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A Model of the Kinetics of Insulin in Man
Open accessAbstract
The design of the present study of the kinetics of insulin in man combines experimental features which obviate two of the major problems in previous insulin studies. (a) The use of radioiodinated insulin as a tracer has been shown to be inappropriate since its metabolism differs markedly from that of the native hormone. Therefore porcine insulin was administered by procedures which raised insulin levels in arterial plasma into the upper physiologic range. Hypoglycemia was prevented by adjusting the rate of an intravenous infusion of glucose in order to control the blood glucose concentration (the glucose-clamp technique). (b) Estimation of a single biological half-time of insulin after pulse injection of the hormone has been shown to be inappropriate since plasma insulin disappearance curves are multiexponential. Therefore the SAAM 25 computer program was used in order to define the parameters of a three compartment insulin model. The combined insulin mass of the three compartments (expressed as plasma equivalent volume) is equal to inulin space (15.7% body wt). Compartment 1 is apparently the plasma space (4.5%). The other two compartments are extra-vascular; compartment 2 is small (1.7%) and equilibrates rapidly with plasma, and compartment 3 is large (9.5%) and equilibrates slowly with plasma. The SAAM 25 program can simulate the buildup and decay of insulin in compartments 2 and 3 which cannot be assayed directly. Insulin in compartment 3 was found to correlate remarkably with the time-course of the servo-controlled glucose infusion. Under conditions of a steady-state arterial glucose level, glucose infusion is a measure of glucose utilization. We conclude that compartment 3 insulin (rather than plasma insulin) is a more direct determinant of glucose utilization. We suggest that the combined use of glucose-clamp and kinetic-modeling techniques should aid in the delineation of pathophysiologic states affecting glucose and insulin metabolism.
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“Many authors [13, 14] have demonstrated that insulin is best modeled using multiple compartments.”
From Pharmacokinetic modeling of the glucoregulatory system (2008) · cites this paper as [14]
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Insulin Resistance and Diabetes due to a Genetic Defect in Insulin Receptors*
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6 Insulin sensitivity in the intact organism
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Anderwald, C. H., Anderwald-Stadler, M., Promintzer, M., Prager, G., Mandl, M., Nowotny, P., Bischof, M. G., Wolzt, M., Ludvik, B. H., Kästenbauer, T., et al. (2007) · Diabetes Care · doi:10.2337/dc07-0422 · Cited by 48
“Insulin’s biological action on insulinsensitive tissues has a much longer halflife ( 30–40 min) than that in blood because it acts in compartments other than blood without continuous degradation by the liver (31,32).”
BackgroundFeedback inhibition by biosynthetic human insulin of insulin release in healthy human subjects
Waldhäusl, W. K., Gasic, S., Bratusch-Marrain, P. R., Korn, A., & Nowotny, P. (1982) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1982.243.6.e476 · Cited by 49
Alterations of insulin and glucose metabolism during cardiopulmonary bypass under normothermia
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“The relationships between insulin and the MCR of glucose was also determined in man from the examination of the response of glucose utilization to an injection of insulin [ 54 ].”
Diabetic ketoacidosis : current views on pathogenesis and treatment
Keller, U. B. (1986) · Diabetologia · doi:10.1007/bf00456113 · Cited by 48
“"Low-doses" of insulin are usually infused continuously at rates between 5 and 10 U/h [1], representing rates which are still approximately 5 times higher than the normal basal insulin secretion rate [ 79 ].”
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“The simplest explanation for this apparent relationship between the microvascular volume perfused within skeletal muscle and metabolic insulin resistance arises from understanding that the delivery of glucose and insulin to skeletal muscle appears to be a limiting process for insulin action within skeletal muscle (6,7…”
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Advancing Our Understanding of the Glucose System via Modeling: A Perspective
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Acute hyperinsulinemia induces sodium retention and a blood pressure decline in diabetes mellitus.
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“By correcting for differences in steady-state plasma insulin levels, M/I is a better index for comparison of possible changes or differences in tissue sensitivity to insulin.(29) For convenience M/I ratio was multiplied by 100.”
MethodWaldhäusl, W. K., Gasic, S., Bratusch-Marrain, P. R., & Nowotny, P. (1983) · Diabetologia · doi:10.1007/bf00284457 · Cited by 45
Developing the UVA/Padova Type 1 Diabetes Simulator: Modeling, Validation, Refinements, and Utility
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“This was a model ingredient requested by data and modeling methodology, in agreement with Sherwin et al. 45 Later, this remote compartment was experimentally proven in dog studies to be the interstitial fluid.”
MethodCalculation of the Systemic Delivery Rate of Insulin in Normal Man*
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The role of endothelial insulin signaling in the regulation of glucose metabolism
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Insulin Clearance in Obesity and Type 2 Diabetes
Koh, H. E., Cao, C., & Mittendorfer, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020596 · Cited by 52
“Lastly, the insulin fractional catabolic rate provides an assessment of the turnover rate of the plasma insulin pool and is expressed as pools/minute, where pools refers to the total amount of insulin in the circulation (plasma insulin concentration × volume) [20,24,32].”
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Post-traumatic insulin resistance in uninjured forearm tissue
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“73 m(2) for a distribution volume of about 11 L in a 70-kg adult [7].”
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Sandqvist, M., Strindberg, L., Schmelz, M., Lönnroth, P., & Jansson, P.-A. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0233 · Cited by 39
“It is well established that peripheral insulin effects correlate with the insulin level attained in the interstitial fluid surrounding target cells (1).”
BackgroundVISENTIN, R., Cobelli, C., & Man, C. D. (2020) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2020.0110 · Cited by 39
“23,24 A two-compartment model is also added to describe C-peptide kinetics.”
