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Cell Reports Dec 2023The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine...
The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling.
Topics: Humans; Animals; Mice; Cell Line; Mice, Inbred C57BL; Male; Female; Epinephrine; Enzyme Activation; Protein Serine-Threonine Kinases; Phosphatidylinositols; Gene Deletion; Colforsin; Insulin; Phosphorylation; Hippo Signaling Pathway
PubMed: 38060450
DOI: 10.1016/j.celrep.2023.113535 -
Diabetologia Aug 2023This study compared the frequency of hypoglycaemia, time to hypoglycaemia and recovery from hypoglycaemia after double or triple doses of once-weekly insulin icodec vs... (Randomized Controlled Trial)
Randomized Controlled Trial
Hypoglycaemia frequency and physiological response after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100 in type 2 diabetes: a randomised crossover trial.
AIMS/HYPOTHESIS
This study compared the frequency of hypoglycaemia, time to hypoglycaemia and recovery from hypoglycaemia after double or triple doses of once-weekly insulin icodec vs once-daily insulin glargine U100. Furthermore, the symptomatic and counterregulatory responses to hypoglycaemia were compared between icodec and glargine U100 treatment.
METHODS
In a randomised, single-centre (Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria), open-label, two-period crossover trial, individuals with type 2 diabetes (age 18-72 years, BMI 18.5-37.9 kg/m, HbA ≤75 mmol/mol [≤9.0%]) treated with basal insulin with or without oral glucose-lowering drugs received once-weekly icodec (for 6 weeks) and once-daily glargine U100 (for 11 days). Total weekly doses were equimolar based on individual titration of daily glargine U100 during the run-in period (target fasting plasma glucose [PG]: 4.4-7.2 mmol/l). Randomisation was carried out by assigning a randomisation number to each participant in ascending order, which encoded to one of two treatment sequences via a randomisation list prepared prior to the start of the trial. At steady state, double and triple doses of icodec and glargine U100 were administered followed by hypoglycaemia induction: first, euglycaemia was maintained at 5.5 mmol/l by variable i.v. infusion of glucose; glucose infusion was then terminated, allowing PG to decrease to no less than 2.5 mmol/l (target PG). The PG was maintained for 15 min. Euglycaemia was restored by constant i.v. glucose (5.5 mg kg min). Hypoglycaemic symptoms score (HSS), counterregulatory hormones, vital signs and cognitive function were assessed at predefined PG levels towards the PG.
RESULTS
Hypoglycaemia induction was initiated in 43 and 42 participants after double dose of icodec and glargine U100, respectively, and in 38 and 40 participants after triple doses, respectively. Clinically significant hypoglycaemia, defined as PG <3.0 mmol/l, occurred in comparable proportions of individuals treated with icodec vs glargine U100 after double (17 [39.5%] vs 15 [35.7%]; p=0.63) and triple (20 [52.6%] vs 28 [70.0%]; p=0.14) doses. No statistically significant treatment differences were observed in the time to decline from PG values of 5.5 mmol/l to 3.0 mmol/l (2.9-4.5 h after double dose and 2.2-2.4 h after triple dose of the insulin products). The proportion of participants with PG ≤2.5 mmol/l was comparable between treatments after double dose (2 [4.7%] for icodec vs 3 [7.1%] for glargine U100; p=0.63) but higher for glargine U100 after triple dose (1 [2.6%] vs 10 [25.0%]; p=0.03). Recovery from hypoglycaemia by constant i.v. glucose infusion took <30 min for all treatments. Analyses of the physiological response to hypoglycaemia only included data from participants with PG <3.0 mmol/l and/or the presence of hypoglycaemic symptoms; in total 20 (46.5%) and 19 (45.2%) individuals were included after a double dose of icodec and glargine U100, respectively, and 20 (52.6%) and 29 (72.5%) individuals were included after a triple dose of icodec and glargine U100, respectively. All counterregulatory hormones (glucagon, adrenaline [epinephrine], noradrenaline [norepinephrine], cortisol and growth hormone) increased during hypoglycaemia induction with both insulin products at both doses. Following triple doses, the hormone response was greater with icodec vs glargine U100 for adrenaline at PG (treatment ratio 2.54 [95% CI 1.69, 3.82]; p<0.001), and cortisol at PG (treatment ratio 1.64 [95% CI 1.13, 2.38]; p=0.01) and PG (treatment ratio 1.80 [95% CI 1.09, 2.97]; p=0.02). There were no statistically significant treatment differences in the HSS, vital signs and cognitive function.
