BADERC- Gordon Williams

Gordon Williams, M.D.

Non-Modulation Phenotype and Vascular Dysfunction in Diabetes Mellitus

Diabetes Mellitus is a major risk factor for cardiovascular (CV) diseases. Despite substantial progress in developing therapeutic agents to treat CV diseases, success has been limited in implementing personalize medicine programs because identifying the various mechanisms underlying these diseases in the individual diabetic subject has been difficult. Furthermore, abnormal glucose homeostasis or factors predisposing insulin resistance further confound our ability to target specific therapy to the individual patient. The CV complications of diabetes have a substantial genetic component. Thus, this supplement will accelerate research in the field of genetics and intermediate phenotyping to identify the genetics roots of CV risk in diabetes mellitus. The proposed new studies will expand the scope of the parent grant that in itself is a cutting edge program. If funded because of the resources available in the parent grant, the supplement will be able to reach its goals by the end of the two year grant period. Finally, with the completion of this study, we will be closer to testing a genetic based approach to personalized medicine to specifically prevent and/or treat CV complications in patients with diabetes mellitus.

Cardiovascular (CV) mortality is increased in subjects with diabetes mellitus (DM) compared to the general population. Glycemic control has long been the cornerstone of treatment to reduce diabetic complications. However, it has become increasingly evident that other factors also are involved with the leading candidate being the genetic background of the diabetic subject. A parallel change in thinking about CV complications in hypertension (HTN) has taken place over the past decade: control of blood pressure is important, but not sufficient to maximally reduce CV complications. Again the genetic background has come to the fore as a major contributor. Interestingly the CV complications of HTN and DM are similar.

For the past 20 years, we have studied the genetic underpinnings of hormonal factors leading to HTN and its associated CV risks. From these studies, we have identified a specific intermediate phenotype, comprising 25-30% of the hypertensive population, whom we have termed non-modulators. Non-modulators are insulin resistant, even in the absence of obesity, and have abnormalities in renal function and an increased risk of CV damage. This intermediate phenotype has been associated with specific polymorphisms in the genes of the renin-angiotensin-aldosterone (ALDO) system (RAAS). An increasing body of data supports the concept that the fundamental pathophysiology in non-modulators is dysregulation of tissue angiotensin II (ANGII) production leading to inappropriately increased tissue levels of ANGII, particularly in the presence of an average dietary sodium intake. In support of this concept, administration of an angiotensin converting enzyme (ACE) inhibitor reverses the pathophysiologic characteristics associated with the non-modulating phenotype. While this intermediate phenotype was identified first by our group, it has been confirmed in studies performed around the world. Recent data suggest that the non-modulating phenotype is secondary to both increased ANGII production (secondary to increased angiotensinogen (AGT) gene expression) and decreased metabolism (secondary to decreased adipocyte-derived leucine aminopeptidase (ALAP) levels. Intriguingly for this proposal, reduction in ALAP activity also is associated with insulin resistance.

Many theories have been postulated to explain the increased CV and renal risk in DM. These theories are useful for explaining risk in a population, but are not as useful to explain the risk in an individual subject. Similar to hypertensive subjects, diabetic subject are not at equal risk for complications. Thus, there are clearly environmental and genetic factors that predispose certain individuals to a greater risk of complications. A genetic predisposition compounded by adverse environmental factors may highlight those at greatest risk.

References:

Perlstein TS, Gerhard-Herman M, Hollenberg NK, Williams GH, Thomas A. Insulin induces renal vasodilation, increases plasma renin activity, and sensitizes the renal vasculature to angiotensin receptor blockade in healthy subjects. J Am Soc Nephrol. 2007;18:944-51
Zee RY, Germer S, Thomas A, Raji A, Rhees B, Ridker PM, Lindpaintner K, Williams GH, Nathan DM, Martin M. C-reactive protein gene variation and type 2 diabetes mellitus: A case-control study. Atherosclerosis. 2007; 931-36;
Pojoga LH, Yao TM, Sinha S, Ross RL, Lin JC, Raffetrto JD, Adler GK, Williams, GH, Khalil RA. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol. 2008; 294: H1258-65.
Mirza FS, Ong P, Collins P, Okamura K, Gerhard-Herman M, Williams GH, Seely EW. Effects of estradiol and the angiotensin II receptor blocker irbesartan on vascular function in postmenopausal women. Menopause. 2008; 15:44-50.
Guo C, Ricchiuti V, Lian BQ, Yao TM, Coutinho P, Romero JR, Li J, Williams GH, Adler GK. Mineralocorticoid receptor blockade reverses obesity-related changes in epxression of adiponectin, peroxisome proliferator-activated receptor- and proinflammatory adipokines. Circulation. 2008;117:2253-61.
Patel TV, Williams GH, Fisher ND: Angiotensinogen Genotype Predicts Abnormal Renal Hemodynamics in Young Hypertensives. J Hypertension 2008; 26: 1353-59.
Ricchituti V, Lian CG, Oestreicher EM, Tran L, Stone JR, Yao T, Seely EW, Williams GH, Adler GK. Estradiol increases angiotensin II type 1 receptor in hearts of ovariectomized rats. J Endocrinol 2009; 200: 75-84.






