Oncogenic Mutations Rewire Signaling Pathways by Switching Protein Recruitment to Phosphotyrosine Sites.

Tyrosine phosphorylation regulates multi-layered signaling networks with broad implications in (patho)physiology, but high-throughput methods for functional annotation of phosphotyrosine sites are lacking. To decipher phosphotyrosine signaling directly in tissue samples, we developed a mass-spectrometry-based interaction proteomics approach. We measured the in vivo EGF-dependent signaling network in lung tissue quantifying >1,000 phosphotyrosine sites. To assign function to all EGF-regulated sites, we determined their recruited protein signaling complexes in lung tissue by interaction proteomics. We demonstrated how mutations near tyrosine residues introduce molecular switches that rewire cancer signaling networks, and we revealed oncogenic properties of such a lung cancer EGFR mutant. To demonstrate the scalability of the approach, we performed >1,000 phosphopeptide pulldowns and analyzed them by rapid mass spectrometric analysis, revealing tissue-specific differences in interactors. Our approach is a general strategy for functional annotation of phosphorylation sites in tissues, enabling in-depth mechanistic insights into oncogenic rewiring of signaling networks.

Flash glucose monitoring and automated bolus calculation in type 1 diabetes treated with multiple daily insulin injections: a 26 week randomised, controlled, multicentre trial.

AIMS/HYPOTHESIS: We aimed to compare the effects of intermittently scanned continuous glucose monitoring (isCGM) and carbohydrate counting with automated bolus calculation (ABC) with usual care. METHODS: In a randomised, controlled, open-label trial carried out at five diabetes clinics in the Capital Region of Denmark, 170 adults with type 1 diabetes for ≥1 year, multiple daily insulin injections and HbA1c > 53 mmol/mol (7.0%) were randomly assigned 1:1:1:1 with centrally prepared envelopes to usual care (n = 42), ABC (n = 41), isCGM (n = 48) or ABC+isCGM (n = 39). Blinded continuous glucose monitoring data, HbA1c and patient-reported outcomes were recorded at baseline and after 26 weeks. The primary outcome was change in time in range using isCGM vs usual care. RESULTS: Baseline characteristics were comparable across arms: mean age 47 (SD 13.7) years, median (IQR) diabetes duration 18 (10-28) years and HbA1c 65 (61-72) mmol/mol (8.1% [7.7-8.7%]). Change in time in range using isCGM was comparable to usual care (% difference of 3.9 [-12-23], p = 0.660). The same was true for the ABC and ABC+isCGM arms and for hypo- and hyperglycaemia. Also compared with usual care, using ABC+isCGM reduced HbA1c (4 [95% CI 1, 8] mmol/mol) (0.4 [0.1, 0.7] %-point) and glucose CV (11% [4%, 17%]) and improved treatment satisfaction, psychosocial self-efficacy and present life quality. Treatment satisfaction also improved by using isCGM alone vs usual care. Statistical significance was maintained after multiple testing adjustment concerning glucose CV and treatment satisfaction with ABC+isCGM, and treatment satisfaction with isCGM. Discontinuation was most common among ABC only users, and among completers the ABC was used 4 (2-5) times/day and the number of daily isCGM scans was 5 (1-7) at study end. CONCLUSIONS/INTERPRETATION: isCGM alone did not improve time in range, but treatment satisfaction increased in technology-naive people with type 1 diabetes and suboptimal HbA1c. The combination of ABC+isCGM appears advantageous regarding glycaemic variables and patient-reported outcomes, but many showed resistance towards ABC. TRIAL REGISTRATION: ClinicalTrials.gov NCT03682237. FUNDING: The study is investigator initiated and financed by the Capital Region of Denmark.

Breastfeeding at night is rarely followed by hypoglycaemia in women with type 1 diabetes using carbohydrate counting and flexible insulin therapy.

