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Physiological Reports Jan 2021Hypoxia is common with preterm birth and may lead to long-term effects on adult pancreatic endocrine function and insulin sensitivity. This phenomenon may be sexually...
Hypoxia is common with preterm birth and may lead to long-term effects on adult pancreatic endocrine function and insulin sensitivity. This phenomenon may be sexually dimorphic due to the hypoxia-induced augmentation of the neonatal androgen surge in male newborns. We evaluated this phenomenon by pretreating neonatal rats on postnatal days (PD) 1, 6, 13, or 20 with flutamide (a nonsteroidal androgen receptor antagonist) at a standard or a high dose (10 or 50 mg/kg) compared to vehicle control. One day later, neonatal rats were exposed to either acute normoxic or hypoxic separation (fasting) for 90 min, and blood was sampled for the measurement of insulin and glucose and the calculation of HOMA-IR as an index of insulin resistance. During normoxic and hypoxic separation (fasting), flutamide increased insulin secretion in PD2, PD7, and PD14 pups, high dose flutamide attenuated insulin secretion, and high dose flutamide attenuated the increase in HOMA-IR due to hypoxia. Our studies suggest a unique role of the androgen receptor in the control of neonatal pancreatic function, possibly by blocking a direct effect of neonatal testosterone or in response to indirect regulatory effects of androgens on insulin sensitivity.
Topics: Androgen Receptor Antagonists; Animals; Animals, Newborn; Disease Models, Animal; Female; Flutamide; Glucose; Hypoxia; Insulin; Insulin Resistance; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Androgen
PubMed: 33393733
DOI: 10.14814/phy2.14663 -
The EMBO Journal Dec 2023The immune response is an energy-demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system....
The immune response is an energy-demanding process that must be coordinated with systemic metabolic changes redirecting nutrients from stores to the immune system. Although this interplay is fundamental for the function of the immune system, the underlying mechanisms remain elusive. Our data show that the pro-inflammatory polarization of Drosophila macrophages is coupled to the production of the insulin antagonist ImpL2 through the activity of the transcription factor HIF1α. ImpL2 production, reflecting nutritional demands of activated macrophages, subsequently impairs insulin signaling in the fat body, thereby triggering FOXO-driven mobilization of lipoproteins. This metabolic adaptation is fundamental for the function of the immune system and an individual's resistance to infection. We demonstrated that analogically to Drosophila, mammalian immune-activated macrophages produce ImpL2 homolog IGFBP7 in a HIF1α-dependent manner and that enhanced IGFBP7 production by these cells induces mobilization of lipoproteins from hepatocytes. Hence, the production of ImpL2/IGFBP7 by macrophages represents an evolutionarily conserved mechanism by which macrophages alleviate insulin signaling in the central metabolic organ to secure nutrients necessary for their function upon bacterial infection.
Topics: Animals; Insulin Antagonists; Drosophila; Insulin; Macrophages; Bacterial Infections; Insulin Resistance; Mammals; Insulin-Like Growth Factor Binding Proteins; Drosophila Proteins
PubMed: 37807855
DOI: 10.15252/embj.2023114086 -
International Journal of Environmental... Oct 2016Bisphenol A (BPA) is an organic synthetic compound employed to produce plastics and epoxy resins. It is used as a structural component in polycarbonate beverage bottles... (Review)
Review
Bisphenol A (BPA) is an organic synthetic compound employed to produce plastics and epoxy resins. It is used as a structural component in polycarbonate beverage bottles and as coating for metal surface in food containers and packaging. The adverse effects of BPA on human health are widely disputed. BPA has been recently associated with a wide variety of medical disorders and, in particular, it was identified as potential endocrine-disrupting compound with diabetogenic action. Most of the clinical observational studies in humans reveal a positive link between BPA exposure, evaluated by the measurement of urinary BPA levels, and the risk of developing type 2 diabetes mellitus. Clinical studies on humans and preclinical studies on in vivo, ex vivo, and in vitro models indicate that BPA, mostly at low doses, may have a role in increasing type 2 diabetes mellitus developmental risk, directly acting on pancreatic cells, in which BPA induces the impairment of insulin and glucagon secretion, triggers inhibition of cell growth and apoptosis, and acts on muscle, hepatic, and adipose cell function, triggering an insulin-resistant state. The current review summarizes the available evidences regarding the association between BPA and type 2 diabetes mellitus, focusing on both clinical and preclinical studies.
