The pancreatic β-cell in ageing: Implications in age-related diabetes.

The prevalence of type 2 diabetes (T2D) and impaired glucose tolerance (IGT) increases with ageing. T2D generally results from progressive impairment of the pancreatic islets to adapt β-cell mass and function in the setting of insulin resistance and increased insulin demand. Several studies have shown an age-related decline in peripheral insulin sensitivity.

The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice.

Aims/hypothesis: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity.

Methods: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.

The Effects of Aging on Male Mouse Pancreatic β-Cell Function Involve Multiple Events in the Regulation of Secretion: Influence of Insulin Sensitivity.

Aging is associated with a decline in peripheral insulin sensitivity and an increased risk of impaired glucose tolerance and type 2 diabetes. During conditions of reduced insulin sensitivity, pancreatic β cells undergo adaptive responses to increase insulin secretion and maintain euglycemia. However, the existence and nature of β-cell adaptations and/or alterations during aging are still a matter of debate.

AAV8 Ins1-Cre can produce efficient β-cell recombination but requires consideration of off-target effects.

In vivo genetic manipulation is used to study the impact of gene deletion or re-expression on β-cell function and organism physiology. Cre-LoxP is a system wherein LoxP sites flanking a gene are recognized by Cre recombinase. Cre transgenic mice are the most prevalent technology used to deliver Cre but many models have caveats of off-target recombination, impaired β-cell function, and high cost of animal production.

SNAP23 depletion enables more SNAP25/calcium channel excitosome formation to increase insulin exocytosis in type 2 diabetes.

SNAP23 is the ubiquitous SNAP25 isoform that mediates secretion in non-neuronal cells, similar to SNAP25 in neurons. However, some secretory cells like pancreatic islet β cells contain an abundance of both SNAP25 and SNAP23, where SNAP23 is believed to play a redundant role to SNAP25. We show that SNAP23, when depleted in mouse β cells in vivo and human β cells (normal and type 2 diabetes [T2D] patients) in vitro, paradoxically increased biphasic glucose-stimulated insulin secretion corresponding to increased exocytosis of predocked and newcomer insulin granules.

Morphological and functional adaptations of pancreatic alpha-cells during late pregnancy in the mouse.

Background: Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-cell to maintain normoglycemia. However, although pancreatic alpha-cells play a key role in glucose homeostasis and seem to be involved in gestational diabetes, there is no information about their potential adaptations or changes during pregnancy.

Material And Methods: Non-pregnant (controls) and pregnant C57BL/6 mice at gestational day 18.

AAV GCG-EGFP, a new tool to identify glucagon-secreting α-cells.

The study of primary glucagon-secreting α-cells is hampered by their low abundance and scattered distribution in rodent pancreatic islets. We have designed a double-stranded adeno-associated virus containing a rat proglucagon promoter (700 bp) driving enhanced green fluorescent protein (AAV GCG-EGFP), to specifically identify α-cells. The administration of AAV GCG-EGFP by intraperitoneal or intraductal injection led to EGFP expression selectively in the α-cell population.

Early overnutrition reduces Pdx1 expression and induces β cell failure in Swiss Webster mice.

Childhood obesity and early rapid growth increase the risk for type 2 diabetes. Such early overnutrition can be modeled in mice by reducing litter size. We investigated the effects of early overnutrition and increased dietary fat intake on β cell function in Swiss Webster mice.

Timing of Exposure and Bisphenol-A: Implications for Diabetes Development.

Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDCs). It is used as the base compound in the production of polycarbonate and other plastics present in many consumer products. It is also used as a building block in epoxy can coating and the thermal paper of cash register receipts.

Mitochondria as target of endocrine-disrupting chemicals: implications for type 2 diabetes.

Type 2 diabetes is a chronic, heterogeneous syndrome characterized by insulin resistance and pancreatic β-cell dysfunction or death. Among several environmental factors contributing to type 2 diabetes development, endocrine-disrupting chemicals (EDCs) have been receiving special attention. These chemicals include a wide variety of pollutants, from components of plastic to pesticides, with the ability to modulate endocrine system function.

A Calcium-Dependent Chloride Current Increases Repetitive Firing in Mouse Sympathetic Neurons.

Ca-activated ion channels shape membrane excitability in response to elevations in intracellular Ca. The most extensively studied Ca-sensitive ion channels are Ca-activated K channels, whereas the physiological importance of Ca-activated Cl channels has been poorly studied. Here we show that a Ca-activated Cl currents (CaCCs) modulate repetitive firing in mouse sympathetic ganglion cells.

Endocrine-disrupting chemicals and the regulation of energy balance.

Energy balance involves the adjustment of food intake, energy expenditure and body fat reserves through homeostatic pathways. These pathways include a multitude of biochemical reactions, as well as hormonal cues. Dysfunction of this homeostatic control system results in common metabolism-related pathologies, which include obesity and type 2 diabetes mellitus.

