelial-to-mesenchymal transition and inflammatory processes. Both telmisartan and linagliptin suppressed the induction of pro-fibrotic miRNAs, such as miR-199a-3p, and restored levels of anti-fibrotic miR-29c. In conclusion, the linagliptin and telmisartan-induced restorative effects on miR-29c expression were reflected in urinary exosomes, suggesting that miRNA profiling of urinary exosomes might be used as a biomarker for CKD progression and monitoring of treatment effects.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Exosomes/metabolism , Gene Expression Regulation/drug effects , Kidney/metabolism , Linagliptin/pharmacology , MicroRNAs/metabolism , Telmisartan/pharmacology , Animals , Kidney/pathology , Kidney/surgery , Nephrectomy , Principal Component Analysis , RNA, Messenger/metabolism , Rats , Rats, Wistar , Urinary Tract/metabolism
2.
PLoS One ; 11(3): e0150154, 2016.
Article in English | MEDLINE | ID: mdl-26930277

ABSTRACT

MicroRNAs (miRNAs) are short non-coding RNA species which are important post-transcriptional regulators of gene expression and play an important role in the pathogenesis of diabetic nephropathy. miRNAs are present in urine in a remarkably stable form packaged in extracellular vesicles, predominantly exosomes. In the present study, urinary exosomal miRNA profiling was conducted in urinary exosomes obtained from 8 healthy controls (C), 8 patients with type II diabetes (T2D) and 8 patients with type II diabetic nephropathy (DN) using Agilent´s miRNA microarrays. In total, the expression of 16 miRNA species was deregulated (>2-fold) in DN patients compared to healthy donors and T2D patients: the expression of 14 miRNAs (miR-320c, miR-6068, miR-1234-5p, miR-6133, miR-4270, miR-4739, miR-371b-5p, miR-638, miR-572, miR-1227-5p, miR-6126, miR-1915-5p, miR-4778-5p and miR-2861) was up-regulated whereas the expression of 2 miRNAs (miR-30d-5p and miR-30e-5p) was down-regulated. Most of the deregulated miRNAs are involved in progression of renal diseases. Deregulation of urinary exosomal miRNAs occurred in micro-albuminuric DN patients but not in normo-albuminuric DN patients. We used qRT-PCR based analysis of the most strongly up-regulated miRNAs in urinary exosomes from DN patients, miRNAs miR-320c and miR-6068. The correlation of miRNA expression and micro-albuminuria levels could be replicated in a confirmation cohort. In conclusion, urinary exosomal miRNA content is altered in type II diabetic patients with DN. Deregulated miR-320c, which might have an impact on the TGF-ß-signaling pathway via targeting thrombospondin 1 (TSP-1) shows promise as a novel candidate marker for disease progression in type II DN that should be evaluated in future studies.


Subject(s)
Albuminuria/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetic Nephropathies/metabolism , Exosomes/metabolism , MicroRNAs/urine , Adult , Aged , Albuminuria/genetics , Albuminuria/urine , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/urine , Diabetic Nephropathies/genetics , Diabetic Nephropathies/urine , Exosomes/genetics , Female , Humans , Male , Middle Aged , Signal Transduction/physiology , Young Adult
3.
J Clin Pharmacol ; 53(3): 256-63, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23444281

ABSTRACT

Sipoglitazar is a peroxisome proliferator-activated receptor α, δ, and γ agonist. During phase I, a wide distribution of clearance between individuals was observed. Hypothesized to result from a polymorphism in the uridine 5'-diphospate-glucuronosyltransferase (UGT)2B15 enzyme, pharmacogenetic samples were collected from each individual for genotyping UGT2B15 in a subsequent phase I trial in healthy subjects (n = 524) and in 2 phase II trials in type 2 diabetes subjects (n = 627), total genotype frequency was as follows: *1/*1 (22%), *1/*2 (51%), and *2/*2 (27%). The impact of genotype on exposure was assessed using a pharmacokinetic modeling approach; the influence of genotype on efficacy was evaluated using 12-week HbA1c change from baseline. Model analysis demonstrated UGT2B15 genotype accounted significantly for the variability in sipoglitazar clearance; however, a small fraction of subjects had a clearance that could not be explained entirely by genotype. HbA1c drop increased with daily drug dose. When stratified by both dose and genotype, HbA1c drop was larger in the UGT2B15*2/*2 compared with UGT2B15*1/*1 and UGT2B15*1/*2 genotypes (P < .05). In summary, UGT2B15 genotype is a strong predictor for sipoglitazar clearance; a greater clinical response observed in the UGT2B15*2/*2 genotype appears to confirm this. However, overlap in individual rates of clearance across genotypes remains after accounting for genotype.


