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Cited by 35Pancreatic function and diabetesDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes Treatment and Management

β-cell activity and hepatic insulin extraction following dexamethasone administration in healthy subjects

Kautzky-Willer, Alexandra, Thomaseth, Karl, Clodi, Martin, Ludvik, Bernhard, Waldhäusl, Werner, Prager, Rudolf, Pacini, Giovanni·1996·Metabolism
DOI 10.1016/s0026-0495(96)90224-3
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Abstract

Glucocorticoids induce an increase of hepatic glucose production and peripheral resistance to insulin action. It is further assumed that dexamethasone administration in humans causes insulin hypersecretion, although inferences on beta-cell activity have been made in absolute terms and mostly from observations of systemic insulin concentration. In fact, the role of hepatic insulin extraction in humans treated long-term with glucocorticoids has not been investigated. The aim of the present study was to factor out quantitatively the main components of the insulin pathway that are responsible for the peripheral hypersecretion observed after steroids. Frequently sampled intravenous (FSIGT) and oral (OGTT) glucose tolerance tests were performed in healthy subjects before and after 5 days of oral dexamethasone administration (4 mg/d). Insulin sensitivity, beta-cell secretion, and hepatic insulin extraction were estimated by means of mathematical modeling. After steroids, insulin sensitivity decreased from 6.00 +/- 1.29 to 4.23 +/- 1.04 min-1/(microU/mL) (P < .04). Basal beta-cell secretion increased from 45 +/- 7 to 104 +/- 26 pmol/L . min-1 (P < .004) during the FSIGT and from 40 +/- 6 to 88 +/- 21 (P < .05) during the OGTT; total insulin release increased from 19 +/- 5 to 36 +/- 7 nmol/L in 180 minutes (P < .005) and from 33 +/- 5 to 50 +/- 10 (P < .02), respectively, FSIGT data also showed that first-phase beta-cell sensitivity increased from 236 +/- 39 to 309 +/- 33 pmol/L . min-1/(mg/dL) (P < .04), and second-phase from 631 +/- 154 to 1,103 +/ 196 10(4) pmol/L . min-2/(mg/dL) (P < .03). Posthepatic insulin delivery increased only insignificantly during the FSIGT (from 3.4 +/- 0.6 to 4.5 +/- 0.5 nmol/L, P = .073) due to an augmented hepatic insulin extraction from 73.0% +/- 7.2% to 83.0% +/- 3.5% (P < .05). During the OGTT, posthepatic insulin delivery increased after treatment from 6.6 +/- 1.2 to 11.4 +/- 2.5 nmol/L (P < .035) due to an increase, although slight, of hepatic insulin extraction from 77.4% +/- 1.9% to 79.3% +/- 3.3% (P = .319). The increased overall beta-cell activity during both tests was observed also by analyzing OGTT profiles of islet amyloid polypeptide (IAPP), the secretion of which was higher after steroids (basal, 0.081 +/- 0.012 v 0.272 +/- 0.082 pmol/L/min, P < .02; total, 35 +/- 8 v 116 +/- 48 mpmol/L in 3 hours, P < .05). In conclusion, after dexamethasone administration, peripheral hyperinsulinemia due to marked prehepatic beta-cell insulin hypersecretion is partially ameliorated by a concomitant increase of hepatic insulin clearance, which is more evident during a FSIGT. Model-derived secretion parameters from the OGTT and FSIGT produced comparable results, indicating that both tests, when properly analyzed, are feasible tools to evaluate insulin secretion.

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  • At days-long timescales, dexamethasone increases insulin secretion.

    “At these days-long timescales, dexamethasone increases insulin secretion ( 36, 43 )”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [43]

  • The model parameters were estimated from the literature and recalibrated by fitting the model output to data from OGTTs in healthy humans and to clinical data from OGTTs in diabetics.

    “The model parameters were estimated from the literature and recalibrated by fitting the model output to data from OGTTs in healthy humans ( 43 ) and to clinical data from OGTTs in diabetics ( 21 ).”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [43]

  • Parameters associated with glucose uptake in peripheral cells and maximum rates of production and utilisation were estimated from prior data.

    “the parameters associated to glucose uptake in peripheral cells, as well as maximum rates of production and utilisation, were estimated from ( 31, 43, 44 ).”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [43]

  • The model reproduces OGTT glucose and insulin dynamics in humans, matching continuously sampled blood levels during the first 30 min and then every 30 min until 3 hrs after the glucose bolus.

    “The model predicts dynamic transient responses that match continuously sampled levels of glucose and insulin in blood every 10 min during the first 30 min, and then every 30 min until 3 hrs following the glucose bolus ( 43 ) (Fig. 2A).”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [43]

  • The dexamethasone prediction agrees with data from OGTTs in humans following 5-day treatment with dexamethasone.

    “This prediction agrees with data from OGTTs in humans following 5-day treatment with dexamethasone ( 43 ) (Fig. 3A).”

    From Dynamic modulation of glucose utilisation by glucocorticoid rhythms in health and disease (2020) · cites this paper as [43]

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Authors
Kautzky-Willer, A., Thomaseth, K., Clodi, M., Ludvik, B., Waldhäusl, W., Prager, R., & Pacini, G.
Affiliations
University of Vienna (AT)
Corresponding author
Pacini, Giovanni
ORCID
Venue
Metabolism
Publisher
Elsevier BV
Published
1996-04
Volume
45
Issue
4
Pages
486-491
ISSN
0026-0495 (ISSN-L)
DOI
10.1016/s0026-0495(96)90224-3
OpenAlex
W2097984448
Cited by
35
References
39
Citations by year
2023: 1 · 2021: 1 · 2020: 2 · 2019: 3 · 2017: 2 · 2016: 1 · 2013: 1 · 2012: 1
FWCI
0.86
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Metabolism (publishedVersion)
  • PubMed (publishedVersion)
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 Treatment and Management
Keywords
dexamethasone, glucocorticoids, hepatic insulin extraction, insulin secretion, insulin sensitivity, insulin resistance, hepatic glucose production, insulin hypersecretion, first-phase insulin response, second-phase insulin response, glucose tolerance test, oral glucose tolerance test, healthy volunteers
MeSH terms
Insulin Secretion, Administration, Oral, Adult, Amyloid, Blood Glucose, C-Peptide, Dexamethasone, Female, Glucocorticoids, Glucose Tolerance Test, Humans, Infusions, Intravenous, Insulin, Islets of Langerhans, Liver, Male, Time Factors, Islet Amyloid Polypeptide

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