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Diabetologia

, Volume 57, Issue 10, pp 2094–2102 | Cite as

Estimates of insulin sensitivity from the intravenous-glucose-modified-clamp test depend on suppression of lipolysis in type 2 diabetes: a randomised controlled trial

  • Sabine Kahl
  • Bettina Nowotny
  • Simon Piepel
  • Peter J. Nowotny
  • Klaus Strassburger
  • Christian Herder
  • Giovanni Pacini
  • Michael Roden
Article

Abstract

Aims/hypothesis

The combined IVGTT–hyperinsulinaemic–euglycaemic clamp (Botnia clamp) allows the assessment of insulin secretion and sensitivity in one experiment. It remains unclear whether this clamp yields results comparable with those of the standard hyperinsulinaemic–euglycaemic clamp (SHEC) in diabetes patients. We hypothesised that the IVGTT induces responses affecting insulin sensitivity assessment.

Methods

Of 22 randomised diet- or metformin-treated patients with well-controlled type 2 diabetes, 19 randomly underwent a Botnia clamp and an SHEC, spaced by 2 weeks, in one clinical research centre in a crossover study. The main outcomes were whole-body and hepatic insulin sensitivity as measured by the clamp and [6,6-2H2]glucose. Substrate utilisation was assessed from indirect calorimetry and beta cell function from insulin dynamics during IVGTT.

Results

The values of whole-body insulin sensitivity obtained from Botnia clamp and SHEC were correlated (r = 0.87, p < 0.001), but also revealed intra-individual variations. Hepatic insulin sensitivity did not differ between experiments during the clamp, but differed after IVGTT. The contribution of glucose oxidation to glucose disposal increased by 2.2 ± 0.3 and 1.2 ± 0.4 mg kg fat-free mass (FFM)−1 min−1 (Botnia and SHEC, p < 0.05), whereas lipid oxidation decreased by 0.8 ± 0.1 and 0.4 ± 0.1 mg kg FFM−1 min−1 (p < 0.05) from baseline. Differences in NEFA (r = −0.60, p < 0.01), but not C-peptide (r = −0.16, p = 0.52) or hepatic insulin sensitivity between IVGTT and placebo before the clamps correlated with individual variations of insulin sensitivity.

Conclusions/interpretation

The Botnia clamp provides similar estimates of insulin sensitivity as SHEC in patients with type 2 diabetes, but changes in NEFA during IVGTT may affect insulin sensitivity and thereby the discrimination between insulin-sensitive and insulin-resistant individuals.

Trial registration: ClinicalTrials.gov NCT01397279

Funding: The study was funded by the Ministry of Science and Research of the State of North Rhine-Westphalia and the German Federal Ministry of Health, and supported in part by grants from the Federal Ministry for Research to the Centers for Diabetes Research, Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases and the Schmutzler-Stiftung.

Keywords

Glucose transport Insulin resistance Insulin sensitivity Lipid metabolism Metabolic physiology 

Abbreviations

ACPR

Acute C-peptide response

AIR

Acute insulin response

BSA

Body surface area

CSI

Calculated sensitivity index

DI

Disposition index

EGP

Endogenous glucose production

FFM

Fat-free mass

GIR

Glucose infusion rate

GOX

Glucose oxidation

I

Mean insulin concentration

IGT

Impaired glucose tolerance

IL-1RA

IL-1 receptor antagonist

LOX

Lipid oxidation

M

Whole-body insulin sensitivity

MCP-1

Monocyte chemoattractant protein 1

POX

Protein oxidation

RdFFM

Rate of whole-body glucose disappearance

REE

Resting energy expenditure

SHEC

Standard hyperinsulinaemic–euglycaemic clamp

Notes

Acknowledgements

We thank F. Schwarz for her assistance in the clamp experiments and U. Partke, I. Latta, R. Schreiner, D. Scheibelhut, D. Seeger, B. Platzbecker and C. Preuß for technical assistance (all at the German Diabetes Center, Düsseldorf, Germany). We thank A. Mari (Institute of Biomedical Engineering, Padova, Italy) for the calculation of the non-steady-state EGP. Some of the data have previously been presented as an abstract at the 73rd Scientific Sessions of the American Diabetes Association in Chicago, IL, USA in 2013.

Funding

This work was supported by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW) and the German Federal Ministry of Health (BMG). This study was supported in part by grants from the Federal Ministry for Research (BMBF) to the Centers for Diabetes Research (DZD e.V.), Helmholtz Alliance Imaging and Curing Environmental Metabolic Diseases (ICEMED) and the Schmutzler-Stiftung.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

MR designed the study and headed the clinical experiments. SK, SP and BN researched the data. SK wrote the first draft of the manuscript and coordinated the inclusion of specific sections as outlined. PJN and CH conducted and wrote aspects of the laboratory analyses. KS supervised and interpreted the statistical analyses of the data. GP calculated indices of beta cell function and wrote the respective sections. All the authors contributed substantially to aspects of study design or the acquisition of data, contributed to drafting of the article or revised it critically for important intellectual content and gave final approval to the version to be published. MR is responsible for the integrity of the work as a whole.

Supplementary material

125_2014_3328_MOESM1_ESM.pdf (12 kb)
ESM Fig. 1 (PDF 11 kb)
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ESM Fig. 2 (PDF 94 kb)
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ESM Fig. 3 (PDF 88 kb)
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ESM Fig. 4 (PDF 85 kb)
125_2014_3328_MOESM5_ESM.pdf (82 kb)
ESM Table 1 (PDF 81 kb)
125_2014_3328_MOESM6_ESM.pdf (149 kb)
ESM Table 2 (PDF 149 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sabine Kahl
    • 1
    • 2
    • 3
  • Bettina Nowotny
    • 1
    • 2
    • 3
  • Simon Piepel
    • 2
  • Peter J. Nowotny
    • 2
    • 3
  • Klaus Strassburger
    • 3
    • 4
  • Christian Herder
    • 2
    • 3
  • Giovanni Pacini
    • 5
  • Michael Roden
    • 1
    • 2
    • 3
  1. 1.Department of Endocrinology and DiabetologyHeinrich-Heine University DüsseldorfDüsseldorfGermany
  2. 2.Institute of Clinical Diabetology, German Diabetes CenterLeibniz Institute for Diabetes Research at Heinrich-Heine UniversityDüsseldorfGermany
  3. 3.German Center for Diabetes ResearchPartner DüsseldorfGermany
  4. 4.Institute of Biometrics and Epidemiology, German Diabetes CenterLeibniz Institute for Diabetes Research at Heinrich-Heine UniversityDüsseldorfGermany
  5. 5.Metabolic Unit, Institute of Biomedical EngineeringNational Research CouncilPadovaItaly

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