? There is a wealth of information about the physiology of rodent islets, but the biology of human islets of Langerhans remains poorly understood. Because there is growing evidence that human islets are strikingly different in terms of architecture and cellular composition, human islet biology needs to be reevaluated. Our long-term goal is to contribute to the understanding of human islet biology. This proposal addresses one aspect of human islet function: the regulation of glucagon release. Despite its importance to prevent hypoglycemia and therefore for survival, the mechanisms for the regulation of glucagon secretion by pancreatic islets are still controversial. Glucagon secretion is stimulated by decreasing plasma glucose levels. However, when isolated, glucagon-secreting alpha cells are stimulated by high glucose levels. To reconcile these contradictory observations, it has been suggested that paracrine or autocrine signaling is the primary regulatory mechanism governing alpha cell activity and glucagon release. ? Glutamate is a major neurotransmitter in the brain that has been recently proposed as a paracrine signaling molecule providing negative feedback on glucagon secretion in rodent islets. Studies on rodent islets have shown that alpha cells release glutamate and that beta cells and alpha cells express ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors, respectively. In striking contrast to these results, our preliminary studies on human and monkey islets show that glutamate induces Ca2+ responses exclusively in alpha cells. Glutamate strongly stimulates glucagon release but not insulin release. These responses to glutamate are mediated by iGluRs of the AMPA type. Glucagon release in response to decreasing glucose levels is strongly reduced when the AMPA receptors are blocked. Based on these results, we hypothesize that glutamate signaling provides an autocrine loop that is necessary for alpha cell responses to hypoglycemia. This positive feedback allows for propagation of glucagon responses throughout the islet.
Three Specific Aims will test this innovative idea: ? 1) Determine that glutamate is released by alpha cells in primate islets ? 2) Determine that primate alpha cells express functional glutamate receptors ? 3) Determine that glutamate autocrine loops in primate islets are necessary for glucagon responses ? If validated, this research will direct clinicians to consider therapies that activate AMPA receptors to prevent recurrent hypoglycemia in type 1 diabetic patients treated with insulin. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK075487-01
Application #
7133484
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2006-09-15
Project End
2008-08-31
Budget Start
2006-09-15
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$152,625
Indirect Cost
Name
University of Miami School of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Faleo, Gaetano; Berggren, Per-Olof; Pileggi, Antonello (2014) Intravital imaging of cytotoxic T lymphocytes. Methods Mol Biol 1186:121-9
Caicedo, Alejandro (2013) Paracrine and autocrine interactions in the human islet: more than meets the eye. Semin Cell Dev Biol 24:11-21
Abdulreda, Midhat H; Caicedo, Alejandro; Berggren, Per-Olof (2013) Transplantation into the anterior chamber of the eye for longitudinal, non-invasive in vivo imaging with single-cell resolution in real-time. J Vis Exp :e50466
Leibiger, I B; Caicedo, A; Berggren, P-O (2012) Non-invasive in vivo imaging of pancreatic *-cell function and survival - a perspective. Acta Physiol (Oxf) 204:178-85
Perez, V L; Caicedo, A; Berman, D M et al. (2011) The anterior chamber of the eye as a clinical transplantation site for the treatment of diabetes: a study in a baboon model of diabetes. Diabetologia 54:1121-6
Abdulreda, Midhat H; Faleo, Gaetano; Molano, Ruth Damaris et al. (2011) High-resolution, noninvasive longitudinal live imaging of immune responses. Proc Natl Acad Sci U S A 108:12863-8
Nyqvist, Daniel; Speier, Stephan; Rodriguez-Diaz, Rayner et al. (2011) Donor islet endothelial cells in pancreatic islet revascularization. Diabetes 60:2571-7
Jacques-Silva, M Caroline; Correa-Medina, Mayrin; Cabrera, Over et al. (2010) ATP-gated P2X3 receptors constitute a positive autocrine signal for insulin release in the human pancreatic beta cell. Proc Natl Acad Sci U S A 107:6465-70
Speier, Stephan; Nyqvist, Daniel; Kohler, Martin et al. (2008) Noninvasive high-resolution in vivo imaging of cell biology in the anterior chamber of the mouse eye. Nat Protoc 3:1278-86
Kim, Joung Woul; Roberts, Craig D; Berg, Stephanie A et al. (2008) Imaging cyclic AMP changes in pancreatic islets of transgenic reporter mice. PLoS One 3:e2127

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