AIMS/HYPOTHESIS: Hypoglycaemia in association with breastfeeding is a feared condition in mothers with type 1 diabetes. Thus, routine carbohydrate intake at each breastfeed, particularly at night, is often recommended despite lack of evidence. We aimed to evaluate glucose levels during breastfeeding, focusing on whether night-time breastfeeding induced hypoglycaemia in mothers with type 1 diabetes. METHODS: Of 43 consecutive mothers with type 1 diabetes, 33 (77%) were included prospectively 1 month after a singleton delivery. Twenty-six mothers (mean [SD] age 30.7 [5.8] years, mean [SD] duration of diabetes 18.6 [10.3] years) were breastfeeding and seven mothers (mean [SD] age 31.7 [5.6] years, mean [SD] duration of diabetes 20.4 [6.2] years) were bottle-feeding their infants with formula. All were experienced in carbohydrate counting using individually tailored insulin therapy with insulin analogues (45% on insulin pump, 55% on multiple daily injections). Thirty-two women with type 1 diabetes, matched for age ±1 year and BMI ±1 kg/m2, who had not given birth or breastfed in the previous year, served as a control group. Blinded continuous glucose monitoring (CGM) for 6 days was applied at 1, 2 and 6 months postpartum in the breastfeeding mothers who recorded breastfeeds and carbohydrate intake at each CGM period. CGM was applied at 1 month postpartum in the formula-feeding mothers and once in the control women. The insulin dose was individually tailored after each CGM period. RESULTS: The percentage of night-time spent with CGM <4.0 mmol/l was low (4.6%, 3.1% and 2.7% at each CGM period in the breastfeeding mothers vs 1.6% in the control women, p = 0.77), and the breastfeeding mothers spent a greater proportion of the night-time in the target range of 4.0-10.0 mmol/l (p = 0.01). Symptomatic hypoglycaemia occurred two or three times per week at 1, 2 and 6 months postpartum in both breastfeeding mothers and the control women. Severe hypoglycaemia was reported by one mother (3%) during the 6 month postpartum period and by one control woman (3%) in the previous year (p = 0.74). In breastfeeding mothers at 1 month, the insulin dose was 18% (-67% to +48%) lower than before pregnancy (p = 0.04). In total, carbohydrate was not consumed in relation to 438 recorded night-time breastfeeds, and CGM <4.0 mmol/l within 3 h occurred after 20 (4.6%) of these breastfeeds. CONCLUSIONS/INTERPRETATION: The percentage of night-time spent in hypoglycaemia was low in the breastfeeding mothers with type 1 diabetes and was similar in the control women. Breastfeeding at night-time rarely induced hypoglycaemia. The historical recommendation of routine carbohydrate intake at night-time breastfeeding may be obsolete in mothers with type 1 diabetes who have properly reduced insulin dose with sufficient carbohydrate intake. TRIAL REGISTRATION: ClinicalTrials.gov NCT02898428.

The impact of restricted gestational weight gain by dietary intervention on fetal growth in women with gestational diabetes mellitus.

AIMS/HYPOTHESIS: We aimed to investigate the impact of maternal gestational weight gain (GWG) during dietary treatment on fetal growth in pregnancies complicated by gestational diabetes (GDM). METHODS: This was a retrospective cohort study of 382 women consecutively diagnosed with GDM before 34 weeks' gestation with live singleton births in our centre (Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark) between 2011 and 2017. The women were stratified into three groups according to restricted (53%), appropriate (16%) and excessive (31%) weekly GWG during dietary treatment (using the Institute of Medicine guidelines) to estimate compliance with an energy-restricted 'diabetes diet' (6000 kJ/day [1434 kcal/day], with approximately 50% of energy intake coming from carbohydrates with a low glycaemic index, and a carbohydrate intake of 175 g/day). Insulin therapy was initiated if necessary, according to local clinical guidelines. RESULTS: Glucose tolerance, HbA1c, weekly GWG before dietary treatment (difference between weight at GDM diagnosis and pre-pregnancy weight, divided by the number of weeks) and SD score for fetal abdominal circumference were comparable across the three groups at diagnosis of GDM at 276 ± 51 weeks (gestation time is given as weeksdays). The women were followed for 100 ± 51 weeks, during which 54% received supplementary insulin therapy and the average (mean) GWG during dietary treatment was 0 kg, 3 kg and 5 kg in the three groups, respectively. Excessive weekly GWG during dietary treatment, reflecting poor dietary adherence was associated with increasing HbA1c (p = 0.014) from diagnosis of GDM to late pregnancy and infants with a birthweight-SD score of 0.59 ± 1.6. In contrast, restricted weekly GWG during dietary treatment, reflecting strict dietary adherence, was associated with decreasing HbA1c (p = 0.001) from diagnosis of GDM to late pregnancy and infants with a birthweight-SD score of 0.15 ± 1.1, without increased prevalence of infants born small for gestational age. Excessive GWG during dietary treatment and late-pregnancy HbA1c were identified as potentially modifiable clinical predictors of infant birthweight-SD score (p = 0.02 for both variables) after correction for confounders. CONCLUSIONS/INTERPRETATION: Restricted GWG during dietary treatment was associated with healthier fetal growth in women with GDM. GWG during dietary treatment and late-pregnancy HbA1c were identified as potentially modifiable clinical predictors of infant birthweight-SD score.