Topics: Air Pollutants, Occupational; Benzhydryl Compounds; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Insulin Antagonists; Male; Phenols; Plastics; Polycarboxylate Cement
PubMed: 27782064
DOI: 10.3390/ijerph13100989 -
Journal of Physiology and Pharmacology... Feb 2020Adropin is a peptide hormone which is produced in brain and peripheral tissues such as liver. It was found that adropin modulates lipid and glucose homeostasis by...
Adropin is a peptide hormone which is produced in brain and peripheral tissues such as liver. It was found that adropin modulates lipid and glucose homeostasis by interacting with hepatocytes and myocytes. Adropin enhances insulin sensitivity and alleviates hyperinsulinemia in animal models with high-fat diet-induced insulin resistance. However, it is unknown whether adropin regulates insulin secretion and proliferation of beta cells. Therefore, we studied the effects of adropin on insulin secretion in INS-1E cells as well as isolated pancreatic islets. Furthermore, we assessed the influence of adropin on insulin mRNA expression, cell viability and proliferation in INS-1E cells. Pancreatic islets were isolated from male Wistar rats. mRNA expression was evaluated using real-time PCR and cell viability by MTT assay. Cell replication was measured by BrdU incorporation and insulin secretion by RIA. We found that adropin suppresses insulin mRNA expression in INS-1E cells. Moreover, adropin attenuates glucose-induced insulin secretion in INS-1E cells as well as in isolated pancreatic islets. In addition, using INS-1E cells we found that adropin suppresses glucose-induced cAMP production. However, adropin fails to modulate INS-1E cell viability and proliferation. In summary, we found adropin suppresses insulin mRNA expression and secretion, without affecting beta cell viability or proliferation.
Topics: Animals; Blood Proteins; Cell Line; Dose-Response Relationship, Drug; Humans; Insulin; Insulin Antagonists; Insulin Secretion; Islets of Langerhans; Male; Mice; Peptides; Rats; Rats, Wistar
PubMed: 32554844
DOI: 10.26402/jpp.2020.1.09 -
Basic & Clinical Pharmacology &... Jun 2011The α(2A)-adrenoceptor has been identified as an important regulator of blood glucose homeostasis. α(2A)-Adrenoceptors on pancreatic β-cells inhibit insulin... (Review)
Review
The α(2A)-adrenoceptor has been identified as an important regulator of blood glucose homeostasis. α(2A)-Adrenoceptors on pancreatic β-cells inhibit insulin secretion, and α(2A)-adrenoceptors on sympathetic nerves and on adrenomedullary chromaffin cells limit sympathoadrenal output. Recently, human α(2A)-adrenoceptor gene polymorphisms that influence α(2A)-adrenoceptor expression and function have been described. Increased α(2A)-adrenoceptor expression has been associated with impaired glucose-stimulated insulin secretion, elevated fasting blood glucose levels and an increased risk of type 2 diabetes. Accordingly, administration of α(2)-adrenoceptor agonists generally increases blood glucose levels, in spite of the ensuing sympatholysis that would be expected to lower blood glucose as a result of diminished α(1)- and β-adrenoceptor activation. α(2)-Adrenoceptor antagonists increase insulin secretion and reduce blood glucose levels by inhibiting tonically active α(2A)-adrenoceptors on pancreatic β-cells, but may also enhance sympathoadrenal output. In addition, α(2)-adrenoceptor antagonists potentiate the insulinotropic effect of sulphonylurea drugs, pointing to a potentially serious adverse drug interaction when the two classes of drugs are combined. The α(2)-adrenoceptor antagonist atipamezole is widely used in veterinary medicine, and sulphonylureas are prescribed for the treatment of type 2 diabetes in cats and dogs. Even if no dedicated α(2)-adrenoceptor antagonists are in clinical use in humans, some antipsychotic and antidepressant drugs are relatively potent α(2)-adrenoceptor antagonists. In the treatment of type 2 diabetes, α(2)-adrenoceptor agonists could possibly protect against sulphonylurea-induced hypoglycaemia, and α(2)-adrenoceptor antagonist drugs could improve insulin secretion. The potential usefulness of such drugs may vary between individuals, depending on α(2A)-adrenoceptor genetics, sympathetic tone and concomitant pathological conditions, such as cardiovascular disease and obesity.
