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. 1993 Jul;92(1):262–271. doi: 10.1172/JCI116560

Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non-insulin-dependent diabetes mellitus.

N M O'Meara 1, J Sturis 1, E Van Cauter 1, K S Polonsky 1
PMCID: PMC293585  PMID: 8325993

Abstract

Normal subjects demonstrate the presence of ultradian oscillations (period 80-150 min) in insulin secretion rate (ISR) tightly coupled to glucose oscillations of similar period. These oscillations appear to be a function of the feedback loop linking glucose and insulin. The present study was undertaken to determine whether the control by glucose of the ultradian oscillations in insulin secretion is altered in impaired glucose tolerance IGT and in non-insulin-dependent diabetes mellitus (NIDDM). Patients with NIDDM (n = 7), IGT (n = 4), and matched nondiabetic controls (n = 5) were studied under three separate protocols that involved administration of glucose at either a constant rate of 6 mg/kg per min for 28 h or in one of two oscillatory patterns at the same overall mean rate. The amplitude of the oscillations was 33% above and below the mean infusion rate, and their respective periods were 144 min (slow oscillatory infusion) or 96 min (rapid oscillatory infusion). Insulin, C-peptide, and glucose were sampled at 10-min intervals during the last 24 h of each study. ISRs were calculated by deconvolution of C-peptide levels. Analysis of the data showed that (a) the tight temporal coupling between glucose and ISR in the nondiabetic controls was impaired in the IGT and NIDDM groups as demonstrated by pulse analysis, cross-correlation analysis, and spectral analysis; (b) the absolute amplitude of the ISR pulses progressively declined with the transition from obesity to IGT to NIDDM; and (c) the absolute amplitude of the ISR oscillations failed to increase appropriately with increasing absolute amplitude of glucose oscillations in the IGT and NIDDM subjects compared with the control group. In conclusion, the present study demonstrates that important dynamic properties of the feedback loop linking insulin secretion and glucose are disrupted not only in established NIDDM but also in conditions where glucose tolerance is only minimally impaired. Further studies are needed to determine how early in the course of beta-cell dysfunction this lack of control by glucose of the ultradian oscillations in insulin secretion occurs and to define more precisely if this phenomenon plays a pathogenetic role in the onset of hyperglycemia in genetically susceptible individuals.

