4 results on '"Egan, Josephine M."'
Search Results
2. Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice.
- Author
-
Aseer, Kanikkai Raja, Mazucanti, Caio Henrique, O'Connell, Jennifer F., González-Mariscal, Isabel, Verma, Anjali, Yao, Qin, Dunn, Christopher, Liu, Qing-Rong, Egan, Josephine M., and Doyle, Máire E.
- Abstract
Type 1 diabetes (T1D) occurs because of islet infiltration by autoreactive immune cells leading to destruction of beta cells and it is becoming evident that beta cell dysfunction partakes in this process. We previously reported that genetic deletion and pharmacological antagonism of the cannabinoid 1 receptor (CB1) in mice improves insulin synthesis and secretion, upregulates glucose sensing machinery, favors beta cell survival by reducing apoptosis, and enhances beta cell proliferation. Moreover, beta cell specific deletion of CB1 protected mice fed a high fat high sugar diet against islet inflammation and beta cell dysfunction. Therefore, we hypothesized that it would mitigate the dysfunction of beta cells in the precipitating events leading to T1D. We genetically deleted CB1 specifically from beta cells in non-obese diabetic (NOD; NOD RIP Cre
+ Cnr1fl/fl ) mice. We evaluated female NOD RIP Cre+ Cnr1fl/fl mice and their NOD RIP Cre− Cnr1fl/fl and NOD RIP Cre+ Cnr1Wt/Wt littermates for onset of hyperglycemia over 26 weeks. We also examined islet morphology, islet infiltration by immune cells and beta cell function and proliferation. Beta cell specific deletion of CB1 in NOD mice significantly reduced the incidence of hyperglycemia by preserving beta cell function and mass. Deletion also prevented beta cell apoptosis and aggressive insulitis in NOD RIP Cre+ Cnr1fl/fl mice compared to wild-type littermates. NOD RIP Cre+ Cnr1fl/fl islets maintained normal morphology with no evidence of beta cell dedifferentiation or appearance of extra islet beta cells, indicating that protection from autoimmunity is inherent to genetic deletion of beta cell CB1. Pancreatic lymph node T reg cells were significantly higher in NOD RIP Cre+ Cnr1fl/fl vs NOD RIP Cre− Cnr1fl/fl . Collectively these data demonstrate how protection of beta cells from metabolic stress during the active phase of T1D can ameliorate destructive insulitis and provides evidence for CB1 as a potential pharmacologic target in T1D. • Beta cell specific CB1 deletion protects islets from the detrimental effects of prolonged nutrient overload and inflammation. • Beta cells in T1D are subjected to endoplasmic reticulum stress because of increasing demands to synthesize insulin. • Beta cell specific CB1 deletion in NOD mice prevents hyperglycemia and insulitis and preserves beta cell mass and function. • NOD beta cells lacking CB1 had reduced expression of the beta cell antigen presenting molecule MHC class I. • CB1 blockade should be considered a target for prevention of T1D as it protects beta cells and improves beta cell function. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
3. AAV5-mediated manipulation of insulin expression in choroid plexus has long-term metabolic and behavioral consequences.
- Author
-
Mazucanti, Caio Henrique, Kennedy, Vernon, Premathilake, Hasitha U., Doyle, Maire E., Tian, Jane, Liu, Qing-Rong, O'Connell, Jennifer, Camandola, Simonetta, and Egan, Josephine M.
- Abstract
The choroid plexus (CP) is a source of trophic factors for the developing and mature brain. Insulin is produced in epithelial cells of the CP (EChPs), and its secretion is stimulated by Htr2c-mediated signaling. We modulated insulin expression in EChPs with intracerebroventricular injections of AAV5. Insulin overexpression in CP decelerates food intake, whereas its knockdown has the opposite effect. Insulin overexpression also results in reduced anxious behavior. Transcriptomic changes in the hypothalamus, especially in synapse-related processes, are also seen in mice overexpressing insulin in CP. Last, activation of Gq signaling in CP leads to acute Akt phosphorylation in neurons of the arcuate nucleus, indicating a direct action of CP-derived insulin on the hypothalamus. Taken together, our findings signify that CP is a relevant source of insulin in the central nervous system and that CP-derived insulin should be taken into consideration in future work pertaining to insulin actions in the brain. [Display omitted] • AAV5 selectively infects epithelial cells of the choroid plexus when injected i.c.v. • Insulin overexpression in the CP modulates feeding behavior and decreases anxiety in mice • CP-derived insulin affects the transcriptome of hypothalamic neurons • Acute secretion of CP insulin decreases food intake by activating hypothalamic circuitry Beyond its role in cerebrospinal fluid production, the choroid plexus (CP) is a source of insulin in the CNS. Mazucanti et al. describe one role of this locally produced hormone in brain physiology. Chronic and acute manipulations of CP insulin expression alter feeding behavior by activating neurons in the hypothalamus. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. Pancreatic β cell derived extracellular vesicles containing surface preproinsulin are involved in glucose stimulated insulin secretion.
- Author
-
Ghosh, Paritosh, Liu, Qing-Rong, Chen, Qinghua, Zhu, Min, and Egan, Josephine M.
- Subjects
- *
INSULIN , *INSULIN receptors , *EXTRACELLULAR vesicles , *GLUCOSE clamp technique , *WESTERN immunoblotting , *SECRETION , *CELL communication - Abstract
Extracellular vesicles (EVs) are involved in intercellular communication and are a topic of increasing interest due to their therapeutic potential. The aim of this study was to determine whether human islet-derived EVs contain insulin, and if so, what role do they play in glucose stimulated insulin secretion. We isolated EVs from human islets culture and plasma to probe for insulin. Plasma from hyperglycemic glucose clamp experiments were also used to isolate and measure EV insulin content in response to a secretory stimulus. We performed immunogold electron microscopy for insulin presence in EVs. Co-culture experiments of isolated EVs with fresh islets were performed to examine the effect of EV cargo on insulin receptor signaling. EVs isolated from culture medium contained insulin. Glucose treatment of islets increased the level of EV insulin. Hyperglycemic glucose clamp experiments in humans also lead to increased levels of insulin in plasma-derived EVs. Immunogold electron microscopy and proteinase K-digestion experiments demonstrated that insulin in EVs predominantly associated with the exterior surface of EVs while western blot analyses uncovered the presence of only preproinsulin in EVs. Membrane-bound preproinsulin in EVs was capable of activating insulin signaling pathway in an insulin receptor-dependent manner. The physiological relevance of this finding was observed in priming of human naïve islets by EVs during glucose stimulated insulin secretion. Our data suggest that (1) human islets secret insulin via an alternate pathway (EV-mediated) other than conventional granule-mediated insulin secretion, and (2) EV membrane bound preproinsulin is biologically active. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.