Laparoscopic Roux-Y-gastric bypass versus laparoscopic one-anastomosis gastric bypass for obesity: clinical & metabolic results of a prospective randomized controlled trial.

BACKGROUND: One anastomosis gastric bypass (OAGB) has been proposed as an effective alternative to the current standard procedure in Switzerland, Roux-en-Y gastric bypass (RYGB). Prospective data comparing both procedures are scarce. Therefore, we performed a non-inferiority randomized controlled trial assessing the effectiveness and safety of these 2 operative techniques. METHOD: Eighty patients were randomized 1:1. OAGB consisted of a very long gastric pouch with a 200 cm biliopancreatic limb, RYGB of a 150 cm ante-colic alimentary and a 60 cm biliopancreatic limb, respectively. Primary endpoint was the percent excess weight loss (%EWL) at 12 months after surgery. RESULTS: Mean %EWL at 12 months was 87.9% (SD24.4) in the RYGB group and 104.1% (SD24.6) in the OAGB group (p = 0.006). There was no mortality. The rate of marginal ulcers was higher in patients with OAGB compared to those with RYGB (p = 0.011), while the total number of late complications did not statistically differ between the two groups. Except for the remission of GERD, which was higher in the RYGB group compared to OAGB, there was no difference between the groups regarding the remission of comorbidities. OAGB showed improved glucose control compared to the RYGB after 1 year (p = 0.001). Furthermore, glucagon-like peptide-1 increase was significantly higher in OAGB at 6 weeks (p = 0.041) and 1 year after surgery (p = 0.029). Quality of life improved after both surgeries, without differences between the groups. CONCLUSIONS: %EWL 1 year after surgery was higher in OAGB than in RYGB. A better glycemic control with a higher increase in GLP-1 was observed after OAGB compared to RYGB. TRIAL REGISTRATION: This trial is registered on ClinicalTrials.gov under the identifier NCT02601092.

Recently acquired HCV infection in men who have sex with men in Germany in the direct-acting antivirals era and during the COVID-19 pandemic.

INTRODUCTION: Direct-acting antivirals (DAAs) are key to eliminating hepatitis C virus (HCV). In men who have sex with men (MSM) with HIV co-infection, recently acquired HCV infection is common. Sexual practices and reinfection rates may hamper micro-elimination despite high treatment rates. METHODS: The cohort included MSM with recently acquired HCV infection from 2014 to 2021. The patients' demographic, clinical, behavioural, and laboratory data and treatment and reinfection outcomes were documented. RESULTS: A total of 237 men with recently acquired HCV infection were included: 216 (91%) had HIV. The median age was 46 years (interquartile range [IQR] 39-52), and the median CD4 count was 660/mm3 (IQR 527-835). The annual incidence of recently acquired HCV remained between 0.28% and 0.43% but dropped to 0.02% in 2021 during the COVID pandemic, almost reaching micro-elimination. The reinfection incidence was 15.5 per 100 patient-years (95% confidence interval 12.6-18.8), and reinfection was associated with the use of crystal methamphetamine (p = 0.032) and ketamine (p = 0.042). In total, 31.3% had multiple reinfections, and four reinfections occurred in users of pre-exposure prophylaxis. CONCLUSIONS: High treatment and cure rates did not lead to HCV elimination. A change in sexual behaviour, potentially imposed by COVID-19 restrictions, led to micro-elimination in the NoCo cohort. As recently acquired HCV is prevalent in MSM with and without HIV, surveillance is necessary to consolidate elimination goals.

Still trouble with bleeding: Risk factors for HCV transmission in men who have sex with men and behavioural trajectories from 2019 to 2021.

