Characterization of the expression, localization, regulation and role of pancreatic derived factor (PANDER, FAM3B) in pancreatic alpha cells.

Format:

Book

Thesis/Dissertation

Author/Creator:

Carnegie, Jason R.

Contributor:

Wolf, Bryan A., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Genetics.

Molecular biology.

0307.

0369.

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

0307.

0369.

Physical Description:

196 pages

Contained In:

Dissertation Abstracts International 70-10B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Pancreatic Islets of Langerhans are critical regulators of serum glucose, exerting substantial control over the balance of systemic energy availability and fluctuating demand. The release of the antagonistic hormones insulin and glucagon as well as other paracrine messengers elicits responses within the islet and at peripheral tissues to maintain euglycemia. PANcreatic DERived Factor (PANDER; FAM3B), a recently identified islet-specific protein, has been extensively characterized by our group and others almost entirely with respect to insulin-secreting beta-cells. An in-vivo role for PANDER in glucose homeostasis is suggested by a number of homeostatic aberrations in two PANDER mouse models. In a transgenic mouse islet-specifically over-expressing PANDER, we observe impaired glucose tolerance and elevated hepatic glucose production (HGP), while in a global PANDER knockout mouse model; there is reduced HGP and gluconeogenic enzyme expression as compared with wild type control animals. These aberrations suggest a biological role for PANDER in regulating glucose homeostasis similar to glucagon.

Glucagon-secreting alpha-cells comprise the second largest islet cell population and influence serum glucose levels via the stimulation of Hepatic Glucose Production (HGP). The aim of this dissertation is to evaluate PANDER expression in alpha-cells, evaluate the effect of typical glucagon secretagogues on the regulation of PANDER secretion from these cells, and investigate the influence of PANDER on serum glucagon levels in mice. pander mRNA and protein are detected in alpha-cell lines and in the beta- and alpha-cell-enriched fractions of FACS sorted islets, and is predominantly localized to glucagon-negative secretory granules within the cytosol. Sharing both regulatory similarities and differences with glucagon, the amino acid L-arginine has a robust positive effect on PANDER release while there is no effect of either hyperglycemia or hypoglycemia. Interestingly low levels of insulin known to suppress glucagon have a robust stimulatory effect on PANDER release, mediated by signaling through the insulin receptor (IR) downstream of PI3-kinase (PI3K) via the Akt/PKB node. The observed similarities and differences are consistent with the minimal co-localization of PANDER and glucagon, with predominant sequestration of PANDER to a separate granular cytoplasmic compartment.

Despite absence of observed effect of PANDER over-expression in-vitro on hypoglycemia-induced glucagon release from alpha-TC1-6 cells, there is a complete loss of the typical glucagon response to fasting in PANDER transgenic mice, associated with mild basal hyperglucagonemia (that is in the fed state) as compared with WT controls. This may reflect a paracrine/autocrine effect of PANDER on glucagon release, also with a potential direct effect of PANDER on Hepatic Glucose Production.

Together the data demonstrate nutritional and paracrine regulation of PANDER release from a granular cytoplasmic compartment within alpha-cells, which directly or indirectly influences post-absorptive glucagon, and the normal glucagon response to hypoglycemia in-vivo.

Notes:

Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2009.

Source: Dissertation Abstracts International, Volume: 70-10, Section: B, page: 5986.

Adviser: Bryan A. Wolf.

Local Notes:

School code: 0175.

ISBN:

9781109428308

Access Restriction:

Restricted for use by site license.