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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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Virtual metabolic human dynamic model for pathological analysis and therapy design for diabetes
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“Two-compartment kinetics justifies the non-linear changes in peripheral C-peptide during the dynamic increase in insulin secretion measured in vivo [74, 75].”
BackgroundModeling the Autonomic and Metabolic Effects of Obstructive Sleep Apnea: A Simulation Study
Cheng, L., & Khoo, M. C. K. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2011.00111 · Cited by 27
“However, there are also many models that have more complex structures, such as those used for quantifying β-cell mass, glucose disappearance, β-cell glucose sensitivity, and insulin secretion and resistance (Srinivasan et al., 1970; Sherwin et al., 1974; Insel et al., 1975; Howard et al., 1984; Berger and Rodbard, 198…”
A Model for the Estimation of Hepatic Insulin Extraction After a Meal
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“268 min−1 because of the hepatic plasma flow observed in normal subjects [16]; and m3 (min−1) is a time-varying parameter which, according to Dalla Man et al.”
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Owens, D. R., Tm, H., Alberti, K. G. M. M., Jones, M. K., Hedïng, L. G., Home, P. D., & Burrin, J. M. (1981) · The Lancet · doi:10.1016/s0140-6736(81)90300-7 · Cited by 25
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“Because equilibration between plasma insulin concentrations and insulin concentrations in the extravascular compartment is slow and takes at least 90 min [16], only the glucose infusion rates over the last 30 min of each insulin infusion period were used for the assessment of insulin action and were referred to as ste…”
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“At time 120 min, a primed constant IV infusion of insulin 12 pmol/kg/min in type 2 diabetes and 9 pmol/kg/min in healthy controls [15] was started and continued until 240 min (Figure 1).”
MethodFusion pore in exocytosis: More than an exit gate? A β-cell perspective
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“MODEL STRUCTURES The level of the glucose inside the human being body changes significantly in response to food intake and other physiological and environment conditions, it is necessary to derive mathematics models to capture such dynamics for control design [11-13, 22-24].”
BackgroundA new dynamic index of insulin sensitivity
Pillonetto, G., Caumo, A., Sparacino, G., & Cobelli, C. (2006) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.2005.869654 · Cited by 23
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RetractedInsulin kinetics and insulin binding to adipocytes in physically trained and food-restricted rats
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INSULIN INFUSION INTO THE PORTAL AND PERIPHERAL CIRCULATIONS OF UNANAESTHETIZED DOGS
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“Linear 4-compartment model The first example deals with a linear 4-compartment model (Sherwin et al., 1974).”
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Khoo, M. C. K., Oliveira, F., & Cheng, L. (2012) · IEEE Reviews in Biomedical Engineering · doi:10.1109/rbme.2012.2232651 · Cited by 24
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On Insulin Action in Vivo: The Single Gateway Hypothesis
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Glucose Tolerance in Ewes and Susceptibility to Pregnancy Toxaemia
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Differing physiological effects of epinephrine in type 1 diabetes and nondiabetic humans
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“At that time, a primed continuous infusion of insulin was administered at a rate of 9 pmol kg 1 min 1 from time 120 until time 240 in all subjects (44).”
MethodIdentification and low-complexity regime-switching insulin control of type I diabetic patients
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“Since the level of the glucose inside the human being body changes significantly in response to food intake and other physiological and environment conditions, for control design it is necessary to derive mathematics models to capture such dynamics [8-10,19-21].”
BackgroundInsulin clearance is different in men and women
Jensen, M. D., Nielsen, S., Gupta, N., Basu, R., & Rizza, R. A. (2011) · Metabolism · doi:10.1016/j.metabol.2011.08.009 · Cited by 21
Relationship between insulin's haemodynamic effects and insulin‐mediated glucose uptake
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Pharmacokinetics of Insulin Implications for Continuous Subcutaneous Insulin Infusion Therapy
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The cardiovascular effects of insulin
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“Intravenously injected insulin equilibrates rapidly between plasma and visceral compartments but much more slowly between the plasma and skeletal muscle [30].”
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“165,166 A 2-compartment model is also added to describe C-peptide kinetics.”
MethodSingh, P., Beyl, R. A., Stephens, J. M., Noland, R. C., Richard, A. J., Boudreau, A., Hebert, R. C., Ravussin, É., Broussard, J. L., St‐Onge, M., et al. (2023) · Obesity · doi:10.1002/oby.23739 · Cited by 22
“The metabolic clearance rate of insulin (MCRI) was calculated as the insulin infusion rate (mIU/min/m(2)) divided by the increase in plasma insulin concentration above the basal concentration (μU/mL), as previously described [22, 26].”
