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J Clin Invest. 1997 September 1; 100(5): 1107–1113.
PMCID: PMC508285

Effects of prolonged hyperinsulinemia on serum leptin in normal human subjects.


We have studied the effect of prolonged hyperinsulinemia and hyperglycemia on serum leptin levels in young nonobese males during 72-h euglycemic-hyperinsulinemic and hyperglycemic ( approximately 8.5 and 12.6 mM) clamps. Hyperinsulinemia increased serum leptin concentrations (by RIA) dose-dependently. An increase in serum insulin concentration of > 200 pM for > 24 h was needed to significantly increase serum leptin. An increase of approximately 800 pM increased serum leptin by approximately 70% over 72 h. Changes in plasma glucose concentrations (from approximately 5.0 to approximately 12.6 mM) or changes in plasma FFA concentrations (from < 100 to > 1,000 microM) had no effect on serum leptin. Serum leptin concentrations changed with circadian rhythmicity. The cycle length was approximately 24 h, and the cycle amplitude (peak to trough) was approximately 50%. The circadian leptin cycles and the circadian cycles of total body insulin sensitivity (i.e., GIR, the glucose infusion rates needed to maintain euglycemia during hyperinsulinemic clamping) changed in a mirror image fashion. Moreover, GIR decreased between Days 2 and 3 (from 11.4+/-0.2 to 9. 8+/-0.2 mg/kg min, P< 0.05) when mean 24-h leptin levels reached a peak. In summary, we found (a) that 72 h of hyperinsulinemia increased serum leptin levels dose-dependently; (b) that hyperglycemia or high plasma FFA levels did not affect leptin release; (c) that leptin was released with circadian rhythmicity, and (d) that 24-h leptin cycles correlated inversely with 24-h cycles of insulin sensitivity. We speculate that the close positive correlation between body fat and leptin is mediated, at least in part, by insulin.

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Selected References

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  • Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994 Dec 1;372(6505):425–432. [PubMed]
  • Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995 Jul 28;269(5223):540–543. [PubMed]
  • Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995 Jul 28;269(5223):543–546. [PubMed]
  • Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995 Jul 28;269(5223):546–549. [PubMed]
  • Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995 Nov;1(11):1155–1161. [PubMed]
  • Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996 Feb 1;334(5):292–295. [PubMed]
  • Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab. 1996 Sep;81(9):3419–3423. [PubMed]
  • Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF. Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes. 1996 Nov;45(11):1511–1515. [PubMed]
  • Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF. Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes. 1996 May;45(5):699–701. [PubMed]
  • Segal KR, Landt M, Klein S. Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes. 1996 Jul;45(7):988–991. [PubMed]
  • Dagogo-Jack S, Fanelli C, Paramore D, Brothers J, Landt M. Plasma leptin and insulin relationships in obese and nonobese humans. Diabetes. 1996 May;45(5):695–698. [PubMed]
  • Ryan AS, 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. 1996 Dec;81(12):4433–4438. [PubMed]
  • Pratley RE, Nicolson M, Bogardus C, Ravussin E. Effects of acute hyperinsulinemia on plasma leptin concentrations in insulin-sensitive and insulin-resistant Pima Indians. J Clin Endocrinol Metab. 1996 Dec;81(12):4418–4421. [PubMed]
  • Caprio S, Tamborlane WV, Silver D, Robinson C, Leibel R, McCarthy S, Grozman A, Belous A, Maggs D, Sherwin RS. Hyperleptinemia: an early sign of juvenile obesity. Relations to body fat depots and insulin concentrations. Am J Physiol. 1996 Sep;271(3 Pt 1):E626–E630. [PubMed]
  • Utriainen T, Malmström R, Mäkimattila S, Yki-Järvinen H. Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. Diabetes. 1996 Oct;45(10):1364–1366. [PubMed]
  • Lukaski HC, Bolonchuk WW, Hall CB, Siders WA. Validation of tetrapolar bioelectrical impedance method to assess human body composition. J Appl Physiol (1985) 1986 Apr;60(4):1327–1332. [PubMed]
  • Boden G, Ruiz J, Urbain JL, Chen X. Evidence for a circadian rhythm of insulin secretion. Am J Physiol. 1996 Aug;271(2 Pt 1):E246–E252. [PubMed]
  • Klein S, Coppack SW, Mohamed-Ali V, Landt M. Adipose tissue leptin production and plasma leptin kinetics in humans. Diabetes. 1996 Jul;45(7):984–987. [PubMed]
  • Boden G, Chen X, Rosner J, Barton M. Effects of a 48-h fat infusion on insulin secretion and glucose utilization. Diabetes. 1995 Oct;44(10):1239–1242. [PubMed]
  • Saladin R, De Vos P, Guerre-Millo M, Leturque A, Girard J, Staels B, Auwerx J. Transient increase in obese gene expression after food intake or insulin administration. Nature. 1995 Oct 12;377(6549):527–529. [PubMed]
  • Leroy P, Dessolin S, Villageois P, Moon BC, Friedman JM, Ailhaud G, Dani C. Expression of ob gene in adipose cells. Regulation by insulin. J Biol Chem. 1996 Feb 2;271(5):2365–2368. [PubMed]
  • Cusin I, Sainsbury A, Doyle P, Rohner-Jeanrenaud F, Jeanrenaud B. The ob gene and insulin. A relationship leading to clues to the understanding of obesity. Diabetes. 1995 Dec;44(12):1467–1470. [PubMed]
  • MacDougald OA, Hwang CS, Fan H, Lane MD. Regulated expression of the obese gene product (leptin) in white adipose tissue and 3T3-L1 adipocytes. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9034–9037. [PubMed]
  • Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H. Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes. 1996 Oct;45(10):1435–1438. [PubMed]
  • Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, Marco C, Caro JF. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects. J Clin Invest. 1996 Mar 1;97(5):1344–1347. [PMC free article] [PubMed]
  • Laughlin GA, Yen SS. Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. J Clin Endocrinol Metab. 1997 Jan;82(1):318–321. [PubMed]
  • Havel PJ, Kasim-Karakas S, Mueller W, Johnson PR, Gingerich RL, Stern JS. Relationship of plasma leptin to plasma insulin and adiposity in normal weight and overweight women: effects of dietary fat content and sustained weight loss. J Clin Endocrinol Metab. 1996 Dec;81(12):4406–4413. [PubMed]

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