The hereditability of insulin resistance has been demonstrated in both familial and twin studies. The effects of renin-angiotensin-aldosterone system gene polymorphisms on insulin resistance remain inconclusive.
Methods:
This is a sibling-based association study. Polymorphisms of renin-angiotensin-aldosterone system genes were examined in 1113 hypertension and 676 normotension siblings from Chinese and Japanese hypertensive families. The generalized estimation equations method was used to compare the differences in metabolic variables between hypertension and normotensive siblings.
Results:
For the G-6A polymorphism of AGT, GG siblings had lower 2-h insulin than siblings carrying the A allele (p=0.006). Siblings with different variants of the angiotensin II type 1 receptor A1166C had no difference in metabolic variables. Siblings carrying the D allele of the angiotensin converting enzyme gene had higher levels of fasting glucose, fasting insulin, area under the curve of insulin levels and the homeostasis model assessment of insulin resistance than II siblings (all p<0.05). Lower levels of fasting glucose and 2-h glucose were observed in siblings with the T allele than their CC homozygotes for the C-344T polymorphism of CYP11B2 (p<0.05). Siblings carrying three high-risk genotypes of the angiotensin converting enzyme, angiotensinogen and CYP11B2 had higher fasting glucose level than siblings carrying no high-risk genotypes (p=0.011).
Conclusion:
Our comprehensive analysis of renin-angiotensin-aldosterone system gene polymorphisms demonstrates that the angiotensin converting enzyme and CYP11B2 gene polymorphisms are associated with insulin resistance in hypertensive families.
MartinBCWarramJHRosnerB. Familial clustering of insulin sensitivity. Diabetes1992; 41: 850–854.
2.
CarmelliDCardonLRFabsitzR. Clustering of hypertension, diabetes, and obesity in adult male twins: same genes or same environments?Am J Hum Genet1994; 55: 566–573.
3.
MollerDEBjøbrœkCVidal-PuigA. Candidate genes for insulin resistance. Diabetes Care1995; 19: 396–400.
4.
MontagnaniMQuonMJ. Insulin action in vascular endothelium: potential mechanisms linking insulin resistance with hypertension. Diabetes Obes Metab2000; 2: 285–292.
5.
WuKDHsioCFHoLT. Clustering and heritability of insulin resistance in Chinese and Japanese hypertensive families: a SAPPHIRe sib study. Hypertens Res2002; 25: 529–536.
6.
TaylorSIMollerDE. Mutations of the insulin receptor gene. In: MollerDE (ed.) Insulin resistance. Chichester, New York: Wiley, 1993, pp.83–111.
7.
ElbeinSCChiuKCHoffmanMD. Linkage analysis of 19 candidate regions for insulin resistance in familial NIDDM. Diabetes1995; 44: 1259–1265.
8.
TownsendRRDiPetteD. Pressor doses of angiotensin II increase insulin-mediated glucose uptake in normotensive men. Am J Physiol1993; 265: E362–E366.
9.
De WittLMPutneyJW. Stimulation of glycogenolysis in hepatocytes by angiotensin II may involve both calcium release and calcium influx. FEBS Lett1983; 160: 259–263.
10.
KneerNMLardyHA. Regulation of gluconeogenesis by norepinephrine, vasopressin and angiotensin II: a comparative study in the absence and presence of extracellular calcium. Arch Biochem Biophys1983; 225: 187–195.
11.
FolliFKahnCRHansenH. Angiotensin II inhibits insulin signaling in aortic smooth muscle cells at multiple levels: A potential role for serine phosphorylation in insulin/angiotensin II crosstalk. J Clin Invest1997; 100: 2158–2169.
12.
HenriksenEJJacobSKinnickTR. Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension2001; 38: 884–890.
13.
FujimotoMMasuzakiHTanakaT. An angiotensin II AT1 receptor antagonist, telmisartan augments glucose uptake and GLUT4 protein expression in 3T3-L1 adipocytes. FEBS Lett2004; 576: 492–497.
14.
ChuKYLauTCarlssonPO. Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes. Diabetes2006; 55: 367–374.
15.
TorloneEBrittaMRambottiAM. Improved insulin action and glycemic control after long-term angiotensin-converting enzyme inhibition in subjects with arterial hypertension and type II diabetes. Diabetes Care1993; 16: 1347–1355.
16.
LindholmLHIbsenHBorch-JohnsenK. Risk of new-onset diabetes in the losartan intervention for endpoint reduction in hypertension study. J Hypertens2002; 20: 1879–1886.
17.
JuliusSKjeldsenSEWeberM. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004; 363: 2022–2031.
18.
PanahlooAAndresCMohamed-AliV. The insertion allele of the ACE gene I/D polymorphism. A candidate gene for insulin resistance. Circulation1995; 92: 3390–3393.
19.
HuangXHRantalaihoVWirtaO. Relationship of the angiotensin-converting enzyme gene polymorphism to glucose intolerance, insulin resistance, and hypertension in NIDDM. Hum Genet1998; 102: 372–378.
20.
CongNDHamaguchiKSaikawaT. The I/D polymorphism of angiotensin-converting enzyme gene but not the angiotensinogen gene is associated with insulin response to oral glucose in Japanese. P Soc Exp Biol Med1999; 220: 46–51.
21.
YamamotoJKageyamaSSakuraiT. Insulin resistance and angiotensin converting enzyme polymorphism in Japanese hypertensive subjects. Hypertens Res1999; 22: 81–84.
22.