Translating HbA1c measurements into estimated average glucose values in pregnant women with diabetes.

AIMS/HYPOTHESIS: This study aimed to examine the relationship between average glucose levels, assessed by continuous glucose monitoring (CGM), and HbA1c levels in pregnant women with diabetes to determine whether calculations of standard estimated average glucose (eAG) levels from HbA1c measurements are applicable to pregnant women with diabetes. METHODS: CGM data from 117 pregnant women (89 women with type 1 diabetes; 28 women with type 2 diabetes) were analysed. Average glucose levels were calculated from 5-7 day CGM profiles (mean 1275 glucose values per profile) and paired with a corresponding (±1 week) HbA1c measure. In total, 688 average glucose-HbA1c pairs were obtained across pregnancy (mean six pairs per participant). Average glucose level was used as the dependent variable in a regression model. Covariates were gestational week, study centre and HbA1c. RESULTS: There was a strong association between HbA1c and average glucose values in pregnancy (coefficient 0.67 [95% CI 0.57, 0.78]), i.e. a 1% (11 mmol/mol) difference in HbA1c corresponded to a 0.67 mmol/l difference in average glucose. The random effects model that included gestational week as a curvilinear (quadratic) covariate fitted best, allowing calculation of a pregnancy-specific eAG (PeAG). This showed that an HbA1c of 8.0% (64 mmol/mol) gave a PeAG of 7.4-7.7 mmol/l (depending on gestational week), compared with a standard eAG of 10.2 mmol/l. The PeAG associated with maintaining an HbA1c level of 6.0% (42 mmol/mol) during pregnancy was between 6.4 and 6.7 mmol/l, depending on gestational week. CONCLUSIONS/INTERPRETATION: The HbA1c-average glucose relationship is altered by pregnancy. Routinely generated standard eAG values do not account for this difference between pregnant and non-pregnant individuals and, thus, should not be used during pregnancy. Instead, the PeAG values deduced in the current study are recommended for antenatal clinical care.

Vitamin D insufficiency, preterm delivery and preeclampsia in women with type 1 diabetes - an observational study.

INTRODUCTION: The aim of this study was to evaluate whether vitamin D insufficiency is associated with preterm delivery and preeclampsia in women with type 1 diabetes. MATERIAL AND METHODS: An observational study of 198 pregnant women with type 1 diabetes. 25-Hydroxy-Vitamin D and HbA1c were measured in blood samples in early (median 8 weeks, range 5-14) and late (34 weeks, range 32-36) pregnancy. Kidney involvement (microalbuminuria or nephropathy) at inclusion, smoking status at inclusion, preterm delivery (<37 weeks) and preeclampsia (blood pressure ≥140/90 mmHg and proteinuria) were registered. Vitamin D supplementation of 10 µg daily was routinely recommended. RESULTS: Thirty-nine (20%) of the 198 women delivered preterm and 16 (8%) developed preeclampsia. Vitamin D insufficiency (<50 nmol/L) was present in 68 women (34%) in early pregnancy and in 73 women (37%) in late pregnancy. Preterm delivery occurred more frequently in women with vitamin D insufficiency in late pregnancy (27% vs. 15%, crude odds ratio 2.1; 95% confidence interval 1.0-4.3, p = 0.04). After adjustment for preexisting kidney involvement, HbA1c in late pregnancy and smoking the association became nonsignificant (adjusted odds ratio 1.8; 95% confidence interval 0.8-3.7). Preeclampsia developed in 11% of women with vitamin D insufficiency vs. 6% of the remaining women (crude odds ratio 1.8; 95% confidence interval 0.9-4.1, p = 0.25). CONCLUSION: In women with type 1 diabetes, preterm delivery was twice as frequent in women with vitamin D insufficiency in late pregnancy in crude analysis, but in this small study, low vitamin D was not independently associated with preterm birth or preeclampsia.