CONCLUSIONS/INTERPRETATION
Double or triple doses of once-weekly icodec lead to a similar risk of hypoglycaemia compared with double or triple doses of once-daily glargine U100. During hypoglycaemia, comparable symptomatic and moderately greater endocrine responses are elicited by icodec vs glargine U100.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03945656.
FUNDING
This study was funded by Novo Nordisk A/S.
Topics: Humans; Adolescent; Young Adult; Adult; Middle Aged; Aged; Insulin Glargine; Diabetes Mellitus, Type 2; Cross-Over Studies; Hydrocortisone; Hypoglycemia; Hypoglycemic Agents; Insulin; Glucose; Epinephrine; Blood Glucose
PubMed: 37308751
DOI: 10.1007/s00125-023-05921-8 -
Annals of Allergy, Asthma & Immunology... Aug 2023The current standard of first-line emergency treatment of anaphylaxis is intramuscular (IM) epinephrine, mostly administered through epinephrine autoinjector (EAI) in... (Review)
Review
PURPOSE OF REVIEW
The current standard of first-line emergency treatment of anaphylaxis is intramuscular (IM) epinephrine, mostly administered through epinephrine autoinjector (EAI) in the outpatient setting. However, undercarriage and underuse of EAIs are common, and delayed epinephrine use is associated with increased morbidity and mortality. Patients, caregivers, and healthcare professionals have expressed a strong desire for small, needle-free devices and products that would offer improved carriage, ease of use, and more convenient, less invasive routes of epinephrine administration. Novel mechanisms of epinephrine administration are under investigation to help address several recognized EAI limitations. This review explores innovative nasal and oral products under investigation for the outpatient emergency treatment of anaphylaxis.
FINDINGS
Human studies of epinephrine administered through nasal epinephrine spray, a nasal powder spray, and a sublingual film have been conducted. Data from these studies indicate promising pharmacokinetic results comparable to those of the standard of outpatient emergency care (0.3-mg EAI) and syringe and needle IM epinephrine administration. Several products have shown maximum plasma concentration values higher than those of the 0.3-mg EAI and manual IM injection, although it remains unclear whether this has clinical relevancy in patient outcomes. Generally, these modalities show comparable time to maximum concentrations. Pharmacodynamic changes observed with these products are comparable to or more robust than those seen with EAI and manual IM injection.
SUMMARY
Given comparable or superior pharmacokinetic and pharmacodynamic results and safety of innovative epinephrine therapies to those of current standards of care, US Food and Drug Administration approval of these products may help address numerous barriers that EAIs present. The ease of use and carriage and favorable safety profiles of needle-free treatments may make them an attractive alternative to patients and caregivers, potentially addressing injection fears, needle-based safety risks, and other reasons for lack of or delayed use.
Topics: Humans; Anaphylaxis; Epinephrine; Injections, Intramuscular; Emergency Medical Services; Outpatients
PubMed: 37279803
DOI: 10.1016/j.anai.2023.05.033 -
Italian Journal of Pediatrics Mar 2024Anaphylaxis is a life-threatening reaction characterized by the acute onset of symptoms involving different organ systems and requiring immediate medical intervention.... (Review)
Review
Anaphylaxis is a life-threatening reaction characterized by the acute onset of symptoms involving different organ systems and requiring immediate medical intervention. The incidence of fatal food anaphylaxis is 0.03 to 0.3 million/people/year. Most fatal food-induced anaphylaxis occurs in the second and third decades of life. The identified risk factors include the delayed use of epinephrine, the presence of asthma, the use of recreational drugs (alcohol, nicotine, cannabis, etc.), and an upright position. In the United Kingdom (UK) and Canada, the reported leading causal foods are peanuts and tree nuts. In Italy, milk seems to be the most common cause of fatal anaphylaxis in children < 18 years. Fatal food anaphylaxis in Italian children and adolescents almost always occurs outside and is characterized by cardiorespiratory arrest; auto-injectable adrenaline intramuscular was available in few cases. Mortality from food anaphylaxis, especially in children, is a very rare event with stable incidence, but its risk deeply impacts the quality of life of patients with food allergy and their families. Prevention of fatal food anaphylaxis must involve patients and their families, as well as the general public, public authorities, and patients' associations.
Topics: Adolescent; Adult; Child; Humans; Anaphylaxis; Quality of Life; Epinephrine; Arachis; Asthma
PubMed: 38439086
DOI: 10.1186/s13052-024-01608-x -
PloS One 2023To evaluate the efficacy and safety of 0.01% atropine alone and in combination with orthokeratology for myopia control using a meta-analysis. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To evaluate the efficacy and safety of 0.01% atropine alone and in combination with orthokeratology for myopia control using a meta-analysis.
