Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1986 Jan;77(1):98–105. doi: 10.1172/JCI112308

Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.

K S Polonsky, J Licinio-Paixao, B D Given, W Pugh, P Rue, J Galloway, T Karrison, B Frank
PMCID: PMC423314  PMID: 3511094

Abstract

We undertook this study to examine the accuracy of plasma C-peptide as a marker of insulin secretion. The peripheral kinetics of biosynthetic human C-peptide (BHCP) were studied in 10 normal volunteers and 7 insulin-dependent diabetic patients. Each subject received intravenous bolus injections of BHCP as well as constant and variable rate infusions. After intravenous bolus injections the metabolic clearance rate of BHCP (3.8 +/- 0.1 ml/kg per min, mean +/- SEM) was not significantly different from the value obtained during its constant intravenous infusion (3.9 +/- 0.1 ml/kg per min). The metabolic clearance rate of C-peptide measured during steady state intravenous infusions was constant over a wide concentration range. During experiments in which BHCP was infused at a variable rate, the peripheral concentration of C-peptide did not change in proportion to the infusion rate. Thus, the infusion rate of BHCP could not be calculated accurately as the product of the C-peptide concentration and metabolic clearance rate. However, the non-steady infusion rate of BHCP could be accurately calculated from peripheral C-peptide concentrations using a two-compartment mathematical model when model parameters were derived from the C-peptide decay curve in each subject. Application of this model to predict constant infusions of C-peptide from peripheral C-peptide concentrations resulted in model generated estimates of the C-peptide infusion rate that were 101.5 +/- 3.4% and 100.4 +/- 2.8% of low and high dose rates, respectively. Estimates of the total quantity of C-peptide infused at a variable rate over 240 min based on the two-compartment model represented 104.6 +/- 2.4% of the amount actually infused. Application of this approach to clinical studies will allow the secretion rate of insulin to be estimated with considerable accuracy. The insulin secretion rate in normal subjects after an overnight fast was 89.1 pmol/min, which corresponds with a basal 24-h secretion of 18.6 U.

