Early adolescent second-generation antipsychotic exposure produces long-term, post-treatment increases in body weight and metabolism-associated gene expression.

The use of second-generation antipsychotic (SGA) medications in pediatric patients raises concerns about potential long-term adverse outcomes. The current study evaluated the long-term effects of treatment with risperidone or olanzapine on body weight, caloric intake, serum insulin, blood glucose, and metabolism-associated gene expression in C57Bl/6J female mice. Compared to mice treated with vehicle, female mice treated with risperidone or olanzapine gained weight at higher rates during treatment and maintained higher body weights for months following treatment cessation.

From pre-clinical efficacy to promising clinical trials that delay Type 1 diabetes.

Recent advancements in immunology and islet biology have unveiled remarkable prospects for the postponement of Type 1 diabetes (T1D) through the strategic modulation of the immune system. In this Perspective, we discuss the pharmaceutical strides achieved, traversing from pre-clinical validation to the execution of impactful clinical trials. We begin with the initial investigations involving cyclosporine and glucocorticoids in rodent models, such as the non-obese diabetic (NOD) mouse, which guided early clinical trials.

Channel Expansion in the Ligand-Binding Domain of the Glucocorticoid Receptor Contributes to the Activity of Highly Potent Glucocorticoid Analogues.

Glucocorticoids (GCs) act through the glucocorticoid receptor (GR) and are commonly used as anti-inflammatory and immunosuppressant medications. Chronic GC use has been linked with unwanted complications such as steroid-induced diabetes mellitus (SIDM), although the mechanisms for these effects are not completely understood. Modification of six GC parent molecules with 2-mercaptobenzothiazole resulted in consistently less promoter activity in transcriptional activation assays using a 3xGRE reporter construct while constantly reducing inflammatory pathway activity.

Accelerated onset of diabetes in non-obese diabetic mice fed a refined high-fat diet.

Aim: Type 1 diabetes results from autoimmune events influenced by environmental variables, including changes in diet. This study investigated how feeding refined versus unrefined (aka 'chow') diets affects the onset and progression of hyperglycaemia in non-obese diabetic (NOD) mice.

Methods: Female NOD mice were fed either unrefined diets or matched refined low- and high-fat diets.

Lysosomal glucose sensing and glycophagy in metabolism.

Lysosomes are cellular organelles that function to catabolize both extra- and intracellular cargo, act as a platform for nutrient sensing, and represent a core signaling node integrating bioenergetic cues to changes in cellular metabolism. Although lysosomal amino acid and lipid sensing in metabolism has been well characterized, lysosomal glucose sensing and the role of lysosomes in glucose metabolism is unrefined. This review will highlight the role of the lysosome in glucose metabolism with a focus on lysosomal glucose and glycogen sensing, glycophagy, and lysosomal glucose transport and how these processes impact autophagy and energy metabolism.

Islet beta-cells and intercellular adhesion molecule-1 (ICAM-1): Integrating immune responses that influence autoimmunity and graft rejection.

Type 1 diabetes (T1D) develops due to autoimmune targeting of the pancreatic islet β-cells. Clinical symptoms arise from reduced insulin in circulation. The molecular events and interactions between discrete immune cell populations, infiltration of such leukocytes into pancreatic and islet tissue, and selective targeting of the islet β-cells during autoimmunity and graft rejection are not entirely understood.

NOD mice have distinct metabolic and immunologic profiles when compared with genetically similar MHC-matched ICR mice.

Nonobese diabetic (NOD) mice are the most commonly used rodent model to study mechanisms relevant to the autoimmunity and immunology of type 1 diabetes. Although many different strains of mice have been used as controls for studies comparing nondiabetic lines to the NOD strain, we hypothesized that the parental strain that gave rise to the NOD line might be one of the best options. Therefore, we compared female ICR and NOD mice, which are matched at key major histocompatibility complex (MHC) loci, to understand their metabolic and immunologic similarities and differences.

