Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Dec 1;100(11):2729–2736. doi: 10.1172/JCI119818

Leptin rapidly suppresses insulin release from insulinoma cells, rat and human islets and, in vivo, in mice.

R N Kulkarni 1, Z L Wang 1, R M Wang 1, J D Hurley 1, D M Smith 1, M A Ghatei 1, D J Withers 1, J V Gardiner 1, C J Bailey 1, S R Bloom 1
PMCID: PMC508476  PMID: 9389736

Abstract

Obesity is associated with diabetes, and leptin is known to be elevated in obesity. To investigate whether leptin has a direct effect on insulin secretion, isolated rat and human islets and cultured insulinoma cells were studied. In all cases, mouse leptin inhibited insulin secretion at concentrations within the plasma range reported in humans. Insulin mRNA expression was also suppressed in the cultured cells and rat islets. The long form of the leptin receptor (OB-Rb) mRNA was present in the islets and insulinoma cell lines. To determine the significance of these findings in vivo, normal fed mice were injected with two doses of leptin. A significant decrease in plasma insulin and associated rise in glucose concentration were observed. Fasted normal and leptin receptor-deficient db/db mice showed no response to leptin. A dose of leptin, which mimicked that found in normal mice, was administered to leptin-deficient, hyperinsulinemic ob/ob mice. This caused a marked lowering of plasma insulin concentration and a doubling of plasma glucose. Thus, leptin has a powerful acute inhibitory effect on insulin secretion. These results suggest that the action of leptin may be one mechanism by which excess adipose tissue could acutely impair carbohydrate metabolism.