OBJECTIVES: To identify sexual/sex-associated risk factors for hepatitis C transmission among men who have sex with men (MSM) and visualise behavioural trajectories from 2019 to 2021. METHODS: We linked a behavioural survey to a hepatitis C cohort study (NoCo), established in 2019 across six German HIV/hepatitis C virus (HCV) treatment centres, and performed a case-control analysis. Cases were MSM with recent HCV infection, and controls were matched for HIV status (model 1) or proportions of sexual partners with HIV (model 2). We conducted conditional univariable and multivariable regression analyses. RESULTS: In all, 197 cases and 314 controls completed the baseline questionnaire and could be matched with clinical data. For regression models, we restricted cases to those with HCV diagnosed since 2018 (N = 100). Factors independently associated with case status included sex-associated rectal bleeding, shared fisting lubricant, anal douching, chemsex, intravenous and intracavernosal injections, with population-attributable fractions of 88% (model 1) and 85% (model 2). These factors remained stable over time among cases, while sexual partner numbers and group sex decreased during COVID-19 measures. CONCLUSIONS: Sexual/sex-associated practices leading to blood exposure are key factors in HCV transmission in MSM. Public health interventions should emphasize the importance of blood safety in sexual encounters. Micro-elimination efforts were temporarily aided by reduced opportunities for sexual encounters during the COVID-19 pandemic.

Weight loss in adult male Wistar rats by Roux-en-Y gastric bypass is primarily explained by caloric intake reduction and presurgery body weight.

Diets varying in macronutrient composition, energy density, and/or palatability may cause differences in outcome of bariatric surgery. In the present study, rats feeding a healthy low-fat (LF) diet or an obesogenic high-fat/sucrose diet (HF/S) were either subjected to Roux-en-Y gastric bypass surgery (RYGB) or sham surgery, and weight loss trajectories and various energy balance parameters were assessed. Before RYGB, rats eating an HF/S (n = 14) diet increased body weight relative to rats eating an LF diet (n = 20; P < 0.01). After RYGB, absolute weight loss was larger in HF/S (n = 6) relative to LF feeding (n = 6) rats, and this was associated with reduced cumulative energy intake (EI; P < 0.05) and increased locomotor activity (LA; P < 0.05-0.001), finally leading to similar levels of reduced body fat content in HF/S and LF rats 3 wk after surgery. Regression analysis revealed that variation in RYGB-induced body weight loss was best explained by models including 1) postoperative cumulative EI and preoperative body weight (R2 = 0.87) and 2) postoperative cumulative EI and diet (R2 = 0.79), each without significant contribution of LA. Particularly rats on the LF diet became transiently more hypothermic and circadianally arrhythmic following RYGB (i.e., indicators of surgery-associated malaise) than HF/S feeding rats. Our data suggest that relative to feeding an LF diet, continued feeding an HF/S diet does not negatively impact recovery from RYGB surgery, yet it promotes RYGB-induced weight loss. The RYGB-induced weight loss is primarily explained by reduced cumulative EI and higher preoperative body weight, leading to comparably low levels of body fat content in HF/S and LF feeding rats.NEW & NOTEWORTHY Relative to feeding an LF diet, continued feeding an HF/S diet does not negatively impact recovery from RYGB surgery in rats. Relative to feeding an LF diet, continued feeding an HF/S diet promotes RYGB-induced weight loss. The RYGB-induced weight loss is primarily explained by reduced cumulative EI and higher preoperative body weight, leading to comparably low levels of body fat content in HF/S and LF feeding rats.

Characterization of winged helix domain fusion endonucleases as N6-methyladenine-dependent type IV restriction systems.

