CARDIOVASCULAR AND RENAL DYSFUNCTION IN EARLY DIABETES

Project: Research project

Project Details

Description

DESCRIPTION: There is a clear association between hypertension and
increased morbidity and mortality in IDDM. The studies in this revised
proposal will test the central hypothesis that poor glycemic control in
early-onset diabetes shifts the pressure natriuresis relationship and
increases arterial pressure by increasing activity of the renin angiotensin
system. The studies will be conducted in a unique model of IDDM, in
chronically instrumented and monitored rats, that will enable immediate
assessment of the relationship between glycemic control and cardiovascular
and renal function before renal damage has occurred. In this model, 24-hour
per day i.v. insulin infusion is begun immediately following the removal of
endogenous insulin by streptozotocin (STZ) administration and is adjusted on
an individual rat basis to maintain any desired level of diabetes or
glycemic control. The response to induction of IDDM then can be studied
independently of potential indirect effects of STZ. The central hypothesis
of this proposal will be tested by: I. Testing the hypothesis that poor
glycemic control in early-onset diabetes increases mean arterial pressure.
II. Testing the hypothesis that poor glycemic control in IDDM raises blood
pressure through an angiotensin II-mediated shift in pressure natriuresis
by: A. quantifying the changes in renal sodium handling, fluid balance, and
cardiac output, that are associated with the rise in blood pressure induced
by onset of poor glycemic control in IDDM. B. determining if pressure
natriuresis is shifted in IDDM and what is the role of pressure natriuresis
in mediating the associated changes in cardiovascular and renal function.
C. quantifying the importance of hyperglycemia per se, independent of the
loss of circulating insulin, in mediating the changes in renal function and
systemic hemodynamics. D. testing the hypothesis that increased angiotensin
II mediates the rise in blood pressure. III. Testing the hypothesis that
oscillations in the degree of glycemic control will lead to earlier onset
and/or a more rapid increase in severity of albuminuria through angiotensin
II-mediated variation in blood pressure, by: A. determining whether
repeated episodes of hyperglycemia, during a period in which the overall
average glycemic control is moderate, will cause proportionate variation in
arterial pressure and earlier onset of albuminuria than if that level of
moderate glycemic control was maintained steadily. B. testing the
hypothesis that chronically clamping plasma angiotensin II at control levels
will attenuate the effect of episodic hyperglycemia to accelerate the
development of albuminuria. C. determining whether increased variability in
daily arterial pressure, without an increase in the 24-hour-averaged
arterial pressure, will accelerate the development of albuminuria in
diabetes with steadily-maintained, poor metabolic control.
StatusNot started