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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Cardiovascular and Renal Study Section (CVB)
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University of Mississippi Medical Center
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Manhiani, M Marlina; Duggan, A Daniel; Wilson, Hunter et al. (2012) Chronic intrarenal insulin replacement reverses diabetes mellitus-induced natriuresis and diuresis. Hypertension 59:421-30
Brands, Michael W; Manhiani, M Marlina (2012) Sodium-retaining effect of insulin in diabetes. Am J Physiol Regul Integr Comp Physiol 303:R1101-9
Manhiani, M Marlina; Cormican, Michael T; Brands, Michael W (2011) Chronic sodium-retaining action of insulin in diabetic dogs. Am J Physiol Renal Physiol 300:F957-65
Banes-Berceli, Amy K L; Al-Azawi, Hind; Proctor, Daniel et al. (2011) Angiotensin II utilizes Janus kinase 2 in hypertension, but not in the physiological control of blood pressure, during low-salt intake. Am J Physiol Regul Integr Comp Physiol 301:R1169-76
Brands, Michael W; Banes-Berceli, Amy K L; Inscho, Edward W et al. (2010) Interleukin 6 knockout prevents angiotensin II hypertension: role of renal vasoconstriction and janus kinase 2/signal transducer and activator of transcription 3 activation. Hypertension 56:879-84
Brands, Michael W; Bell, Tracy D; Rodriquez, Nancy A et al. (2009) Chronic glucose infusion causes sustained increases in tubular sodium reabsorption and renal blood flow in dogs. Am J Physiol Regul Integr Comp Physiol 296:R265-71
Sturgis, LaShon C; Cannon, Joseph G; Schreihofer, Derek A et al. (2009) The role of aldosterone in mediating the dependence of angiotensin hypertension on IL-6. Am J Physiol Regul Integr Comp Physiol 297:R1742-8
Brands, Michael W; Labazi, Hicham (2008) Role of glomerular filtration rate in controlling blood pressure early in diabetes. Hypertension 52:188-94
Brands, M W; Hall, J E; Keen, H L (1998) Is insulin resistance linked to hypertension? Clin Exp Pharmacol Physiol 25:70-6