Topics: Adrenergic alpha-2 Receptor Agonists; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Homeostasis; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Receptors, Adrenergic, alpha-2; Sulfonylurea Compounds
PubMed: 21418144
DOI: 10.1111/j.1742-7843.2011.00699.x -
Cells Jun 2021Hyperglycemia linked to diabetes results in endothelial dysfunction. In the present work, we comprehensively characterized effects of short-term hyperglycemia induced by...
Hyperglycemia linked to diabetes results in endothelial dysfunction. In the present work, we comprehensively characterized effects of short-term hyperglycemia induced by administration of an insulin receptor antagonist, the S961 peptide, on endothelium and perivascular adipose tissue (PVAT) in mice. Endothelial function of the thoracic and abdominal aorta in 12-week-old male C57Bl/6Jrj mice treated for two weeks with S961 infusion via osmotic pumps was assessed in vivo using magnetic resonance imaging and ex vivo by detection of nitric oxide (NO) production using electron paramagnetic resonance spectroscopy. Additional methods were used to analyze PVAT, aortic segments and endothelial-specific plasma biomarkers. Systemic disruption of insulin signaling resulted in severe impairment of NO-dependent endothelial function and a loss of vasoprotective function of PVAT affecting the thoracic as well as abdominal parts of the aorta, however a fall in adiponectin expression and decreased uncoupling protein 1-positive area were more pronounced in the thoracic aorta. Results suggest that dysfunctional PVAT contributes to vascular pathology induced by altered insulin signaling in diabetes, in the absence of fat overload and obesity.
Topics: Adiponectin; Adipose Tissue; Animals; Endothelium, Vascular; Hyperglycemia; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Receptor, Insulin; Uncoupling Protein 1
PubMed: 34207844
DOI: 10.3390/cells10061448 -
Frontiers in Pharmacology 2021Dopamine is a key regulator of glucose metabolism in the central nervous system. However, dopamine is also present in the periphery and may have direct effects on...
Dopamine is a key regulator of glucose metabolism in the central nervous system. However, dopamine is also present in the periphery and may have direct effects on insulin-sensitive tissues. Dopamine receptor 2 (D2R) agonist bromocriptine is a FDA-approved drug for type 2 diabetes. Herein, we explored the role of peripheral dopamine and its receptors in regulating glucose uptake and metabolism on insulin-sensitive tissues. Peripheral dopamine effect in [3H]2-deoxyglucose uptake in insulin-sensitive tissues was tested in rats. Direct effects on [3H]2-deoxyglucose uptake, insulin receptor phosphorylation, and regulation of metabolic function were tested ex in the liver, soleus muscle, and white and brown adipose tissues. Bromocriptine and the antagonists domperidone, D2R antagonist, and haloperidol, antagonist of both dopamine receptor 1 (D1R) and D2R, were used to disclose dopamine receptors' involvement. Peripheral dopamine increases glucose uptake . Ex only dopamine increased glucose uptake in the soleus, while bromocriptine increased it in the liver; the effects were reverted by haloperidol and domperidone, respectively. In adipose tissue, domperidone reverted dopamine- and bromocriptine-mediated potentiation of insulin-induced glucose uptake, but in turn increased the insulin receptor, Akt, AMPK, HSL, ACC, and ACL, phosphorylation. In the soleus muscle, AMPK-phosphorylation increased with bromocriptine and dopamine whose effects were suppressed by domperidone and haloperidol. In conclusion, peripheral dopamine stimulates glucose uptake with its receptors being differentially involved in glucose uptake in insulin-sensitive tissues. Dopamine also has a role in lipid metabolism in white adipose tissue. Altogether, these results suggest that peripheral modulation of the dopaminergic system should be further evaluated as a putative therapeutic approach for metabolic disorders.
PubMed: 34566639
DOI: 10.3389/fphar.2021.713418 -
Methods in Molecular Biology (Clifton,... 2021The application of forward chemical genetics to insulin secretion in high-throughput has been uncommon because of high costs and technical challenges. However, with the...
