Awardees 2006

PI: Zhengyu Liu, Ph.D.
Abstract:Glucagon-like-peptide-1 (GLP-1) is one of the most potent insulintropic hormones known.  A major effort from both academia and pharmaceutical industry is being directed to ascertain the role of GLP-1 and its therapeutic potential in treatment of Type 2 diabetes.  Previous studies from our lab and others suggested one of the major actions of GLP-1 is stimulation of islet beta-cell apoptosis.  Here we propose that GLP-1 activates cells from precursor stem cells and inhibition of beta-cell apoptosis.  Here we propose that GLP-1 activates Wnt signaling and Wnt signaling cascade plays key roles in GLP-1 mediated functions.  This hypotheses is based on our recent finding that more than a dozen of wnt signaling related genes were robustl up-regulated by acute treatment of mouse pancreatic islets with a potent GLP-1 analog, exendin-4.  Furthermore, Wnt signaling pathway and GLP-1 signaling pathway share common downstream signaling molecules, implicating the existence of cross-talk between the two pathways.  We plan to use well-studied anmimal models and diabetes models as well as in vitro studies to investigate the role of Wnt signalig in GLP-1/exendin-4 mediated functions and to determine whether Wnt ligands enhance GLP-1/exendin-4 biological activity.  We believe that these studies may open new directions for the understanding of GLP-1 action and lead to discovery of novel therapeutic approaches for the cure of diabetes.

 


 PI: Fawaz George Haj, Ph.D.
Abstract:Type 2 diabetes mellitus is a highly prevalent disease characterized by increased insulin resistance.  The detailed mechanism underlying insulin resistance remains incompletely understood, although it is thought that protein-tyrosine phosphatases (PTPs) are among the key regulators of insulin signaling.  Src homology phosphatase 2 (Shp2) has been implicated in the regulation of insulin signaling through binding to several key downstream components, including insulin receptor substrates (IRSs), in particular IRS1/2, and Grb2-associated binder 1 (Gab1).  Transgenic mice over-expressing a putative dominant negative mutant of Shp2 in peripheral insulin-responsive tissues reportedly exhibit insulin resistance in vivo, but the effects of this mutant are potentially difficult to interpret.  On the other hand, heterozygous Shp2 mice show no significant difference in their insulin response compared to wild type littermates.  In addition, homozygous disruption of Shp2 results in embryonic lethality, preventing additional analysis of its function in adult mice.  Thus, the mechanism of in vivo regulation of glucose homeostasis and insulin signaling by Shp2 is controversial. 

To definitively resolve the role of Shp2 in the regulation of glucose homeostasis, I began using mice containing an inducible (floxed) allele of Shp2.  I plan to utilize this genetic mouse model to create mice with specific Shp2 deletion in the liver, muscle and adipose tissue.  My preliminary data indicate that Shp2 plays distinct roles in different peripheral insulin responsive tissues, acting as positive mediator of insulin’s action in some tissues and as negative mediator in others.  My research plan will focus initially on several important areas: (1) Determine the in vivo role of Shp2 in glucose homeostasis in liver using a tissue-specific deletion approach, (2) Determine the in vivo role of Shp2 in glucose homeostasis in muscle using a tissue-specific deletion approach, and (3) Generate adipose tissue-specific Shp2 knockout mice.

To definitively resolve the role of Shp2 in the regulation of glucose homeostasis, I began using mice containing an inducible (floxed) allele of Shp2.  I plan to utilize this genetic mouse model to create mice with specific Shp2 deletion in the liver, muscle and adipose tissue.  My preliminary data indicate that Shp2 plays distinct roles in different peripheral insulin responsive tissues, acting as positive mediator of insulin’s action in some tissues and as negative mediator in others.  My research plan will focus initially on several important areas: (1) Determine the in vivo role of Shp2 in glucose homeostasis in liver using a tissue-specific deletion approach, (2) Determine the in vivo role of Shp2 in glucose homeostasis in muscle using a tissue-specific deletion approach, and (3) Generate adipose tissue-specific Shp2 knockout mice.

 

 PI:Fransis Hayes, M.D.
Abstract:Insulin resistance plays a key role in the pathogenesis of the metabolic syndrome and type 2 diabetes (DM2).  Thus, elucidating factors that alter insulin action has important clinical implications.  Epidemiologic studies show an inverse relationship between insulin and testosterone (T) levels in men.  However, data on causality are lacking.  It is also unclear if T might modulate insulin action directly via the androgen receptor or indirectly by aromatization to estradiol (E2).  Thus, the overall goal of this proposal is to define the role of gonadal sex steroids in modulating insulin action in men.

Specific Aim (SA)#1 will examine the impact of 2 and 4 weeks of sex steroid suppression on insulin sensitivity in normal men.  Hypogonadism will be induced with a gonadotropin-releasing hormone antagonist.  Insulin sensitivity will be assessed by a hyperinsulinemic-euglycemic clamp.  The mechanisms underlying changes in insulin sensitivity will be explored by assessing body composition, and detailed studies of fat metabolism (rates of lipolysis & lipid oxidation) and skeletal muscle (muscle fiber type, intramyocellular lipid content, gene expression profiles).  Protocol 2 will examine the impact of 3 months of T therapy on men with metabolic syndrome (SA#2), the mechanism underlying any changes in insulin sensitivity, and the role of E2 in mediating T’s effect on insulin action (SA#3)

It is estimated that 20% of men over 60 yr have low T levels.  Therefore, if low T levels promote insulin resistance, T may represent a novel therapeutic modality for preventing and treating the metabolic syndrome and DM2 in men.



 

 

 

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