Intra-islet α-cell Gs signaling promotes glucagon release.

Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell G signaling on modulating α-cell function.

Evaluating glucose-dependent insulinotropic polypeptide and glucagon as key regulators of insulin secretion in the pancreatic islet.

The incretin axis is an essential component of postprandial insulin secretion and glucose homeostasis. There are two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert multiple actions throughout the body. A key cellular target for the incretins are pancreatic β-cells, where they potentiate nutrient-stimulated insulin secretion.

The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.

The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity.

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.

The ubiquitination status of the glucagon receptor determines signal bias.

The pancreatic hormone glucagon activates the glucagon receptor (GCGR), a class B seven-transmembrane G protein-coupled receptor that couples to the stimulatory heterotrimeric G protein and provokes PKA-dependent signaling cascades vital to hepatic glucose metabolism and islet insulin secretion. Glucagon-stimulation also initiates recruitment of the endocytic adaptors, βarrestin1 and βarrestin2, which regulate desensitization and internalization of the GCGR. Unlike many other G protein-coupled receptors, the GCGR expressed at the plasma membrane is constitutively ubiquitinated and upon agonist-activation, internalized GCGRs are deubiquitinated at early endosomes and recycled via Rab4-containing vesicles.

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems.

Objective: Glucose-dependent insulinotropic polypeptide (GIP) is one of the two major incretin factors that regulate metabolic homeostasis. Genetic ablation of its receptor (GIPR) in mice confers protection against diet-induced obesity (DIO), while GIPR neutralizing antibodies produce additive weight reduction when combined with GLP-1R agonists in preclinical models and clinical trials. Conversely, GIPR agonists have been shown to promote weight loss in rodents, while dual GLP-1R/GIPR agonists have proven superior to GLP-1R monoagonists for weight reduction in clinical trials.

Vitamin D in healthy Tunisian population: Preliminary results.

Background: Vitamin D deficiency is one of the most common medical conditions worldwide. In Tunisia, several studies evaluated Vitamin D status, but this was concerning specific populations (pregnant women, obese or diabetic patients and children with asthma). The only study that evaluated Vitamin D status in a healthy Tunisian population was conducted by Meddeb and associeties in 2002.

GIP mediates the incretin effect and glucose tolerance by dual actions on α cells and β cells.

Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on β cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon secretion; however, the role of this action in the postprandial state is unknown. Here, we demonstrate that GIP potentiates amino acid-stimulated glucagon secretion, documenting a similar nutrient-dependent action to that described in β cells.

The utility of a fidelity measure to monitor implementation of new early psychosis services across Australia.

Aim: Early psychosis delivery models have proliferated worldwide, but there is limited research into establishing model fidelity. In this context, this article aims to describe the development and implementation of a fidelity tool in a national network of early psychosis services across Australia-the headspace Early Psychosis program.

Methods: Following a detailed consultation process, and based on the Australian Early Psychosis model, an 80-item Early Psychosis Prevention and Intervention Centre Model Integrity Tool (EMIT) was developed along with predefined thresholds for fidelity.

Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion.

Metabolic fuels regulate insulin secretion by generating second messengers that drive insulin granule exocytosis, but the biochemical pathways involved are incompletely understood. Here we demonstrate that stimulation of rat insulinoma cells or primary rat islets with glucose or glutamine + 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (Gln + BCH) induces reductive, "counter-clockwise" tricarboxylic acid (TCA) cycle flux of glutamine to citrate. Molecular or pharmacologic suppression of isocitrate dehydrogenase-2 (IDH2), which catalyzes reductive carboxylation of 2-ketoglutarate to isocitrate, results in impairment of glucose- and Gln + BCH-stimulated reductive TCA cycle flux, lowering of NADPH levels, and inhibition of insulin secretion.

Repositioning the Alpha Cell in Postprandial Metabolism.

Glucose homeostasis is maintained in large part due to the actions of the pancreatic islet hormones insulin and glucagon, secreted from β- and α-cells, respectively. The historical narrative positions these hormones in opposition, with insulin primarily responsible for glucose-lowering and glucagon-driving elevations in glucose. Recent progress in this area has revealed a more complex relationship between insulin and glucagon, highlighted by data demonstrating that α-cell input is essential for β-cell function and glucose homeostasis.

A 12-lipoxygenase-Gpr31 signaling axis is required for pancreatic organogenesis in the zebrafish.

12-Lipoxygenase (12-LOX) is a key enzyme in arachidonic acid metabolism, and alongside its major product, 12-HETE, plays a key role in promoting inflammatory signaling during diabetes pathogenesis. Although 12-LOX is a proposed therapeutic target to protect pancreatic islets in the setting of diabetes, little is known about the consequences of blocking its enzymatic activity during embryonic development. Here, we have leveraged the strengths of the zebrafish-genetic manipulation and pharmacologic inhibition-to interrogate the role of 12-LOX in pancreatic development.

Inside the black box of youth participation and engagement: Development and implementation of an organization-wide strategy for Orygen, a national youth mental health organization in Australia.