Full text

PDF
98

Selected References

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

  1. Blix P. M., Boddie-Willis C., Landau R. L., Rochman H., Rubenstein A. H. Urinary C-peptide: an indicator of beta-cell secretion under different metabolic conditions. J Clin Endocrinol Metab. 1982 Mar;54(3):574–580. doi: 10.1210/jcem-54-3-574. [DOI] [PubMed] [Google Scholar]
  2. Bonora E., Zavaroni I., Coscelli C., Butturini U. Decreased hepatic insulin extraction in subjects with mild glucose intolerance. Metabolism. 1983 May;32(5):438–446. doi: 10.1016/0026-0495(83)90004-5. [DOI] [PubMed] [Google Scholar]
  3. Bratusch-Marrain P. R., Waldhäusl W. K., Gasić S., Hofer A. Hepatic disposal of biosynthetic human insulin and porcine C-peptide in humans. Metabolism. 1984 Feb;33(2):151–157. doi: 10.1016/0026-0495(84)90128-8. [DOI] [PubMed] [Google Scholar]
  4. Eaton R. P., Allen R. C., Schade D. S., Erickson K. M., Standefer J. Prehepatic insulin production in man: kinetic analysis using peripheral connecting peptide behavior. J Clin Endocrinol Metab. 1980 Sep;51(3):520–528. doi: 10.1210/jcem-51-3-520. [DOI] [PubMed] [Google Scholar]
  5. Eaton R. P., Allen R. C., Schade D. S. Hepatic removal of insulin in normal man: dose response to endogenous insulin secretion. J Clin Endocrinol Metab. 1983 Jun;56(6):1294–1300. doi: 10.1210/jcem-56-6-1294. [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. Faber O. K., Christensen K., Kehlet H., Madsbad S., Binder C. Decreased insulin removal contributes to hyperinsulinemia in obesity. J Clin Endocrinol Metab. 1981 Sep;53(3):618–621. doi: 10.1210/jcem-53-3-618. [DOI] [PubMed] [Google Scholar]
  8. Faber O. K., Hagen C., Binder C., Markussen J., Naithani V. K., Blix P. M., Kuzuya H., Horwitz D. L., Rubenstein A. H., Rossing N. Kinetics of human connecting peptide in normal and diabetic subjects. J Clin Invest. 1978 Jul;62(1):197–203. doi: 10.1172/JCI109106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hendriksen C., Faber O. K., Drejer J., Binder C. Prevalence of residual B-cell function in insulin-treated diabetics evaluated by the plasma C-etide response to intravenous glucagon. Diabetologia. 1977 Dec;13(6):615–619. doi: 10.1007/BF01236316. [DOI] [PubMed] [Google Scholar]
  10. Hoekstra J. B., van Rijn H. J., Erkelens D. W., Thijssen J. H. C-peptide. Diabetes Care. 1982 Jul-Aug;5(4):438–446. doi: 10.2337/diacare.5.4.438. [DOI] [PubMed] [Google Scholar]
  11. Jaspan J., Polonsky K. Glucose ingestion in dogs alters the hepatic extraction of insulin. In vivo evidence for a relationship between biologic action and extraction of insulin. J Clin Invest. 1982 Mar;69(3):516–525. doi: 10.1172/JCI110477. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kaden M., Harding P., Field J. B. Effect of intraduodenal glucose administration on hepatic extraction of insulin in the anesthetized dog. J Clin Invest. 1973 Aug;52(8):2016–2028. doi: 10.1172/JCI107386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Madison L. L. Role of insulin in the hepatic handling of glucose. Arch Intern Med. 1969 Mar;123(3):284–292. [PubMed] [Google Scholar]
  14. Madsbad S., Kehlet H., Hilsted J., Tronier B. Discrepancy between plasma C-peptide and insulin response to oral and intravenous glucose. Diabetes. 1983 May;32(5):436–438. doi: 10.2337/diab.32.5.436. [DOI] [PubMed] [Google Scholar]
  15. Meistas M. T., Rendell M., Margolis S., Kowarski A. A. Estimation of the secretion rate of insulin from the urinary excretion rate of C-peptide. Study in obese and diabetic subjects. Diabetes. 1982 May;31(5 Pt 1):449–453. doi: 10.2337/diab.31.5.449. [DOI] [PubMed] [Google Scholar]
  16. Meistas M. T., Zadik Z., Margolis S., Kowarski A. A. Correlation of urinary excretion of C-peptide with the integrated concentration and secretion rate of insulin. Diabetes. 1981 Aug;30(8):639–643. doi: 10.2337/diab.30.8.639. [DOI] [PubMed] [Google Scholar]
