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Pharmacological Reviews Apr 2020The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important... (Review)
Review
The solute carrier family 16 (SLC16) is comprised of 14 members of the monocarboxylate transporter (MCT) family that play an essential role in the transport of important cell nutrients and for cellular metabolism and pH regulation. MCTs 1-4 have been extensively studied and are involved in the proton-dependent transport of L-lactate, pyruvate, short-chain fatty acids, and monocarboxylate drugs in a wide variety of tissues. MCTs 1 and 4 are overexpressed in a number of cancers, and current investigations have focused on transporter inhibition as a novel therapeutic strategy in cancers. MCT1 has also been used in strategies aimed at enhancing drug absorption due to its high expression in the intestine. Other MCT isoforms are less well characterized, but ongoing studies indicate that MCT6 transports xenobiotics such as bumetanide, nateglinide, and probenecid, whereas MCT7 has been characterized as a transporter of ketone bodies. MCT8 and MCT10 transport thyroid hormones, and recently, MCT9 has been characterized as a carnitine efflux transporter and MCT12 as a creatine transporter. Expressed at the blood brain barrier, MCT8 mutations have been associated with an X-linked intellectual disability, known as Allan-Herndon-Dudley syndrome. Many MCT isoforms are associated with hormone, lipid, and glucose homeostasis, and recent research has focused on their potential roles in disease, with MCTs representing promising novel therapeutic targets. This review will provide a summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease. SIGNIFICANCE STATEMENT: The 14-member solute carrier family 16 of monocarboxylate transporters (MCTs) plays a fundamental role in maintaining intracellular concentrations of a broad range of important endogenous molecules in health and disease. MCTs 1, 2, and 4 (L-lactate transporters) are overexpressed in cancers and represent a novel therapeutic target in cancer. Recent studies have highlighted the importance of MCTs in glucose, lipid, and hormone homeostasis, including MCT8 in thyroid hormone brain uptake, MCT12 in carnitine transport, and MCT11 in type 2 diabetes.
Topics: Animals; Humans; Metabolic Diseases; Monocarboxylic Acid Transporters; Structure-Activity Relationship; Tissue Distribution; Transcription, Genetic
PubMed: 32144120
DOI: 10.1124/pr.119.018762 -
The Journal of Clinical Endocrinology... Feb 2015Various drugs affect body weight as a side effect. (Meta-Analysis)
Meta-Analysis Review
CONTEXT
Various drugs affect body weight as a side effect.
OBJECTIVE
We conducted this systematic review and meta-analysis to summarize the evidence about commonly prescribed drugs and their association with weight change.
DATA SOURCES
MEDLINE, DARE, and the Cochrane Database of Systematic Reviews were searched to identify published systematic reviews as a source for trials.
STUDY SELECTION
We included randomized trials that compared an a priori selected list of drugs to placebo and measured weight change.
DATA EXTRACTION
We extracted data in duplicate and assessed the methodological quality using the Cochrane risk of bias tool.
RESULTS
We included 257 randomized trials (54 different drugs; 84 696 patients enrolled). Weight gain was associated with the use of amitriptyline (1.8 kg), mirtazapine (1.5 kg), olanzapine (2.4 kg), quetiapine (1.1 kg), risperidone (0.8 kg), gabapentin (2.2 kg), tolbutamide (2.8 kg), pioglitazone (2.6 kg), glimepiride (2.1 kg), gliclazide (1.8 kg), glyburide (2.6 kg), glipizide (2.2 kg), sitagliptin (0.55 kg), and nateglinide (0.3 kg). Weight loss was associated with the use of metformin (1.1 kg), acarbose (0.4 kg), miglitol (0.7 kg), pramlintide (2.3 kg), liraglutide (1.7 kg), exenatide (1.2 kg), zonisamide (7.7 kg), topiramate (3.8 kg), bupropion (1.3 kg), and fluoxetine (1.3 kg). For many other remaining drugs (including antihypertensives and antihistamines), the weight change was either statistically nonsignificant or supported by very low-quality evidence.
CONCLUSIONS
Several drugs are associated with weight change of varying magnitude. Data are provided to guide the choice of drug when several options exist and institute preemptive weight loss strategies when obesogenic drugs are prescribed.
Topics: Antipsychotic Agents; Body Weight; Humans; Hypoglycemic Agents; Weight Gain; Weight Loss
PubMed: 25590213
DOI: 10.1210/jc.2014-3421 -
Frontiers in Endocrinology 2021Available data on the effects of anti-diabetic drugs on fracture risk are contradictory. Therefore, our study aimed to analyze all available data on the effects of... (Meta-Analysis)
Meta-Analysis
PURPOSE
Available data on the effects of anti-diabetic drugs on fracture risk are contradictory. Therefore, our study aimed to analyze all available data on the effects of anti-diabetic drugs on fracture risk in type 2 diabetes mellitus (T2DM) patients.
