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

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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.

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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

R dFFM :

Rate of whole-body glucose disappearance

REE:

Resting energy expenditure

SHEC:

Standard hyperinsulinaemic–euglycaemic clamp

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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.

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Authors and Affiliations

  1. Department of Endocrinology and Diabetology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany

    Sabine Kahl, Bettina Nowotny & Michael Roden

  2. Institute of Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Auf’m Hennekamp 65, 40225, Düsseldorf, Germany

    Sabine Kahl, Bettina Nowotny, Simon Piepel, Peter J. Nowotny, Christian Herder & Michael Roden

  3. German Center for Diabetes Research, Partner Düsseldorf, Germany

    Sabine Kahl, Bettina Nowotny, Peter J. Nowotny, Klaus Strassburger, Christian Herder & Michael Roden

  4. Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine University, Düsseldorf, Germany

    Klaus Strassburger

  5. Metabolic Unit, Institute of Biomedical Engineering, National Research Council, Padova, Italy

    Giovanni Pacini

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  1. Sabine Kahl
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  2. Bettina Nowotny
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Corresponding author

Correspondence to Michael Roden.

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Kahl, S., Nowotny, B., Piepel, S. et al. Estimates of insulin sensitivity from the intravenous-glucose-modified-clamp test depend on suppression of lipolysis in type 2 diabetes: a randomised controlled trial. Diabetologia 57, 2094–2102 (2014). https://doi.org/10.1007/s00125-014-3328-3

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