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Experiment

Hyperinsulinemic-euglycemic clamp in p66shc-/- mice on a regular diet

Summary

Data Summary

Investigator	Giorgio, Marco
Description	Longevity of a p66Shc knockout strain (ShcP) was previously attributed to increased stress resistance and altered mitochondria. Microarrays of ShcP tissues indicated alterations in insulin signaling. Consistent with this observation, ShcP mice were more insulin sensitive and glucose tolerant at organismal and tissue levels, as was a novel p66Shc knockout (ShcL). Increasing and decreasing Shc expression in cell lines decreased and increased insulin sensitivity, respectively – consistent with p66Shc's function as a repressor of insulin signaling. However, differences between the two p66Shc knockout strains were also observed. ShcL mice were fatter and susceptible to fatty diets, and their fat was more insulin sensitive than controls. On the other hand, ShcP mice were leaner and resisted fatty diets, and their adipose was less insulin sensitive than controls. ShcL and ShcP strains are both highly inbred on the C57Bl/6 background, so we investigated gene expression at the Shc locus, which encodes three isoforms, p66, p52, and p46. Isoform p66 is absent in both strains; thus, the remaining difference to which to attribute the ‘lean’ phenotype is expression of the other two isoforms. ShcL mice have a precise deletion of p66Shc and normal expression of p52 and p46Shc isoforms in all tissues; thus, a simple deletion of p66Shc results in a ‘fat’ phenotype. However, ShcP mice in addition to p66Shc deletion have a fourfold increase in p46Shc expression in white fat. Thus, p46Shc overexpression in fat, rather than p66Shc deletion, is the likely cause of decreased adiposity and reduced insulin sensitivity in the fat of ShcP mice, which has implications for the longevity of the strain. Applicable research area(s): Diabetes, Obesity, Metabolism
Status	Completed
Public Release	6/11/2011
Data Collected?	Data will not be collected for this catalog item
Animal Age	Measured In: week(s) post-natal (w)
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Data Analysis

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Type	Count
Animals	19
Experimental Conditions	5
Catalog Items	1
Curation Info (# flags)	2
Phenotype Assays	13
Phenotype Measurements	247
Histology Images	0
Publications	0

Animals

Strain Name	Common Name	Females	Males	Unknown
C57BL/6J	C57BL/6J	0	9	0
B6.Cg-Shc1^tm1Pgp	C57BL/6J-p66Shc1^-/-	0	10	0

Animals/Strains

Experimental Factors

	Categorical Values
	Name / Abbreviation	Description
	Experimental Factor: Experimental Group
	Control	This animal belongs to the control group for the experiment.
	Experiment	This animal belongs to experimental group that is homozygous for gene manipulations.
	Experimental Factor: Mouse Diet
	Teklad - 2018S	Harlan-Teklad 2018S 18.8% protein (Calories : 23% protein, 17% Fat, 60% Carbohydrate) Ingredients—Ground wheat, ground corn, wheat middlings, dehulled soybean meal, corn gluten meal, soybean oil, calcium carbonate, brewers dried yeast, dicalcium...

Experimental Factor (Units)
Experimental Group
Fast Duration (hr)
Insulin Infusion Rate - milliUnits (mU/kg/min)
Mouse Diet
Total Time on Diet (mo)

Experimental Factor Values

Phenotype Assays Add / Edit

Name	Abbreviation
average clamp glucose	average clamp glucose
average glucose infusion rate	average glucose infusion rate
insulin, basal	insulin, basal
fat body mass	fat body mass
lean body mass	lean body mass
total body weight	total body weight
glucose, basal	glucose, basal
hepatic glucose production, basal	hepatic glucose production, basal
glucose turnover, whole body	glucose turnover, whole body
glycogen/lipid synthesis, whole body	glycogen/lipid synthesis, whole body
glycolysis, whole body	glycolysis, whole body
insulin, clamp	insulin, clamp
Hepatic Glucose Production, clamp	Hepatic Glucose Production, clamp

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