Winged helix (wH) domains, also termed winged helix-turn-helix (wHTH) domains, are widespread in all kingdoms of life and have diverse roles. In the context of DNA binding and DNA modification sensing, some eukaryotic wH domains are known as sensors of non-methylated CpG. In contrast, the prokaryotic wH domains in DpnI and HhiV4I act as sensors of adenine methylation in the 6mApT (N6-methyladenine, 6mA, or N6mA) context. DNA-binding modes and interactions with the probed dinucleotide are vastly different in the two cases. Here, we show that the role of the wH domain as a sensor of adenine methylation is widespread in prokaryotes. We present previously uncharacterized examples of PD-(D/E)XK-wH (FcyTI, Psp4BI), PUA-wH-HNH (HtuIII), wH-GIY-YIG (Ahi29725I, Apa233I), and PLD-wH (Aba4572I, CbaI) fusion endonucleases that sense adenine methylation in the Dam+ Gm6ATC sequence contexts. Representatives of the wH domain endonuclease fusion families with the exception of the PLD-wH family could be purified, and an in vitro preference for adenine methylation in the Dam context could be demonstrated. Like most other modification-dependent restriction endonucleases (MDREs, also called type IV restriction systems), the new fusion endonucleases except those in the PD-(D/E)XK-wH family cleave close to but outside the recognition sequence. Taken together, our data illustrate the widespread combinatorial use of prokaryotic wH domains as adenine methylation readers. Other potential 6mA sensors in modified DNA are also discussed.

Efficacy and safety of switching to dolutegravir/lamivudine in virologically suppressed people with HIV-1 aged ≥ 50 years: week 48 pooled results from the TANGO and SALSA studies.

BACKGROUND: As the population of people with HIV ages, concerns over managing age-related comorbidities, polypharmacy, immune recovery, and drug-drug interactions while maintaining viral suppression have arisen. We present pooled TANGO and SALSA efficacy and safety results dichotomized by age (< 50 and ≥ 50 years). METHODS: Week 48 data from the open-label phase 3 TANGO and SALSA trials evaluating switch to once-daily dolutegravir/lamivudine (DTG/3TC) fixed-dose combination vs continuing current antiretroviral regimen (CAR) were pooled. Proportions of participants with HIV-1 RNA ≥ 50 and < 50 copies/mL (Snapshot, intention-to-treat exposed) and safety were analyzed by age category. Adjusted mean change from baseline in CD4 + cell count was assessed using mixed-models repeated-measures analysis. RESULTS: Of 1234 participants, 80% of whom were male, 29% were aged ≥ 50 years. Among those aged ≥ 50 years, 1/177 (< 1%) DTG/3TC participant and 3/187 (2%) CAR participants had HIV-1 RNA ≥ 50 copies/mL at 48 weeks; proportions with HIV-1 RNA < 50 copies/mL were high in both treatment groups (≥ 92%), consistent with overall efficacy and similar to observations in participants aged < 50 years (≥ 93%). Regardless of age category, CD4 + cell count increased or was maintained from baseline with DTG/3TC. Change from baseline in CD4 + /CD8 + ratio was similar across age groups and between treatment groups. One CAR participant aged < 50 years had confirmed virologic withdrawal, but no resistance was detected. In the DTG/3TC group, incidence of adverse events (AEs) was similar across age groups. Proportions of AEs leading to withdrawal were low and comparable between age groups. Although drug-related AEs were generally low, across age groups, drug-related AEs were more frequent in participants who switched to DTG/3TC compared with those who continued CAR. While few serious AEs were observed in both treatment groups, more were reported in participants aged ≥ 50 years vs < 50 years. CONCLUSIONS: Among individuals with HIV-1, switching to DTG/3TC maintained high rates of virologic suppression and demonstrated a favorable safety profile, including in those aged ≥ 50 years despite higher prevalence of concomitant medication use and comorbidities. TRIAL REGISTRATION NUMBER: TANGO, NCT03446573 (February 27, 2018); SALSA, NCT04021290 (July 16, 2019).

The processing intermediate of human amylin, pro-amylin(1-48), has in vivo and in vitro bioactivity.

Amylin is released by pancreatic beta-cells in response to a meal and its major soluble mature form (37 amino acid-peptide) produces its biological effects by activating amylin receptors. Amylin is derived from larger propeptides that are processed within the synthesizing beta-cell. There are suggestions that a partially processed form, pro-amylin(1-48) is also secreted. We tested the hypothesis that pro-amylin(1-48) has biological activity and that human pro-amylin(1-48) may also form toxic pre-amyloid species. Amyloid formation, the ability to cross-seed and in vitro toxicity were similar between human pro-amylin(1-48) and amylin. Human pro-amylin(1-48) was active at amylin-responsive receptors, though its potency was reduced at rat, but not human amylin receptors. Pro-amylin(1-48) was able to promote anorexia by activating neurons of the area postrema, amylin's primary site of action, indicating that amylin can tolerate significant additions at the N-terminus without losing bioactivity. Our studies help to shed light on the possible roles of pro-amylin(1-48) which may be relevant for the development of future amylin-based drugs.