Subject(s)
Glucuronosyltransferase/genetics , Hypoglycemic Agents/pharmacology , Peroxisome Proliferator-Activated Receptors/agonists , Propionates/pharmacology , Thiazoles/pharmacology , Adolescent , Adult , Aged , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Female , Genotype , Glycated Hemoglobin/analysis , Humans , Hypoglycemic Agents/pharmacokinetics , Male , Middle Aged , Models, Biological , Polymorphism, Genetic , Propionates/pharmacokinetics , Thiazoles/pharmacokinetics , Young Adult
4.
Eur J Clin Pharmacol ; 69(3): 423-30, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22960998

ABSTRACT

PURPOSE: Sipoglitazar was a novel, azolealkanoic acid derivative that possesses selective activity for the peroxisome proliferator-activated receptors (PPAR) PPARγ, PPARα, and PPARδ. The compound undergoes phase II biotransformation by conjugation catalyzed by UDP-glucuronosyltransferase (UGT). The aim of this analysis was to explore the influence of genetic polymorphism in UGT on the pharmacokinetics of sipoglitazar. METHODS: Three preliminary phase I clinical pharmacology studies were conducted in tandem in healthy human subjects. Genotyping was undertaken in a total of 82 subjects in the phase I program for the purpose of genotyping UGT polymorphisms. Plasma samples were collected for up to 48 h post-dose to characterize the pharmacokinetic profile following a single oral dose of the drug. RESULTS: Plasma concentrations of sipoglitazar and the distribution of dose-normalized individual values for area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) before any stratification were considerably skewed with a multi-modal distribution. The proportion of variability in AUC(0-∞) explained by UGT2B15 was 66.7 % (P < 0.0001); the addition of other genetic or demographic factors was not statistically significant. Subjects homozygous for the UGT2B15 D85Y variant (UGT2B15*2/*2) were exposed to greater plasma concentrations of sipoglitazar than subjects homozygous for the wild-type allele UGT2B15*1/*1 (3.26-fold higher) or heterozygous allele UGT2B15*1/*2 (2.16-fold higher). CONCLUSIONS: These results indicate that sipoglitazar clearance is substantially modified by UGT2B15 enzyme variants, with higher exposure observed in the UGT2B15*2/*2 genotype group.


Subject(s)
Glucuronosyltransferase/genetics , Hypoglycemic Agents/pharmacokinetics , Polymorphism, Genetic , Propionates/pharmacokinetics , Thiazoles/pharmacokinetics , Administration, Oral , Adult , Analysis of Variance , Area Under Curve , Biotransformation , Cross-Over Studies , Double-Blind Method , Female , Glucuronosyltransferase/metabolism , Half-Life , Heterozygote , Homozygote , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/blood , Male , Metabolic Clearance Rate , Middle Aged , Pharmacogenetics , Phenotype , Propionates/administration & dosage , Propionates/blood , Thiazoles/administration & dosage , Thiazoles/blood , United Kingdom , Young Adult
5.
Diabetes Res Clin Pract ; 79(3): 453-60, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18160120

