GLUT4 AND GLUCOSE HOMEOSTASIS

Project: Research project

Project Details

Description

DESCRIPTION (Adapted from the Applicant's Abstract): Insulin resistant
states such as NIDDM and obesity are characterized by a decrease in
insulin stimulated glucose uptake. The insulin responsive glucose
transporter GLUT 4, plays a major role in insulin stimulated glucose
uptake in normal muscle and adipose cells. Although GLUT 4 is thought
to be important in maintaining normal glucose homeostasis, it is not
known whether alterations in GLUT 4 function will cause severe metabolic
consequences. The goal of this proposal is to understand glucose
metabolism in mice having no functional GLUT 4 and in mice where GLUT
4 is overexpressed in skeletal muscle. Two lines of genetically
modified mice have been developed for this purpose. Mice which carry
two disrupted alleles of GLUT 4 (Delta GLUT4/Delta GLUT4) have been
established. The DeltaGLUT4/DeltaGLUT4 mice display post prandial
hyperinsulinemia and represent a model for the study of insulin
resistance similar to that seen in NIDDM and obesity. The other line
of mice overexpressed GLUT 4 specifically in skeletal muscle (MLC GLUT4),
the largest depot for post prandial glucose disposal. The MLC GLUT4
mice are hypersensitive to insulin. Mice genetically modified in GLUT4
will provide an animal paradigm for understanding glucose homeostasis,
the response of glucose metabolism to insulin and the development of
insulin resistance. Major questions which can be answered with the
unique GLUT4 modified mice include:

1. Does the deficiency of the insulin responsive GLUT4 transporter
cause diabetes? The rate of glucose clearance from the circulation can
be compared in normal and DelatGLUT4/DeltaGLUT4 mice by euglycemic clamp
and 2 deoxyglucose uptake experiments. Metabolites, hormones and enzyme
activities of glucose homeostasis can be measured.

2. Does GLUT4 expression in skeletal muscle dictate whole body insulin
sensitivity? The tissue patterns of muscle, adipose cell and liver
enzyme expression can be compared in GLUT4 deficient and GLUT4 excess
to provide unequivocal answers to the metabolic role of insulin
responsive glucose transport effects.

3. Can the amount of GLUT4 expressed modify the response to nutritional
or other stress? The insulin response of GLUT4 deficient and MLC GLUT4
mice can be compared in response to dietary stress (i.e. high fat or
high carbohydrate diets) and to streptozotocin treatment to determine
whether altered GLUT4 function will exacerbate or blunt the onset
insulin resistance and obesity.

4. Does a tissue specific knockout of GLUT4 in skeletal muscle or
adipose tissue have a different phenotype than a general GLUT4 knockout?
The rate of glucose clearance from the blood of mice deficient in
skeletal muscle or adipose tissue GLUT4 can be compared to Delta GLUT
4/Delta GLUT4 and normal mice to separate contributions of GLUT4 in
skeletal muscle and adipose tissue to whole body insulin sensitivity.
StatusFinished
Effective start/end date8/1/957/31/96

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases

ASJC

  • Endocrinology, Diabetes and Metabolism

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