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Selected References

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  1. Barnett A. H., Spiliopoulos A. J., Pyke D. A., Stubbs W. A., Burrin J., Alberti K. G. Metabolic studies in unaffected co-twins of non-insulin-dependent diabetics. Br Med J (Clin Res Ed) 1981 May 23;282(6277):1656–1658. doi: 10.1136/bmj.282.6277.1656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bogardus C., Lillioja S., Howard B. V., Reaven G., Mott D. Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects. J Clin Invest. 1984 Oct;74(4):1238–1246. doi: 10.1172/JCI111533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chou H. F., Ipp E. Pulsatile insulin secretion in isolated rat islets. Diabetes. 1990 Jan;39(1):112–117. doi: 10.2337/diacare.39.1.112. [DOI] [PubMed] [Google Scholar]
  4. Duckworth W. C., Kitabchi A. E. Direct measurement of plasma proinsulin in normal and diabetic subjects. Am J Med. 1972 Oct;53(4):418–427. doi: 10.1016/0002-9343(72)90137-4. [DOI] [PubMed] [Google Scholar]
  5. Efendić S., Luft R., Wajngot A. Aspects of the pathogenesis of type 2 diabetes. Endocr Rev. 1984 Summer;5(3):395–410. doi: 10.1210/edrv-5-3-395. [DOI] [PubMed] [Google Scholar]
  6. Faber O. K., Binder C., Markussen J., Heding L. G., Naithani V. K., Kuzuya H., Blix P., Horwitz D. L., Rubenstein A. H. Characterization of seven C-peptide antisera. Diabetes. 1978;27 (Suppl 1):170–177. doi: 10.2337/diab.27.1.s170. [DOI] [PubMed] [Google Scholar]
  7. Ferner R. E., Ashworth L., Tronier B., Alberti K. G. Effects of short-term hyperglycemia on insulin secretion in normal humans. Am J Physiol. 1986 Jun;250(6 Pt 1):E655–E661. doi: 10.1152/ajpendo.1986.250.6.E655. [DOI] [PubMed] [Google Scholar]
  8. Firth R., Bell P., Rizza R. Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. Metabolism. 1987 Nov;36(11):1091–1095. doi: 10.1016/0026-0495(87)90031-x. [DOI] [PubMed] [Google Scholar]
  9. Garvey W. T., Olefsky J. M., Griffin J., Hamman R. F., Kolterman O. G. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985 Mar;34(3):222–234. doi: 10.2337/diab.34.3.222. [DOI] [PubMed] [Google Scholar]
  10. Glauber H., Wallace P., Brechtel G. Effects of fasting on plasma glucose and prolonged tracer measurement of hepatic glucose output in NIDDM. Diabetes. 1987 Oct;36(10):1187–1194. doi: 10.2337/diab.36.10.1187. [DOI] [PubMed] [Google Scholar]
  11. Hansen B. C., Jen K. C., Belbez Pek S., Wolfe R. A. Rapid oscillations in plasma insulin, glucagon, and glucose in obese and normal weight humans. J Clin Endocrinol Metab. 1982 Apr;54(4):785–792. doi: 10.1210/jcem-54-4-785. [DOI] [PubMed] [Google Scholar]
  12. Horwitz D. L., Starr J. I., Mako M. E., Blackard W. G., Rubenstein A. H. Proinsulin, insulin, and C-peptide concentrations in human portal and peripheral blood. J Clin Invest. 1975 Jun;55(6):1278–1283. doi: 10.1172/JCI108047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kadowaki T., Miyake Y., Hagura R., Akanuma Y., Kajinuma H., Kuzuya N., Takaku F., Kosaka K. Risk factors for worsening to diabetes in subjects with impaired glucose tolerance. Diabetologia. 1984 Jan;26(1):44–49. doi: 10.1007/BF00252262. [DOI] [PubMed] [Google Scholar]
  14. Kolterman O. G., Gray R. S., Griffin J., Burstein P., Insel J., Scarlett J. A., Olefsky J. M. Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus. J Clin Invest. 1981 Oct;68(4):957–969. doi: 10.1172/JCI110350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kosaka K., Hagura R., Kuzuya T. Insulin responses in equivocal and definite diabetes, with special reference to subjects who had mild glucose intolerance but later developed definite diabetes. Diabetes. 1977 Oct;26(10):944–952. doi: 10.2337/diab.26.10.944. [DOI] [PubMed] [Google Scholar]