Quality of life, anxiety and depression symptoms in early and late pregnancy in women with pregestational diabetes.

INTRODUCTION: The aim of this study was to explore changes in health-related quality of life, anxiety and depression symptoms during pregnancy in women with pregestational diabetes. MATERIAL AND METHODS: An observational cohort study including 137 pregnant women with pregestational diabetes (110 with type 1 and 27 with type 2). To evaluate changes from early to late pregnancy, the internationally validated questionnaires 36-Item Short-Form Health Survey (SF-36) and Hospital Anxiety and Depression Scale (HADS) were completed at 8 and 33 gestational weeks. RESULTS: From early to late pregnancy, the SF-36 scales Physical Function, Role Physical, Bodily Pain and Physical Component Summary worsened (p < 0.0001 for all scales). Physical Component Summary score deteriorated from mean 52.3 (SD 6.5) to 40.0 (9.7) (p < 0.0001) and the deterioration was negatively associated with gestational weight gain in multiple linear regression (ß = -0.34/kg, p = 0.03). The SF-36 scale Mental Health improved (p = 0.0009) and the Mental Component Summary score increased moderately from 47.6 (10.6) to 53.5 (8.6) (p < 0.0001). Greater improvement in Mental Component Summary score was seen with lower HbA1c in late pregnancy. The HADS anxiety score improved slightly from 5.0 (3.3) to 4.5 (3.4) (p = 0.04) whereas the HADS depression score remained unchanged. The prevalence of women with HADS anxiety or depression score ≥8 did not change. CONCLUSIONS: Physical quality of life deteriorated whereas mental quality of life improved slightly during pregnancy in women with pregestational diabetes. A minor reduction in anxiety and stable depression symptoms was observed. The results on mental health are reassuring, considering the great demands that pregnancy places on women with pregestational diabetes.

Fetal sonographic characteristics associated with shoulder dystocia in pregnancies of women with type 1 diabetes.

INTRODUCTION: Shoulder dystocia is a rare but severe complication of vaginal delivery and diabetic women are at high risk. The aim of this study was to identify fetal sonographic and maternal glycemic characteristics associated with shoulder dystocia in pregnant women with type 1 diabetes. MATERIAL AND METHODS: Twelve cases (5%) of shoulder dystocia among 241 consecutive vaginal deliveries in women with type 1 diabetes followed at Rigshospitalet University Hospital in 2009-2013 were retrospectively identified in a local database. Fetal sonographic and clinical data were compared with 69 women with type 1 diabetes and uncomplicated vaginal deliveries. RESULTS: Women experiencing shoulder dystocia compared with women with uncomplicated deliveries had a higher glycated hemoglobin (HbA1c) in early pregnancy [median 7.0% (range 5.9-8.1) vs. 6.6% (range 5.4-10.0, P = 0.04)], whereas in late pregnancy, HbA1c in the two groups of women was comparable [6.1% (range 5.5-6.9) vs. 6.0% (range 4.7-8.4, P = 0.30)]. Fetal biometry at 36 weeks showed a higher estimated fetal weight of 3597 g (range 3051-4069) vs. 2989 g (range 2165-4025), P < 0.001, corresponding to 20% (4-41%) vs. 5% (-20 to 44%) above the mean estimated fetal weight for gestational age (P = 0.002) and a greater abdominal circumference SD score of 2.51 (range 1.56-4.20) vs. 1.33 (range -1.08 to 4.25), P = 0.001). Head circumference was comparable. Vacuum extraction was more frequent during deliveries with shoulder dystocia (58 vs. 17%, P = 0.005). Seven (58%) newborns with shoulder dystocia had brachial plexus injuries, fractures, intra-abdominal bleeding or needed resuscitation. CONCLUSIONS: Excessive estimated fetal weight and abdominal circumference at 36 weeks' sonographic examination may help in identifying diabetic women at high risk of later shoulder dystocia.

