Awardee OrganizationBOSTON UNIVERSITY MEDICAL CAMPUS
Description
Abstract Text
Type II diabetes mellitus is characterized by "insulin resistance," a
condition where normal concentrations of serum insulin fail to
adequately clear blood glucose. Although type II diabetes is a
heterogeneous disease caused by several different biochemical defects,
it is already clear that a common cause is failure of insulin to enhance
glucose uptake, primarily into muscle. The mechanism by which insulin
enhances glucose uptake into its main target tissues, muscle and fat,
is to cause a movement or recruitment of tissue-specific glucose
transporter, Glut4, from an intracellular storage pool to the cell
surface, where it can function. It is this movement that is comprised
in many type II diabetics, and therefore, it is the long-term goal of
this work to determine the mechanistic details of the insulin-dependent
translocation process. The intracellular storage pool of Glut4 consists
of two or more vesicular compartments containing a number of additional
cargo protein besides Glut4 itself. The first specific aim is to
determine the composition of the major Glut4 containing compartments,
endosomes and insulin-responsive vesicles (IRVs). These will be
separated from one another by physical and immunological procedures, and
the biochemical features that determine their uniqueness, vis a vis one
another, will be identified. The second specific aim will address the
nature of the regulation of IRV transit to the cell movement in the
absence of insulin. Thus, the cytoplasmic portion of an aminopeptidase
that completely co-localizes with Glut4 will be used as "bait" in the
yeast 2-hybrid systems, and in biochemical interaction assays, to
identify cytosolic and/or cytoskeletal proteins that interact with Glut4
vesicles. The third and last specific aim will exploit the development
of insulin-responsive vesicular trafficking in cultured fat murine cells
as they differentiate from fibroblast into adipocytes. Immunological and
genetic techniques will be used to compare genes expressed just before
and just after the onset of insulin-sensitive vesicular traffic, e.g.,
those mediating the formation of the IRVs. The investigators expect
these aims will identify novel proteins involved in aspects of insulin-
regulated, and these may provide opportune for therapeutic intervention
in type II ( and type I) diabetes mellitus.
Public Health Relevance Statement
Data not available.
NIH Spending Category
No NIH Spending Category available.
Project Terms
3T3 cellsadipocytesaminopeptidasecarbohydrate receptorcell differentiationcell migrationglucose transportglucose transporterhormone regulation /control mechanisminsulininsulin sensitivity /resistanceintracellular transportlaboratory ratmembrane transport proteinsnuclear magnetic resonance spectroscopyprotein transportreceptor expressionvesicle /vacuoleyeast two hybrid system
National Institute of Diabetes and Digestive and Kidney Diseases
CFDA Code
847
DUNS Number
604483045
UEI
FBYMGMHW4X95
Project Start Date
01-January-1982
Project End Date
30-June-2003
Budget Start Date
01-July-2002
Budget End Date
30-June-2003
Project Funding Information for 2002
Total Funding
$258,870
Direct Costs
$158,816
Indirect Costs
$100,054
Year
Funding IC
FY Total Cost by IC
2002
National Institute of Diabetes and Digestive and Kidney Diseases
$258,870
Year
Funding IC
FY Total Cost by IC
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No Sub Projects information available for 5R01DK030425-21
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