A human antibody against pathologic IAPP aggregates protects beta cells in type 2 diabetes models.

In patients with type 2 diabetes, pancreatic beta cells progressively degenerate and gradually lose their ability to produce insulin and regulate blood glucose. Beta cell dysfunction and loss is associated with an accumulation of aggregated forms of islet amyloid polypeptide (IAPP) consisting of soluble prefibrillar IAPP oligomers as well as insoluble IAPP fibrils in pancreatic islets. Here, we describe a human monoclonal antibody selectively targeting IAPP oligomers and neutralizing IAPP aggregate toxicity by preventing membrane disruption and apoptosis in vitro. Antibody treatment in male rats and mice transgenic for human IAPP, and human islet-engrafted mouse models of type 2 diabetes triggers clearance of IAPP oligomers resulting in beta cell protection and improved glucose control. These results provide new evidence for the pathological role of IAPP oligomers and suggest that antibody-mediated removal of IAPP oligomers could be a pharmaceutical strategy to support beta cell function in type 2 diabetes.

Treat-to-target strategies for the management of familial Mediterranean Fever in children.

BACKGROUND: The objective of this initiative was to develop a treat-to-target (T2T) approach for the management of patients with Familial Mediterranean Fever (FMF), including the definition of a complex treatment target, and establish strategies that improve patient care and long-term outcome. METHODS: An initial set of statements as well as a flow chart visualising the proposed concept was developed. To adapt the preliminary statements to the current state of knowledge, a systematic literature search was performed and the modified statements were subject to a Delphi approach. To ensure the applicability of the statements in daily practice, an online survey was conducted among paediatric rheumatologists in Germany. In addition, data from the national AID-NET registry were analysed with respect to therapeutic response. RESULTS: This T2T initiative yielded a total of 26 statements guiding FMF management with respect to diagnosis, treatment targets, treatment strategies and monitoring. The online survey identified cut-off values for inflammatory markers indicating treatment intensification and appropriate measures in case of colchicine intolerance or non-adherence. The analysis of data derived from the national AID-NET showed that colchicine therapy was successfully terminated in 61% of patients (27 out of 44) with heterozygous MEFV mutations. Multidimensional treatment targets incorporating objective and subjective reported outcome measures were developed. These provide the basis for stratifying patients into the following treatment paths: continue colchicine, persisting attacks / inflammation, colchicine intolerance, persisting arthritis, colchicine reduction and adjustment/reduction of biologics. CONCLUSIONS: The proposed consensus treatment plan for the management of FMF incorporates multidimensional targets allowing transparent treatment decisions, which will promote personalised disease management and increase adherence to therapy.

Reinfection incidence and risk among people treated for recent hepatitis C virus infection.