Pharmacological inhibition of lipolysis prevents adverse metabolic outcomes during glucocorticoid administration.

Objective: Glucocorticoids are one of the most commonly prescribed classes of anti-inflammatory drugs; however, chronic treatment promotes iatrogenic (drug-induced) diabetes. As part of their physiological role, glucocorticoids stimulate lipolysis to spare glucose. We hypothesized that persistent stimulation of lipolysis during glucocorticoid therapy plays a causative role in the development of iatrogenic diabetes.

GDF15 Mediates the Effect of Skeletal Muscle Contraction on Glucose-Stimulated Insulin Secretion.

Unlabelled: Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We used electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatment of β-cells with EPS-conditioned medium enhanced glucose-stimulated insulin secretion (GSIS).

Mouse Pancreatic Peptide Hormones Probed at the Sub-Single-Islet Level: The Effects of Acute Corticosterone Treatment.

We combine liquid chromatography coupled with ion mobility spectrometry-mass spectrometry to elucidate how short exposure to corticosterone (Cort) alters the output of mouse pancreatic islet hormones. The workflow enables the robust separation of mouse insulin 1 (Ins1) and insulin 2 (Ins2) and the detection of major islet hormones in a homogenate equivalent to 100-150 islet cells. We show that Ins2 has a unique structure and is degraded much faster than Ins1.

Stereoisomers of an Aryl Pyrazole Glucocorticoid Receptor Agonist Scaffold Elicit Differing Anti-inflammatory Responses.

Glucocorticoids (GCs) are heavily prescribed to control inflammation in various human diseases; however, side effects associated with GCs are well documented and lead to serious metabolic and immunological complications with long-term use. The paradigm for GC function includes two well described modes of activity: dimer formation of the glucocorticoid receptor (GR) promotes transactivation, while monomeric interaction with co-regulators promotes transrepression. Previously, a set of aryl pyrazole-derived glucocorticoid receptor agonists (APGRAs) with potency rivaling current commercially available glucocorticoids were described.

Special Issue: Emerging Paradigms in Insulin Resistance.

This Special Issue was designed to attract articles that focused on different facets of biology relating to insulin resistance, defined as reduced cellular and organismal response to the insulin hormone, and its underlying mechanisms [...

ICAM-1 Abundance Is Increased in Pancreatic Islets of Hyperglycemic Female NOD Mice and Is Rapidly Upregulated by NF-κB in Pancreatic β-Cells.

Type 1 diabetes (T1D) is classified as an autoimmune disease where pancreatic β-cells are specifically targeted by cells of the immune system. The molecular mechanisms underlying this process are not completely understood. Herein, we identified that the Icam1 gene and ICAM-1 protein were selectively elevated in female NOD mice relative to male mice, fitting with the sexual dimorphism of diabetes onset in this key mouse model of T1D.

L. Ethanolic Extract and an Isolated Component, DMC2, Ameliorate Inflammatory Signaling in Pancreatic β-Cells via Inhibition of p38 MAPK.

Non-resolving pancreatic islet inflammation is widely viewed as a contributor to decreases in β-cell mass and function that occur in both Type 1 and Type 2 diabetes. Therefore, strategies aimed at reducing or eliminating pathological inflammation would be useful to protect islet β-cells. Herein, we described the use of 2',4'-dihydroxy-4-methoxydihydrochalcone (DMC2), a bioactive molecule isolated from an ethanolic extract of L.

FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice.

Dietary protein restriction is increasingly recognized as a unique approach to improve metabolic health, and there is increasing interest in the mechanisms underlying this beneficial effect. Recent work indicates that the hormone FGF21 mediates the metabolic effects of protein restriction in young mice. Here we demonstrate that protein restriction increases lifespan, reduces frailty, lowers body weight and adiposity, improves physical performance, improves glucose tolerance, and alters various metabolic markers within the serum, liver, and adipose tissue of wildtype male mice.

The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 engages the glucagon-like peptide-1 incretin hormone axis to lower levels of blood glucose in db/db mice.

