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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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.
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.
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.
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.
KeywordsGlucose transport Insulin resistance Insulin sensitivity Lipid metabolism Metabolic physiology
Acute C-peptide response
Acute insulin response
Body surface area
Calculated sensitivity index
Endogenous glucose production
Glucose infusion rate
Mean insulin concentration
Impaired glucose tolerance
IL-1 receptor antagonist
Whole-body insulin sensitivity
Monocyte chemoattractant protein 1
Rate of whole-body glucose disappearance
Resting energy expenditure
Standard hyperinsulinaemic–euglycaemic clamp
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.
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.
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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