METHODS
PubMed, Cochrane Library, and EMBASE were searched. We included eligible randomized controlled trials (RCTs), non-RCTs, and retrospective cohort studies, published up to August 1, 2022. We calculated the weighted mean difference (WMD) and 95% confidence interval (CI) for all outcomes and plotted them in forest plots.
RESULTS
Fourteen studies were included; 4 and 11 in the 0.01% atropine monotherapy and atropine-orthokeratology (AOK) groups, respectively. Compared with orthokeratology (OK) alone, 0.01% atropine alone had similar effects on slowing the axial elongation (WMD: -0.00 mm; 95% CI: -0.05-0.04, p<0.31), while AOK significantly lowered axial growth. Moreover, the baseline myopic degree and duration of treatment were influential for the change in axial elongation (WMD: -0.12 mm; 95% CI: -0.17--0.07, p = 0.00001 and WMD: -0.11 mm; 95% CI: -0.15--0.108, p<0.00001, respectively). Additionally, the AOK may reduce the change rate of the spherical equivalent refraction and the accommodation amplitude (WMD: -0.13 D; 95% CI: 0.07-0.19, p<0.001 and WMD: -1.08 mm; 95% CI: -1.73--0.43, p<0.0001, respectively), and cause a slight increase in the diameter of the pupil (WMD: 0.56 mm; 95% CI: 0.43-0.70, p = 0.007). No significant differences in the uncorrected distant visual acuity, best corrected visual acuity, intraocular pressure, tear film break-up time, lipid layer thickness, and corneal endothelial cell density were found between the OK and AOK groups.
CONCLUSION
In slowing the axial elongation, 0.01% atropine alone and OK alone have similar effects, while AOK is more effective than OK alone in slowing down the axial elongation. Furthermore, the baseline degree of myopia and treatment duration may affect changes in axial elongation.
Topics: Humans; Child; Atropine; Orthokeratologic Procedures; Myopia; Refraction, Ocular; Visual Acuity; Axial Length, Eye
PubMed: 37494360
DOI: 10.1371/journal.pone.0282286 -
Medicina (Kaunas, Lithuania) Oct 2023The growing incidence of myopia worldwide justifies the search for efficient methods of myopia prevention. Numerous pharmacological, optical, and lifestyle measures have... (Review)
Review
The growing incidence of myopia worldwide justifies the search for efficient methods of myopia prevention. Numerous pharmacological, optical, and lifestyle measures have already been utilized, but there remains a need to explore more practical and predictable methods for myopia control. This paper presents a review of the most recent studies on the prevention of myopia progression using defocus-incorporated multiple-segment spectacle lenses (DIMSsl), repeated low-level red-light (RLRL) therapy, and a combination of low-dose atropine (0.01%) with orthokeratology lenses.
Topics: Humans; Child; Eyeglasses; Disease Progression; Myopia; Atropine
PubMed: 37893579
DOI: 10.3390/medicina59101859 -
Nature Communications Aug 2023α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However,...
α-adrenergic receptors (α-ARs) play critical roles in the cardiovascular and nervous systems where they regulate blood pressure, cognition, and metabolism. However, the lack of specific agonists for all α subtypes has limited our understanding of the physiological roles of different α-AR subtypes, and led to the stagnancy in agonist-based drug development for these receptors. Here we report cryo-EM structures of α-AR in complex with heterotrimeric G-proteins and either the endogenous common agonist epinephrine or the α-AR-specific synthetic agonist A61603. These structures provide molecular insights into the mechanisms underlying the discrimination between α-AR and α-AR by A61603. Guided by the structures and corresponding molecular dynamics simulations, we engineer α-AR mutants that are not responsive to A61603, and α-AR mutants that can be potently activated by A61603. Together, these findings advance our understanding of the agonist specificity for α-ARs at the molecular level, opening the possibility of rational design of subtype-specific agonists.
Topics: Receptors, Adrenergic, alpha-1; Epinephrine; Signal Transduction
PubMed: 37563160
DOI: 10.1038/s41467-023-40524-2 -
JAMA Pediatrics Nov 2023The beneficial effects of increasing outdoor physical activity time on children's myopia onset and physical well-being are widely acknowledged. However, in countries... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The beneficial effects of increasing outdoor physical activity time on children's myopia onset and physical well-being are widely acknowledged. However, in countries with competitive educational systems, such as China, parents and school administrators may be relatively reluctant to increase the extracurricular physical activity time for children due to concerns that this action will compromise children's academic performance.