Full Text

The Full Text of this article is available as a PDF (216.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahima R. S., Prabakaran D., Mantzoros C., Qu D., Lowell B., Maratos-Flier E., Flier J. S. Role of leptin in the neuroendocrine response to fasting. Nature. 1996 Jul 18;382(6588):250–252. doi: 10.1038/382250a0. [DOI] [PubMed] [Google Scholar]
  2. Albano J. D., Ekins R. P., Maritz G., Turner R. C. A sensitive, precise radioimmunoassay of serum insulin relying on charcoal separation of bound and free hormone moieties. Acta Endocrinol (Copenh) 1972 Jul;70(3):487–509. doi: 10.1530/acta.0.0700487. [DOI] [PubMed] [Google Scholar]
  3. Beak S. A., Small C. J., Ilovaiskaia I., Hurley J. D., Ghatei M. A., Bloom S. R., Smith D. M. Glucagon-like peptide-1 (GLP-1) releases thyrotropin (TSH): characterization of binding sites for GLP-1 on alpha-TSH cells. Endocrinology. 1996 Oct;137(10):4130–4138. doi: 10.1210/endo.137.10.8828468. [DOI] [PubMed] [Google Scholar]
  4. Bennet W. M., Wang Z. L., Jones P. M., Wang R. M., James R. F., London N. J., Ghatei M. A., Bloom S. R. Presence of neuropeptide Y and its messenger ribonucleic acid in human islets: evidence for a possible paracrine role. J Clin Endocrinol Metab. 1996 Jun;81(6):2117–2120. doi: 10.1210/jcem.81.6.8964837. [DOI] [PubMed] [Google Scholar]
  5. Bennett B. D., Solar G. P., Yuan J. Q., Mathias J., Thomas G. R., Matthews W. A role for leptin and its cognate receptor in hematopoiesis. Curr Biol. 1996 Sep 1;6(9):1170–1180. doi: 10.1016/s0960-9822(02)70684-2. [DOI] [PubMed] [Google Scholar]
  6. Campfield L. A., Smith F. J., 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. doi: 10.1126/science.7624778. [DOI] [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Cohen B., Novick D., Rubinstein M. Modulation of insulin activities by leptin. Science. 1996 Nov 15;274(5290):1185–1188. doi: 10.1126/science.274.5290.1185. [DOI] [PubMed] [Google Scholar]
  9. Coleman D. L. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia. 1978 Mar;14(3):141–148. doi: 10.1007/BF00429772. [DOI] [PubMed] [Google Scholar]
  10. 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. L. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996 Feb 1;334(5):292–295. doi: 10.1056/NEJM199602013340503. [DOI] [PubMed] [Google Scholar]
  11. Cooney G. J., Vanner M. A., Nicks J. L., Williams P. F., Caterson I. D. Changes in the lipogenic response to feeding of liver, white adipose tissue and brown adipose tissue during the development of obesity in the gold-thioglucose-injected mouse. Biochem J. 1989 May 1;259(3):651–657. doi: 10.1042/bj2590651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Emilsson V., Liu Y. L., Cawthorne M. A., Morton N. M., Davenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes. 1997 Feb;46(2):313–316. doi: 10.2337/diab.46.2.313. [DOI] [PubMed] [Google Scholar]
  13. Frederich R. C., Hamann A., Anderson S., Löllmann B., Lowell B. B., Flier J. S. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med. 1995 Dec;1(12):1311–1314. doi: 10.1038/nm1295-1311. [DOI] [PubMed] [Google Scholar]
  14. Gainsford T., Willson T. A., Metcalf D., Handman E., McFarlane C., Ng A., Nicola N. A., Alexander W. S., Hilton D. J. Leptin can induce proliferation, differentiation, and functional activation of hemopoietic cells. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14564–14568. doi: 10.1073/pnas.93.25.14564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ghilardi N., Ziegler S., Wiestner A., Stoffel R., Heim M. H., Skoda R. C. Defective STAT signaling by the leptin receptor in diabetic mice. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6231–6235. doi: 10.1073/pnas.93.13.6231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Halaas J. L., Gajiwala K. S., Maffei M., Cohen S. L., Chait B. T., Rabinowitz D., Lallone R. L., Burley S. K., Friedman J. M. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995 Jul 28;269(5223):543–546. doi: 10.1126/science.7624777. [DOI] [PubMed] [Google Scholar]
  17. Hardie L. J., Rayner D. V., Holmes S., Trayhurn P. Circulating leptin levels are modulated by fasting, cold exposure and insulin administration in lean but not Zucker (fa/fa) rats as measured by ELISA. Biochem Biophys Res Commun. 1996 Jun 25;223(3):660–665. doi: 10.1006/bbrc.1996.0951. [DOI] [PubMed] [Google Scholar]
  18. Iida M., Murakami T., Ishida K., Mizuno A., Kuwajima M., Shima K. Phenotype-linked amino acid alteration in leptin receptor cDNA from Zucker fatty (fa/fa) rat. Biochem Biophys Res Commun. 1996 May 6;222(1):19–26. doi: 10.1006/bbrc.1996.0691. [DOI] [PubMed] [Google Scholar]
  19. Kieffer T. J., Heller R. S., Habener J. F. Leptin receptors expressed on pancreatic beta-cells. Biochem Biophys Res Commun. 1996 Jul 16;224(2):522–527. doi: 10.1006/bbrc.1996.1059. [DOI] [PubMed] [Google Scholar]
  20. Kieffer T. J., Heller R. S., Leech C. A., Holz G. G., Habener J. F. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. Diabetes. 1997 Jun;46(6):1087–1093. doi: 10.2337/diab.46.6.1087. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Knaack D., Fiore D. M., Surana M., Leiser M., Laurance M., Fusco-DeMane D., Hegre O. D., Fleischer N., Efrat S. Clonal insulinoma cell line that stably maintains correct glucose responsiveness. Diabetes. 1994 Dec;43(12):1413–1417. doi: 10.2337/diab.43.12.1413. [DOI] [PubMed] [Google Scholar]
  22. Kulkarni R. N., Wang Z. L., Akinsanya K. O., Bennet W. M., Wang R. M., Smith D. M., Ghatei M. A., Byfield P. G., Bloom S. R. Pyroglutamyl-phenylalanyl-proline amide attenuates thyrotropin-releasing hormone-stimulated insulin secretion in perifused rat islets and insulin-secreting clonal beta-cell lines. Endocrinology. 1995 Nov;136(11):5155–5164. doi: 10.1210/endo.136.11.7588254. [DOI] [PubMed] [Google Scholar]
  23. Lacy P. E., Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967 Jan;16(1):35–39. doi: 10.2337/diab.16.1.35. [DOI] [PubMed] [Google Scholar]