			Gordon Williams, M.D. Non-Modulation Phenotype and Vascular Dysfunction in Diabetes Mellitus Diabetes Mellitus is a major risk factor for cardiovascular (CV) diseases. Despite substantial progress in developing therapeutic agents to treat CV diseases, success has been limited in implementing personalize medicine programs because identifying the various mechanisms underlying these diseases in the individual diabetic subject has been difficult. Furthermore, abnormal glucose homeostasis or factors predisposing insulin resistance further confound our ability to target specific therapy to the individual patient. The CV complications of diabetes have a substantial genetic component. Thus, this supplement will accelerate research in the field of genetics and intermediate phenotyping to identify the genetics roots of CV risk in diabetes mellitus. The proposed new studies will expand the scope of the parent grant that in itself is a cutting edge program. If funded because of the resources available in the parent grant, the supplement will be able to reach its goals by the end of the two year grant period. Finally, with the completion of this study, we will be closer to testing a genetic based approach to personalized medicine to specifically prevent and/or treat CV complications in patients with diabetes mellitus. Cardiovascular (CV) mortality is increased in subjects with diabetes mellitus (DM) compared to the general population. Glycemic control has long been the cornerstone of treatment to reduce diabetic complications. However, it has become increasingly evident that other factors also are involved with the leading candidate being the genetic background of the diabetic subject. A parallel change in thinking about CV complications in hypertension (HTN) has taken place over the past decade: control of blood pressure is important, but not sufficient to maximally reduce CV complications. Again the genetic background has come to the fore as a major contributor. Interestingly the CV complications of HTN and DM are similar. For the past 20 years, we have studied the genetic underpinnings of hormonal factors leading to HTN and its associated CV risks. From these studies, we have identified a specific intermediate phenotype, comprising 25-30% of the hypertensive population, whom we have termed non-modulators. Non-modulators are insulin resistant, even in the absence of obesity, and have abnormalities in renal function and an increased risk of CV damage. This intermediate phenotype has been associated with specific polymorphisms in the genes of the renin-angiotensin-aldosterone (ALDO) system (RAAS). An increasing body of data supports the concept that the fundamental pathophysiology in non-modulators is dysregulation of tissue angiotensin II (ANGII) production leading to inappropriately increased tissue levels of ANGII, particularly in the presence of an average dietary sodium intake. In support of this concept, administration of an angiotensin converting enzyme (ACE) inhibitor reverses the pathophysiologic characteristics associated with the non-modulating phenotype. While this intermediate phenotype was identified first by our group, it has been confirmed in studies performed around the world. Recent data suggest that the non-modulating phenotype is secondary to both increased ANGII production (secondary to increased angiotensinogen (AGT) gene expression) and decreased metabolism (secondary to decreased adipocyte-derived leucine aminopeptidase (ALAP) levels. Intriguingly for this proposal, reduction in ALAP activity also is associated with insulin resistance. Many theories have been postulated to explain the increased CV and renal risk in DM. These theories are useful for explaining risk in a population, but are not as useful to explain the risk in an individual subject. Similar to hypertensive subjects, diabetic subject are not at equal risk for complications. Thus, there are clearly environmental and genetic factors that predispose certain individuals to a greater risk of complications. A genetic predisposition compounded by adverse environmental factors may highlight those at greatest risk. References: Perlstein TS, Gerhard-Herman M, Hollenberg NK, Williams GH, Thomas A. Insulin induces renal vasodilation, increases plasma renin activity, and sensitizes the renal vasculature to angiotensin receptor blockade in healthy subjects. J Am Soc Nephrol. 2007;18:944-51 Zee RY, Germer S, Thomas A, Raji A, Rhees B, Ridker PM, Lindpaintner K, Williams GH, Nathan DM, Martin M. C-reactive protein gene variation and type 2 diabetes mellitus: A case-control study. Atherosclerosis. 2007; 931-36; Pojoga LH, Yao TM, Sinha S, Ross RL, Lin JC, Raffetrto JD, Adler GK, Williams, GH, Khalil RA. Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol. 2008; 294: H1258-65. Mirza FS, Ong P, Collins P, Okamura K, Gerhard-Herman M, Williams GH, Seely EW. Effects of estradiol and the angiotensin II receptor blocker irbesartan on vascular function in postmenopausal women. Menopause. 2008; 15:44-50. Guo C, Ricchiuti V, Lian BQ, Yao TM, Coutinho P, Romero JR, Li J, Williams GH, Adler GK. Mineralocorticoid receptor blockade reverses obesity-related changes in epxression of adiponectin, peroxisome proliferator-activated receptor- and proinflammatory adipokines. Circulation. 2008;117:2253-61. Patel TV, Williams GH, Fisher ND: Angiotensinogen Genotype Predicts Abnormal Renal Hemodynamics in Young Hypertensives. J Hypertension 2008; 26: 1353-59. Ricchituti V, Lian CG, Oestreicher EM, Tran L, Stone JR, Yao T, Seely EW, Williams GH, Adler GK. Estradiol increases angiotensin II type 1 receptor in hearts of ovariectomized rats. J Endocrinol 2009; 200: 75-84.