Enoksson, S., Caprio, S., Rife, F., Shulman, G. I., Tamborlane, W. V., & Sherwin, R. S. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021013 · Cited by 39
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“At time zero, a primed continuous infusion of insulin ( 12 ) was administered at a rate of 9 pmol/kgzmin for 120 min.”
MethodSvensson, M. K. E., Yu, Z., & Eriksson, J. W. (2002) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2002.00949.x · Cited by 37
Modeling Of Insulin Action In Vivo
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Extrapancreatic effect of somatostatin infusion to increase glucose clearance
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Insulin antagonistic effects of epinephrine and glucagon in the dog.
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Insulin Removal in Man:In VivoEvidence for a Receptor-Mediated Process*
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High Resolution Clinical Model-Based Assessment of Insulin Sensitivity
Lotz, T. (2007) · UC Research Repository (University of Canterbury) · doi:10.26021/2196 · Cited by 34
Insulin Wakayama: familial mutant insulin syndrome in Japan
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“[Leu A3] insulin showed a 10-fold increase in half-life compared to normal human insulin in the dog (Fig. 5). Since the clearance of human insulin in dog and man are similar [23, 24 ], this experiment probably mimics the in vivo situation closely.”
BackgroundInsulin sensitivity tested with a modified euglycemic technique in cats and rats
Xie, H., Zhu, L., Zhang, Y. L., Légaré, D. J., & Lautt, W. W. (1996) · Journal of Pharmacological and Toxicological Methods · doi:10.1016/1056-8719(96)00003-2 · Cited by 33
Patterns of Glucose and Lipid Abnormalities in Black NIDDM Subjects
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Distribution and kinetics of amylin in humans
Clodi, M., Thomaseth, K., Pacini, G., Hermann, K., Kautzky‐Willer, A., Waldhäusl, W. K., Prager, R., & Ludvik, B. H. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.274.5.e903 · Cited by 33
Reconstructing the rate of appearance of subcutaneous insulin by deconvolution
Cobelli, C., Mari, A., Prato, S. D., de Kreutzenberg, S., Nosadini, R., & Jensen, I. (1987) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1987.253.5.e584 · Cited by 34
ODE models for the management of diabetes: A review
Rathee, S., & Nilam (2016) · International Journal of Diabetes in Developing Countries · doi:10.1007/s13410-016-0475-8 · Cited by 33
“He reviewed pancreatic suppression test ([26–28]), glucose clamp ([27, 28]) and minimal model approach ([6, 8]) to find the effect of closed loop feedback relation between insulin action and insulin secretion.”
PACBERG: an adaptive program for controlling the blood sugar.
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Massive insulin overdose: Detailed studies of free insulin levels and glucose requirements
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Modeling of glucose regulation and insulin-signaling pathways
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“By correcting for differences in steady-state plasma insulin concentrations, this provides a better index for comparison of possible changes in tissue sensitivity to insulin.(24) Basal fasting insulin levels were measured before the clamp, and insulin levels were measured during the study at 60, 80, 100, and 120 minut…”
Development of glucose-triggered pH-sensitive liposomes for a potential insulin delivery
Kim, C., Eun-Bin, I., Lim, S.-J., Oh, Y., & Han, S.-K. (1994) · International Journal of Pharmaceutics · doi:10.1016/0378-5173(94)90214-3 · Cited by 30
Oxidative fuel metabolism during mild hypoglycemia: critical role of free fatty acids
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Self-citationRETRACTED: Insulin Binding and Insulin Sensitivity in Isolated Growth Hormone Deficiency
Soman, V., Tamborlane, W. V., DeFronzo, R. A., Genel, M., & Felig, P. (1978) · New England Journal of Medicine · doi:10.1056/nejm197811092991901 · Cited by 30
RetractedInsulin entry into muscle involves a saturable process in the vascular endothelium
Majumdar, S., Genders, A. J., Inyard, A. C., Frison, V., & Barrett, E. J. (2011) · Diabetologia · doi:10.1007/s00125-011-2343-x · Cited by 31
“saturable [12].”
Modeling of plasma disappearance of unlabeled insulin in man.
Tranberg, K. ‐., & DENCKER, H. (1978) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1978.235.6.e577 · Cited by 29
Endothelial Cells Actively Concentrate Insulin During its Transendothelial Transport
Genders, A. J., Frison, V., Abramson, S. R., & Barrett, E. J. (2013) · Microcirculation · doi:10.1111/micc.12044 · Cited by 31
“Studies using compartmental modeling [21], lymphatic sampling [27], and microdialysis [22] for assessing muscle interstitial insulin concentrations each support an important role for insulin’s transendothelial transport (TET) in the regulation of muscle metabolism.”
Recent advances in the determination of insulins from biological fluids
Thomas, A., & Thevis, M. (2019) · Advances in clinical chemistry · doi:10.1016/bs.acc.2019.07.003 · Cited by 30
Metadata
- Authors
- Sherwin, R. S., Kramer, K. J., Tobin, J. D., Insel, P. A., Liljenquist, J. E., Berman, M., & Andres, R.
- Affiliations
- National Institutes of Health (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1974-05-01
- Volume
- 53
- Issue
- 5
- Pages
- 1481-1492
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC302637
- OpenAlex
- W1969759774
- Cited by
- 460
- References
- 48
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 14 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 5 · 2016: 10 · 2015: 8 · 2014: 7 · 2013: 7 · 2012: 9
- FWCI
- 13.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- insulin kinetics, three-compartment model, porcine insulin, glucose clamp, glucose utilization, insulin half-life, inulin space
- MeSH terms
- Adolescent, Adult, Animals, Blood Glucose, Glucose, Half-Life, Humans, Insulin, Kinetics, Male, Middle Aged, Models, Biological, Swine
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