OBJECTIVE: Reinfection poses a challenge to hepatitis C virus (HCV) elimination. This analysis assessed incidence of, and factors associated with reinfection among people treated for recent HCV (duration of infection <12 months). METHODS: Participants treated for recent HCV (primary infection or reinfection) in an international randomized trial were followed at 3-monthly intervals for up to 2 years to assess for reinfection. Reinfection incidence was calculated using person-time of observation. Factors associated with HCV reinfection were assessed using Cox proportional hazards regression analysis. RESULTS: Of 222 participants treated for recent HCV, 196 (62% primary infection, 38% reinfection) were included in the cohort at risk for reinfection, of whom 87% identified as gay or bisexual men, 71% had HIV and 20% injected drugs in the month prior to enrolment. During 198 person-years of follow-up, 28 cases of HCV reinfection were identified among 27 participants, for an incidence of 14.2 per 100 person-years [95% confidence interval (CI) 9.8-20.5]. Reinfection was associated with prior HCV reinfection [adjusted hazards ratio (aHR) 2.42; 95% CI 1.08-5.38], injection drug use posttreatment (aHR 2.53; 95% CI 1.14-5.59), condomless anal intercourse with casual male partners (aHR 3.32; 95% CI 1.14-9.65) and geographic region (United Kingdom, aHR 0.21; 95% CI 0.06-0.75). Among gay and bisexual men (GBM), reinfection was also associated with sexualized drug use involving injecting posttreatment (aHR 2.97; 95% CI 1.10-8.02). CONCLUSION: High reinfection incidence following treatment for recent HCV among people with ongoing sexual and drug use risk behaviour highlights the need for posttreatment surveillance, rapid retreatment of reinfection and targeted harm reduction strategies.

Body weight lowering effect of glucose-dependent insulinotropic polypeptide and glucagon-like peptide receptor agonists is more efficient in RAMP1/3 KO than in WT mice.

The glucose-dependent insulinotropic polypeptide (GIPR) and glucagon-like peptide (GLP-1R) receptor agonists are insulin secretagogues that have long been shown to improve glycemic control and dual agonists have demonstrated successful weight loss in the clinic. GIPR and GLP-1R populations are located in the dorsal vagal complex where receptor activity-modifying proteins (RAMPs) are also present. According to recent literature, RAMPs not only regulate the signaling of the calcitonin receptor, but also that of other class B G-protein coupled receptors, including members of the glucagon receptor family such as GLP-1R and GIPR. The aim of this study was to investigate whether the absence of RAMP1 and RAMP3 interferes with the action of GIPR and GLP-1R agonists on body weight maintenance and glucose control. To this end, WT and RAMP 1/3 KO mice were fed a 45% high fat diet for 22 weeks and were injected daily with GLP-1R agonist (2 nmol/kg/d; NN0113-2220), GIPR agonist (30 nmol/kg/d; NN0441-0329) or both for 3 weeks. While the mono-agonists exerted little to no body weight lowering and anorectic effects in WT or RAMP1/3 KO mice, but at the given doses, when both compounds were administered together, they synergistically reduced body weight, with a greater effect observed in KO mice. Finally, GLP-1R and GIP/GLP-1R agonist treatment led to improved glucose tolerance, but the absence of RAMPs resulted in an improvement of the HOMA-IR score. These data suggest that RAMPs may play a crucial role in modulating the pharmacological actions of GLP-1 and GIP receptors.

Abatacept as Monotherapy and in Combination With Methotrexate in Patients With Juvenile Idiopathic Arthritis: Analysis of 2 Phase III Trials.

OBJECTIVE: To describe the efficacy and safety data of children with polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with abatacept (ABA) + methotrexate (MTX) or ABA monotherapy when prior MTX use was either ineffective or not tolerated. METHODS: Posthoc analysis of 2 phase III trials of subcutaneous (SC) and intravenous (IV) ABA over 2 years in patients with pcJIA (aged 2-17 years). Patients were stratified by treatment with ABA + MTX or ABA monotherapy and further by prior biologic use. Efficacy outcomes included JIA-American College of Rheumatology (JIA-ACR) responses, Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein (JADAS27-CRP), and safety. Descriptive pharmacokinetic analyses were also performed. RESULTS: Efficacy responses (JIA-ACR and JADAS27-CRP) were similar between patients receiving ABA + MTX (n = 310) or ABA monotherapy (n = 99) and persisted over 2 years. Clinical response rates were similar in biologic-naïve patients and prior biologic users; this was independent of MTX use. Across both studies, ABA + MTX and ABA monotherapy displayed similar safety profiles. Pharmacokinetic results revealed similar minimum steady-state trough ABA concentrations between studies. Further, baseline MTX did not influence ABA clearance and was not a significant predictor of JIA-ACR responses. CONCLUSION: ABA monotherapy (SC and IV) was effective and well tolerated in children with pcJIA when prior MTX use was ineffective or not tolerated. Treatment effects of ABA appear to be independent of MTX coadministration. Consequently, ABA monotherapy can be considered for those with prior biologic therapy if MTX use is inappropriate. (ClinicalTrials.gov: NCT01844518 and NCT00095173).

