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A Model of the Kinetics of Insulin in Man
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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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BackgroundObesity and diet affect glucose dynamics and insulin sensitivity in Thoroughbred geldings1
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Self-citationRetractedInsulin Control of Glucose Metabolism in Man
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Self-citationOral Glucose Augmentation of Insulin Secretion
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Insulin Metabolism and Degradation*
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“The present study assessed the ability of an insulin PK model (13) to predict the plasma insulin profile obtained with sc insulin delivery and whether feedback of the profile would allow acceptable closed-loop meal responses to be obtained in humans.”
MethodInsulin Sensitivity and Insulin Binding to Monocytes in Maturity-Onset Diabetes
Defronzo, R., Deibert, D., Hendler, R., Felig, P., & Soman, V. (1979) · Journal of Clinical Investigation · doi:10.1172/jci109394 · Cited by 188
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“There are a number of studies indicating insulin’s transendothelial transport to be rate limiting for its action in stimulating muscle glucose uptake (103, 124, 159, 189).”
BackgroundAn integrated mathematical model of the dynamics of blood glucose and its hormonal control
Cobelli, C., Federspil, G., Pacini, G., Salvan, A., & Scandellari, C. (1982) · Mathematical Biosciences · doi:10.1016/0025-5564(82)90050-5 · Cited by 182
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First-phase insulin secretion: does it exist in real life? Considerations on shape and function
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Insulin regulates its own delivery to skeletal muscle by feed-forward actions on the vasculature
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Feedback inhibition of insulin secretion by insulin: relation to the hyperinsulinemia of obesity
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Self-citationStochastic modelling of insulin sensitivity and adaptive glycemic control for critical care
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“Assumptions for these responses could also compromise control accuracy, as both endogenous insulin and glucose productions are known to vary significantly between patients [25-29] and over time.”
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Systemic delivery of therapeutic peptides and proteins
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“Thus estimates of insulin release were obtained previously by using a model of the kinetics of insulin in man [3, 24].”
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“At 120 min, in all studies, a primed continuous infusion of insulin (9 pmol kg 1 min (1)) was started (18).”
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“Insulin-dependent glucose disposal occurs in the slowly exchanging pool and is assumed to be parametrically controlled, not by plasma, but by insulin in a remote compartment (13).”
BackgroundBell, K. J., Toschi, E., Steil, G. M., & Wolpert, H. A. (2016) · Diabetes Care · doi:10.2337/dc15-2855 · Cited by 121
“First, a metabolic model comprised of an insulin pharmacokinetic/ pharmacodynamic submodel (2), the Bergman minimal model (3,4), and a meal absorption model (5) was identified using a nonlinear generalized reduced gradient algorithm available in”
MethodRadiosurgery of acoustic neurinomas
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Endothelial cell barriers: Transport of molecules between blood and tissues
Yazdani, S., Jaldín‐Fincati, J. R., Pereira, R. V. S., & Klip, A. (2019) · Traffic · doi:10.1111/tra.12645 · Cited by 126
“Insulin in particular is cleared out of tissues as part of the mechanism to terminate its action, and for years it has been postulated that the interstitium of muscle and adipose tissues constitute an insulin compartment important for glucose utilization.(50,77) Hence, the rate of insulin removal from the interstitium…”
BackgroundTura, A., Ludvik, B. H., Nolan, J. J., Pacini, G., & Thomaseth, K. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.281.5.e966 · Cited by 120
“The model presented in this study also allows estimation of systemic insulin clearance; that in the original version (23) was fixed to values obtained from other studies (10–12) or from the literature (18, 21).”
Pathophysiology of Diabetes Mellitus
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Self-citationChronic hyperinsulinemia and blood pressure. Interaction with catecholamines?
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The kinetics of insulin in man. II. Role of the liver
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Influence of hyperglycemia on insulin's in vivo effects in type II diabetes.
REVERS, R. R., Fink, R. I., Griffin, J., Olefsky, J. M., & Kolterman, O. (1984) · Journal of Clinical Investigation · doi:10.1172/jci111258 · Cited by 113
Glucose homeostasis during prolonged suppression of glucagon and insulin secretion by somatostatin.
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Self-citationEffects of antecedent prolonged exercise on subsequent counterregulatory responses to hypoglycemia
Galassetti, P. R., Mann, S. L., Tate, D. B., Neill, R. A., da Costa, F. A. A., Wasserman, D. H., & Davis, S. N. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.6.e908 · Cited by 107
“5 mU zkg21 zmin21) was started (38), and the rate of fall of plasma glucose was controlled so that the target hypoglycemic plateau (;54 mg/dl) was reached by t 5 30 min and was maintained until the end of the experimental period.”
BackgroundInsulin Responsiveness of Adipose Tissue Lipoprotein Lipase Is Delayed but Preserved in Obesity*
SADUR, U. N., Yost, T. J., & Eckel, R. H. (1984) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-59-6-1176 · Cited by 106
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Resistive Training Increases Insulin Action in Postmenopausal Women
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“Insulin leaves the plasma compartment to exert its action at the tissue level; this concentration of insulin at the tissue level was estimated using the previously described model where the insulin concentration at the tissue level is referred to as I3 (compartment 3) (18).”
BackgroundMethodSingh, R., Aguiar, R. B. D., Naik, S., Mani, S., Ostadsharif, K., Wencker, D., Sotoudeh, M., Malekzadeh, R., Sherwin, R. S., & Mani, A. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.01.009 · Cited by 98
“Glucose kinetics were determined in the basal state and during euglycemic hyperinsulinemia (Sherwin et al., 1974).”
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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.
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