METHODS
Embase, Medline, ClinicalTrials.gov, and Cochrane CENTRAL were searched for relevant trials. All data analyses were performed with STATA (12.0) and R language (3.6.0). Risk ratio (RR) with its 95% confidence interval (CI) was calculated by combining data for the fracture effects of anti-diabetic drugs, including sodium-glucose co-transporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, meglitinides, α-glucosidase inhibitors, thiazolidinediones, biguanides, insulin, and sulfonylureas.
RESULTS
One hundred seventeen eligible randomized controlled trials (RCTs) with 221,364 participants were included in this study. Compared with placebo, trelagliptin (RR 3.51; 1.58-13.70) increased the risk of fracture, whereas albiglutide (RR 0.29; 0.04-0.93) and voglibose (RR 0.03; 0-0.11) decreased the risk of fracture. Other medications were comparable in terms of their effects on fracture risk, and no statistical significance was observed. In terms of fractures, voglibose (0.01%) may be the safest option, and trelagliptin (13.64%) may be the worst. Sensitivity analysis results were consistent with those of the main analysis. No statistically significant differences were observed in the regression coefficients of age (1.03; 0.32-2.1), follow-up duration (0.79; 0.27-1.64), and sex distribution (0.63; 0.15-1.56).
CONCLUSIONS
We found varied results on the association between the use of anti-diabetic drugs and fracture risk. Specifically, trelagliptin raised the risk of fracture, whereas voglibose and albiglutide showed benefit with statistical difference. Other drugs were comparable in terms of their effects on fracture risk. Some drugs (omarigliptin, sitagliptin, vildagliptin, saxagliptin, empagliflozin, ertugliflozin, rosiglitazone, pioglitazone, and nateglinide) may increase the risk of fracture, while others (such as dulaglutide, exenatide, liraglutide, semaglutide, lixisenatide, linagliptin, alogliptin, canagliflozin, dapagliflozin, glipizide, gliclazide, glibenclamide, glimepiride, metformin, and insulin) may show benefits. The risk of fracture was independent of age, sex distribution, and the duration of exposure to anti-diabetic drugs. When developing individualized treatment strategies, the clinical efficacy of anti-diabetic drugs must be weighed against their benefits and risks brought about by individual differences of patients.
SYSTEMATIC REVIEW REGISTRATION
This Systematic Review was prospectively registered on the PROSPERO (https://www.crd.york.ac.uk/PROSPERO/, registration number CRD42020189464).
Topics: Diabetes Mellitus, Type 2; Fractures, Bone; Humans; Hypoglycemic Agents; Network Meta-Analysis; Risk Factors
PubMed: 34721294
DOI: 10.3389/fendo.2021.735824 -
European Review For Medical and... Dec 2022To investigate the effects of octreotide and nateglinide on ovarian follicle count, ovarian tissue damage, biochemical parameters and free radical scavenging system in...
OBJECTIVE
To investigate the effects of octreotide and nateglinide on ovarian follicle count, ovarian tissue damage, biochemical parameters and free radical scavenging system in letrazole-induced rat model of PCOS.
MATERIALS AND METHODS
Forty-two female Sprague-Dawley rats were divided into six groups. Group 1 (Control Group): after localizing the ovaries and the uterine horns, the abdominal wall was closed without any surgical procedure. Group 2 (PCOS Group): PCOS was induced by administrating Letrozole orally for 21 successive days. At the end of 21 days, rats underwent ovarian biopsies. The experimental PCOS model was considered successful in the presence of atretic follicles without granulosa cell stratification. Group 3 (PCOS + Nateglinide Group): Nateglinide was administered by oral dropper for 30 days to the rats in which PCOS model was created. Group 4 (Nateglinid only Group): 30 days of NG was applied to the rats without PCOS. Group 5 (PCOS+Octreotide Group): 0.1 mg/kg/day Octreotide was given intraperitoneally for 4 weeks to the rats in which PCOS model was created. Group 6 (Octreotide only Group): animals without PCOS given 0.1 mg/kg/day Octreotide at the end of the treatment, bilateral oophorectomy was performed and blood samples were collected from all groups. Ovarian tissue was stained immunohistochemically with TLR-4 in addition to conventional staining. In addition to follicle classification, ovarian damage was graded. Serum insulin, FSH and LH, TNF-α, IL-6, SHBG, SOD, IGF-1, MDA and GSH levels were also measured.
RESULTS
The cystic and degenerated follicle density of PCOS group was high compared with the other groups. Both cystic and degenerated follicles were significantly reduced in PCOS+NG and PCOS+OC groups compared to PCOS group. There was no difference between the groups in terms of serum LH, FSH and insulin levels (p>0.05). Serum testosterone level was significantly higher in the PCOS group compared to the other groups (p<0.01). Adding OC or NG to PCOS groups did not cause significant changes in testosterone levels. TNF-α and IL-6 levels were high in PCOS group (p<0.03). IGF-1 and MDA levels were higher in PCOS than in other groups (p<0.03, p<0.01 respectively). Adding OC or NG to the treatment normalized IGF-1 and MDA levels. Serum GSH levels were significantly lower in the PCOS group (p<0.05). Adding NG to the treatment increased GSH levels.