PerticoneFCeravoloRIacopinoS. Relationship between angiotensin-converting enzyme gene polymorphism and insulin resistance in never-treated hypertensive patients. J Clin Endocrinol Metab2001; 86: 172–178.
23.
BonnetFPatelSLavilleM. Influence of the ACE gene insertion/deletion polymorphism on insulin sensitivity and impaired glucose tolerance in healthy subjects. Diabetes Care2008; 31: 789–794.
24.
SheuWHLeeWJJengCY. Angiotensinogen gene polymorphism is associated with insulin resistance in nondiabetic men with or without coronary heart disease. Am Heart J1998; 136: 125–131.
25.
ThomasGNTomlinsonBChanJCN. Renin-angiotensin system gene polymorphisms, blood pressure, dyslipidemia, and diabetes in Hong Kong Chinese: A significant association of the ACE insertion/deletion polymorphism with type 2 diabetes. Diabetes Care2001; 24: 356–361.
26.
AlbertiKGMMZimmetPShawJ. Metabolic syndrome─a new world-wide definition. A consensus statement from the International Diabetes Federation. Diabet Med2006; 23: 469–480.
27.
ChiuYFChuangLMHsiaoCF. An autosomal genome-wide scan for loci linked to pre-diabetic phenotypes in nondiabetic Chinese subjects from the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Family Study. Diabetes2005; 54: 1200–1206.
LinMWHwuCMHuangYH. Directly measured insulin resistance and the assessment of clustered cardiovascular risks in hypertension. Am J Hypertens2006; 19: 1118–1124.
30.
MattewsDRHoskerJPRudenskiAS. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia1985; 28: 412–419.
31.
ZegerSLLiangKY. Longitudinal data analysis for discrete and continuous outcomes. Biometrics1986; 42: 121–130.
32.
KatoNSugiyamaTMoritaH. Comprehensive analysis of the renin-angiotensin gene polymorphisms with relation to hypertension in the Japanese. J Hypertens2000; 18: 1025–1032.
33.
HaffnerSM. Epidemiology of hypertension and insulin resistance syndrome. J Hypertens1997; 15(suppl 1): S25–S30.
34.
NagiDKFoyCAMohamed-AliV. Angiotensin-1-converting enzyme (ACE) gene polymorphism, plasma ACE levels, and their association with the metabolic syndrome and electrocardiographic coronary artery disease in Pima Indians. Metabolism1998; 47: 622–626.
35.
CooperRMcFarlane-AndersonNBennettFI. ACE, angiotensinogen, and obesity: a potential pathway leading to hypertension. J Hum Hypertens1997; 11: 107–111.
36.
EngeliSBöhnkeJGorzelniakK. Weight loss and the renin-angiotensin-aldosterone system. Hypertension2005; 45: 356–362.
37.
AkasakaHKatsuyaTSaitohS. Effects of angiotensin II type 1 receptor gene polymorphisms on insulin resistance in a Japanese general population: the Tanno-Sobetsu study. Hypertens Res2006; 29: 961–967.
38.
RigatBHubertCAlhenc-GelasF. An insertion/deletion polymorphism in the angiotensin I converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest1990; 86: 1343–1346.
39.
HimitoHKiyomotoHNishiyamaA., Aldosterone suppressed insulin signalling via the downregulation of insulin receptor substrate-1 in vascular smooth muscle cells. Hypertension2005; 50: 750–755.
40.
LastraGHabibiJAdamT. Direct renin inhibition improves systemic insulin resistance and skeletal muscle glucose transport in a transgenic rodent model of tissue renin overexpression. Endocrinology2009; 150: 2561–2568.
41.
HenriskenEJJacobSKinnickTR. Selective angiotensin II receptor antagonism reduces insulin resistance in obese Zucker rats. Hypertension2001; 38: 884–890.
42.
ShephredRRWithersDJSiddleK. Phosphoinositide 3-kinase: The key switch mechanism in insulin signalling. Biochem J1998; 333: 471–490.
43.
GouldABGreenB. Kinetics of the human renin and human rennin substrate reaction. Cardiovasc Res1971; 5: 86–89.
44.
BloemLJManatungAKTewksburyDA. The serum angiotensinogen concentration and variants of the angiotensinogen gene in white and black children. J Clin Invest1995; 95: 948–953.
45.
TakakuraYYoshidaTYoshiokaK. Angiotensinogen gene polymorphism (Met235Thr) influences visceral obesity and insulin resistance in obese Japanese women. Metabolism2006; 55: 819–824.
46.
MelanderOGroopLHulthenUL. Effect of salt on insulin sensitivity differs according to gender and degree of salt sensitivity. Hypertension2000; 35: 827–831.
47.
CampionJMaestroBMataF. Inhibition by aldosterone of insulin receptor mRNA levels and insulin binding in U-937 human promonocytic cells. J Steroid Biochem Mol Biol1999; 7: 211–218.
48.
PojogaLGautierSBlancH. Genetic determination of plasma aldosterone levels in essential hypertension. Am J Hypertens1998; 11: 856–860.
49.
DaviesEHollowayCDIngramMC. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension1999; 33: 703–707.
50.
SianiARussoPCappuccioFP. Combination of renin-angiotensin system polymorphisms is associated with altered renal sodium handling and hypertension. Hypertension2004; 43: 598–602.
51.
ModanMHalkinHAlmogS. Hyperinsulinemia: A link between hypertension, obesity, and glucose intolerance. J Clin Inves1985; 75: 809–817.
