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Background: Fatty acid uptake can be measured using PET and 14-(R,S)‐[18F]fluoro‐6‐thia‐heptadecanoic acid ([18F]FTHA). However, the relatively rapid rate of [18F]FTHA metabolism significantly affects kinetic modeling of tissue uptake. Thus, there is a need for accurate chromatographic methods to analyze the unmetabolized [18F]FTHA (parent fraction). Here we present a new radiometabolite analysis (RMA) method, with comparison to a previous method for parent fraction analysis, and its use in a test-retest clinical study under fasting and postprandial conditions. We developed a new thin-layer chromatography (TLC) RMA method for analysis of [18F]FTHA parent fraction and its radiometabolites from plasma, by testing stationary phases and eluent combinations. Next, we analyzed [18F]FTHA, its radiometabolites, and plasma radioactivity from subjects participating in a clinical study. A total of 17 obese or overweight participants were dosed with [18F]FTHA twice under fasting, and twice under postprandial conditions and plasma samples were obtained between 14 min (mean of first sample) and 72 min (mean of last sample) post-injection. Aliquots of 70 plasma samples were analyzed using both methods, enabling head-to-head comparisons. We performed test-retest and group comparisons of the parent fraction and plasma radioactivity. Results: The new TLC method separated seven [18F]FTHA radiometabolite peaks, while the previous method separated three. The new method revealed at least one radiometabolite that was not previously separable from [18F]FTHA. From the plasma samples, the mean parent fraction value was on average 7.2 percentage points lower with the new method, compared to the previous method. Repeated [18F]FTHA investigations on the same subject revealed reproducible plasma SUV and parent fractions, with different kinetics between the fasted and postprandial conditions. Conclusions: The newly developed improved radio-TLC method for [18F]FTHA RMA enables accurate parent fraction correction, which is required to obtain quantitative data for modelling [18F]FTHA PET data. Our test-retest study of fasted and postprandial conditions showed robust reproducibility, and revealed clear differences in the [18F]FTHA metabolic rate under different study settings. Trial registration: EudraCT No: 2020-005211-48, 04Feb2021; and Clinical Trials registry NCT05132335, 29Oct2021, URL: https://classic.clinicaltrials.gov/ct2/show/NCT05132335. [ABSTRACT FROM AUTHOR]

Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide–1 receptor agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin-sensitizing thiazolidinedione (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR-null mice dosed with rosiglitazone had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while improving its insulin-sensitizing efficacy at the same time. Article Highlights: Body weight gain resulting from treatment with the insulin-sensitizing thiazolidinedione rosiglitazone does not require the glucose-dependent insulinotropic polypeptide receptor (GIPR). Treatment with a GIPR agonist prevents the hyperphagic and obesogenic activity of rosiglitazone. Activation of the GIPR improves the insulin-sensitizing actions of rosiglitazone. [ABSTRACT FROM AUTHOR]

Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r-null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual- receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide., Introduction Type 2 diabetes mellitus (T2DM) is a global pandemic, placing significant strain on healthcare systems world wide (1). Driven primarily by excess body weight, systemic insulin resistance (IR) is [...]

Author(s): Paul J Emmerson [1]; Feng Wang [2]; Yong Du [2]; Qian Liu [2]; Richard T Pickard [1]; Malgorzata D Gonciarz [1]; Tamer Coskun [1]; Matthew J Hamang [1]; Dana [...]

The operation conditions for the implementation of the Fenton process are of utmost importance because there are problems related to the proportion of H2O2 dosage to COD and Fe2+ dosage to the specified H2O2 amount. The relevant lite-rature shows that COD/H2O2 ratios range between 0.0084 and 113.9. Similarly, the COD/Fe2+ ratio varies between 0.079 and 292.6, while the H2O2/Fe2+ ratio varies between 0.09 and 287. Moreover, the ratio of the maximum value to the minimum value used in the operations on the basis of COD is 13560 for COD/ /H2O2 (0.0084-113.9), 2210 for COD/Fe2+ (0.079-174.7), and finally 3190 for H2O2/Fe2+ (0,09-287). The aim of this study was to re-evaluate these values that significantly differ from each other with specific emphasis on textile wastewater and considering stoichiometric ratios. Results showed that values ranging between 0.43 and 4.0 for COD/H2O2 and those ranging between 0.75 and 3.0 for H2O2/Fe2+ are more suitable. The results showed that in a Fenton process con-ducted by dosing H2O2 at different times, the TOC reduction efficiencies inc-reased from 80.8 up to 88.9%. Similarly, the color reduction efficiency also rose from 96.5 to 98.7%. This article has been corrected. Link to the correction 10.2298/CICEQ170425016E

Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in healthy participants. Materials and Methods: This was a double‐blind, placebo‐controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single‐dose orforglipron, with four cohorts receiving escalating doses (0.3‐6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2‐24 mg). Results: Ninety‐two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract‐related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3‐6 mg). On Day 28, the mean t1/2 was 48.1 to 67.5 hours across the dose range (2‐24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron‐treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. Conclusions: Orforglipron's long half‐life (25‐68 hours) allows once‐daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP‐1RAs, which supports continued clinical development. [ABSTRACT FROM AUTHOR]

