ROLE OF HEMODYNAMICS IN IN VIVO INSULIN RESISTANCE

Project: Research project

Description

In vivo insulin mediated glucose uptake (IMGU) occurs principally in
skeletal muscle and is determined by the arteriovenous glucose difference
(AVGd) across and the rate of blood flow (F) into muscle, such that IMGU =
AVGD X F. Human obesity, Type II and Type I diabetes are associated with
decreased rates of IMGU, which have been attributed in large part to
binding and post-binding cellular defects in insulin action. These defects
would be predicted to decrease cellular and thus tissue glucose uptake
i.e., AVGd. However, the contribution of hemodynamic defects in glucose
and insulin delivery (F) to in vivo insulin resistance has received little
attention. Yet, information regarding this is crucial to our understanding
of the pathophysiology of in vivo insulin resistance. The studies outlined in this proposal are designed to test the overall
hypothesis that a defect(s) in insulin's normal ability to generate
increments in blood flow to skeletal muscle is an important contributor to
in vivo insulin resistance. It is postulated that obesity and the diabetic
state are associated with hemodynamic defects which contribute
significantly to postprandial glucose intolerance and frank hyperglycemia,
respectively. The specific aims of the proposed studies are: (1) to
assess the ability of insulin and glucose to generate increases in skeletal
blood flow in obese non-diabetic, Type II and Type I diabetic subjects; (2)
to determine the ability of blood flow to independently increase skeletal
muscle glucose uptake; (3) to characterize the impact of increments in
skeletal muscle blood flow on the volume of distribution of glucose and the
kinetics of insulin action; (4) to quantitate postprandial hemodynamic
changes in Type II diabetic and obese subjects, respectively. To
accomplish these goals, cardia output (dye dilution technique), leg blood
flow (thermodilution technique), whole body glucose uptake (glucose clamp +
isotopic dilution technique) and leg muscle glucose uptake (limb balance
technique) will be quantitated under various perturbations of circulating
serum insulin and glucose levels to determine the role of peripheral blood
flow to glucose uptake and its contribution to in vivo insulin resistance.
The results of these studies should result in an enhanced understanding of
in vivo insulin resistance and more rational therapeutic approaches.
StatusFinished
Effective start/end date2/1/906/30/04

Funding

  • National Institutes of Health: $277,609.00

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Insulin Resistance
Endothelin-1
Hemodynamics
Vasodilation
Insulin
Obesity
Nonesterified Fatty Acids
Intra Arterial Infusions
Endothelins
Nitric Oxide
Vasoconstrictor Agents
Vasodilator Agents
Glucose
Blood Vessels
Leg
Glucose Clamp Technique
Methacholine Chloride
Abdominal Obesity
Vascular Endothelium
Nitroprusside

ASJC

  • Medicine(all)