GPR55 and the regulation of glucose homeostasis.

Pathophysiological conditions such as obesity and type 2 diabetes (T2D) are reportedly associated to over-activation of the endocannabinoid system (ECS). Therefore, modulation of the ECS offers potential therapeutic benefits on those diseases. GPR55, the receptor for L-α-lysophosphatidylinositol (LPI) that has also affinity for various cannabinoid ligands, is distributed at the central and peripheral level and it is involved in several physiological processes.

GPR55: a new promising target for metabolism?

GPR55 is a G-protein-coupled receptor (GPCR) that has been identified as a new cannabinoid receptor. Given the wide localization of GPR55 in brain and peripheral tissues, this receptor has emerged as a regulator of multiple biological actions. Lysophosphatidylinositol (LPI) is generally accepted as the endogenous ligand of GPR55.

The role of autonomic efferents and uncoupling protein 1 in the glucose-lowering effect of leptin therapy.

Objective: Leptin reverses hyperglycemia in rodent models of type 1 diabetes (T1D). Direct application of leptin to the brain can lower blood glucose in diabetic rodents, and can activate autonomic efferents and non-shivering thermogenesis in brown adipose tissue (BAT). We investigated whether leptin reverses hyperglycemia through a mechanism that requires autonomic innervation, or uncoupling protein 1 (UCP1)-mediated thermogenesis.

Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo.

Disrupted Leptin Signaling in the Lateral Hypothalamus and Ventral Premammillary Nucleus Alters Insulin and Glucagon Secretion and Protects Against Diet-Induced Obesity.

Leptin signaling in the central nervous system, and particularly the arcuate hypothalamic nucleus, is important for regulating energy and glucose homeostasis. However, the roles of extra-arcuate leptin responsive neurons are less defined. In the current study, we generated mice with widespread inactivation of the long leptin receptor isoform in the central nervous system via Synapsin promoter-driven Cre (Lepr(flox/flox) Syn-cre mice).

Glucagon-Like Peptide 1 Analogs and their Effects on Pancreatic Islets.

Glucagon-like peptide 1 (GLP-1) exerts many actions that improve glycemic control. GLP-1 stimulates glucose-stimulated insulin secretion and protects β cells, while its extrapancreatic effects include cardioprotection, reduction of hepatic glucose production, and regulation of satiety. Although an appealing antidiabetic drug candidate, the rapid degradation of GLP-1 by dipeptidyl peptidase 4 (DPP-4) means that its therapeutic use is unfeasible, and this prompted the development of two main GLP-1 therapies: long-acting GLP-1 analogs and DPP-4 inhibitors.

Partial ablation of leptin signaling in mouse pancreatic α-cells does not alter either glucose or lipid homeostasis.

The role of glucagon in the pathological condition of diabetes is gaining interest, and it has been recently reported that its action is essential for hyperglycemia to occur. Glucagon levels, which are elevated in some diabetic models, are reduced following leptin therapy. Likewise, hyperglycemia is corrected in type 1 diabetic mice treated with leptin, although the mechanisms have not been fully determined.

Impaired Ca(2+) signaling in β-cells lacking leptin receptors by Cre-loxP recombination.

Obesity is a major risk factor for diabetes and is typically associated with hyperleptinemia and a state of leptin resistance. The impact of chronically elevated leptin levels on the function of insulin-secreting β-cells has not been elucidated. We previously generated mice lacking leptin signaling in β-cells by using the Cre-loxP strategy and showed that these animals develop increased body weight and adiposity, hyperinsulinemia, impaired glucose-stimulated insulin secretion and insulin resistance.

Leptin administration enhances islet transplant performance in diabetic mice.

Islet transplantation is an effective method to obtain long-term glycemic control for patients with type 1 diabetes, yet its widespread use is limited by an inadequate supply of donor islets. The hormone leptin has profound glucose-lowering and insulin-sensitizing action in type 1 diabetic rodent models. We hypothesized that leptin administration could reduce the dose of transplanted islets required to achieve metabolic control in a mouse model of type 1 diabetes.

Restoring insulin production for type 1 diabetes.

Current therapies for the treatment of type 1 diabetes include daily administration of exogenous insulin and, less frequently, whole-pancreas or islet transplantation. Insulin injections often result in inaccurate insulin doses, exposing the patient to hypo- and/or hyperglycemic episodes that lead to long-term complications. Islet transplantation is also limited by lack of high-quality islet donors, early graft failure, and chronic post-transplant immunosuppressive treatment.

Pancreatic islet cells: a model for calcium-dependent peptide release.

In mammals the concentration of blood glucose is kept close to 5 mmol∕l. Different cell types in the islet of Langerhans participate in the control of glucose homeostasis. β-cells, the most frequent type in pancreatic islets, are responsible for the synthesis, storage, and release of insulin.