  16. Lang D. A., Matthews D. R., Burnett M., Turner R. C. Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes. 1981 May;30(5):435–439. doi: 10.2337/diab.30.5.435. [DOI] [PubMed] [Google Scholar]
  17. Lang D. A., Matthews D. R., Burnett M., Ward G. M., Turner R. C. Pulsatile, synchronous basal insulin and glucagon secretion in man. Diabetes. 1982 Jan;31(1):22–26. doi: 10.2337/diab.31.1.22. [DOI] [PubMed] [Google Scholar]
  18. Lang D. A., Matthews D. R., Peto J., Turner R. C. Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N Engl J Med. 1979 Nov 8;301(19):1023–1027. doi: 10.1056/NEJM197911083011903. [DOI] [PubMed] [Google Scholar]
  19. Mako M. E., Starr J. I., Rubenstein A. H. Circulating proinsulin in patients with maturity onset diabetes. Am J Med. 1977 Dec;63(6):865–869. doi: 10.1016/0002-9343(77)90538-1. [DOI] [PubMed] [Google Scholar]
  20. Matthews D. R., Hosker J. P., Rudenski A. S., Naylor B. A., Treacher D. F., Turner R. C. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412–419. doi: 10.1007/BF00280883. [DOI] [PubMed] [Google Scholar]
  21. Matthews D. R., Lang D. A., Burnett M. A., Turner R. C. Control of pulsatile insulin secretion in man. Diabetologia. 1983 Apr;24(4):231–237. doi: 10.1007/BF00282705. [DOI] [PubMed] [Google Scholar]
  22. Mitrakou A., Kelley D., Mokan M., Veneman T., Pangburn T., Reilly J., Gerich J. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med. 1992 Jan 2;326(1):22–29. doi: 10.1056/NEJM199201023260104. [DOI] [PubMed] [Google Scholar]
  23. Nesher R., Della Casa L., Litvin Y., Sinai J., Del Rio G., Pevsner B., Wax Y., Cerasi E. Insulin deficiency and insulin resistance in type 2 (non-insulin-dependent) diabetes: quantitative contributions of pancreatic and peripheral responses to glucose homeostasis. Eur J Clin Invest. 1987 Jun;17(3):266–274. doi: 10.1111/j.1365-2362.1987.tb01247.x. [DOI] [PubMed] [Google Scholar]
  24. O'Rahilly S., Turner R. C., Matthews D. R. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med. 1988 May 12;318(19):1225–1230. doi: 10.1056/NEJM198805123181902. [DOI] [PubMed] [Google Scholar]
  25. Pfeifer M. A., Halter J. B., Porte D., Jr Insulin secretion in diabetes mellitus. Am J Med. 1981 Mar;70(3):579–588. doi: 10.1016/0002-9343(81)90579-9. [DOI] [PubMed] [Google Scholar]
  26. Polonsky K. S., Given B. D., Hirsch L. J., Tillil H., Shapiro E. T., Beebe C., Frank B. H., Galloway J. A., Van Cauter E. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988 May 12;318(19):1231–1239. doi: 10.1056/NEJM198805123181903. [DOI] [PubMed] [Google Scholar]
  27. Polonsky K. S., Given B. D., Hirsch L., Shapiro E. T., Tillil H., Beebe C., Galloway J. A., Frank B. H., Karrison T., Van Cauter E. Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest. 1988 Feb;81(2):435–441. doi: 10.1172/JCI113338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Polonsky K. S., Given B. D., Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest. 1988 Feb;81(2):442–448. doi: 10.1172/JCI113339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Polonsky K. S., Licinio-Paixao J., Given B. D., Pugh W., Rue P., Galloway J., Karrison T., Frank B. Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients. J Clin Invest. 1986 Jan;77(1):98–105. doi: 10.1172/JCI112308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Powrie J. K., Smith G. D., Hennessy T. R., Shojaee-Moradie F., Kelly J. M., Sönksen P. H., Jones R. H. Incomplete suppression of hepatic glucose production in non-insulin dependent diabetes mellitus measured with [6,6-2H2]glucose enriched glucose infusion during hyperinsulinaemic euglycaemic clamps. Eur J Clin Invest. 1992 Apr;22(4):244–253. doi: 10.1111/j.1365-2362.1992.tb01458.x. [DOI] [PubMed] [Google Scholar]
  31. Saad M. F., Kahn S. E., Nelson R. G., Pettitt D. J., Knowler W. C., Schwartz M. W., Kowalyk S., Bennett P. H., Porte D., Jr Disproportionately elevated proinsulin in Pima Indians with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1990 May;70(5):1247–1253. doi: 10.1210/jcem-70-5-1247. [DOI] [PubMed] [Google Scholar]
