In Praise of the Hyperglycemic Clamp: A method for assessment of β-cell sensitivity and insulin resistance
Abstract
The most widely used methods for the assessment of beta-cell response and peripheral tissue sensitivity to insulin include the oral glucose tolerance test (OGTT), the frequently sampled intravenous glucose tolerance test, and the hyperinsulinemiceuglycemic clamp technique. During an OGTT, glucose levels increase after a variable lag period, then reach a peak and fall variably among individuals. The response even varies in the same subject upon repeat testing. A more reproducible glucose curve is achieved with an intravenous glucose tolerance test in which the plasma glucose levels rise rapidly to a very high level and fall exponentially. In neither of the two methods is a steady-state glucose level achieved. In the hyperinsulinemic-euglycemic clamp technique, a steady-state glucose level can be maintained at any level of hyperinsulinemia. However, an assessment of beta-cell sensitivity is not obtained. The less used hyperglycemic clamp technique can assess beta-cell sensitivity as well as peripheral tissue sensitivity. Moreover, a measure of glucose effectiveness or non-insulin-mediated glucose uptake can also be determined. With this technique the beta-cells of all subjects are stimulated with the same arterial glucose concentration, thus enabling assessment of beta-cell response to identical plasma glucose levels. Comparison of responses to stable hyperglycemic stimuli can be made in glucose-tolerant and -intolerant states with the addition of various substances, either alone or in combination. The use of the hyperglycemic clamp and several of its variant forms is reviewed as an alternative method for assessment of glucose homeostasis.
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GIR during steady-state hyperglycemia (60-90 min) allows a fairly good direct measurement of insulin sensitivity, though not as accurate as euglycemic hyperinsulinemic clamps.
“Although not as accurate as euglycemic hyperinsulinemic clamps for measuring insulin sensitivity, GIR during steady-state hyperglycemia (i.e., 60–90 min) allows a fairly good direct measurement of insulin sensitivity (34).”
From Assessment of the incretin effect in healthy subjects: concordance between clamp and OGTT methods (2023) · cites this paper as [34]
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“Using the glucose clamp procedure of the methodology of the hyperglycemic glucose clamp (DeFronzo, Tobin, & Andres, 1979; Elahi, 1996; Fanelli, et al., 1998), a variable rate infusion of 20% dextrose maintained the blood glucose level above 130 mg/dl. Samples for blood glucose were drawn every 5…”
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Mokhlesi, B., Tjaden, A. H., Temple, K. A., Edelstein, S. L., Sam, S., Nadeau, K. J., Hannon, T. S., Manchanda, S., Mather, K. J., Kahn, S. E., et al. (2021) · Diabetes Care · doi:10.2337/dc20-2127 · Cited by 26 · see citing works
“state (second phase) C-peptide was calculated as themeanof themeasurements at 100, 110,and120minof the clamp(20).”
MethodSalvatori, B., Linder, T., Eppel, D., Morettini, M., Burattini, L., Göbl, C. S., & Tura, A. (2022) · Cardiovascular Diabetology · doi:10.1186/s12933-022-01649-8 · Cited by 25 · see citing works
The Belgian Diabetes Registry, Vandemeulebroucke, E., Keymeulen, B., Decochez, K., Weets, I., Block, C. E. M. D., Féry, F., de Velde, U. V., Vermeulen, I., Pauw, P. E. M. D., et al. (2009) · Diabetologia · doi:10.1007/s00125-009-1569-3 · Cited by 25 · see citing works
“Relatives were prospectively followed (median [range]: 64[3–99] months) for glucose tolerance and diabetes onset (OGTT after 3, 9, 15, 18, 21, 27, 30, 33, 36, 42 and 48 months; glucose self-monitoring) and for beta cell function (hyperglycaemic clamp after 6, 12, 24, 36 and 48 months).”
BackgroundZhang, Y., Qin, P., Lou, Y., Zhao, P., Li, X., Qie, R., Wu, X., Han, M., Huang, S., Zhao, Y., et al. (2020) · Journal of Diabetes · doi:10.1111/1753-0407.13123 · Cited by 25 · see citing works
Impact of family history of diabetes on the assessment of β-cell function
ALFORD, F. P., Henriksen, J. E., Rantzau, C., Vaag, A. A., Hew, L. F., Ward, G. M., & Beck‐Nielsen, H. (1998) · Metabolism · doi:10.1016/s0026-0495(98)90234-7 · Cited by 23 · see citing works
Hahn, M., Chintoh, A. F., Remington, G. J., Teo, C., Mann, S. W., Arenovich, T., Fletcher, P. J., Lam, L., Nóbrega, J. N., Guenette, M. D., et al. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.07.011 · Cited by 22 · see citing works
Zawalich, W. S., Yamazaki, H., Zawalich, K. C., et al. (2004) · Journal of Endocrinology · doi:10.1677/joe.1.05832 · Cited by 22 · see citing works
“Qualitatively and quantitatively similar responses have been noted during in vivo hyperglycemic clamp studies in humans (Van Haeften et al. 1990, Elahi 1996 ) suggesting that the same biochemical processes operative in rat islets also play an important role in human islets.”
