Hyperglucagonemia and glucagon hypersecretion in early type 2 diabetes result from multifaceted dysregulation of pancreatic mouse α-cells.

Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeutic strategies.

β2-Chimaerin, a GTPase-Activating Protein for Rac1, Is a Novel Regulator of Hepatic Insulin Signaling and Glucose Metabolism.

Glucose homeostasis is a complex process regulated by multiple organs and hormones, with insulin playing a central role. Recent evidence underscores the role of small GTP-binding proteins, particularly Rac1, in regulating insulin secretion and glucose uptake. However, the role of Rac1-regulatory proteins in these processes remains largely unexplored.

Pharmacological activation of insulin-degrading enzyme improves insulin secretion and glucose tolerance in diet-induced obese mice.

Aim: To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose-stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes.

Materials And Methods: We used a preclinical murine model of type 2 diabetes (T2D) induced by high-fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini-pumps for 25 days.

Altered Surface Expression of Insulin-Degrading Enzyme on Monocytes and Lymphocytes from COVID-19 Patients Both at Diagnosis and after Hospital Discharge.

Although the COVID-19 disease has developed into a worldwide pandemic, its pathophysiology remains to be fully understood. Insulin-degrading enzyme (IDE), a zinc-metalloprotease with a high affinity for insulin, has been found in the interactomes of multiple SARS-CoV-2 proteins. However, the relevance of IDE in the innate and adaptative immune responses elicited by circulating peripheral blood mononuclear cells is unknown.

Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation.

Aims/hypothesis: Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo.

The Relationship between Angiogenic Factors and Energy Metabolism in Preeclampsia.

Antiangiogenic factors are currently used for the prediction of preeclampsia. The present study aimed to evaluate the relationship between antiangiogenic factors and lipid and carbohydrate metabolism in maternal plasma and placenta. We analyzed 56 pregnant women, 30 healthy and 26 with preeclampsia (including early and late onset).

Effects of Fasting and Feeding on Transcriptional and Posttranscriptional Regulation of Insulin-Degrading Enzyme in Mice.

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed Zn-metallopeptidase that regulates hepatic insulin sensitivity, albeit its regulation in response to the fasting-to-postprandial transition is poorly understood. In this work, we studied the regulation of IDE mRNA and protein levels as well as its proteolytic activity in the liver, skeletal muscle, and kidneys under fasting (18 h) and refeeding (30 min and 3 h) conditions, in mice fed a standard (SD) or high-fat (HFD) diets. In the liver of mice fed an HFD, fasting reduced IDE protein levels (~30%); whereas refeeding increased its activity (~45%) in both mice fed an SD and HFD.

Targeting Insulin-Degrading Enzyme in Insulin Clearance.

Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50-80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven.

Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme.

Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells.

Placental Compartmentalization of Lipid Metabolism: Implications for Singleton and Twin Pregnancies.

The study of placental lipid metabolism in uncomplicated pregnancies has not been developed in the literature to date. Its importance lies in expanding the knowledge of placental function to enable comparison with pathological pregnancies in future research. The aim of the present study was to compare the lipid metabolic activity and storage of the maternal and fetal sides of the placenta in healthy pregnancies.

Hepatic insulin-degrading enzyme regulates glucose and insulin homeostasis in diet-induced obese mice.

Unlabelled: The insulin-degrading enzyme (IDE) is a metalloendopeptidase with a high affinity for insulin. Human genetic polymorphisms in Ide have been linked to increased risk for T2DM. In mice, hepatic Ide ablation causes glucose intolerance and insulin resistance when mice are fed a regular diet.

Assessment of Insulin Tolerance Ex Vivo.

Insulin is a hormone produced and secreted by the β-cells of the pancreatic islets of Langerhans in response to increased blood glucose levels after a meal. The hormone binds to its receptor located on the plasma membrane triggering an intracellular signaling cascade. This signaling pathway is responsible for the pleiotropic actions of insulin on different tissues, such as regulation of glucose and lipid metabolism, proliferation, and differentiation.

Assessment of Insulin Tolerance In Vivo in Mice.

Insulin resistance in humans and mice is an important hallmark of metabolic diseases. Therefore, assessment of insulin sensitivity/resistance in animal models provides valuable information in the pathophysiology of diabetes and obesity. Depending on the nature of the information required, we can choose between direct and indirect techniques available for the determination of insulin sensitivity.

Intestinal Fructose and Glucose Metabolism in Health and Disease.

The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease.

Use of eltrombopag for patients 65 years old or older with immune thrombocytopenia.

Background: Eltrombopag is useful for immune thrombocytopenia (ITP). However, results of clinical trials may not accurately mirror clinical practice reality. Here we evaluated eltrombopag for primary and secondary ITP in our ≥65-year-old population.

Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity.

Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling.

Manipulation of Transmembrane Transport by Synthetic K Ionophore Depsipeptides and Its Implications in Glucose-Stimulated Insulin Secretion in β-Cells.

The cyclic depsipeptide cereulide toxin it is a very well-known potassium electrogenic ionophore particularly sensitive to pancreatic beta cells. The mechanistic details of its specific activity are unknown. Here, we describe a series of synthetic substituted cereulide potassium ionophores that cause impressive selective activation of glucose-induced insulin secretion in a constitutive manner in rat insulinoma INS1E cells.

Hepatic Insulin Clearance: Mechanism and Physiology.

Upon its secretion from pancreatic β-cells, insulin reaches the liver through the portal circulation to exert its action and eventually undergo clearance in the hepatocytes. In addition to insulin secretion, hepatic insulin clearance regulates the homeostatic level of insulin that is required to reach peripheral insulin target tissues to elicit proper insulin action. Receptor-mediated insulin uptake followed by its degradation constitutes the basic mechanism of insulin clearance.

Excess Hydrocortisone Hampers Placental Nutrient Uptake Disrupting Cellular Metabolism.

Low birth weight increases neonatal morbidity and mortality, and surviving infants have increased risk of metabolic and cardiovascular disturbances later in life, as well as other neurological, psychiatric, and immune complications. A gestational excess of glucocorticoids (GCs) is a well-known cause for fetal growth retardation, but the biological basis for this association remains elusive. Placental growth is closely related to fetal growth.

Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice.

Unlabelled: The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood.

Objective: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance.

Methods: We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action.

Insulin degrading enzyme is up-regulated in pancreatic β cells by insulin treatment.

Insulin Degrading Enzyme (IDE) is an endopeptidase that degrades insulin and glucagon. Ide gene has been associated with type-2 diabetes mellitus (DM2). However, the physiological role(s) of IDE in glucose homeostasis and its potential therapeutic benefit remain not completely known.

LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is due to the selective destruction of islet beta cells by immune cells. Current therapies focused on repressing the immune attack or stimulating beta cell regeneration still have limited clinical efficacy. Therefore, it is timely to identify innovative targets to dampen the immune process, while promoting beta cell survival and function.

Chloro-Furanocembranolides from Leptogorgia sp. Improve Pancreatic Beta-Cell Proliferation.

Two new chloro-furanocembranolides (, ) and two new 1,4-diketo cembranolides (, ) were isolated from the crude extract of sp. together with a new -furanocembranolide () and the known -deoxypukalide (), rubifolide (), scabrolide D () and epoxylophodione (). Their structures were determined based on spectroscopic evidence.