1. 1 Metabolic syndrome and renal sodium handling in three ethnic groups living in England A Barbato § †, FP Cappuccio §, EJ Folkerd §, P Strazzullo †, B Sampson #, KGMM Alberti ‡ Published in: Diabetologia 2004; 47: 40-46

2. 2 Background  ↑ proximal renal sodium re-absorption associated with ‘metabolic syndrome’ in white men (JAMA 1993;270:354-9 & J Hypertens 1996;14:909-14)

3. 3 Background  ↑ proximal renal sodium re-absorption associated with ‘metabolic syndrome’ in white men (JAMA 1993;270:354-9 & J Hypertens 1996;14:909-14)  ↑ proximal renal sodium re-absorption associated with abdominal adiposity in white men (J Hypertens 2001;19:2157- 64)

4. 4 Na + Li + Na + Uric acid Segmental renal sodium handling studied by the clearance of ‘exogenous’ or ‘endogenous’ lithium

5. 5 Lithium Clearance: non-invasive assessment of renal tubular sodium handling in vivo in man Exogenous  Oral load  Li + carbonate 150-900mg  Li + 4-24 mmol  Serum & urine Li + in mM  Detectable with A.A.S. Disadvantages  natriuretic effect  not suitable for serial tests  difficult in epidemiology  compliance  ethics Endogenous  No load needed  Serum & urine Li + in  M  Detectable with A.A.S. with electrothermal atomisation and tantalum-coated graphite  Detection limit 0.05  M Advantages  avoidance of Li + effect  suitable for serial tests  applicable to epidemiology Disadvantages  special equipment & skill  high cost Clin Sci 1988;74:651-7 JAMA 1993;270:354-9 Am J Physiol 1995;268:F718-22 Diabetologia 2004;47:40-6

6. 6 Questions  Does the association exist?  Is it consistent in men and women?  Is it present in different ethnic groups with different degrees of metabolic syndrome?

7. 7 Study design  Population-based cross-sectional survey  Men and women aged 40-59 yrs  Whites, South Asians, African origin  Random selection from GPs age-sex registers after stratification by sex and ethnic group  Fieldwork between March 1994 and July 1996  Sample size: 1,577  1,257 (80%) timed urine collections  1,190 complete data set available

8. 8 Measurements  Questionnaire (migration, religion, language, smoking,medical history, therapy)  Physical (height, weight, waist & hip circumferences)  Blood Pressure (by Arteriosonde)  Fasting blood (biochemistry, lipids, glucose, insulin, HOMA index)  Timed Urine after overnight fast (Na, K, Cr, endogenous Li) Endogenous Li clearance  Between CV%: serum 10.8% (n=100); urine 6.2% (n=185)  Within CV%: serum 6.2% (n=23); urine 4.6% (n=27)

9. 9 Results 1. Characteristics by ethnic group White African originSouth Asian n=426n=397 n=367 B.M.I. (kg/m 2 )25.927.9 25.9 W:H ratio0.8610.876 0.895 Systolic BP (mmHg) 125.2133.5 128.7 Diastolic BP (mmHg)79.586.2 82.7 Cholesterol (mM)6.215.61 5.71 Triglycerides § (mM)1.210.82 1.38 HDL-cholesterol § (mM)1.341.45 1.15 Fasting glucose § (mM)5.135.43 5.64 Fasting insulin § (mU/l)6.848.18 10.70 HOMA index § 1.541.89 2.58 BP Rx (%)9.631.2 14.3 MS ATP III (%)16.416.1 26.7 F.E. sodium (%)0.810.79 0.99 F.E. lithium (%)18.415.6 18.2 All p<0.001 § log-transformed valuesAdjusted for age and sex

10. 10 Results 2. F.E.Li vs Metabolic variables P<0.001 adjusted for age and sex ^ log-transformed values White African origin S Asian

11. 11 Results 3. Multiple Regression analyses  White (n=426) African origin (n=397) South Asian (n=367) Lg HOMA per % FELi -1.25 P=0.024 -0.670.13 Waist per % FELi -0.10 P=0.002 -0.020.01 Lg Triglycerides per % FELi -1.91 P=0.009 -0.64-0.67 Lg HDL-Chol per % FELi 2.70 P=0.04 -0.19-1.09 Adjusted for age and sex

12. 12 Results 3. Multiple Regression analyses  White (n=426) African origin (n=397) South Asian (n=367) R 2 white Lg HOMA per % FELi -1.25 P=0.024 -0.670.130.040 Waist per % FELi -0.10 P=0.002 -0.020.010.049 Lg Triglycerides per % FELi -1.91 P=0.009 -0.64-0.670.043 Lg HDL-Chol per % FELi 2.70 P=0.04 -0.19-1.090.037 Adjusted for age and sex

13. 13 Results 4. F.E.Li and Metabolic Syndrome by ATP III criteria* WITH WITHOUT 15.9% 19.0% 15.0% 15.7% 17.9% 18.2% * >3 of: waist>102cm (M) >88 (W); Tg >1.7mM; HDL-c 6.11mM; BP>130/85mmHg P=0.003 Mean (95%CI)

14. 14 Summary  An independent association exists between ↑ proximal sodium re-absorption and metabolic indices of vascular risk in white men and women

15. 15 Summary  An independent association exists between ↑ proximal sodium re-absorption and metabolic indices of vascular risk in white men and women  Insulin levels also relate to renal Na + handling

16. 16 Summary  An independent association exists between ↑ proximal sodium re-absorption and metabolic indices of vascular risk in white men and women  Insulin levels also relate to renal Na + handling  The association is not present in men and women of African or South Asian origin, despite raised insulin levels and more prevalent metabolic syndrome

17. 17 Summary & Conclusions  An independent association exists between ↑ proximal sodium re-absorption and metabolic indices of vascular risk in white men and women  Insulin levels also relate to renal Na + handling  The association is not present in men and women of African or South Asian origin, despite raised insulin levels and more prevalent metabolic syndrome  Potential mechanisms (ethnic-specific) to be elucidated Long-term proximal effect of insulin  ↑ Na + -H + ? - ↓ hepatic cAMP - ↑ SNS activity Possible effects of ↑ glucose Possible changes in membrane fluidity and ion transport Role of genetic polymorphisms

18. 18 Summary & Conclusions  An independent association exists between ↑ proximal sodium re-absorption and metabolic indices of vascular risk in white men and women  Insulin levels also relate to renal Na + handling  The association is not present in men and women of African or South Asian origin, despite raised insulin levels and more prevalent metabolic syndrome  Potential mechanisms (ethnic-specific) to be elucidated Long-term proximal effect of insulin  ↑ Na + -H + ? - ↓ hepatic cAMP - ↑ SNS activity Possible effects of ↑ glucose Possible changes in membrane fluidity and ion transport Role of genetic polymorphisms  In whites insulin resistance may not involve the kidney!