Expanding epidemic of recently acquired HCV in HIV-coinfected patients over a period of 10 years.

Background & Aims: Ongoing transmission of HCV infections is associated with risk factors such as drug injection, needlestick injuries, and men who have sex with men (MSM). Ways of transmission, the course of acute infection, changes of virologic features, and incidence over time are not well known. Methods: Over a period of 10 years, n = 161 patients with recently acquired HCV infection (RAHC) (median follow-up 6.8 years) were prospectively enrolled. NS5B sequencing was performed to re-evaluate the HCV genotype (GT) and for phylogenetic analyses. Results: Patients with RAHC were mainly male (92.5%), MSM (90.1%), and HIV-coinfected (86.3%). Transmission risk factors for MSM and non-MSM were sexual risk behaviour (100 and 6.3%, respectively), injection drug use (9.7 and 37.5%, respectively), and nasal drug use (15.2 and 0%, respectively). Spontaneous and interferon- or direct-acting antiviral-based clearance rates were 13.6, 84.3 and 93.4%, respectively. Mean RAHC declined from 19.8 in the first to 13.2 in the past five study years. Although the majority of infections was caused by HCV GT1a, the frequency of HCV GT4d and slightly HCV GT3a increased over time. No relevant clustering of HCV isolates was observed in non-MSM. However, 45% of HCV GT1a and 100% of HCV GT4d MSM cases clustered with MSM isolates from other countries. Travel-associated infections were supported by personal data in an MSM subgroup. No international clustering was detected in MSM with HCV GT1b or HCV GT3a. Conclusions: RAHCs were mainly diagnosed in HIV-coinfected MSM patients and were associated with sexual risk behaviour. Spontaneous clearance rates were low, and phylogenetic clusters were observed in the majority of patients. Impact and Implications: We evaluated the occurrence and transmission of recently acquired HCV infections (RAHCs) over a period of 10 years. Our data demonstrate that the presence of RAHC was mainly found in HIV-coinfected MSM, with internationally connected transmission networks being observed in the majority of patients. Spontaneous clearance rates were low, and reinfection rates increased mainly driven by a small subset of MSM patients with high-risk behaviour.

Assessing the Virologic Impact of Archived Resistance in the Dolutegravir/Lamivudine 2-Drug Regimen HIV-1 Switch Study TANGO through Week 144.

The TANGO study (ClinicalTrials.gov, NCT03446573) demonstrated that switching to dolutegravir/lamivudine (DTG/3TC) was non-inferior to continuing tenofovir alafenamide-based regimens (TBR) through week 144. Retrospective baseline proviral DNA genotypes were performed for 734 participants (post-hoc analysis) to assess the impact of archived, pre-existing drug resistance on 144-week virologic outcomes by last on-treatment viral load (VL) and Snapshot. A total of 320 (86%) participants on DTG/3TC and 318 (85%) on TBR had both proviral genotype data and ≥1 on-treatment post-baseline VL results and were defined as the proviral DNA resistance analysis population. Archived International AIDS Society-USA major nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, and integrase strand transfer inhibitor resistance-associated mutations (RAMs) were observed in 42 (7%), 90 (14%), 42 (7%), and 11 (2%) participants, respectively, across both groups; 469 (74%) had no major RAMs at baseline. M184V/I (1%), K65N/R (<1%), and thymidine analogue mutations (2%) were infrequent. Through week 144, >99% of participants on DTG/3TC and 99% on TBR were virologically suppressed (last on-treatment VL <50 copies/mL) regardless of the presence of major RAMs. Results from the sensitivity analysis by Snapshot were consistent with the last available on-treatment VL. In TANGO, archived, pre-existing major RAMs did not impact virologic outcomes through week 144.