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Impaired insulin degradation in a patient with insulin resistance and acanthosis nigricans
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Interstitial insulin during euglycemic-hyperinsulinemic clamp in obese and lean individuals
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Development and testing of a simple algorithm for a glucose clamp
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Transient diabetes mellitus in a neonate
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Modelling and control of hyperglycemia in critical care patients
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“This point has been addressed by several authors [ 24-26 ] and in some cases physiologic significance has been attributed to the characteristics of a peripheral tissue pharmacokinetic compartment.”
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Garvey, W. T., & Kolterman, O. (1988) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610040602 · Cited by 18
On a simple model of insulin secretion
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Potential Developments in Systemic Delivery of Insulin
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Galderisi, A., Sims, E. K., Evans‐Molina, C., Petrelli, A., Cuthbertson, D. D., Nathan, B. M., Ismail, H. M., Herold, K. C., & Moran, A. (2024) · Diabetologia · doi:10.1007/s00125-024-06323-0 · Cited by 19
Continuous Subcutaneous Insulin Infusion—An Historical Perspective
Skyler, J. S. (2010) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2010.0068 · Cited by 17
Models for the Pharmacokinetics and Pharmacodynamics of Insulin in Alloxan-Induced Diabetic Dogs
Brown, S. A., Nelson, R. W., & Bottoms, G. D. (1987) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600760406 · Cited by 17
Fugleberg, S., K�lendorf, K., Thorsteinsson, B., Bliddal, H., Lund, B. V., & Bojsen, F. (1982) · Diabetologia · doi:10.1007/bf00282586 · Cited by 17
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“The parameters of the model of insulin kinetics were taken from the paper by Sherwin and co-workers [7].”
BackgroundMethodInfluentialShamoon, H., & Sherwin, R. S. (1984) · Diabetologia · doi:10.1007/bf00252404 · Cited by 16
“Insulin infusates contained 2 ml of the subjects' whole blood per 50 ml saline to prevent adherence to glassware and tubing [12].”
MethodSelf-citationThe Insulin Receptor Mediates Insulin’s Early Plasma Clearance by Liver, Muscle, and Kidney
Meijer, R. I., & Barrett, E. J. (2021) · Biomedicines · doi:10.3390/biomedicines9010037 · Cited by 16
“[13] found that a 3-compartment model -with plasma as the compartment that fills immediately, liver (splanchnic) next, and muscle more slowly- adequately described the kinetics of injected insulin’s plasma appearance and clearance.”
BackgroundFabricius, T. W., Verhulst, C. E. M., Kristensen, P. L., Tack, C. J., McCrimmon, R. J., Heller, S. R., Evans, M. L., Amiel, S. A., Pieber, T. R., de Galan, B. E., et al. (2021) · Diabetologia · doi:10.1007/s00125-020-05361-8 · Cited by 17
“In the 1970s, the hyperinsulinaemic–normoglycaemic clamp technique was developed for quantification of beta cell sensitivity to glucose and of tissue sensitivity to insulin [2, 3].”
MethodInsulin Resistance in Pima Indians
Lillioja, S., & Bogardus, C. (1987) · Acta Medica Scandinavica · doi:10.1111/j.0954-6820.1987.tb05934.x · Cited by 16
Saccà, L., Vitale, D. F., Cicala, M., Trimarco, B., & Ungaro, B. (1981) · Metabolism · doi:10.1016/0026-0495(81)90180-3 · Cited by 16
Systems Analysis of Hormone Action
Yates, F. E. (1982) · Springer eBooks · doi:10.1007/978-1-4684-1125-6_2 · Cited by 16
Why is there still Disagreement over Insulin Secretion in Non‐insulin‐dependent Diabetes?
Ferner, R. E., & Alberti, K. G. M. M. (1986) · Diabetic Medicine · doi:10.1111/j.1464-5491.1986.tb00698.x · Cited by 15
Insulin time‐dependent effects on the leg exchange of glucose and amino acids in man
Lundgren, F., Edén, E., Arfvidsson, B., & Lundholm, K. (1991) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.1991.tb01390.x · Cited by 15
Kolterman, O. (1985) · The American Journal of Medicine · doi:10.1016/s0002-9343(85)80004-8 · Cited by 15
Muscle, liver, and pancreas: Three Musketeers fighting to control glycemia
Klip, A., & Vranić, M. (2006) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/classicessays.00043.2006 · Cited by 15
“(11) and others buttressed the concept.”