Glucagon-like peptide-1 receptors in nucleus accumbens, ventral hippocampus, and lateral septum reduce alcohol reinforcement in mice.

Glucagon-like peptide 1 (GLP-1) receptor agonists can decrease alcohol intake by central mechanisms that are still poorly understood. The lateral septum (LS) and the ventral/caudal part of the hippocampus are enriched in GLP-1 receptors, and activity in these regions was shown to modulate reward-related behaviors. Using microinfusions of the GLP-1 receptor agonist exendin-4 in mice trained to self-administer oral alcohol in an operant assay, we tested whether pharmacological stimulation of GLP-1 receptors in hippocampus and LS decrease alcohol self-administration. We report that infusion of exendin-4 in the ventral hippocampus or LS was sufficient to reduce alcohol self-administration with as large effect sizes as we previously reported with systemic exendin-4 administration. Infusion of exendin-4 into the nucleus accumbens also reduced alcohol self-administration, as anticipated based on earlier reports, while infusion of exendin-4 into the caudate-putamen (dorsal striatum) had little effect, consistent with lack of GLP-1 receptor expression in this region. The distribution of exendin-4 after infusion into the LS or caudate putamen was visualized using a fluorescently labeled ligand. These findings add to our understanding of the circuit-level mechanisms underlying the ability of GLP-1 receptor agonists to reduce alcohol self-administration. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Identification of Hypothalamic Glucoregulatory Neurons That Sense and Respond to Changes in Glycemia.

To investigate whether glucoregulatory neurons in the hypothalamus can sense and respond to physiological variation in the blood glucose (BG) level, we combined continuous arterial glucose monitoring with continuous measures of the activity of a specific subset of neurons located in the hypothalamic ventromedial nucleus that express pituitary adenylate cyclase activating peptide (VMNPACAP neurons) obtained using fiber photometry. Data were collected in conscious, free-living mice during a 1-h baseline monitoring period and a subsequent 2-h intervention period during which the BG level was raised either by consuming a chow or a high-sucrose meal or by intraperitoneal glucose injection. Cross-correlation analysis revealed that, following a 60- to 90-s delay, interventions that raise the BG level reliably associate with reduced VMNPACAP neuron activity (P < 0.01). In addition, a strong positive correlation between BG and spontaneous VMNPACAP neuron activity was observed under basal conditions but with a much longer (∼25 min) temporal offset, consistent with published evidence that VMNPACAP neuron activation raises the BG level. Together, these findings are suggestive of a closed-loop system whereby VMNPACAP neuron activation increases the BG level; detection of a rising BG level, in turn, feeds back to inhibit these neurons. To our knowledge, these findings constitute the first evidence of a role in glucose homeostasis for glucoregulatory neurocircuits that, like pancreatic ß-cells, sense and respond to physiological variation in glycemia. ARTICLE HIGHLIGHTS: By combining continuous arterial glucose monitoring with fiber photometry, studies investigated whether neurons in the murine ventromedial nucleus that express pituitary adenylate cyclase activating peptide (VMNPACAP neurons) detect and respond to changes in glycemia in vivo. VMNPACAP neuron activity rapidly decreases (within <2 min) when the blood glucose level is raised by either food consumption or glucose administration. Spontaneous VMNPACAP neuron activity also correlates positively with glycemia, but with a longer temporal offset, consistent with reports that hyperglycemia is induced by experimental activation of these neurons. Like pancreatic ß-cells, neurons in the hypothalamic ventromedial nucleus appear to sense and respond to physiological variation in glycemia.

Screening for type 2 diabetes and hypertension in seafarers' medical examinations.