ABSTRACT

AIM: We report the effectiveness of the thiazolidinedione, pioglitazone, as add-on medication to metformin or sulfonylurea in reducing post-load serum glucose levels, as assessed by 3-h oral glucose tolerance testing (OGTT). METHODS: Adult patients with Type 2 diabetes took part in one of two large-scale, 2-year clinical trials. One study compared pioglitazone treatment as add-on to failing metformin therapy (N=317) with add-on gliclazide treatment to metformin (N=313). The other study compared combination therapy with pioglitazone added to existing failing sulfonylurea therapy (N=319) with metformin treatment in addition to sulfonylurea (N=320). HbA(1c) and fasting plasma glucose concentrations were measured at baseline and throughout the study and at the final visit at week 104. At selected centers (N=299 patients), a 3-h OGTT was performed at baseline and at week 104. RESULTS: At week 104, mean HbA(1c) reduction from baseline was 0.89% for pioglitazone and 0.77% for gliclazide addition to metformin (p=0.200) and 1.03% with pioglitazone and 1.16% with metformin addition to sulfonylurea (p=0.173) in the total patient cohort. In the 299 patients who underwent OGTT, 2 years of treatment with pioglitazone, whether added to existing metformin or sulfonylurea medication, resulted in decreases in glucose excursions after an oral glucose load without increasing post-load serum insulin concentrations. In contrast, gliclazide in combination with metformin therapy caused increases in both post-load serum glucose and insulin excursions after 2 years, whereas metformin add-on to sulfonylurea did not have a significant effect on post-load serum glucose concentrations and resulted in an increase in insulin levels. CONCLUSIONS: There were no significant differences in HbA(1c) levels between groups. However, 2-year treatment with pioglitazone as an add-on to either failing metformin or sulfonylurea therapy improved post-load glucose excursions without affecting insulin secretion. In contrast, glucose excursions were not improved by gliclazide or metformin add-on therapy, despite increases in post-load insulin levels. These data suggest that pioglitazone reduces peripheral insulin resistance via mechanisms different from those of metformin.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Metformin/therapeutic use , Sulfonylurea Compounds/therapeutic use , Thiazolidinediones/therapeutic use , Adult , Aged , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Drug Therapy, Combination , Female , Glucose Tolerance Test , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Male , Middle Aged , Pioglitazone
6.
J Pharmacokinet Pharmacodyn ; 33(3): 313-43, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16552630

ABSTRACT

Effective long-term treatment of Type 2 Diabetes Mellitus (T2DM) implies modification of the disease processes that cause this progressive disorder. This paper proposes a mechanism-based approach to disease progression modeling of T2DM that aims to provide the ability to describe and quantify the effects of treatment on the time-course of the progressive loss of beta-cell function and insulin-sensitivity underlying T2DM. It develops a population pharmacodynamic model that incorporates mechanism-based representations of the homeostatic feedback relationships between fasting levels of plasma glucose (FPG) and fasting serum insulin (FSI), and the physiological feed-forward relationship between FPG and glycosylated hemoglobin A1c (HbA1c). This model was developed on data from two parallel one-year studies comparing the effects of pioglitazone relative to metformin or sulfonylurea treatment in 2,408 treatment-naïve T2DM patients. It was found that the model provided accurate descriptions of the time-courses of FPG and HbA1c for different treatment arms. It allowed the identification of the long-term effects of different treatments on loss of beta-cell function and insulin-sensitivity, independently from their immediate anti-hyperglycemic effects modeled at their specific sites of action. Hence it avoided the confounding of these effects that is inherent in point estimates of beta-cell function and insulin-sensitivity such as the widely used HOMA-%B and HOMA-%S. It was also found that metformin therapy did not result in a reduction in FSI levels in conjunction with reduced FPG levels, as expected for an insulin-sensitizer, whereas pioglitazone therapy did. It is concluded that, although its current implementation leaves room for further improvement, the mechanism-based approach presented here constitutes a promising conceptual advance in the study of T2DM disease progression and disease modification.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Gliclazide/pharmacology , Metformin/pharmacology , Models, Biological , Thiazolidinediones/pharmacology , Adult , Aged , Algorithms , Blood Glucose/metabolism , Clinical Trials, Phase III as Topic , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Disease Progression , Double-Blind Method , Female , Gliclazide/therapeutic use , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Insulin/blood , Insulin/metabolism , Insulin Resistance , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Male , Metformin/therapeutic use , Middle Aged , Multicenter Studies as Topic , Pioglitazone , Randomized Controlled Trials as Topic , Thiazolidinediones/therapeutic use , Treatment Outcome
7.
Diabetes Res Clin Pract ; 70(1): 53-62, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16002175