Cahill, G. F. (1976) · doi:10.1007/978-1-349-02718-7_6 · Cited by 15
Pye, S., Watarai, T., Davies, G., & Radziuk, J. (1993) · Metabolism · doi:10.1016/0026-0495(93)90028-m · Cited by 14
Relation between insulin kinetics and insulin sensitivity in pregnancy
Jolly, M. C., Hovorka, R., Godsland, I. F., Amin, R., Lawrence, N., Anyaoku, V., Johnston, D. G., & Robinson, S. (2003) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.2003.01193.x · Cited by 14
Dose-response relationship of insulin to glucose fluxes in the awake and unrestrained mouse
Shen, H.-Q., Zhu, J. S., & Baron, A. (1999) · Metabolism · doi:10.1016/s0026-0495(99)90191-9 · Cited by 14
Cobelli, C., & TOFFOLO, G. M. (1985) · IFAC Proceedings Volumes · doi:10.1016/s1474-6670(17)60762-6 · Cited by 14
Gerbitz, K.-D., KEMMLER, W. K., EDELMANN, A., Summer, J., Mehnert, H., & WIELAND, O. H. (1979) · European Journal of Clinical Investigation · doi:10.1111/j.1365-2362.1979.tb00916.x · Cited by 14
Factors regulating the disposal of an oral glucose load in normal, diabetic, and obese subjects
Waldhäusl, W. K., & Bratusch-Marrain, P. R. (1987) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610030105 · Cited by 14
Effects of glycemic control on target organ responses to epinephrine in type 1 diabetes
Guy, D. L. A., Sandoval, D. A., Richardson, M. A., Tate, D. B., & Davis, S. N. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00311.2004 · Cited by 13
“administered at a rate of 9 pmol/kg/min from time 120 until time 240 in all subjects ( 38 ).”
BackgroundReduced Insulin Clearance in Normal Subjects Due to Extreme Hyperinsulinemia
Nestler, J. E., Clore, J. N., & Blackard, W. G. (1988) · The American Journal of the Medical Sciences · doi:10.1097/00000441-198801000-00005 · Cited by 13
Insulin delivery rate in response to glucose and arginine infusion in hyperthyroidism
Asano, T., & Okumura, M. (1982) · Diabetologia · doi:10.1007/bf01271170 · Cited by 13
“The rate constants for insulin disappearance in the present study were estimated from the early rapidly declining phase as shown in Figure 1, although studies of the disappearance rate using a single injection of insulin are complicated by the presence of more than one exponential component in the plasma disappearance…”
MethodLo Presti, J., Galderisi, A., Doyle, F. J., Zisser, H. C., Dassau, E., Renard, E., Toffanin, C., & Cobelli, C. (2023) · Journal of Diabetes Science and Technology · doi:10.1177/19322968221076559 · Cited by 12
Chen, Y., Wang, Q. Q., Wang, Y. H., Zhuo, H. L., & Dai, R. (2020) · Journal of Nuclear Cardiology · doi:10.1007/s12350-020-02219-9 · Cited by 12
Ishibashi, K., Kageyama, S., Sakurai, T., Murakawa, Y., Aihara, K., Yokota, K., Taniguchi, I., Hashimoto, Y., Fujita, T., & Tajima, N. (1997) · Hypertension Research · doi:10.1291/hypres.20.225 · Cited by 11
Nosadini, R., de Kreutzenberg, S., Duner, E., Iori, E., Avogaro, A., Trevisan, R., Fioretto, P., Doria, A., Merkel, C., Cobelli, C., et al. (1988) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-67-3-551 · Cited by 12
Pratt, M. C., Lewis‐Barned, N., & Walker, R. J. (1993) · Australian and New Zealand Journal of Medicine · doi:10.1111/j.1445-5994.1993.tb04721.x · Cited by 12
Hyperinsulinemia After Pancreatic Transplantation
Earnhardt, R. C., Kindler, D. D., Weaver, A. M., Cornett, G., Elahi, D., Veldhuis, J. D., & Hanks, J. B. (1993) · Annals of Surgery · doi:10.1097/00000658-199310000-00004 · Cited by 12
Insulin Resistance and the Metabolic Syndrome
Banerji, M. A., & Chaiken, R. L. (2009) · Springer eBooks · doi:10.1007/978-0-387-09841-8_34 · Cited by 12
Normalization of Insulin Delivery to Diabetics by Pulsed Insulin Infusion
Martin, P. J., & GENUTH, S. M. (1977) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.1977.326114 · Cited by 11
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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