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.

Impact of coronavirus disease 2019 on patients with primary adrenal insufficiency: a cross-sectional study.

Objective: Patients with primary adrenal insufficiency (PAI) are thought to be particularly vulnerable to coronavirus disease 2019 (COVID-19); however, little is known about its true impact on this group. We assessed morbidity and health promotion attitudes during the pandemic amongst a large cohort of patients with PAI. Design: Cross-sectional, single-centre study. Methods: In May 2020, COVID-19 advice on social distancing and sick-day rules was distributed to all patients with PAI registered with a large secondary/tertiary care centre. A semi-structured questionnaire was used to survey patients in early 2021. Results: Of 207 contacted patients, 162 responded (82/111 with Addison's disease, AD; 80/96 with congenital adrenal hyperplasia, CAH). Patients with AD were older than those with CAH (median age 51 vs 39 years; P < 0.001) and had more comorbidities (Charlson comorbidity index ≥2 47.6% vs 10.0%; P< 0.001). By the time of the survey, 47 patients (29.0%) had been diagnosed with COVID-19, the second commonest cause of sick-day dosing during the study and the leading trigger of adrenal crises (4/18 cases). Patients with CAH had a higher risk of COVID-19 compared to AD (adjusted odds ratio 2.53 (95% CI 1.07-6.16), P= 0.036), were less inclined to have the COVID-19 vaccine (80.0% vs 96.3%; P = 0.001), and were less likely to have undergone hydrocortisone self-injection training (80.0% vs 91.5%; P = 0.044) or wear medical alert jewellery (36.3% vs 64.6%; P = 0.001). Conclusions: COVID-19 was a principal trigger for adrenal crises and sick-day dosing in patients with PAI. Despite a higher risk of COVID-19, patients with CAH showed less engagement with self-protective attitudes. Significance statement: We conducted a cross-sectional study on a large and well-characterised group of patients with PAI and demonstrated that COVID-19 was a leading cause of morbidity during the early phases of the pandemic. Patients with AD were older and had a greater burden of comorbidity than those with CAH, including non-adrenal autoimmune disorders. However, patients with CAH were more likely to develop COVID-19 and demonstrated reduced engagement with healthcare services and health promotion strategies.

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.

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.

Management of endocrine conditions at the end of life.

An important facet to end-of-life care is deprescribing. This can be challenging when reviewing life-sustaining endocrine medications but, unlike for diabetes, there is no national guidance to support patients and clinicians faced with care planning. This article reviews the limited current evidence to highlight areas for further discussion and research with the aim of moving towards consensus opinion. Discontinuation of certain endocrine medications, including corticosteroids, desmopressin and levothyroxine, is likely to precipitate an 'endocrine-driven mechanism of death', while it may be reasonable to discontinue other endocrine medications without the risk of hastening death or causing unnecessary symptoms. However, the over-arching theme should be that early discussion with patients regarding conversion or discontinuation of endocrine medications or monitoring is central to care planning.

Maternal hypothyroidism in mice influences glucose metabolism in adult offspring.

AIMS/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.

Retinopathy and microalbuminuria are common microvascular complications in cystic fibrosis-related diabetes.

AIMS: To study the prevalence of microvascular complications and renal changes associated with cystic fibrosis-related diabetes (CFRD). METHODS: This retrospective cohort study was conducted at the West Midlands Adult Cystic Fibrosis centre, United Kingdom. Data regarding age, sex, microalbuminuria, retinopathy neuropathy, and biochemical results were collected for all people with CFRD who had an annual review from 1 January 2018 to 31 December 2018 at the centre. Descriptive statistics were analysed using STATAv15.1. RESULTS: A total of 189 patients were included, of which 56.6% were male and median age (interquartile range) was 33 (27-39) years; 79.4% (150/189) had their annual review in 2018. Those with a biochemically impaired renal function numbered 7.2% (13/180) and 22.7% (32/141) had microalbuminuria; 17.2% (10/58) had diabetes related retinopathy. No one in our cohort had diabetic ulcers; however, 10.3% (13/126) had absent foot pulses. CONCLUSION: We found a higher prevalence of microalbuminuria compared with retinopathy in a large cohort of cystic fibrosis adults. This study demonstrates the need for regular specialist follow-up to facilitate early identification of such complications and a long-term prospective cohort to understand underlying mechanisms.

Regular performance feedback may be key to maintain good quality DKA management: results from a five-year study.

Objectives: We postulate that performance feedback is a prerequisite to ensure sustained improvement in diabetic ketoacidosis (DKA) management. Design: The study was based on 'theory of change' concept that suggests changes of primary drivers determine the main outcome. A set of secondary drivers can be implemented to achieve improvements in these primary drivers and thus the main outcome. Setting: This study was conducted at a large tertiary care center in the West Midlands, UK. The region has above average prevalence of diabetes and DKA admissions in the country. Participants: All participants diagnosed with DKA as per national guidelines, except those managed in intensive care unit from April 2014 to March 2018, were included in this study. Interventions: Monthly feedback of performance was the main intervention. Development of a real-time live DKA audit tool, automatic referral system of DKA to the specialist team, electronic monitoring of blood gas measurements and education and redesigning of local (trust) guidelines were the other interventions in this study. Main outcome measures: Total DKA duration, appropriateness of fixed rate intravenous insulin infusion, fluid prescription, glucose monitoring, ketone monitoring and referral to specialists. Results: There was a significant reduction in the duration of DKA postintervention compared with baseline results. However, in the absence of regular feedback, the duration of DKA showed an upward trend nearing baseline values. Similar trends were noted in secondary drivers influencing DKA duration. Conclusion: Based on these results, we recommend regular audit and feedback is required to sustain improvements in DKA management.

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. LEARNING POINTS: Aggressive behaviour of prolactinomas can manifest even decades after first treatment highlighting the unpredictable clinical course these tumours can demonstrate.Escape from control of hyperprolactinaemia in the absence of sellar adenomatous tissue requires careful and systematic search for the anatomical localisation of the lesion responsible for the prolactin excess.Temozolomide is a valuable agent in the therapeutic armamentarium for aggressive/invasive prolactinomas, particularly if they are not amenable to other treatment modalities.