Aim: The involvement of young people in the development, implementation and evaluation of youth mental health services, policy and research programs is essential to ensure they are appropriate and responsive to the needs of young people. Despite the increasingly central role that youth engagement and participation plays internationally, such activities are rarely described in detail. This article aims to provide a thorough description of the development and implementation of an organization-wide, 3-year Youth Engagement and Participation Strategy for Orygen, a national youth mental health organization in Australia.

Discordance between GLP-1R gene and protein expression in mouse pancreatic islet cells.

The insulinotropic actions of glucagon-like peptide 1 receptor (GLP-1R) in β-cells have made it a useful target to manage type 2 diabetes. Metabolic stress reduces β-cell sensitivity to GLP-1, yet the underlying mechanisms are unknown. We hypothesized that expression is heterogeneous among β-cells and that metabolic stress decreases the number of GLP-1R-positive β-cells.

Compensatory Interventions for Cognitive Impairments in Psychosis: A Systematic Review and Meta-Analysis.

Objective: Cognitive compensatory interventions aim to alleviate psychosocial disability by targeting functioning directly using aids and strategies, thereby minimizing the impact of cognitive impairment. The aim was to conduct a systematic review and meta-analysis of cognitive compensatory interventions for psychosis by examining the effects on functioning and symptoms, and exploring whether intervention factors, study design, and age influenced effect sizes.

Methods: Electronic databases (Ovid Medline, PsychINFO) were searched up to October 2018.

The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition.

Glucagon is classically described as a counterregulatory hormone that plays an essential role in the protection against hypoglycemia. In addition to its role in the regulation of glucose metabolism, glucagon has been described to promote ketosis in the fasted state. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs that act primarily in the kidney, but some reports have described direct effects of SGLT2i on α-cells to stimulate glucagon secretion.

The role of GIP in α-cells and glucagon secretion.

Glucose-dependent insulinotropic polypeptide (GIP) is an intestinally derived peptide that is secreted in response to feeding. The GIP receptor (GIPR) is expressed in many cell types involved in the regulation of metabolism, including α- and β-cells. Glucagon and insulin exert tremendous control over glucose metabolism.

Thematic analysis of youth mental health providers' perceptions of neuropsychological assessment services.

Aim: A growing number of quantitative studies have investigated the utility of neuropsychological assessment in mental health settings. However, to the best of our knowledge, no previous study has qualitatively explored youth mental health providers' perceptions of neuropsychological assessment services. A more in-depth understanding of the perceived advantages and barriers associated with neuropsychological assessment in youth mental health settings is critical to better inform policy, practice and service uptake.

Perceived need for neuropsychological assessment according to geographic location: A survey of Australian youth mental health clinicians.

Recent studies have shown that neuropsychological assessment is a scarce resource in youth mental health settings. The need for neuropsychological assessment might differ in metropolitan and nonmetropolitan areas due to characteristics inherent to these different regions. However, no formal studies have investigated this question.

Can antipsychotic dose reduction lead to better functional recovery in first-episode psychosis? A randomized controlled-trial of antipsychotic dose reduction. The reduce trial: Study protocol.

Unlabelled: Antipsychotic medication has been the mainstay of treatment for psychotic illnesses for over 60 years. This has been associated with improvements in positive psychotic symptoms and a reduction in relapse rates. However, there has been little improvement in functional outcomes for people with psychosis.

Vocational engagement among young people entering mental health treatment compared with their general population peers.

Aim: To compare rates of vocational engagement for youth entering specialist mental health treatment with the general population.

Methods: A file audit retrieved vocational data for 145 youth aged 15 to 25 entering treatment. Clinical and population data were stratified by age and sex and compared between cohorts.

Effects of Preview on Human Control Behavior in Tracking Tasks With Various Controlled Elements.

This paper investigates how humans use a previewed target trajectory for control in tracking tasks with various controlled element dynamics. The human's hypothesized "near" and "far" control mechanisms are first analyzed offline in simulations with a quasi-linear model. Second, human control behavior is quantified by fitting the same model to measurements from a human-in-the-loop experiment, where subjects tracked identical target trajectories with a pursuit and a preview display, each with gain, single-, and double-integrator controlled element dynamics.

An Empirical Human Controller Model for Preview Tracking Tasks.

Real-life tracking tasks often show preview information to the human controller about the future track to follow. The effect of preview on manual control behavior is still relatively unknown. This paper proposes a generic operator model for preview tracking, empirically derived from experimental measurements.

Endodontic 'solutions' part 1: a literature review on the use of endodontic lubricants, irrigants and medicaments.

Endodontic lubricants, irrigants and medicaments help prepare and disinfect root canal systems (RCS) but primary and secondary cases involve different microbes and therefore it is unlikely that one protocol will be effective for both case types. Each individual 'solution' or sequence of'solutions' could play a significant role in each case type, but there are no detailed published guidelines in existence. To help inform clinical practice it was decided to undertake a literature review followed by a UK and Republic of Ireland wide audit on current endodontic'solution' usage within dental schools.