  17. Polonsky K. S., Pugh W., Jaspan J. B., Cohen D. M., Karrison T., Tager H. S., Rubenstein A. H. C-peptide and insulin secretion. Relationship between peripheral concentrations of C-peptide and insulin and their secretion rates in the dog. J Clin Invest. 1984 Nov;74(5):1821–1829. doi: 10.1172/JCI111601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Polonsky K. S., Rubenstein A. H. C-peptide as a measure of the secretion and hepatic extraction of insulin. Pitfalls and limitations. Diabetes. 1984 May;33(5):486–494. doi: 10.2337/diab.33.5.486. [DOI] [PubMed] [Google Scholar]
  19. Polonsky K., Jaspan J., Emmanouel D., Holmes K., Moossa A. R. Differences in the hepatic and renal extraction of insulin and glucagon in the dog: evidence for saturability of insulin metabolism. Acta Endocrinol (Copenh) 1983 Mar;102(3):420–427. doi: 10.1530/acta.0.1020420. [DOI] [PubMed] [Google Scholar]
  20. Polonsky K., Jaspan J., Pugh W., Cohen D., Schneider M., Schwartz T., Moossa A. R., Tager H., Rubenstein A. H. Metabolism of C-peptide in the dog. In vivo demonstration of the absence of hepatic extraction. J Clin Invest. 1983 Sep;72(3):1114–1123. doi: 10.1172/JCI111036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Rossell R., Gomis R., Casamitjana R., Segura R., Vilardell E., Rivera F. Reduced hepatic insulin extraction in obesity: relationship with plasma insulin levels. J Clin Endocrinol Metab. 1983 Mar;56(3):608–611. doi: 10.1210/jcem-56-3-608. [DOI] [PubMed] [Google Scholar]
  22. Rubenstein A. H., Pottenger L. A., Mako M., Getz G. S., Steiner D. F. The metabolism of proinsulin and insulin by the liver. J Clin Invest. 1972 Apr;51(4):912–921. doi: 10.1172/JCI106886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sando H., Lee Y. S., Iwamoto Y., Ikeuchi M., Kosaka K. Isoproterenol-stimulated C-peptide and insulin secretion in diabetic and nonobese normal subjects: decreased hepatic extraction of endogenous insulin in diabetes. J Clin Endocrinol Metab. 1980 Nov;51(5):1143–1149. doi: 10.1210/jcem-51-5-1143. [DOI] [PubMed] [Google Scholar]
  24. Savage P. J., Flock E. V., Mako M. E., Blix P. M., Rubenstein A. H., Bennett P. H. C-Peptide and insulin secretion in Pima Indians and Caucasians: constant fractional hepatic extraction over a wide range of insulin concentrations and in obesity. J Clin Endocrinol Metab. 1979 Apr;48(4):594–598. doi: 10.1210/jcem-48-4-594. [DOI] [PubMed] [Google Scholar]
  25. Scarlett J. A., Mako M. E., Rubenstein A. H., Blix P. M., Goldman J., Horwitz D. L., Tager H., Jaspan J. B., Stjernholm M. R., Olefsky J. M. Factitious hypoglycemia. Diagnosis by measurement of serum C-peptide immunoreactivity and insulin-binding antibodies. N Engl J Med. 1977 Nov 10;297(19):1029–1032. doi: 10.1056/NEJM197711102971903. [DOI] [PubMed] [Google Scholar]
  26. Sherwin R. S., Kramer K. J., Tobin J. D., Insel P. A., Liljenquist J. E., Berman M., Andres R. A model of the kinetics of insulin in man. J Clin Invest. 1974 May;53(5):1481–1492. doi: 10.1172/JCI107697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Waldhäusl W. K., Gasić S., Bratusch-Marrain P., Korn A., Nowotny P. Feedback inhibition by biosynthetic human insulin of insulin release in healthy human subjects. Am J Physiol. 1982 Dec;243(6):E476–E482. doi: 10.1152/ajpendo.1982.243.6.E476. [DOI] [PubMed] [Google Scholar]
  28. Waldhäusl W. K., Gasić S., Bratusch-Marrain P., Nowotny P. The 75-g oral glucose tolerance test: effect on splanchnic metabolism of substrates and pancreatic hormone release in healthy man. Diabetologia. 1983 Dec;25(6):489–495. doi: 10.1007/BF00284457. [DOI] [PubMed] [Google Scholar]
  29. Waldhäusl W., Bratusch-Marrain P., Gasic S., Korn A., Nowotny P. Insulin production rate following glucose ingestion estimated by splanchnic C-peptide output in normal man. Diabetologia. 1979 Oct;17(4):221–227. doi: 10.1007/BF01235858. [DOI] [PubMed] [Google Scholar]
  30. Waldhäusl W., Bratusch-Marrain P., Gasić S., Korn A., Nowotny P. Insulin production rate, hepatic insulin retention and splanchnic carbohydrate metabolism after oral glucose ingestion in hyperinsulinaemic Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1982 Jul;23(1):6–15. doi: 10.1007/BF00257722. [DOI] [PubMed] [Google Scholar]

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

RESOURCES