ABSTRACT

This analysis compares the safety and tolerability of pioglitazone (a thiazolidinedione), metformin (a biguanide), and gliclazide (a sulfonylurea). Data collected from four 1-year, double-blind studies comparing treatment of over 3700 patients with type 2 diabetes with pioglitazone, metformin, or gliclazide have been combined to provide comparative tolerability and safety profiles. All treatments were well tolerated with approximately 6% of patients withdrawing from treatment because of side-effects. The side-effects profile varied between treatments, with pioglitazone being associated with edema, metformin with gastrointestinal side-effects, and gliclazide with hypoglycemia. Cardiovascular outcome was similar with all treatments, with no excess reports of cardiac failure with pioglitazone treatment. Both pioglitazone and gliclazide resulted in mean weight gain, whilst with metformin there was mean weight loss. Mean liver enzyme values decreased with pioglitazone and to a lesser extent with metformin. With gliclazide, mean liver enzyme values increased. The expected small decreases in mean hemoglobin and hematocrit seen with pioglitazone also occurred with metformin and to a lesser degree with gliclazide. The results show that all three drugs are safe, but that tolerability profiles vary. Each treatment provides an alternative therapy for type 2 diabetes, dependent on the particular needs of individual patients.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Gliclazide/therapeutic use , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Thiazolidinediones/therapeutic use , Adult , Aged , Alanine Transaminase/blood , Alkaline Phosphatase/blood , Aspartate Aminotransferases/blood , Blood Glucose/metabolism , Body Weight , Diabetes Mellitus, Type 2/blood , Double-Blind Method , Female , Gliclazide/adverse effects , Glycated Hemoglobin/metabolism , Hematocrit , Humans , Hypoglycemic Agents/adverse effects , Leukocyte Count , Male , Metformin/adverse effects , Middle Aged , Pioglitazone , Platelet Count , Thiazolidinediones/adverse effects , gamma-Glutamyltransferase/blood
8.
Diabetes Care ; 28(3): 544-50, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15735185

ABSTRACT

OBJECTIVE: The hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control for up to 2 years in patients with type 2 diabetes was tested. RESEARCH DESIGN AND METHODS: This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study. Approximately 600 patients from 98 centers participated. Eligible patients had completed a previous 12-month study and consented to continue treatment for a further year. To avoid selection bias, all patients from all centers were included in the primary analysis (a comparison of the time-to-failure distributions of the two groups by using a log-rank test) regardless of whether they continued treatment for a 2nd year. By using repeated-measures ANOVA, time course of least square means of HbA(1c) and homeostasis model of assessment (HOMA) indexes (HOMA-%S and HOMA-%B) were analyzed. RESULTS: A greater proportion of patients treated with pioglitazone maintained HbA(1c) <8% over the 2-year period than those treated with gliclazide. A difference between the Kaplan-Meier curves was apparent as early as week 32 and widened at each time point thereafter, becoming statistically significant from week 52 onward. At week 104, 129 (47.8%) of 270 pioglitazone-treated patients and 110 (37.0%) of 297 gliclazide-treated patients maintained HbA(1c) <8%. Compared with gliclazide treatment, pioglitazone treatment produced a larger decrease in HbA(1c), a larger increase in HOMA-%S, and a smaller increase in HOMA-%B during the 2nd year of treatment. CONCLUSIONS: Pioglitazone is superior to gliclazide in sustaining glycemic control in patients with type 2 diabetes during the 2nd year of treatment.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/drug therapy , Gliclazide/therapeutic use , Hypoglycemic Agents/therapeutic use , Thiazolidinediones/therapeutic use , Blood Glucose/drug effects , Body Weight , Diabetes Mellitus, Type 2/blood , Double-Blind Method , Female , Glycated Hemoglobin/analysis , Humans , Male , Middle Aged , Pioglitazone , Time Factors , Treatment Failure
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