LEPTIN AND PERIPHERAL GLUCOSE METABOLISM

Project: Research project

Project Details

Description

Leptin is a protein produced by adipose tissue and hypothesized to be
a circulating lipostatic factor (82). Our preliminary data shows that
leptin infusion into normal mice inhibits insulin release in response
to a glucose challenge, induces insulin resistance in adipocytes, but
promotes insulin-stimulated glycogen synthesis in muscle. An impaired
acute insulin release in response to glucose is a risk factor for
development of non-insulin dependent diabetes (NIDDM) (25) and increased
insulin-stimulated glycogen synthesis in muscle is characteristic of the
early metabolic changes observed during the development of insulin
resistance in high-fat fed rats (48). We hypothesize that leptin
mediates development of an impaired glucose tolerance that precedes
early NIDDM by suppressing glucose stimulated insulin release and
modifying insulin-stimulated glucose utilization in a tissue and pathway
specific manner. Experiments described in Specific Aim 1 will examine
the effects of leptin infusion on glucose and fatty acid metabolism of
the three major insulin-responsive tissues in lean mice and will
determine whether the effects on insulin responsiveness are mediated by
the long-form leptin receptor, OB-Rb. Experiments in Specific Aim 2
will investigate the role of leptin in modifying insulin signaling to
determine whether leptin changes tissue insulin receptor number, glucose
transporter number or translocation, and insulin receptor tyrosine
kinase activity. These processes represent the first stage of the
insulin signaling cascade and the results of these experiments will
determine how leptin modifies the initial stages of insulin signaling
to change peripheral tissue glucose utilization. The studies described
in this proposal will provide the information required to understand how
leptin treatment modifies insulin responsiveness in peripheral tissues
and the mechanisms by which this is achieved. It is essential to
elucidate this aspect of leptin activity as it may account for the
increased risk of development of glucose intolerance that is associated
with obesity.
StatusFinished
Effective start/end date3/1/992/28/19

ASJC

  • Medicine(all)