Elevated levels of leptin and insulin but not of TNF alpha are associated with hypertension in type 2 diabetic males

Summary:

Leptin and TNF alpha are thought to influence blood pressure. Therefore, the aim of our study was to investigate leptin and TNF alpha levels and their association with blood pressure, sex steroids, insulin, creatinine and lipids in type 2 diabetic patients. In 424 type 2 diabetic patients (79 hypertensive females [+Hf], 79 normotensive females [-Hf]; 133 hypertensive males [+Hm], 133 normotensive males [-Hm]) matched for sex, age and BMI serum leptin levels were measured by RIA and TNF alpha, insulin, estradiol, progesterone by ELISA as well as free testosterone by RIA. Leptin levels were comparable in +Hf and -Hf (16.5 ± 1.0 μg/l vs 16.3 ± 1.0 μg/l) but higher in +Hm as compared to -Hm (8.3 ± 0.47 μg/l vs 6.5 ± 0.34 μg/l; p < 0.05). In addition, in comparison to -Hm serum levels of insulin (190 ± 10 pmol/l vs 161 ± 11 pmol/l; p < 0.005) and also of creatinine (118.6 ± 3.6 μmol/l vs 101.7 ± 2.3; p < 0.0001) were higher in +Hm. Pearson's Correlation coefficient revealed a positive correlation between levels of leptin and diastolic blood pressure (p < 0.05) and also between leptin and insulin (p < 0.001) in males, however, only before correction for BMI. No correlation between leptin and creatinine was found in males and females. Levels of TNF alpha were comparable in all subgroups. No correlation between levels of TNF alpha and serum leptin levels, blood pressure and insulin was found. In females TNF alpha was positively correlated with creatinine (p < 0.001) and in males positively with progesterone (p < 0.001). Taken together, higher serum leptin levels were found in hypertensive type 2 diabetic males as compared to normotensives, which may be related to the BMI and higher levels of insulin. These findings are accompanied by a trend to lower levels of free testosterone in hypertensive type 2 diabetic males. TNF alpha levels were comparable in female and male hypertensive and normotensive type 2 diabetic subjects.

Key words:

Hypertension - leptin - TNF alpha - diabetes mellitus

References

• 1 Agata J, Masuda A, Takada M, Higashiura K, Murakami H, Miyazaki Y, Shimamoto K. High plasma immunoreactive leptin level in essential hypertension.  Am J Hypertens. 10 1171-1174 1997; 
• 2 Baumgartner R N, Waters D L, Morley J E, Patrick P, Montoya G D, Garry P J. Age-related changes in sex hormones affect the sex difference in serum leptin independently of changes in body fat.  Metabolism. 48 378-384 1999; 
• 3 Christensen N J. Acute effects of insulin on cardiovascular function and noradrenaline uptake and release.  Diabetologia. 25 377-381 1983; 
• 4 Fruehwald-Schultes B, Kern W, Beyer J, Forst T, Pfutzner A, Peters A. Elevated serum leptin concentrations in type 2 diabetic patients with microalbuminuria and macroalbuminuria.  Metabolism. 48 1290-1293 1999; 
• 5 Hall J E. Mechanisms of abnormal renal sodium handling in obesity hypertension.  Am J Hypertens. 10 S49-S55 1997; 
• 6 Hall J E, Brands M W, Henegar J R, Shek E W. Abnormal kidney function as a cause and a consequence of obesity hypertension.  Clin Exp Pharmacol Physiol. 25 58-64 1998; 
• 7 Haynes W G, Morgan D A, Walsh S A, Mark A L, Sivitz W I. Receptor-mediated regional sympathetic nerve activation by leptin.  J Clin Invest. 100 270-278 1997; 
• 8 Hiraoka J, Hosoda K, Ogawa Y, Ikeda K, Nara Y, Masuzaki H, Takaya K, Nakagawa K, Mashimo T, Sawamura M, Koletsky R J, Yamori Y, Nakao K. Augmentation of obese (ob) gene expression and leptin secretion in obese spontaneously hypertensive rats (obese SHR or Koletsky rats).  Biochem Biophys Res Commun. 231 582-585 1997; 
• 9 Hirose H, Saito I, Tsujikoa M, Mori M, Kawabe H, Saruta T. The obese gene product, leptin: possible role in obesity-related hypertension in adolescents.  J Hypertension. 16 2007-2012 1998; 
• 10 Hotamisligil G S, Shargill N S, Spiegelmann B M. Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance.  Science. 259 87-91 1993; 
• 11 Isidori A M, Caprio M, Strollo F, Moretti C, Frajese G, Isidori A, Fabri A C. Leptin and androgens in male obesity: Evidence for leptin contribution to reduced androgen levels.  J Clin Endocrinol Metab. 84 3673-3680 1999; 
• 12 Jockenhövel F, Blum W F, Vogel E, Englaro P, Müller-Wieland D, Reinwein D, Rascher W, Krone W. Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men.  J Clin Endocrinol Metab. 82 2510-2513 1997; 
• 13 Katsuki A, Sumida Y, Murashima S, Murata K, Takarada Y, Ito K, Fujii M, Tsuchihashi K, Goto H, Nakatani K, Yano Y. Serum levels of tumor necrosis factor-α are increased in obese patients with noninsulin-dependent diabetes mellitus.  J Clin Endocrinol Metab. 83 859-862 1998; 
• 14 Luukkaa V, Personen U, Huhtaniemi I, Lehtonen A, Tilvis R, Tuomilehto J, Koulu M, Huupponen R. Inverse correlation between serum testosterone and leptin in men.  J Clin Endocrinol Metab. 83 3243-3246 1998; 
• 15 Mantzoros C S, Moschos S, Avramopoulos I, Kaklamani V, Liolios A, Doulgerakis D E, Griveas I, Katsilambros N, Flier J S. Leptin concentrations in relation to body mass index and the tumor necrosis factor-α system in humans.  J Clin Endocrinol Metab. 82 3408-3413 1997; 
• 16 McGarry J D. Glucose-fatty acid interactions in health and disease.  Am J Clin Nutr. 67 500S-504S 1998; 
• 17 Modan M, Halkin H, Almog S, Lusky A, Eshkol A, Shefi M, Shitrit A, Fuchs Z. Hyperinsulinemia: A link between hypertension obesity and glucose intolerance.  J Clin Invest. 75 809-817 1985; 
• 18 Narkiewicz K, Somers V K, Mos L, Kato M, Accurso V, Palatini P. An independent relationship between plasma leptin and heart rate in untreated patients with essential hypertension.  J Hypertens. 17 245-249 1999; 
• 19 Onions K L, Hunt S C, Rutowski M P, Klanke C A, Su Y R, Reif M, Menon A B. Genetic markers at the leptin (ob) locus are not significantly linked to hypertension in African Americans.  Hypertension. 31 1230-1234 1998; 
• 20 Ozata M, Ozdemir I C, Licinio J. Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and sponateous correction of leptin-mediated defects.  J Clin Endocrinol Metab. 84 3686-3695 1999; 
• 21 Rooney D P, Edgar J DM, Sheridan B, Atkinson A B, Bell P M. The effect of low dose insulin infusion on the renin angiotensin and sympathetic nervous system in normal man.  Eur J Clin Invest. 21 430-435 1991; 
• 22 Schorr U, Blaschke K, Turan S, Distler A, Sharma A M. Relationsship between angiotensinogen, leptin and blood pressure levels in young normotensive men.  J Hypertens. 16 1475-1480 1998; 
• 23 Shek E W, Brands M W, Hall J E. Chronic leptin infusion increases arterial pressure.  Hypertension. 31 409-414 1998; 
• 24 Sheu W H, Lee W J, Chen Y T. High plasma leptin concentrations in hypertensive men but not in hypertensive women.  J Hypertens. 17 1289-1295 1999; 
• 25 Shoji T, Nishizawa Y, Emoto M, Maekawa K, Hirura Y, Tanaka S, Kawagishi T, Okuno Y, Morii H. Renal function and insulin resistance as determinants of plasma leptin levels in patients with NIDDM.  Diabetologia. 40 676-679 1997; 
• 26 SPSS Inc .SPSS for Windows 95, V. 7.5. SPSS Inc. Chicago 1997
• 27 Suter P M, Locher R, Häsler E, Vetter W. Is there a role for the ob gene product leptin in essential hypertension?.  Am J Hypertension. 11 1305-1311 1998; 
• 28 Vettor R, De Pergola G, Pagano C, Englaro P, Laudadio E, Giorgino F, Blum W F, Giorgino R, Federspil G. Gender differences in serum leptin in obese people: relationships with testosterone, body fat distribution and insulin sensitivity.  Eur J Clin Invest. 27 1016-1024 1997; 
• 29 Zumbach M S, Boehme M WJ, Wahl P, Stremmel W, Ziegler R, Nawroth P P. Tumor necrosis factor increases serum leptin.  J Clin Endocrinol Metab. 82 4080-4082 1997;