  24. Leclercq-Meyer V., Considine R. V., Sener A., Malaisse W. J. Do leptin receptors play a functional role in the endocrine pancreas? Biochem Biophys Res Commun. 1996 Dec 24;229(3):794–798. doi: 10.1006/bbrc.1996.1882. [DOI] [PubMed] [Google Scholar]
  25. Levin N., Nelson C., Gurney A., Vandlen R., de Sauvage F. Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1726–1730. doi: 10.1073/pnas.93.4.1726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Maffei M., Halaas J., Ravussin E., Pratley R. E., Lee G. H., Zhang Y., Fei H., Kim S., Lallone R., Ranganathan S. 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. doi: 10.1038/nm1195-1155. [DOI] [PubMed] [Google Scholar]
  27. Malmström R., Taskinen M. R., Karonen S. L., Yki-Järvinen H. Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM. Diabetologia. 1996 Aug;39(8):993–996. doi: 10.1007/BF00403921. [DOI] [PubMed] [Google Scholar]
  28. Morgan N. G., Montague W. Studies on the mechanism of inhibition of glucose-stimulated insulin secretion by noradrenaline in rat islets of Langerhans. Biochem J. 1985 Mar 1;226(2):571–576. doi: 10.1042/bj2260571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Nånberg E., Rozengurt E. Temporal relationship between inositol polyphosphate formation and increases in cytosolic Ca2+ in quiescent 3T3 cells stimulated by platelet-derived growth factor, bombesin and vasopressin. EMBO J. 1988 Sep;7(9):2741–2747. doi: 10.1002/j.1460-2075.1988.tb03128.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pelleymounter M. A., Cullen M. J., Baker M. B., 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. doi: 10.1126/science.7624776. [DOI] [PubMed] [Google Scholar]
  31. Rentsch J., Levens N., Chiesi M. Recombinant ob-gene product reduces food intake in fasted mice. Biochem Biophys Res Commun. 1995 Sep 5;214(1):131–136. doi: 10.1006/bbrc.1995.2266. [DOI] [PubMed] [Google Scholar]
  32. 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. doi: 10.1038/377527a0. [DOI] [PubMed] [Google Scholar]
  33. Schwartz M. W., Baskin D. G., Bukowski T. R., Kuijper J. L., Foster D., Lasser G., Prunkard D. E., Porte D., Jr, Woods S. C., Seeley R. J. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes. 1996 Apr;45(4):531–535. doi: 10.2337/diab.45.4.531. [DOI] [PubMed] [Google Scholar]
  34. Schwartz M. W., Peskind E., Raskind M., Boyko E. J., Porte D., Jr Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat Med. 1996 May;2(5):589–593. doi: 10.1038/nm0596-589. [DOI] [PubMed] [Google Scholar]
  35. Segal K. R., Landt M., Klein S. Relationship between insulin sensitivity and plasma leptin concentration in lean and obese men. Diabetes. 1996 Jul;45(7):988–991. doi: 10.2337/diab.45.7.988. [DOI] [PubMed] [Google Scholar]
  36. Shimabukuro M., Koyama K., Chen G., Wang M. Y., Trieu F., Lee Y., Newgard C. B., Unger R. H. Direct antidiabetic effect of leptin through triglyceride depletion of tissues. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4637–4641. doi: 10.1073/pnas.94.9.4637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. 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. 1996 Mar 1;97(5):1344–1347. doi: 10.1172/JCI118551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sinha M. K., Opentanova I., Ohannesian J. P., Kolaczynski J. W., Heiman M. L., Hale J., Becker G. W., Bowsher R. R., Stephens T. W., Caro J. F. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J Clin Invest. 1996 Sep 15;98(6):1277–1282. doi: 10.1172/JCI118913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Smith D. M., Bloom S. R., Sugden M. C., Holness M. J. Glucose transporter expression and glucose utilization in skeletal muscle and brown adipose tissue during starvation and re-feeding. Biochem J. 1992 Feb 15;282(Pt 1):231–235. doi: 10.1042/bj2820231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Stephens T. W., Basinski M., Bristow P. K., Bue-Valleskey J. M., Burgett S. G., Craft L., Hale J., Hoffmann J., Hsiung H. M., Kriauciunas A. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 1995 Oct 12;377(6549):530–532. doi: 10.1038/377530a0. [DOI] [PubMed] [Google Scholar]
  41. Tartaglia L. A., Dembski M., Weng X., Deng N., Culpepper J., Devos R., Richards G. J., Campfield L. A., Clark F. T., Deeds J. Identification and expression cloning of a leptin receptor, OB-R. Cell. 1995 Dec 29;83(7):1263–1271. doi: 10.1016/0092-8674(95)90151-5. [DOI] [PubMed] [Google Scholar]
  42. Truett G. E., Bahary N., Friedman J. M., Leibel R. L. Rat obesity gene fatty (fa) maps to chromosome 5: evidence for homology with the mouse gene diabetes (db). Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7806–7809. doi: 10.1073/pnas.88.17.7806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Tsien R. Y., Pozzan T., Rink T. J. T-cell mitogens cause early changes in cytoplasmic free Ca2+ and membrane potential in lymphocytes. Nature. 1982 Jan 7;295(5844):68–71. doi: 10.1038/295068a0. [DOI] [PubMed] [Google Scholar]
  44. Wang Z. L., Bennet W. M., Ghatei M. A., Byfield P. G., Smith D. M., Bloom S. R. Influence of islet amyloid polypeptide and the 8-37 fragment of islet amyloid polypeptide on insulin release from perifused rat islets. Diabetes. 1993 Feb;42(2):330–335. doi: 10.2337/diab.42.2.330. [DOI] [PubMed] [Google Scholar]
  45. Wang Z., Wang R. M., Owji A. A., Smith D. M., Ghatei M. A., Bloom S. R. Glucagon-like peptide-1 is a physiological incretin in rat. J Clin Invest. 1995 Jan;95(1):417–421. doi: 10.1172/JCI117671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Yu W. H., Kimura M., Walczewska A., Karanth S., McCann S. M. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci U S A. 1997 Feb 4;94(3):1023–1028. doi: 10.1073/pnas.94.3.1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J. M. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994 Dec 1;372(6505):425–432. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES