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Cited by 244Pancreatic function and diabetesDiabetes Management and ResearchDiabetes, Cardiovascular Risks, and Lipoproteins

Insulin Control of Glucose Metabolism in Man

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Insel, Paul A., Liljenquist, John E., Tobin, Jordan D., Sherwin, Robert S., Watkins, Paul, Andres, Reubin, Berman, Mones·1975·Journal of Clinical Investigation
DOI 10.1172/jci108006PMC PMC301852
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Abstract

Analyses of the control of glucose metabolism by insulin have been hampered by changes in bloog glucose concentration induced by insulin administration with resultant activation of hypoglycemic counterregulatory mechanisms. To eliminate such mechanisms, we have employed the glucose clamp technique which allows maintenance of fasting blood glucose concentration during and after the administration of insulin. Analyses of six studies performed in young healthy men in the postabsorptive state utilizing the concurrent administration of [14C]glucose and 1 mU/kg per min (40 mU/m2 per min) porcine insulin led to the development of kinetic models for insulin and for glucose. These models account quantitatively for the control of insulin on glucose utilization and on endogenous glucose production during nonsteady states. The glucose model, a parallel three-compartment model, has a central compartment (mass = 68 +/- 7 mg/kg; space of distribution = blood water volume) in rapid equilibrium with a smaller compartment (50 +/- 17 mg/kg) and in slow equilibrium with a larger compartment (96 +/-21 mg/kg). The total plasma equivalent space for the glucose system averaged 15.8 liters or 20.3% body weight. Two modes of glucose loss are introduced in the model. One is a zero-order loss (insulin and glucose independent) from blood to the central nervous system; its magnitude was estimated from published data. The other is an insulin-dependent loss, occurring from the rapidly equilibrating compartment and, in the basal period, is smaller than the insulin-independent loss. Endogenous glucose production averaged 1.74 mg/kg per min in the basal state and enters the central compartment directly. During the glucose clamp experiments plasma insulin levels reached a plateau of 95 +/-8 microU/ml. Over the entire range of insulin levels studied, glucose losses were best correlated with levels of insulin in a slowly equilibrating insulin compartment of a three-compartment insulin model. A proportional control by this compartment on glucose utilization was adequate to satisfy the observed data. Insulin also rapidly decreased the endogenous glucose production to 33% of its basal level (0.58 mg/kg per min), this suppression being maintained for at least 40 min after exogenous insulin infusion was terminated and after plasma insulin concentrations had returned to basal levels. The change in glucose utilization per unit change in insulin in the slowly equilibrating insulin compartment is proposed as a new measure for insulin sensitivity. This defines insulin effects more precisely than previously used measures, such as plasma glucose/plasma insulin concentration ratios. Glucose clamp studies and the modeling of the coupled kinetics of glucose and insulin offers a new and potentially valuable tool to the study of altered states of carbohydrate metabolism.

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Authors
Insel, P. A., Liljenquist, J. E., Tobin, J. D., Sherwin, R. S., Watkins, P., Andres, R., & Berman, M.
Affiliations
National Institutes of Health (US)
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1975-05-01
Volume
55
Issue
5
Pages
1057-1066
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci108006
PMC
PMC301852
OpenAlex
W1860443407
Cited by
244
References
45
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 3 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 6 · 2015: 4 · 2014: 3 · 2013: 1 · 2012: 4
FWCI
12.50
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Surgery › 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, glucose metabolism, glucose utilization, endogenous glucose production, insulin sensitivity, glucose kinetics, insulin kinetics, hypoglycemic counterregulation, postabsorptive state, glucose clamp, kinetic modeling, hyperinsulinemic-euglycemic clamp
MeSH terms
Adolescent, Adult, Blood Glucose, Carbon Radioisotopes, Glucose, Glucose Tolerance Test, Humans, Infusions, Intravenous, Insulin, Kinetics, Male, Glucose Clamp Technique, Feedback, Physiological

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