MICROVASCULAR CHARACTERISTIC OF DIABETES MELLITUS

Project: Research project

Description

The proposed studies will evaluate the impaired endothelial cell
dependent dilation and enhanced vasoconstrictor responses which occur in
the diabetic microvasculature. The arteriolar response to
acetylcholine, mediated by endothelial derived relaxing factor(EDRF), is
greatly suppressed. This could be due to inadequate production or
inactivation of EDRF as well as competition by constrictor stimuli. The
suppression of EDRF dilation occurs in about one week in streptozotocin
diabetic rats and is duplicated in normal arterioles by one hour of
local exposure to isotonic hyperglycemia (300-500 mg%). Pretreatment
with superoxide dismutase protects EDRF function during exposure to 500
mg% glucose, and post-treatment substantially restores EDRF function.
These results suggest that oxygen or hydroxyl radicals produced in
response to hyperglycemia may be the mechanism(s) responsible for EDRF
suppression. Specific scavengers of oxygen or hydoxyl radicals will be
used to determine which radical species is primarily responsible for
impaired EDRF function in acute and chronic hyperglycemia. A potential
source of radicals is increased ecosanoid synthesis during
hyperglycemia; cycloxygenase, inhibition partially restores EDRF
function in diabetic rats. If cycloxygenase inhibition substantially
decreases radical formation during hyperglycemia, eicosanoid synthesis
will be implicated as the primary source of radicals. The extent to
which loss of EDRF function, hyperglycemia, and decreased insulin action
contribute to the enhanced vasoconstrictor responses in diabetic rats is
not known. The potential contributions of each factor to the
constrictor responses to norepinephrine, angiotensin II, and myogenic
pressor stimuli, all of which act directly on vascular smooth muscle
cells, will be determined. EDRF function of normal arterioles will be
suppressed with an arginine analog(NMMA) or local isotonic hyperglycemia
so that the modulation of constrictor regulation by EDRF and additional
complications caused by hyperglycemia can be determined. Comparison of
EDRF and constrictor functions in Zucker diabetic rats maintained in a
hyperglycemic insulin-resistant or normoglycemic insulin-resistant state
will be used to determine whether hyperglycemia or insulin-resistance
primarily influences altered vascular regulation. In vitro studies
indicate that hyperglycemia increases sorbitol formation by 2 to 3-fold
in endothelial cells. Conversion of excess glucose to sorbitol by
aldose reductase may be an attempt to protect the intracellular
environment from hyperglycemia. Whether aldose reductase expression is
increased in microvascular cells during diabetic hyperglycemia is not
known. Vascular cells may initially increase expression of aldose
reductase to compensate for the excess glucose, but eventually, cell
damage may attenuate expression, leading to unchecked cytoplasmic
hyperglycemia. Expression of aldose reductase mRNA in intestinal
microvessels of early and advanced insulin-resistant and dependent
diabetic rats will be measured using in situ hybridization. These
results will be used to determine the time-dependent expression of
aldose reductase, temporal correlation to disturbances in microvascular
regulation, and whether the cause of hyperglycemia influences aldose
reductase expression.
StatusFinished
Effective start/end date8/1/804/30/04

Funding

  • National Institutes of Health: $120,796.00
  • National Institutes of Health
  • National Institutes of Health: $138,245.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $134,258.00
  • National Institutes of Health
  • National Institutes of Health: $121,648.00
  • National Institutes of Health: $146,580.00
  • National Institutes of Health
  • National Institutes of Health: $150,298.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $142,352.00
  • National Institutes of Health: $128,354.00
  • National Institutes of Health

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Diabetes Mellitus
Hyperglycemia
Nitric Oxide
Arterioles
Insulin Resistance
Protein Kinase C beta
Vasoconstrictor Agents
Insulin
Oxidants
Dilatation
Blood Vessels
Arteries
Aldehyde Reductase
Endothelial Cells
Zucker Rats
Vascular Smooth Muscle
Vasodilator Agents
Smooth Muscle Myocytes
Glucose
Eicosanoids

ASJC

  • Medicine(all)