Exp Clin Endocrinol Diabetes 2000; Vol. 108(3): 208-213
DOI: 10.1055/s-2000-7888
Articles

© Johann Ambrosius Barth

Determinants of within-subject variation of fasting serum leptin concentrations in healthy subjects [*]

A. Widjaja 1 , J. C. Levy 2 , R. J. Morris 2 , K. N. Frayn 3 , S. M. Humphreys 3 , R. Horn 1 , A. von zur Mühlen 1 , R. C. Turner 2 , G. Brabant 1
  • 1 Department of Clinical Endocrinology, Hannover Medical School, Germany
  • 2 Diabetes Research Laboratories, Oxford University, UK
  • 3 Lipid Metabolism Group, Oxford University, UK
Further Information

Publication History

Publication Date:
31 December 2000 (online)

 

Summary:

The hormone leptin is considered to contribute to body weight regulation through modulation of feeding behavior and energy expenditure. The aim of the present study was 1) to assess the day-to-day within-subject variation (biovariability) of serum leptin concentrations in healthy subjects and 2) to investigate whether this variation is associated with food intake, exercise, anthropometric measurements or various metabolic covariates (insulin, C-peptide and glucagon, glucose, lactate, 3-hydroxy-butyrate (3-OHB), triglycerides, non-esterified-fatty acids and glycerol). Serum leptin levels were taken daily on 12 consecutive days after an overnight fast in 12 healthy subjects with a mean (SD) age of 22.7 (1.5) yr. and a BMI of 22.8 (1.6) kg/m2. Food intake, exercise, anthropometric measurements and various metabolic covariates were also determined during this period.

The overall mean of serum leptin concentration was 33.3 pmol/L with a within-subject SD range of 27-41 pmol/L and a between-subject SD range of 18-61 pmol/L. The within-subject variance of serum leptin as a proportion of total variance was 9.5%. Within-subject variation of serum leptin concentrations is small in relation to between-subject variation in healthy, normal weight subjects. This has implications for the power of interventional or prospective studies. In men, 6.7% of the variation in serum leptin concentration was associated with body weight measured on the same day (p = 0.037). In women, however, 66% of the variation was negatively associated with 3-OHB measured on both the same and the previous day (p = 0.0003 and 0.002), and positively associated with triglyceride concentration measured on the previous day (p = 0.0017) and insulin measured on the same day (p = 0.0002). Within-subject associations in women could be due to phasic changes in unmeasured variables, possibly related to the menstrual cycle or might suggest that energy balance may exert a delayed influence on serum leptin levels, with plasma 3-OHB and triglycerides acting as markers for the state of the fat stores that regulate leptin secretion. The differences between the genders remain unexplained, however.

1 * It is with great sorrow that we must report the sudden and unexpected death of Prof. Turner.