BACKGROUND: The aims of the study are: 1) to replace the urine glucose test for diabetes with more than 50% false negatives, with an accurate screening for type 2 diabetes and hypertension in the mandatory biannual fit-for-duty medical examinations of seafarers; 2) to produce data driven "Green Ship" health pro-motion in the ships. A new health promotion and disease prevention public health intervention programme integrated in the fit-for-duty medical examinations for seafarers is being developed. MATERIALS AND METHODS: The lack of an accurate diagnosis of type 2 diabetes is replaced by accurate HbA1c and/or fasting glucose tests and the test for hypertension in various disease stages is based on the International Associations' Guidelines. A "Green Ship" health promotion programme is proposed for all on board, not only for diseased crew members. RESULTS: A protocol for an accurate biannual screening for diabetes and hypertension is presented. Educational programmes for medical doctors and seafarers on the management of hypertension and diabetes on board will be developed. Presuming that all crew members are potentially on their way to be pre-diseased or are diseased, the "Green Ship" health promotion programme is implemented for the whole crew. CONCLUSIONS: The International Labour Organization and the National Maritime Authorities are prompted to revise the International and the National Guidelines for Seafarers Medical Examinations, respectively. Con-certed actions are requested to implement public health promotion projects in shipping. Maritime medical doctors are prompted to use health dialogues and to report the clinical data in the Excel file. Sustainability is obtained by complying with the Sustainable Development Goals (3, 4, 8, 10, and 17).

Rethinking the use of urine dipstick for early diagnosis of Type 2 diabetes mellitus.

Transport workers, seafarers and fishers have biannual mandatory fit-for duty medical examinations. Urinedipstick is used for early diagnosis of Type 2 diabetes mellitus. Due to low sensitivity with more than 80% false negatives the method should be replaced by highly sensitive blood tests, Hb1Ac or similar for diagnosis of Type 2 diabetes mellitus to pursue the UN Global Sustainable Goals, especially Goal 3: Good health and well-being for all workers and Goal 8: Decent Work and Economic Growth.

Early diagnosis of T2DM using high sensitive tests in the mandatory medical examinations for fishers, seafarers and other transport workers.

Transport workers like seafarers, truck-, bus-, train- and taxi drivers and fishers have a known great inequity in health at work including high risk of developing type 2 diabetes. Their routine mandatory medical examinations use urine glucose for diabetes check with more than 50% false negatives, which should be replaced by high sensitive tests for diabetes-2, like A1C, Fasting Glucose (FPG) or Oral Glucose Tolerance Test (OGTT).

Acute changes in systemic glycemia gate access and action of GLP-1R agonist on brain structures controlling energy homeostasis.

Therapies based on glucagon-like peptide-1 (GLP-1) long-acting analogs and insulin are often used in the treatment of metabolic diseases. Both insulin and GLP-1 receptors are expressed in metabolically relevant brain regions, suggesting a cooperative action. However, the mechanisms underlying the synergistic actions of insulin and GLP-1R agonists remain elusive. In this study, we show that insulin-induced hypoglycemia enhances GLP-1R agonists entry in hypothalamic and area, leading to enhanced whole-body fat oxidation. Mechanistically, this phenomenon relies on the release of tanycyctic vascular endothelial growth factor A, which is selectively impaired after calorie-rich diet exposure. In humans, low blood glucose also correlates with enhanced blood-to-brain passage of insulin, suggesting that blood glucose gates the passage other energy-related signals in the brain. This study implies that the preventing hyperglycemia is important to harnessing the full benefit of GLP-1R agonist entry in the brain and action onto lipid mobilization and body weight loss.

Role of hypothalamic MAPK/ERK signaling and central action of FGF1 in diabetes remission.

The capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family, is induced for at least 24 h. Further, we show that this prolonged response is required for the sustained antidiabetic action of FGF1 since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration.

A genetic map of the mouse dorsal vagal complex and its role in obesity.

The brainstem dorsal vagal complex (DVC) is known to regulate energy balance and is the target of appetite-suppressing hormones, such as glucagon-like peptide 1 (GLP-1). Here we provide a comprehensive genetic map of the DVC and identify neuronal populations that control feeding. Combining bulk and single-nucleus gene expression and chromatin profiling of DVC cells, we reveal 25 neuronal populations with unique transcriptional and chromatin accessibility landscapes and peptide receptor expression profiles. GLP-1 receptor (GLP-1R) agonist administration induces gene expression alterations specific to two distinct sets of Glp1r neurons-one population in the area postrema and one in the nucleus of the solitary tract that also expresses calcitonin receptor (Calcr). Transcripts and regions of accessible chromatin near obesity-associated genetic variants are enriched in the area postrema and the nucleus of the solitary tract neurons that express Glp1r and/or Calcr, and activating several of these neuronal populations decreases feeding in rodents. Thus, DVC neuronal populations associated with obesity predisposition suppress feeding and may represent therapeutic targets for obesity.

Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity.

Insulin acts on neurons and glial cells to regulate systemic glucose metabolism and feeding. However, the mechanisms of insulin access in discrete brain regions are incompletely defined. Here we show that insulin receptors in tanycytes, but not in brain endothelial cells, are required to regulate insulin access to the hypothalamic arcuate nucleus. Mice lacking insulin receptors in tanycytes (IR∆Tan mice) exhibit systemic insulin resistance, while displaying normal food intake and energy expenditure. Tanycytic insulin receptors are also necessary for the orexigenic effects of ghrelin, but not for the anorexic effects of leptin. IR∆Tan mice exhibit increased agouti-related peptide (AgRP) neuronal activity, while displaying blunted AgRP neuronal adaptations to feeding-related stimuli. Lastly, a highly palatable food decreases tanycytic and arcuate nucleus insulin signalling to levels comparable to those seen in IR∆Tan mice. These changes are rooted in modifications of cellular stress responses and of mitochondrial protein quality control in tanycytes. Conclusively, we reveal a critical role of tanycyte insulin receptors in gating feeding-state-dependent regulation of AgRP neurons and systemic insulin sensitivity, and show that insulin resistance in tanycytes contributes to the pleiotropic manifestations of obesity-associated insulin resistance.

Risperidone treatment increases CB1 receptor binding in rat brain.

BACKGROUND/AIMS: Body weight gain is a common side effect of treatment with antipsychotics, but the mechanisms underlying this weight gain are unknown. Several factors may be involved in antipsychotic-induced body weight gain including the cannabinoid receptor 1 (CB(1)), the serotonin receptor 2C, the ghrelin receptor, neuropeptide Y, adiponectin and proopiomelanocortin. We investigated whether the expression of these factors was affected in rats chronically treated with the antipsychotic risperidone. METHODS: Male Sprague-Dawley rats were treated with risperidone (1.0 mg/kg/day) or vehicle (20% hydroxypropyl beta-cyclodextrin) for 28 days. Expression of the aforementioned factors were examined together with plasma prolactin and ghrelin levels. RESULTS: No difference in body weight gained during treatment was observed between risperidone and vehicle treated rats, but plasma risperidone levels positively correlated with visceral fat mass. Risperidone treatment increased CB(1) receptor binding in the arcuate nucleus (40%), hippocampus (25-30%) and amygdala (35%) without concurrent alterations in the CB(1) receptor mRNA. Risperidone treatment increased adiponectin mRNA. CONCLUSION: The present study showed that risperidone treatment altered CB(1) receptor binding in the rat brain. Risperidone-induced adiposity and metabolic dysfunction in the clinic may be explained by increased CB(1) receptor density in brain regions involved in appetite and regulation of metabolic function.

Continuous glucose monitoring-enabled insulin-pump therapy in diabetic pregnancy.

We describe the feasibility of continuous glucose monitoring (CGM)-enabled insulin-pump therapy during pregnancy in a woman with type 1 diabetes, who was treated with CGM-enabled insulin-pump therapy in her third pregnancy. During her first pregnancy, the woman was treated with multiple daily injections and baseline HbA1c was 8.9%. Due to pre-eclampsia, the child was born preterm, and had neonatal hypoglycemia. In the planning of the second pregnancy, insulin-pump therapy was initiated, resulting in an HbA1c of 6.8% in early pregnancy. Due to pre-eclampsia, the second child was born preterm, but without neonatal morbidity. Before her third pregnancy, CGM-enabled insulin-pump therapy was introduced, and HbA1c was 6.4% in early pregnancy. The patient was satisfied with this therapy, pre-eclampsia did not occur, and the child was born at term without neonatal morbidity. CGM-enabled insulin-pump therapy appears feasible in diabetic pregnancies.