The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying Keywords: GIP; GLP-1; glucagon; type 2 diabetes; weight control EN GIP GLP-1 glucagon type 2 diabetes weight control 2784 2788 5 08/03/23 20230901 NES 230901 INTRODUCTION Delayed gastric emptying (GE) is a well-known effect of glucagon-like peptide-1 (GLP-1).[[1]] Similarly, glucagon (GCG) has been shown to slow GE in rodents and humans,[[3]] while glucose-dependent insulinotropic polypeptide (GIP) does not appear to impact GE.[[1]] Retatrutide (LY3437943) is a novel GIP/GLP-1/GCG receptor agonist (RA) under investigation for chronic weight management and its complications. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial. The maximum extent of GE delay observed with retatrutide was similar to that previously noted with tirzepatide.[12] The magnitude of GE inhibition was lower following subsequent retatrutide doses and appeared to be diminishing at Days 30 and 79, despite ongoing dose escalation in the two highest dose retatrutide groups. [Extracted from the article]

Aim: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabetes (T2D). Materials and Methods: This was a double‐blind, placebo‐controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel‐arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). Results: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal‐related, and occurred early in treatment, similar to findings with other GLP‐1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from −1.5% to −1.8% across orforglipron doses, versus −0.4% with placebo, and body weight change was −0.24 to −5.8 kg across orforglipron doses, versus 0.5 kg with placebo. Conclusions: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP‐1RAs. Orforglipron may provide a safe and effective once‐daily oral treatment alternative to injectable GLP‐1RAs or peptide oral formulations without water and food restrictions. [ABSTRACT FROM AUTHOR]

Background: Many surgical treatment methods have been presented for Kienböck's disease. The most current treatment method is the surgical procedure with 4+5 extensor compartmental artery (ECA) bone graft. However, the graft harvest site is very close to the radioulnar and radiocarpal joints. Objectives: This study aimed at determining the efficacy of intraoperative fluoroscopy evaluation of 4+5 ECA. Methods: Intraoperative fluoroscopic visualization of the 4+5 ECA may facilitate the surgical procedure. Patients with lunate avascular necrosis at stage II-IIIA according to Lichtman classification who underwent 4+5 ECA bone graft were included in the study. A total of 13 patients (3 females, 10 males) participated in the study. Results: The mean follow-up period of the patients was 15 months. In all patients, 4+5 ECA localizations were determined fluoroscopically. None of the patients experienced complications related to graft harvest. Conclusion: Locating the intraoperative fluoroscopic 4+5 ECA may make the surgical procedure safer. [ABSTRACT FROM AUTHOR]

Aim: Morphological variations in carpal bone may affect wrist pathologies. In this study, we examined the relationship between carpal bone morphologies and scaphoid fractures. Materials and Methods: Patients with a prominent scaphoid fracture on posteroanterior and ulnar deviation X-rays were included in the study. Morphological types of lunate, hamate, capitate, presence of capitate-fourth metacarpal joint, and scaphoid fracture location were documented retrospectively. A total of 68 patients, 65 (95.6%) male, and 3 (4.4%) female were included in the study. Results: Considering the scaphoid fracture types, 40 (58.8%) patients had waist fractures, and 28 (41.2%) patients had proximal pole fractures. The association of fracture type and morphology of carpal bones was examined. Conclusion: In our study, we found that lunate, capitate, hamatum morphology and ulnar variance, fourth metacarpal articulation did not affect the scaphoid fracture pattern. [ABSTRACT FROM AUTHOR]

Aim: To investigate the role of glucose‐dependent insulinotropic polypeptide receptor (GIPR) agonists alone or combined with glucagon‐like peptide‐1 receptor (GLP‐1R) agonists to regulate palatable food intake and the role of specific macronutrients in these preferences. Methods: To understand this regulation, we treated mice and rats on several choice diet paradigms of chow and a palatable food option with individual or dual GIPR and GLP‐1R agonists. Results: In mice, the dual agonist tirzepatide suppressed total caloric intake, while promoting the intake of chow over a high fat/sucrose diet. Surprisingly, GIPR agonism alone did not alter food choice. The food intake shift observed with tirzepatide in wild‐type mice was completely absent in GLP‐1R knockout mice, suggesting that GIPR signalling does not regulate food preference. Tirzepatide also selectively suppressed the intake of palatable food but not chow in a rat two‐diet choice model. This suppression was specific to lipids, as GLP‐1R agonist and dual agonist treatment in rats on a choice paradigm assessing individual palatable macronutrients robustly inhibited the intake of Crisco (lipid) without decreasing the intake of a sucrose (carbohydrate) solution. Conclusions: Decreasing preference for high‐caloric, high‐fat foods is a powerful action of GLP‐1R and dual GIPR/GLP‐1R agonist therapeutics, which may contribute to the weight loss success of these drugs. [ABSTRACT FROM AUTHOR]