Glucose-induced desensitization of the pancreatic β-cell is species dependent
Zawalich, W. S., Bonnet-Eymard, M., & Zawalich, K. C. (1998) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1998.275.6.e917 · Cited by 21 · see citing works
Loutseiko, M., Voskanyan, G. R., Keenan, D. B., & Steil, G. M. (2011) · Journal of Diabetes Science and Technology · doi:10.1177/193229681100500605 · Cited by 22 · see citing works
Assessment of Insulin Sensitivity in Older Adults Using the Hyperglycemic Clamp Technique
Meneilly, G. S., & Elliott, T. G. (1998) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1998.tb01019.x · Cited by 21 · see citing works
Dalem, A. V., Demeester, S., Balti, E. V., Keymeulen, B., Gillard, P., Lapauw, B., Block, C. E. M. D., Abrams, P. J., Weber, E., Vermeulen, I., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0166702 · Cited by 21 · see citing works
The Artificial Pancreas: Is it Important to Understand How the β Cell Controls Blood Glucose?
Steil, G. M., & Grodsky, G. M. (2013) · Journal of Diabetes Science and Technology · doi:10.1177/193229681300700528 · Cited by 20 · see citing works
Karstoft, K., Clark, M. A., Jakobsen, I., Knudsen, S. H., van Hall, G., Pedersen, B. K., & Solomon, T. P. J. (2017) · Diabetologia · doi:10.1007/s00125-017-4406-0 · Cited by 20 · see citing works
Henderson, M., Baillargeon, J., RABASA-LHORET, R. P. R., Chiasson, J. L., Hanley, J., & Lambert, M. A. (2012) · Diabetes & Metabolism · doi:10.1016/j.diabet.2012.02.002 · Cited by 18 · see citing works
Yamazaki, H., Philbrick, W. M., Zawalich, K. C., & Zawalich, W. S. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00149.2005 · Cited by 17 · see citing works
Zawalich, W. S. (1997) · Frontiers in bioscience · doi:10.2741/a180 · Cited by 17 · see citing works
Temple, K. A., Tjaden, A. H., Atkinson, K. M., Barengolts, E., Hannon, T. S., Mather, K. J., Utzschneider, K. M., Edelstein, S. L., Ehrmann, D. A., Mokhlesi, B., et al. (2019) · Diabetes Care · doi:10.2337/dc19-0538 · Cited by 16 · see citing works
Resistive Training Improves Insulin Sensitivity after Stroke
Ivey, F. M., & Ryan, A. S. (2013) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2012.12.014 · Cited by 15 · see citing works
Li, M., Liu, Y., Jin, L., Zeng, N., Wang, L., Zhao, K., Lv, H., Zhang, M., Xu, W., Zhang, P., et al. (2019) · Obesity Surgery · doi:10.1007/s11695-019-04067-0 · Cited by 15 · see citing works
Pancreatic β-Cell Dysfunction Is Associated with Nonalcoholic Fatty Liver Disease
Chen, X., Xiao, J., Pang, J., Chen, S., Wang, Q., & Ling, W. (2021) · Nutrients · doi:10.3390/nu13093139 · Cited by 16 · see citing works
“Second, we assessed the β-cell function of DI based on the HOMA2 model, which was simple and easy-to-use, but less accurate in reflecting β-cell function compared to other indices derived from the glucose challenge test and hyperglycemic clamp method (the gold standard) [33].”
MethodPrediction of Diabetic Kidney Disease in Newly Diagnosed Type 2 Diabetes Mellitus
Mu, X., Wu, A., Hu, H., Zhou, H., & Yang, M. (2023) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s417300 · Cited by 14 · see citing works
Liu, Y., Jiang, H., Luo, L., & Gao, Z. (2024) · BMC Endocrine Disorders · doi:10.1186/s12902-024-01718-x · Cited by 14 · see citing works
“However, the benchmark for assessing insulin resistance—the high insulin-normal glucose clamp technique—is impractical for large sample populations because of its expensive price, invasive nature, and lengthy duration [17].”
BackgroundInsulin secretion and IP levels in two distant lineages of the genusMus: comparisons with rat islets
Zawalich, W. S., Zawalich, K. C., Tesz, G. J., Sterpka, J., & Philbrick, W. M. (2001) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2001.280.5.e720 · Cited by 13 · see citing works
- Authors
- Elahi, D.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Elahi, Dariush
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 1996-03-01
- Volume
- 19
- Issue
- 3
- Pages
- 278-286
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- OpenAlex
- W2027219674
- Cited by
- 168
- References
- 0
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 8 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 5 · 2019: 10 · 2018: 3 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 6 · 2012: 4
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes Care (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P60AG012583, P60 AG12583)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- hyperglycemic clamp, insulin resistance, glucose homeostasis, oral glucose tolerance test, intravenous glucose tolerance test, hyperinsulinemic-euglycemic clamp, glucose effectiveness
- MeSH terms
- Insulin Secretion, Adult, Aged, Glucose Tolerance Test, Humans, Hyperglycemia, Insulin, Insulin Resistance, Islets of Langerhans, Middle Aged, Models, Biological, Glucose Clamp Technique
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