"To brain or not to brain": evaluating the possible direct effects of the satiety factor oleoylethanolamide in the central nervous system.

Introduction: Oleoylethanolamide (OEA), an endogenous N-acylethanolamine acting as a gut-to-brain signal to control food intake and metabolism, has been attracting attention as a target for novel therapies against obesity and eating disorders. Numerous observations suggested that the OEA effects might be peripherally mediated, although they involve central pathways including noradrenergic, histaminergic and oxytocinergic systems of the brainstem and the hypothalamus. Whether these pathways are activated directly by OEA or whether they are downstream of afferent nerves is still highly debated. Some early studies suggested vagal afferent fibers as the main route, but our previous observations have contradicted this idea and led us to consider the blood circulation as an alternative way for OEA's central actions. Methods: To test this hypothesis, we first investigated the impact of subdiaphragmatic vagal deafferentation (SDA) on the OEA-induced activation of selected brain nuclei. Then, we analyzed the pattern of OEA distribution in plasma and brain at different time points after intraperitoneal administration in addition to measuring food intake. Results: Confirming and extending our previous findings that subdiaphragmatic vagal afferents are not necessary for the eating-inhibitory effect of exogenous OEA, our present results demonstrate that vagal sensory fibers are also not necessary for the neurochemical effects of OEA. Rather, within a few minutes after intraperitoneal administration, we found an increased concentration of intact OEA in different brain areas, associated with the inhibition of food intake. Conclusion: Our results support that systemic OEA rapidly reaches the brain via the circulation and inhibits eating by acting directly on selected brain nuclei.

Mammalian models of diabetes mellitus, with a focus on type 2 diabetes mellitus.

Although no single animal model replicates all aspects of diabetes mellitus in humans, animal models are essential for the study of energy balance and metabolism control as well as to investigate the reasons for their imbalance that could eventually lead to overt metabolic diseases such as type 2 diabetes mellitus. The most frequently used animal models in diabetes mellitus research are small rodents that harbour spontaneous genetic mutations or that can be manipulated genetically or by other means to influence their nutrient metabolism and nutrient handling. Non-rodent species, including pigs, cats and dogs, are also useful models in diabetes mellitus research. This Review will outline the advantages and disadvantages of selected animal models of diabetes mellitus to build a basis for their most appropriate use in biomedical research.

High Dietary Cation and Anion Difference and High-Dose Ascorbic Acid Modify Acid-Base and Antioxidant Balance in Dairy Goats Fed under Tropical Conditions.

High ambient temperature (HTa) causes acid-base imbalance and systemic oxidative stress, and this may indirectly affect the mammary gland. Furthermore, HTa induces intracellular oxidative stress, which has been proposed to affect cell metabolism directly. We previously showed in dairy goats that the negative effect of HTa was compromised by enhancing heat dissipation during a high dietary cation and anion difference (DCAD) regimen. Moreover, high-dose vitamin C or ascorbic acid (AA) supplements have been used to manage oxidative stress in ruminants. The present study hypothesized that high DCAD and AA supplements that could alleviate the HTa effect would influence the milk synthesis pathway and mammary gland function. The results showed that goats fed with high DCAD had higher blood pH than control goats in the 4th week. The high dose of AA supplement decreases urine pH in the 8th week. The percent reduction of urine pH from the AA supplement was significant in the DCAD group. The high-dose AA supplement decreased plasma glutathione peroxidase activity and malonaldehyde. This effect was enhanced by a high DCAD supplement. In addition, supplementation with AA increased milk protein and citrate and decreased milk FFA. These alterations indicate the intracellular biochemical pathway of energy metabolism and milk synthesis. It can be concluded that a high DCAD regimen and AA supplement in dairy goats fed under HTa could influence the milk synthesis pathway. The evidence suggests that HTa decreases mammary gland function by modification of acid-base homeostasis and oxidative stress.