  32. Shapiro E. T., Tillil H., Polonsky K. S., Fang V. S., Rubenstein A. H., Van Cauter E. Oscillations in insulin secretion during constant glucose infusion in normal man: relationship to changes in plasma glucose. J Clin Endocrinol Metab. 1988 Aug;67(2):307–314. doi: 10.1210/jcem-67-2-307. [DOI] [PubMed] [Google Scholar]
  33. Simon C., Brandenberger G., Follenius M., Schlienger J. L. Alteration in the temporal organisation of insulin secretion in type 2 (non-insulin-dependent) diabetic patients under continuous enteral nutrition. Diabetologia. 1991 Jun;34(6):435–440. doi: 10.1007/BF00403183. [DOI] [PubMed] [Google Scholar]
  34. Simon C., Brandenberger G., Follenius M. Ultradian oscillations of plasma glucose, insulin, and C-peptide in man during continuous enteral nutrition. J Clin Endocrinol Metab. 1987 Apr;64(4):669–674. doi: 10.1210/jcem-64-4-669. [DOI] [PubMed] [Google Scholar]
  35. Simon C., Follenius M., Brandenberger G. Postprandial oscillations of plasma glucose, insulin and C-peptide in man. Diabetologia. 1987 Oct;30(10):769–773. doi: 10.1007/BF00275742. [DOI] [PubMed] [Google Scholar]
  36. Stagner J. I., Samols E., Weir G. C. Sustained oscillations of insulin, glucagon, and somatostatin from the isolated canine pancreas during exposure to a constant glucose concentration. J Clin Invest. 1980 Apr;65(4):939–942. doi: 10.1172/JCI109750. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Steiner D. F. On the role of the proinsulin C-peptide. Diabetes. 1978;27 (Suppl 1):145–148. doi: 10.2337/diab.27.1.s145. [DOI] [PubMed] [Google Scholar]
  38. Sturis J., Polonsky K. S., Mosekilde E., Van Cauter E. Computer model for mechanisms underlying ultradian oscillations of insulin and glucose. Am J Physiol. 1991 May;260(5 Pt 1):E801–E809. doi: 10.1152/ajpendo.1991.260.5.E801. [DOI] [PubMed] [Google Scholar]
  39. Sturis J., Van Cauter E., Blackman J. D., Polonsky K. S. Entrainment of pulsatile insulin secretion by oscillatory glucose infusion. J Clin Invest. 1991 Feb;87(2):439–445. doi: 10.1172/JCI115015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Temple R. C., Carrington C. A., Luzio S. D., Owens D. R., Schneider A. E., Sobey W. J., Hales C. N. Insulin deficiency in non-insulin-dependent diabetes. Lancet. 1989 Feb 11;1(8633):293–295. doi: 10.1016/s0140-6736(89)91306-8. [DOI] [PubMed] [Google Scholar]
  41. Van Cauter E. Estimating false-positive and false-negative errors in analyses of hormonal pulsatility. Am J Physiol. 1988 Jun;254(6 Pt 1):E786–E794. doi: 10.1152/ajpendo.1988.254.6.E786. [DOI] [PubMed] [Google Scholar]
  42. Van Cauter E., Mestrez F., Sturis J., Polonsky K. S. Estimation of insulin secretion rates from C-peptide levels. Comparison of individual and standard kinetic parameters for C-peptide clearance. Diabetes. 1992 Mar;41(3):368–377. doi: 10.2337/diab.41.3.368. [DOI] [PubMed] [Google Scholar]
  43. Ward W. K., Bolgiano D. C., McKnight B., Halter J. B., Porte D., Jr Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984 Oct;74(4):1318–1328. doi: 10.1172/JCI111542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Ward W. K., LaCava E. C., Paquette T. L., Beard J. C., Wallum B. J., Porte D., Jr Disproportionate elevation of immunoreactive proinsulin in type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance. Diabetologia. 1987 Sep;30(9):698–702. doi: 10.1007/BF00296991. [DOI] [PubMed] [Google Scholar]
  45. Yoshioka N., Kuzuya T., Matsuda A., Taniguchi M., Iwamoto Y. Serum proinsulin levels at fasting and after oral glucose load in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1988 Jun;31(6):355–360. doi: 10.1007/BF02341503. [DOI] [PubMed] [Google Scholar]

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