Maternal hypothyroidism in mice influences glucose metabolism in adult offspring

International audienceAims/hypothesis: During pregnancy, maternal metabolic disease and hormonal imbalance may alter fetal beta cell development and/or proliferation, thus leading to an increased risk for developing type 2 diabetes in adulthood. Although thyroid hormones play an important role in fetal endocrine pancreas development, the impact of maternal hypothyroidism on glucose homeostasis in adult offspring remains poorly understood.Methods: We investigated this using a mouse model of hypothyroidism, induced by administration of an iodine-deficient diet supplemented with propylthiouracil during gestation.Results: Here, we show that, when fed normal chow, adult mice born to hypothyroid mothers were more glucose-tolerant due to beta cell hyperproliferation (two- to threefold increase in Ki67-positive beta cells) and increased insulin sensitivity. However, following 8 weeks of high-fat feeding, these offspring gained 20% more body weight, became profoundly hyperinsulinaemic (with a 50% increase in fasting insulin concentration), insulin-resistant and glucose-intolerant compared with controls from euthyroid mothers. Furthermore, altered glucose metabolism was maintained in a second generation of animals.Conclusions/interpretation: Therefore, gestational hypothyroidism induces long-term alterations in endocrine pancreas function, which may have implications for type 2 diabetes prevention in affected individuals

Acid‐Resistant BODIPY Amino Acids for Peptide‐based Fluorescence Imaging of GPR54 Receptors in Pancreatic Islets

The G protein-coupled kisspeptin receptor (GPR54 or KISS1R) is an important mediator in reproduction, metabolism and cancer biology; however, there are limited fluorescent probes or antibodies for direct imaging of these receptors in cells and intact tissues, which can help to interrogate their multiple biological roles. Herein, we describe the rational design and characterization of a new acid-resistant BODIPY-based amino acid (Trp-BODIPY PLUS), and its implementation for solid-phase synthesis of fluorescent bioactive peptides. Trp-BODIPY PLUS retains the binding capabilities of both short linear and cyclic peptides and displays notable turn-on fluorescence emission upon target binding for wash-free imaging. Finally, we employed Trp-BODIPY PLUS to prepare some of the first fluorogenic kisspeptin-based probes and visualized the expression and localization of GPR54 receptors in human cells and in whole mouse pancreatic islets by fluorescence imaging

Macroprolactinoma causing VI, X, XII cranial nerve palsies nearly 30 years after initial treatment

A 48-year-old man was diagnosed with a large macroprolactinoma in 1982 treated with surgery, adjuvant radiotherapy and bromocriptine. Normal prolactin was achieved in 2005 but in 2009 it started rising. Pituitary MRIs in 2009, 2012, 2014 and 2015 were reported as showing empty pituitary fossa. Prolactin continued to increase (despite increasing bromocriptine dose). Trialling cabergoline had no effect (prolactin 191,380 mU/L). In January 2016, he presented with right facial weakness and CT head was reported as showing no acute intracranial abnormality. In late 2016, he was referred to ENT with hoarse voice; left hypoglossal and recurrent laryngeal nerve palsies were found. At this point, prolactin was 534,176 mU/L. Just before further endocrine review, he had a fall and CT head showed a basal skull mass invading the left petrous temporal bone. Pituitary MRI revealed a large enhancing mass within the sella infiltrating the clivus, extending into the left petrous apex and occipital condyle with involvement of the left Meckel’s cave, internal acoustic meatus, jugular foramen and hypoglossal canal. At that time, left abducens nerve palsy was also present. CT thorax/abdomen/pelvis excluded malignancy. Review of previous images suggested that this lesion had started becoming evident below the fossa in pituitary MRI of 2015. Temozolomide was initiated. After eight cycles, there is significant tumour reduction with prolactin 1565 mU/L and cranial nerve deficits have remained stable. Prolactinomas can manifest aggressive behaviour even decades after initial treatment highlighting the unpredictable clinical course they can demonstrate and the need for careful imaging review

Effect of HLA DR epitope de-immunization of Factor VIII \u3ci\u3ein vitro\u3c/i\u3e and \u3ci\u3ein vivo\u3c/i\u3e

T cell-dependent development of anti-Factor VIII (FVIII) antibodies that neutralize FVIII activity is a major obstacle to replacement therapy in hemophilia A. To create a less immunogenic therapeutic protein, recombinant FVIII can be modified to reduce HLA binding of epitopes based on predicted anchoring residues. Here, we used immunoinformatic tools to identify C2 domain HLA DR epitopes and predict site-specific mutations that reduce immunogenicity. Epitope peptides corresponding to original and modified sequences were validated in HLA binding assays and in immunizations of hemophilic E16 mice, DR3 and DR4 mice and DR3 × E16 mice. Consistent with immunoinformatic predictions, original epitopes are immunogenic. Immunization with selected modified sequences lowered immunogenicity for particular peptides and revealed residual immunogenicity of incompletely de-immunized modified peptides. The stepwise approach to reduce protein immunogenicity by epitope modification illustrated here is being used to design and produce a functional full-length modified FVIII for clinical use

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics’ ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) — brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways

Glycaemic outcomes in people living with diabetes under 65 and over 65 years old using an intermittently scanned continuous glucose monitoring system

OBJECTIVE: Intermittently scanned continuous glucose monitoring (isCGM) has revolutionised the care of people with diabetes but its uptake and benefits in older adults are not well known. We examined the impact of isCGM (Freestyle Libre, FSL) on glycaemic outcomes in younger (⩽65 years) and older adults (>65 years) with diabetes. DESIGN AND METHODS: In total, 2260 adult patients registered on the Libreview account at University Hospitals Birmingham NHS Foundation Trust, UK, were included. Inclusion criteria: all patients with type 1 and type 2 diabetes aged >18 years, use of isCGM >6 months, scanning at least 6 times/day. Demographics, diabetes history and glycaemic outcomes (time in range (TIR), time above range and time below range (TBR), estimated HbA1c, HbA1c at start and at end of study) were collected by accessing electronic patient records and Libreview. Outcomes were compared between age groups ⩽65 or >65 years old. RESULTS: Most patients were of Caucasian ethnicity (⩽65 years 68%, >65 years 73%) and had type 1 diabetes. Mean duration of diabetes was 19.5 years (range 0-65 years) and 34.5 years (range 0-79 years) for ⩽65 and >65 years, respectively. Only a quarter of those ⩽65 years achieved (219/943; 23.2%) their age specific TIR target compared to 69% (78/113) of those >65 years cohort, while 70.1% (663/946) of ⩽65 years and 40.7% (46/113) of >65 years achieved their age-specific TBR target. When the less strict ⩽65 years TBR target was applied, 75% (85/113) of >65 years cohort achieved this. CONCLUSION: FSL use was associated with improved glycaemic outcomes across all age groups. Individualised targets may be needed to improve TBR in those aged >65 years

Ultimate precision in cosmic-ray radio detection - The SKA

As of 2023, the low-frequency part of the Square Kilometre Array will go online in Australia. It will constitute the largest and most powerful low-frequency radio-astronomical observatory to date, and will facilitate a rich science programme in astronomy and astrophysics. With modest engineering changes, it will also be able to measure cosmic rays via the radio emission from extensive air showers. The extreme antenna density and the homogeneous coverage provided by more than 60,000 antennas within an area of one km 2 will push radio detection of cosmic rays in the energy range around 10 17 eV to ultimate precision, with superior capabilities in the reconstruction of arrival direction, energy, and an expected depth-of-shower-maximum resolution of < 10 g/cm 2

Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile

BACKGROUND: In mice, GPR146 (G-protein-coupled receptor 146) deficiency reduces plasma lipids and protects against atherosclerosis. Whether these findings translate to humans is unknown. METHODS: Common and rare genetic variants in the GPR146 gene locus were used as research instruments in the UK-Biobank. The Lifelines, and The Copenhagen-City Heart Study, and a cohort of individuals with familial hypobetalipoproteinemia were used to find and study rare GPR146 variants. RESULTS: In the UK-Biobank, carriers of the common rs2362529-C allele present with lower low-density lipoprotein cholesterol, apo (apolipoprotein) B, high-density lipoprotein cholesterol, apoAI, CRP (C-reactive protein), and plasma liver enzymes compared with noncarriers. Carriers of the common rs1997243-G allele, associated with higher GPR146 expression, present with the exact opposite phenotype. The associations with plasma lipids of the above alleles are allele dose-dependent. Heterozygote carriers of a rare coding variant (p.Pro62Leu; n=2615), predicted to be damaging, show a stronger reductions in the above parameters compared with carriers of the common rs2362529-C allele. The p.Pro62Leu variant is furthermore shown to segregate with low low-density lipoprotein cholesterol in a family with familial hypobetalipoproteinemia. Compared with controls, carriers of the common rs2362529-C allele show a marginally reduced risk of coronary artery disease (P=0.03) concomitant with a small effect size on low-density lipoprotein cholesterol (average decrease of 2.24 mg/dL in homozygotes) of this variant. Finally, mendelian randomization analyses suggest a causal relationship between GPR146 gene expression and plasma lipid and liver enzyme levels. CONCLUSIONS: This study shows that carriers of new genetic GPR146 variants have a beneficial cardiometabolic risk profile, but it remains to be shown whether genetic or pharmaceutical inhibition of GPR146 protects against atherosclerosis in humans

Genome-wide association of functional traits linked with<i> Campylobacter jejuni </i>survival from farm to fork

Campylobacter jejuni is a major cause of bacterial gastroenteritis worldwide, primarily associated with the consumption of contaminated poultry. C. jejuni lineages vary in host range and prevalence in human infection, suggesting differences in survival throughout the poultry processing chain. From 7,343 MLST-characterised isolates, we sequenced 600 C. jejuni and C. coli isolates from various stages of poultry processing and clinical cases. A genome-wide association study (GWAS) in C. jejuni ST-21 and ST-45 complexes identified genetic elements over-represented in clinical isolates that increased in frequency throughout the poultry processing chain. Disease-associated SNPs were distinct in these complexes, sometimes organised in haplotype blocks. The function of genes containing associated elements was investigated, demonstrating roles for cj1377c in formate metabolism, nuoK in aerobic survival and oxidative respiration, and cj1368-70 in nucleotide salvage. This work demonstrates the utility of GWAS for investigating transmission in natural zoonotic pathogen populations and provides evidence that major C. jejuni lineages have distinct genotypes associated with survival, within the host specific niche, from farm to fork. </p