References

  • 1 Blum W F, Englaro P, Hanitsch S, Juul A, Hertel N T, Muller J, Skakkebaeck N E, Heiman M L, Birkett M, Attanasio A M, Kiess W, Rascher W. Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone.  J Clin Endocrinol Metab. 82 2904-2910 1997; 
  • 2 Caro J F, Sinha M K, Kolaczynski J W, Zhang P L, Considine R V. Perspectives in Diabetes. Leptin: the tale of an obesity gene.  Diabetes. 45 1455-1462 1997; 
  • 3 Considine R V, Sinha M K, Heiman M L, Kriauciunas A, Stephens T W, Nyce M R, Ohannesian J P, Marco C C, McKee L J, Bauer T R, Caro J F. Serum immunoreactive-leptin concentrations in normal-weight and obese humans.  N Engl J Med. 334 294-295 1996; 
  • 4 Fraser C G, Harris E K. Generation and application of data on biological variation in clinical chemistry.  Crit Rev Clin Lab Sci. 27 409-437 1989; 
  • 5 Forestfield Software .Dietplan 5. Horsham: Forestfield Software 1992
  • 6 Fulcher G R, Farrer M, Walker M, Rodham D, Clayton B, Alberti K M. A comparison of measurements of lean body mass derived by bioelectrical impedance, skinfold thickness and total body potassium. A study in obese and non-obese normal subjects.  Scand J Clin Lab Invest. 51 245-253 1991; 
  • 7 Geldszus R, Mayr B, Horn R, Geisthovl F, von zur Mühlen A, Brabant G. Serum leptin and weight reduction in female obesity.  Eur J Endocrinol. 135 659-662 1996; 
  • 8 Grinspoon S K, Askari H, Landt M L, Nathan D M, Schoenfeld D A, Hayden D L, Laposata M, Hubbard J, Klibanski A. Effects of fasting and glucose infusion on basal and overnight leptin concentrations in normal-weight women.  Am J Clin Nutr. 66 1352-1356 1997; 
  • 9 Havel P J, Kasim-Karacas S, Mueller W, Johnson P R, Gingerich R L, Stern J S. Relationship of plasma leptin to plasma insulin in normal weight and overweight women: effects of dietary fat content and sustained weight loss.  J Clin Endocrinol Metab. 81 4406-4413 1996; 
  • 10 Hickey M S, Houmard J A, Considine R V, Tyndall G L, Midgette J B, Gavigan K E, Weidner M L, McCammon M R, Israel R G, Caro J F. Gender-dependent effects of exercise training on serum leptin levels in humans.  Am J Physiol. 272 E562-E566 1997; 
  • 11 Holland B, Welch A A, Unwin I D, Buss D H, Paul A A, Southgate D AT. McCance and Widdowson's `The Composition of Foods', 5th edn. Royal Society of Chemistry, London 1991
  • 12 Horn R, Geldszus R, Pötter E, von zur Mühlen A, Barbant G. Radioimmunoassay for the detection of leptin in human serum.  Exp Clin Endocrinol Diabetes. 104 454-458 1996; 
  • 13 Humphreys S M, Frayn K N. Micro-method for preparing perchloric extracts of blood.  Clin Chem. 34 1657 1988; 
  • 14 Jenkins A B, Markovic T P, Fleury A, Campbell L V. Carbohydrate intake and short-term regulation of leptin in humans.  Diabetologia. 40 348-351 1996; 
  • 15 Kolaczynski J W, Nyce M R, Considine R V, Boden G, Nolan J J, Henry R, Mudaliar S R, Olefsky J, Caro J F. Acute and chronic effects of insulin on leptin production in humans.  Diabetes. 45 699-701 1996 a; 
  • 16 Kolaczynski J W, Ohannesian J P, Considine R V, Marco C C, Caro J F. Response to leptin to short-term and prolonged overfeeding in humans.  J Clin Endocrinol Metab. 81 4162-4165 1996 b; 
  • 17 Larsson H, Ahren B. Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women.  J Clin Endocrinol Metab. 81 4428-4432 1996; 
  • 18 Larsson H, Elmstahl S, Berglund G, Ahren B. Evidence for Leptin regulation of food intake in humans.  J Clin Endocrinol Metab. 83 4382-4285 1999; 
  • 19 Licinio J, Mantzoros C, Negrao A B, Cizza G, Wong M L, Bongiorno P B, Chrousos G P, Karp B, Allen C, Flier J S, Gold P W. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function.  Nat Med. 3 575-579 1997; 
  • 20 Licinio J, Negrao A B, Mantzoros C, Kaklamani V, Wong M L, Bongiorno P B, Mulla A, Cearnal L, Veldhuis J D, Flier J S, McCann S M, Gold P W. Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women.  Proc Natl Acad Sci USA. 95 2541-2546 1998 a; 
