Browsing by Subject "insulin"
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Item Characterization of the Meal-Stimulated Incretin Response and Relationship With Structural Brain Outcomes in Aging and Alzheimer's Disease(Frontiers Media S.A., 2020-11-30) Morris, Jill K.; John, Casey S.; Green, Zachary D.; Wilkins, Heather M.; Wang, Xiaowan; Kamat, Ashwini; Swerdlow, Russell S.; Vidoni, Eric D.; Petersen, Melissa E.; O'Bryant, Sid E.; Honea, Robyn A.; Burns, Jeffrey M.Background: Individuals with Alzheimer's Disease (AD) are often characterized by systemic markers of insulin resistance; however, the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear. Methods: Here, we leveraged a physiologically relevant meal tolerance test to assess diagnostic differences in these metabolic responses in cognitively healthy older adults (CH; n = 32) and AD (n = 23) participants. All individuals also underwent a comprehensive clinical examination, cognitive evaluation, and structural magnetic resonance imaging. Results: The meal-stimulated response of glucose, insulin, and peptide tyrosine tyrosine (PYY) was significantly greater in individuals with AD as compared to CH. Voxel-based morphometry revealed negative relationships between brain volume and the meal-stimulated response of insulin, C-Peptide, and glucose-dependent insulinotropic polypeptide (GIP) in primarily parietal brain regions. Conclusion: Our findings are consistent with prior work that shows differences in metabolic regulation in AD and relationships with cognition and brain structure.Item The Phosphorylation of Endogenous Substrates by Calcium/Calmodulin-Dependent Protein Kinase II in Pancreatic β-Cells(1998-06-01) Krueger, Kimberly A.; Richard Easom; Rafael Alvarez; S. Dan DimitrijevichKrueger, Kimberly A., The Phosphorylation of Endogenous Substrates by Calcium/Calmodulin-dependent Protein Kinase II in Pancreatic β-cells. Doctor of Philosophy (Biomedical Sciences), June, 1998, 165 pp., 35 illustrations, references, 259 titles. Increasing evidence supports a physiological role for calcium/calmodulin-dependent protein kinase II (CaM kinase II) in the secretion of insulin from pancreatic β-cell. While it has been previously demonstrated that CaM kinase II is activated by glucose in isolated rat islets implicating this enzyme in the secretion process, its cellular targets are unidentified. Potential candidates would likely exhibit strong binding to the enzyme, an association with the cytoskeleton, or an involvement in the secretion process. Based on these criteria, the following study represents an evaluation, in situ, of two proteins to function as substrates for CaM kinase II. Microtubule-associated protein, MAP-2 is one of the best substrates of CaM kinase II in vitro thought to be involved in secretion process. Synapsin I phosphorylation in the neuron by CaM kinase II is essential for neurotransmitter release. Unique to this study, both proteins were determined to be expressed in clonal mouse β-cells (βTC3) and primary rat islet β-cells. By immunoprecipation, in situ phosphorylation of MAP-2 and synapsin I was induced in permeabilized βTC3 cells within a calcium range shown to activate endogenous CaM kinase II under identical conditions. Two-dimensional tryptic phosphopeptide mapping of both proteins revealed that sites phosphorylated by CaM kinase II in vitro, while distinct from sites phosphorylated by protein kinase A in vitro, were largely homologous to those sites phosphorylated in situ upon incubation of the βTC3 cells with increased free calcium. Immunofluorescence verified expression of both proteins in βTC3 cells and pancreatic slices, however, synapsin I exhibited little co-localization with insulin containing dense core granules as demonstrated by immunogold electron microscopy. These data provide evidence that MAP-2 and synapsin I are phosphorylated by CaM kinase II in the pancreatic β-cell in situ. While the data suggest that synapsin I may not be involved in insulin secretion, an association with other known microvesicles of the β-cell, similarly secreted, may be possible. The phosphorylation of these CaM kinase II substrates may reveal an important intermediate step in the mediation of the glucose response in the pancreatic β-cell.Item The Role of Fibroblast Growth Factor-2 in the Expansion of Pancreatic Islets IN VITRO(2004-05-01) Ettinger, Eve Sari; S. Dan Dimitrijevich; Julian Borejdo; Richard EasomEttinger, Eve Sari, The Role of Fibroblast Growth Factor-2 in the Expansion of Pancreatic Islets In Vitro. Doctor of Philosophy (Biomedical Sciences, Biochemistry and Molecular Biology), May 2004, 181 pp., 7 tables, 46 figures, 109 references. The focus of these studies was to identify a pool of progenitor cells within the adult islet, which can be expanded in vitro and aggregated into glucose responsive neoislets as a potential source for transplantation in diabetic patients. We hypothesize that normal adult islets contain an unspecialized proliferative progenitor cell population that can be expanded, aggregated by FGF-2 via PKC mechanism in 2-D culture or in a Rotating Wall Vessel Cell Culture System and matured into glucose-sensitive neoislets through the differential expression or activation of one or more PKC isoform(s). It was shown by immunofluorescence that normal adult islets from several species (rat, porcine, human and canine) contain proliferative endocrine precursor (endocrine epithelial) cells, which coexpress insulin, glucagon and somatostatin. These cells also express PDX-1, a marker of mature B cells and endocrine precursors as well as glut 2 and glucokinase, which are necessary components of glucose metabolism. Endocrine epithelial cells were shown to aggregate into neoislets either spontaneously in 2-D culture or via a rotating wall vessel cell culture system in the presence of fibroblast growth factor-2. FGF2 has been implicated in the aggregation of endocrine epithelial cells into neoislets via the FGFR-cadherin-catenin complex or through PKC signal transduction. Due to the variations in islet isolation, Ins-1 cells were used as a model of B cell aggregation. PKC profiles of endocrine epithelial cells, neoislets, native islets, Ins-1 cells and Ins-1 neoislets were determined. PKC-α, BII, ε and ζ were the only isoforms expressed in these cells and are potential targets for modulation in the differentiation of endocrine epithelial cells. Insulin secretion in response to a glucose challenge was examined in normal islets, neoislets, endocrine epithelial cells, and Ins-1 cells. Although endocrine epithelial cells express insulin, show dense secretory granules and contain two critical proteins in the glucose-sensing cascade, they are immature with respect to glucose-responsive insulin secretion. Neoislets show insignificant insulin secretion in response to elevated glucose when compared to normal islets. Aggregation of endocrine epithelial cells may be the first step in differentiation into mature β cells, however glucose-responsive insulin secretion must be achieved in vitro for use as an alternate source of islets for transplantation in diabetic patients.