OBJECTIVE
To investigate whether additional extracurricular physical activity time after school compromises the academic performance of schoolchildren.
DESIGN, SETTING, AND PARTICIPANTS
This cluster randomized clinical trial was conducted from October 2020 to June 2021 in Yudu, Jiangxi, China. Eligible children in grades 3 and 4 from 24 elementary schools were randomized to the intervention or control group. Primary analysis was conducted in the full sample using the intention-to-treat principle.
INTERVENTIONS
The intervention group received 2 hours of after-school physical activity time outdoors on school days. The control group was free to arrange their after-school activity.
MAIN OUTCOMES AND MEASURES
The primary outcome was the between-group mean difference in mathematics test scores at the end of 1 academic year, with a noninferiority margin of -3.3 points. Standardized mathematics tests, physical fitness assessments (in reference to the 2018 National Physical Fitness Survey Monitoring Programme in China), and cycloplegic autorefraction were performed at baseline and the end of 1 academic year. Myopia was defined as a cycloplegic spherical equivalent refraction of -0.5 diopters or less in either eye.
RESULTS
A total of 2032 children (mean [SD] age, 9.22 [0.62] years; 1040 girls [51.2%]) from 24 schools were randomized to the intervention group (12 schools; 1012 children) or control group (12 schools; 1020 children). The mean (SD) mathematics score at the end of 1 academic year was 78.01 (17.56) points in the intervention group and 77.70 (17.29) points in the control group. The adjusted between-group mean difference was 0.65 points (95% CI, -2.85 to 4.15). The adjusted between-group mean difference in physical fitness score was 4.95 points (95% CI, 3.56-6.34; P < .001) and -1.90% (95% CI, -18.72% to 14.91%; P > .99) in myopia incidence.
CONCLUSIONS AND RELEVANCE
Results of this trial indicate that, compared with the control practice of free play after school, adding 2 hours of extracurricular physical activity outdoors after school was noninferior in academic performance and had superior efficacy in improving physical fitness.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04587765.
Topics: Child; Female; Humans; Mydriatics; Schools; Exercise; Academic Performance; Myopia
PubMed: 37721735
DOI: 10.1001/jamapediatrics.2023.3615 -
Annals of Allergy, Asthma & Immunology... May 2024There are limited data on food allergies among college students. In this article, we review the most current available studies. These self-reported surveys and... (Review)
Review
There are limited data on food allergies among college students. In this article, we review the most current available studies. These self-reported surveys and qualitative interviews reported overall poor avoidance of known allergens and low rates of carrying self-injectable epinephrine among students with food allergy. College students may exhibit risk-taking food behaviors due to a number of factors, including age-appropriate risk-taking predilection, strong social influences, and lack of experience in self-advocacy. Having to disclose an otherwise invisible condition repeatedly in a new environment may also lead to "disclosure fatigue," creating an additional barrier to self-advocacy. Common themes in the narrative include hypervigilance, stigma management, and concern about others' misunderstanding of food allergy. Although there is a paucity of data in this area, it is likely that having greater support at the institution level, along with support from peers and faculty, may help improve awareness, self-injectable epinephrine carriage, and allergen avoidance. This review also discusses strategies for preparedness at school, including specific steps to maximize safety.
Topics: Humans; Food Hypersensitivity; Students; Universities; Epinephrine
PubMed: 38296046
DOI: 10.1016/j.anai.2024.01.023 -
Zoological Research Jul 2023Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia. However, given...
Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia. However, given its inherent complexity, few animal models of delirium have been established and the mechanism underlying the onset of delirium remains elusive. Here, we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors, including anesthesia with surgery (AS), systemic inflammation, and neurotransmission modulation. We found that both bacterial lipopolysaccharide (LPS) and cholinergic receptor antagonist scopolamine (Scop) induction reduced neuronal activities in the delirium-related brain network, with the latter presenting a similar pattern of reduction as found in delirium patients. Consistently, Scop injection resulted in reversible cognitive impairment with hyperactive behavior. No loss of cholinergic neurons was found with treatment, but hippocampal synaptic functions were affected. These findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.
Topics: Animals; Mice; Scopolamine; Brain Diseases; Brain; Cognitive Dysfunction; Delirium
PubMed: 37313848
DOI: 10.24272/j.issn.2095-8137.2022.473