The application of forward chemical genetics to insulin secretion in high-throughput has been uncommon because of high costs and technical challenges. However, with the advancement of secreted luciferase tools, it has become feasible for small laboratories to screen large numbers of compounds for effects on insulin secretion. The purpose of this chapter is to outline the methods involved in high-throughput screening for small molecules that chronically impact pancreatic beta cell function. Attention is given to specific points in the protocol that help to improve the dynamic range and reduce variability in the assay. Using this approach in 384-well format, at least 48 and as many as 144 plates can theoretically be processed per week. This protocol serves as a guideline and can be modified as required for alternate stimulation paradigms and improved upon as new technologies become available.
Topics: Cell Line; High-Throughput Screening Assays; Humans; Insulin; Insulin Antagonists; Insulin Secretion; Insulin-Secreting Cells; Small Molecule Libraries
PubMed: 33222132
DOI: 10.1007/978-1-0716-1044-2_9 -
JCI Insight Sep 2019Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully...
Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully defined. As insulin resistance impairs mitochondrial oxidative metabolism and increases ROS in skeletal muscle, we considered whether similar events occur in the brain, which - like muscle - is rich in insulin receptors and mitochondria. We show that high-fat diet-induced (HFD-induced) brain insulin resistance in mice decreased mitochondrial ATP production rate and oxidative enzyme activities in brain regions rich in insulin receptors. HFD increased ROS emission and reduced antioxidant enzyme activities, with the concurrent accumulation of oxidatively damaged mitochondrial proteins and increased mitochondrial fission. Improvement of insulin sensitivity by both aerobic exercise and metformin ameliorated HFD-induced abnormalities. Moreover, insulin-induced enhancement of ATP production in primary cortical neurons and astrocytes was counteracted by the insulin receptor antagonist S961, demonstrating a direct effect of insulin resistance on brain mitochondria. Further, intranasal S961 administration prevented exercise-induced improvements in ATP production and ROS emission during HFD, supporting that exercise enhances brain mitochondrial function by improving insulin action. These results support that insulin sensitizing by exercise and metformin restores brain mitochondrial function in insulin-resistant states.
Topics: Administration, Intranasal; Administration, Oral; Animals; Astrocytes; Cells, Cultured; Cerebral Cortex; Diet, High-Fat; Disease Models, Animal; Glucose; Humans; Insulin; Insulin Resistance; Metformin; Mice; Mitochondria; Mitochondrial Dynamics; Neurons; Oxidative Stress; Peptides; Physical Conditioning, Animal; Primary Cell Culture; Receptor, Insulin; Sedentary Behavior
PubMed: 31534057
DOI: 10.1172/jci.insight.130681 -
Molecular Metabolism Nov 2021Natural sources of molecular diversity remain of utmost importance as a reservoir of proteins and peptides with unique biological functions. We recently identified such...
OBJECTIVE
Natural sources of molecular diversity remain of utmost importance as a reservoir of proteins and peptides with unique biological functions. We recently identified such a family of viral insulin-like peptides (VILPs). We sought to advance the chemical methods in synthesis to explore the structure-function relationship within these VILPs, and the molecular basis for differential biological activities relative to human IGF-1 and insulin.
METHODS
Optimized chemical methods in synthesis were established for a set of VILPs and related analogs. These modified forms included the substitution of select VILP chains with those derived from human insulin and IGF-1. Each peptide was assessed in vitro for agonism and antagonism at the human insulin and the human insulin-like growth factor 1 receptor (IGF-1R).
RESULTS
We report here that one of these VILPs, lymphocystis disease virus-1 (LCDV1)-VILP, has the unique property to be a potent and full antagonist of the IGF-1R. We demonstrate the coordinated importance of the B- and C-chains of the VILP in regulating this activity. Moreover, mutation of the glycine following the first cysteine in the B-chain of IGF-1 to serine, in concert with substitution to the connecting peptide of LCDV1-VILP, converted native IGF-1 to a high potency antagonist.
CONCLUSIONS
The results reveal novel aspects in ligand-receptor interactions at the IGF-1 receptor and identify a set of antagonists of potential medicinal importance.
Topics: Humans; Iridoviridae; Neuropeptides; Receptor, IGF Type 1
PubMed: 34400347
DOI: 10.1016/j.molmet.2021.101316