Gordon Williams, M.D.
Genetic Underpinnings of Hormonal Mechanisms Contributing to Cardiovascular Risk in Diabetes Mellitus         
 
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 several specific intermediate phenotypes, comprising 50-60% of the hypertensive population. Two examples of these results specifically relevant to diabetes are detailed below.
  1. The initial intermediate phenotype described is termed non-modulators. Non-modulators are insulin resistant, even in the absence of obesity, and have abnormalities in renal function, salt sensitive hypertension 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. Finally, in a recently published study, we have documented that the prevalence of the non-modulation phenotype in patients with diabetes mellitus is twice that in an hypertensive population.

  2. The phenotype associated with polymorphic variants in another gene, caveolin-1, are also relevant to diabetes mellitus.  Those who have inherited the risk allele have a 3 fold greater risk of having the metabolic syndrome (insulin resistance, diabetes mellitus, hypertriglyceridemia, increased LDL and salt sensitive hypertension).  The risk is greater in the non-obese subject.  Intriguingly our animal models where we have specifically modified the caveolin-1 gene, also has all of the phenotypic characteristics of the metabolic syndrome except the mice or lean. 
 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.  The studies in our program are to generate data from a translational research framework to link markers and mechanisms to develop specific preventative and therapeutic treatment programs for modifying CV risk in diabetes mellitus.  

References:


1. Kosachunhanun N, Hunt SC, Hopkins PN, Williams RR, Jeunemaitre X, Corvol P, Ferri C, Mortensen RM, Hollenberg NK, Williams GH.  Genetic determinants of nonmodulating hypertension. Hypertension 2003;42(5):901-908. 

2. Guo C, Martinez-Vasquez D, Mendez GP, Toniolo MF, Yao TM, Oestreicher EM, Kikuchi T, Lapointe N, Pojoga L, Williams GH, Ricchiuti V, Adler GK.. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology 2006;147(11):5363-5373. 

3. 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. PMCID:PMC2268616 

4. 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 expression of adiponectin, peroxisome proliferator-activated receptor- and proinflammatory adipokines.  Circulation. 2008;117:2253-61. PMCID:PMC2746647 

5. Pojoga LH, Adamova Z, Kumar A, Stennett AK, Romero JR, Adler GK, Williams GH, Khalil RA. Sensitivity of NOS-dependent vascular relaxation pathway to mineralocorticoid receptor blockade in caveolin-1-deficient mice. Am J Physiol Heart Circ Physiol. 2010;298:H1776-1788. PMCID:PMC2886646
 

6. Pojoga LH, Underwood PC, Goodarzi MO, Williams JS, Adler GK, Jeunemaitre X, Hopkins PN, Raby BA, Lasky-Su J, Sun B, Cui J, Guo X, Taylor KD, Chen YD, Xiang A, Raffel LJ, Buchanan TA, Rotter JI, Williams GH. Variants of the caveolin-1 gene: a translational investigation linking insulin resistance and hypertension. J Clin Endocrinol Metab. 2011; 96:E1288-92. PMCID:PMC3146791 

7. Underwood PC, Chamarthi B, Williams JS, Vaidya A, Garg R, Adler GK, Grotzke MP, Staskus G, Wadwekar D, Hopkins PN, Ferri C, McCall A, McClain D, Williams GH. Nonmodulation as the Mechanism for Salt Sensitivity of Blood Pressure in Individuals with Hypertension and Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2012; 97:3775-3782. PMCID PMC3462947

 

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