Aim: To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively.

Materials And Methods: Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36 (PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA.

Botanical Interventions to Improve Glucose Control and Options for Diabetes Therapy.

Diabetes mellitus is a major public health problem worldwide. This endocrine disease is clustered into distinct subtypes based on the route of development, with the most common forms associated with either autoimmunity (T1DM) or obesity (T2DM). A shared hallmark of both major forms of diabetes is a reduction in function (insulin secretion) or mass (cell number) of the pancreatic islet beta-cell.

Potent Anti-Inflammatory, Arylpyrazole-Based Glucocorticoid Receptor Agonists That Do Not Impair Insulin Secretion.

Glucocorticoids (GCs) are widely used in medicine for their role in the treatment of autoimmune-mediated conditions, certain cancers, and organ transplantation. The transcriptional activities GCs elicit include transrepression, postulated to be responsible for the anti-inflammatory activity, and transactivation, proposed to underlie the undesirable side effects associated with long-term use. A GC analogue that could elicit only transrepression and beneficial transactivation properties would be of great medicinal value and is highly sought after.

Pioglitazone Reverses Markers of Islet Beta-Cell De-Differentiation in Mice While Modulating Expression of Genes Controlling Inflammation and Browning in White Adipose Tissue from Insulin-Resistant Mice and Humans.

Obesity, insulin resistance, and type 2 diabetes contribute to increased morbidity and mortality in humans. The mouse is an important mouse model that displays many key features of the human disease. Herein, we used the drug pioglitazone, a thiazolidinedione with insulin-sensitizing properties, to investigate blood glucose levels, indicators of islet β-cell health and maturity, and gene expression in adipose tissue.

α-CGRP disrupts amylin fibrillization and regulates insulin secretion: implications on diabetes and migraine.

Despite being relatively benign and not an indicative signature of toxicity, fibril formation and fibrillar structures continue to be key factors in assessing the structure-function relationship in protein aggregation diseases. The inability to capture molecular cross-talk among key players at the tissue level before fibril formation greatly accounts for the missing link toward the development of an efficacious therapeutic intervention for Type II diabetes mellitus (T2DM). We show that human α-calcitonin gene-related peptide (α-CGRP) remodeled amylin fibrillization.

Special Issue: Islet Inflammation and Metabolic Homeostasis.

This special issue was commissioned to offer a source of distinct viewpoints and novel data that capture some of the subtleties of the pancreatic islet, especially in relation to adaptive changes that influence metabolic homeostasis [...

The Ubiquitin Ligase SIAH2 Negatively Regulates Glucocorticoid Receptor Activity and Abundance.

Glucocorticoids are clinically essential drugs used routinely to control inflammation. However, a host of metabolic side effects manifests upon usage beyond a few days. In the present study, we tested the hypothesis that seven-in-absentia mammalian homolog-2 (SIAH2), a ubiquitin ligase that regulates adipogenesis, is important for controlling adipocyte size, inflammation, and the ability of adipose tissue to expand in response to a glucocorticoid challenge.

Pancreatic, but not myeloid-cell, expression of interleukin-1alpha is required for maintenance of insulin secretion and whole body glucose homeostasis.

Objective: The expression of the interleukin-1 receptor type I (IL-1R) is enriched in pancreatic islet β-cells, signifying that ligands activating this pathway are important for the health and function of the insulin-secreting cell. Using isolated mouse, rat, and human islets, we identified the cytokine IL-1α as a highly inducible gene in response to IL-1R activation. In addition, IL-1α is elevated in mouse and rat models of obesity and Type 2 diabetes.

Mechanisms of Artemisia scoparia's Anti-Inflammatory Activity in Cultured Adipocytes, Macrophages, and Pancreatic β-Cells.

Objective: An ethanolic extract of Artemisia scoparia (SCO) improves adipose tissue function and reduces negative metabolic consequences of high-fat feeding. A. scoparia has a long history of medicinal use across Asia and has anti-inflammatory effects in various cell types and disease models.