  • 21 Licinio J, Negrao A B, Mantzoros C, Kaklamani V, Wong M L, Bongiorno P B, Negro P P, Mulla A, Veldhuis J D, Cearnal L, Flier J S, Gold P W. Sex differences in circulating human leptin pulse amplitude: clinical implications.  J Clin Endocrinol Metab. 83 4140-4147 1998 b; 
  • 22 Liu J, Askari H, Dagogo-Jack S. Reproducibility of fasting plasma leptin concentration in lean and obese humans.  Endocr Res. 25 1-10 1999; 
  • 23 Malmström R, Taskinen M R, Karonen S L, Yki-Järvinen H. Insulin increases plasma leptinconcentrations in normal patients and patients with NIDDM.  Diabetologia. 39 993-996 1996; 
  • 24 Miell J P, Englaro P, Blum W F. Dexamethasone induces an acute and sustained rise in circulating leptin levels in normal human patients.  Horm Metab Res. 28 704-707 1996; 
  • 25 Ministry of Agriculture Fisheries and Food .Food portion sizes, 2nd edn. HMSO, London 1988
  • 26 Montague C T, Farooqi I S, Whitehead J P, Soos M A, Rau H, Wareham N J, Sewter C P, Digby J E, Mohammed S N, Hurst J A, Cheetham C H, Earley A R, Barnett A H, Prins J B, O'Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans.  Nature. 387 903-908 1997; 
  • 27 Ostlund R E, Yang J W, Klein S, Gingerich R. Relation between plasma leptin concentration and body fat, gender, diet, age and metabolic covariates.  J Clin Endocrinol Metab. 81 3909-3913 1996; 
  • 28 Ryan A S, Elahi D. The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels: its relationships with body fat, visceral adiposity, and age in women.  J Clin Endocrinol Metab. 81 4433-4438 1996; 
  • 29 Saad M F, Sidhdharth D, Gingerich R L, Riad-Gabriel M G, Khan A, Boyadjian R, Jinagouda S D, El-Tawil K, Rude R K, Kamdar V. Sexual dimorphism in plasma leptin concentration.  J Clin Endocrinol Metab. 82 579-584 1997; 
  • 30 Salbe A D, Nicolson M, Ravussin E. Total energy expenditure and the level of physical activity correlate with plasma leptin concentrations in five-year-old children.  J Clin Invest. 99 592-595 1997; 
  • 31 Sinha M K, Ohannesian J P, Heiman M L, Kriauciunas A, Stephens T W, Magosin S, Marco C, Caro J F. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects.  J Clin Invest. 97 1344-1347 1996 a; 
  • 32 Sinha M K, Sturis J, Ohannesian J, Magosin S, Stephens T W, Heiman M L, Polonsky K S, Caro J F. Ultradian oscillations of leptin secretion in humans.  Biochem Biophys Res Commun. 228 733-738 1996 b; 
  • 33 Schrauwen P, van Marken Lichtenbelt W D, Westerterp K R, Saris W H. Effects of diet composition on leptin concentration in lean subjects.  Metabolism. 46 420-424 1997; 
  • 34 Sir Petermann T, Piwonka V, Perez F, Maliqueo M, Recabarren S E, Wildt L. Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?.  Hum Reprod. 14 1435-1439 1999; 
  • 35 Stout R W, Henry R W, Buchanan K D. Triglyceride metabolism in acute starvation: the role of secretin and glucagon.  Eur J Clin Invest. 6 179-185 1976; 
  • 36 Weigle D S, Barton Duell P, Connor W E, Steiner R A, Soules M R, Kuijper J L. Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels.  J Clin Endocrinol Metab. 82 561-565 1997; 
  • 37 Widjaja A, Levy J C, Morris R J, Frayn K N, Tuner R C. Within and between-subject's variance in commonly measured anthropometric and biochemical variables.  Clin Chem. 45 561-566 1999; 
  • 38 Widjaja A, Stratton I M, Horn R, Holman R R, Turner R C, Brabant G. UKPDS 20: Plasma leptin, obesity, and plasma insulin in type 2 diabetic subjects.  J Clin Endocrinol Metab. 82 654-657 1997; 

1 * It is with great sorrow that we must report the sudden and unexpected death of Prof. Turner.

Dr. A. Widjaja

Department of Clinical Endocrinology

Hannover Medical School

Carl-Neubergstr. 1

D-30625 Hannover

Fax: 49-5 11-5 32 38 25

Email: Widjaja.Adji@mh-hannover.de

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