CONCLUSIONS
Both NG and OCT reverses atretic and degenerate follicle damage due to PCOS through TLR-4, antioxidant and anti-inflammatory pathways.
Topics: Animals; Female; Rats; Disease Models, Animal; Follicle Stimulating Hormone; Free Radicals; Insulin-Like Growth Factor I; Insulins; Interleukin-6; Nateglinide; Octreotide; Polycystic Ovary Syndrome; Rats, Sprague-Dawley; Testosterone; Toll-Like Receptor 4; Tumor Necrosis Factor-alpha; Letrozole
PubMed: 36524509
DOI: 10.26355/eurrev_202212_30563 -
Advanced Science (Weinheim,... Sep 2021Mitogen-activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that...
Mitogen-activated protein kinase (MAPK) signaling plays a significant role in reactive oxygen species (ROS) production. The authors have previously shown that Brahma-related gene 1 (BRG1), a chromatin remodeling protein, contributes to hepatic ROS accumulation in multiple animal and cellular models of liver injury. Here it is reported that DNA damage-induced transcript 4 (DDIT4) is identified as a direct transcriptional target for BRG1. DDIT4 overexpression overcomes BRG1 deficiency to restore ROS production whereas DDIT4 knockdown phenocopies BRG1 deficiency in suppressing ROS production in vitro and in vivo. Mechanistically, DDIT4 coordinates the assembly of the p38-MAPK signaling complex to drive ROS production in an S-nitrosylation dependent manner. Molecular docking identifies several bioactive DDIT4-inteacting compounds including imatinib, nilotinib, and nateglinide, all of which are confirmed to attenuate hepatic ROS production, dampen p38-MAPK signaling, and ameliorate liver injury by influencing DDIT4 S-nitrosylation. Importantly, positive correlation between ROS levels and BRG1/DDIT4/S-nitrosylated DDIT4 levels is detected in human liver biopsy specimens. In conclusion, the data reveal a transcription-based signaling cascade that contributes to ROS production in liver injury.
Topics: Animals; Humans; Liver; Male; Mice; Nitrosation; Reactive Oxygen Species; Signal Transduction; Transcription Factors; p38 Mitogen-Activated Protein Kinases
PubMed: 34310076
DOI: 10.1002/advs.202101957 -
Journal of Investigational Allergology... 2011Meglitinides (repaglinide and nateglinide) are insulin secretagogues used to treat diabetes mellitus. We present a case of hypersensitivity reaction to repaglinide in a...
Meglitinides (repaglinide and nateglinide) are insulin secretagogues used to treat diabetes mellitus. We present a case of hypersensitivity reaction to repaglinide in a 61-year-old man who developed a maculopapular rash 5 days after treatment. Skin prick tests including repaglinide (0.5 g/mL) and patch tests (0.05% in pet and saline) were performed, and the results were negative. A blind oral challenge test with repaglinide was performed and the therapeutic dose was subsequently taken at home every 24 hours for 7 days. The result was positive with a delayed reaction at day 3. A punch biopsy of the skin lesions revealed drug-induced exanthema. The clinical manifestations, the latency period, the reappearance of cutaneous lesions after rechallenge, and the histopathology report of the skin biopsy suggest a type IV mechanism.
Topics: Carbamates; Cyclohexanes; Diabetes Mellitus, Type 2; Drug Hypersensitivity; Erythema; Exanthema; Humans; Hypoglycemic Agents; Male; Middle Aged; Nateglinide; Patch Tests; Phenylalanine; Piperidines
PubMed: 21548456
DOI: No ID Found -
Journal of Separation Science Dec 2022High-performance affinity microcolumns were used to characterize binding by the anti-diabetic drugs repaglinide and nateglinide with normal and glycated forms of human...
High-performance affinity microcolumns were used to characterize binding by the anti-diabetic drugs repaglinide and nateglinide with normal and glycated forms of human serum albumin. The microcolumns contained only nmol amounts of protein and provided a detailed analysis of these drug interactions with good precision and in a matter of minutes per experiment. The overall binding by repaglinide to normal and glycated albumin fits a model with two types of binding sites: a set of one or two moderate-to-high affinity regions and a larger set of weaker regions with association equilibrium constants of ∼10 and 10 M , respectively, at pH 7.4 and 37°C. Competition studies gave site-specific association constants for repaglinide and nateglinide at Sudlow site I of 4.2 × 10 and 5.0 × 10 M for normal albumin, with a decrease of 26%-30% being seen for nateglinide with glycated albumin and no significant change being noted for repaglinide. At Sudlow site II, repaglinide and nateglinide had association constants for normal albumin of 6.1 × 10 and 7.1 × 10 M , with glycated albumin giving an increase in the association constant at this site for repaglinide of 1.6- to 1.8-fold and a decrease for nateglinide of 51%-58%.
Topics: Humans; Nateglinide; Serum Albumin, Human; Albumins
PubMed: 36168862
DOI: 10.1002/jssc.202200686