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

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 [6,6-2 H2]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.