Obesity-induced changes in gene expression in feline adipose and skeletal muscle tissue.

Indoor-confined cats are prone to developing obesity due to a sedentary life and an energy intake exceeding energy requirements. As in humans, feline obesity decreases insulin sensitivity and increases the risk of developing feline diabetes mellitus, but the pathophysiological mechanisms are currently poorly understood. Human obesity-related metabolic alterations seem to relate to changes in the expression of genes involved in glucose metabolism, insulin action and inflammation. The objective of the current study was to investigate changes in the expression of genes relating to obesity, glucose metabolism and inflammation in cats with non-experimentally induced obesity. Biopsies from the sartorius muscle and subcutaneous adipose tissue were obtained from 73 healthy, neutered, indoor-confined domestic shorthaired cats ranging from lean to obese. Quantification of obesity-related gene expression levels relative to glyceraldehyde-3-phosphate dehydrogenase was performed by quantitative real-time polymerase chain reaction. A negative association between obesity and adiponectin expression was observed in the adipose tissue (mean ± SD; normal weight, 27.30 × 10-3 ± 77.14 × 10-3 ; overweight, 2.89 × 10-3 ± 0.38 × 10-3 and obese, 2.93 × 10-3 ± 4.20 × 10-3 , p < 0.05). In muscle, the expression of peroxisome proliferative activated receptor-γ2 and plasminogen activator inhibitor-1 was increased in the obese compared to the normal-weight cats, and resistin was increased in the normal-weight compared to the overweight cats. There were no detectable obesity-related changes in the messenger RNA levels of inflammatory cytokines. In conclusion, a possible obesity-related low-grade inflammation caused by increased expression of key proinflammatory regulators was not observed. This could imply that the development of feline obesity and ensuing insulin resistance may not be based on tissue-derived inflammation, but caused by several determining factors, many of which still need further investigation.

Low Spontaneous Clearance Rates of Recently Acquired Hepatitis C Virus in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men (PROBE-C Study).

BACKGROUND: Using direct-acting antivirals (DAAs) for recently acquired hepatitis C virus (RAHCV) infections, particularly in human immunodeficiency virus (HIV)-positive men who have sex with men (MSM), dramatically reduced the incidence of hepatitis C. However, implementation into clinical practice is challenging. The aim of this study was to analyze spontaneous clearance (SC) rates of RAHCV and to identify predictors of SC. METHODS: The PROBE-C study is an observational European cohort on RAHCV infections in HIV-positive MSM. Between 2007 and 2017, RAHCV infections were documented with ≥12 months of follow-up. Fisher exact, χ2, and Mann-Whitney U tests were used for statistical analysis. RESULTS: A total of 464 RAHCV infections were documented; 457 of 464 patients (98%) were male, and the median age (interquartile range [IQR]) was 41 (38-46) years. The main risk group for hepatitis C virus (HCV) transmission was MSM (98.9%). Most participants were infected with HCV genotype 1 (78.3%). The median baseline HCV RNA level (IQR) was 230 000 (135 000-474 432) IU/mL, and the median CD4+ T-cell count was 574/µL (547-604/µL. Of all cases, 92% received combination antiretroviral therapy, with 91% showing suppressed HIV RNA levels (<200 copies/mL). The median maximum alanine aminotransferase level (IQR) was 445 (402-522) U/L. SC of RAHCV infection occurred in 55 of 464 cases (11.9%). A >2-log decline in HCV RNA levels 4 weeks after diagnosis of RAHCV infection was the strongest predictor of SC (P < .001; sensitivity, 96.4%; specificity, 97.5%; positive predictive value, 84.1%; negative predictive value, 99.5%). CONCLUSIONS: SC of RAHCV in HIV-positive MSM is found in only 11.9% of cases and a <2-log drop in HCV RNA level at week 4 after diagnosis should prompt early DAA-based treatment. However, immediate DAA treatment for RAHCV infection may also be favored in patients with ongoing transmission risk behavior.