Article

Diabetologia

, Volume 46, Issue 9, pp 1211-1219

First online:

Predominant role of reduced beta-cell sensitivity to glucose over insulin resistance in impaired glucose tolerance

  • E. FerranniniAffiliated withMetabolism Unit, C.N.R. Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of MedicineDiabetes Division, University of Texas Health Sciences Center at San Antonio Email author 
  • , A. GastaldelliAffiliated withMetabolism Unit, C.N.R. Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine
  • , Y. MiyazakiAffiliated withDiabetes Division, University of Texas Health Sciences Center at San Antonio
  • , M. MatsudaAffiliated withDiabetes Division, University of Texas Health Sciences Center at San Antonio
  • , M. PettitiAffiliated withMetabolism Unit, C.N.R. Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine
  • , A. NataliAffiliated withMetabolism Unit, C.N.R. Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine
  • , A. MariAffiliated withC.N.R. Institute of Biomedical Engineering
  • , R. A. DeFronzoAffiliated withDiabetes Division, University of Texas Health Sciences Center at San Antonio

Abstract

Aims/hypothesis

Impaired glucose tolerance (IGT) is an insulin-resistant state and a risk factor for Type 2 diabetes. The relative roles of insulin resistance and insulin deficiency in IGT have been disputed.

Methods

In 40 IGT subjects and 63 sex-, age-, and weight-matched controls with normal glucose tolerance (NGT), we measured (i) indices of insulin sensitivity of fasting glucose production (by tracer glucose) and glucose disposal (M value on a 240 pmol·min–1·m–2 insulin clamp) and (ii) indices of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) derived from model analysis (Am J Physiol 283:E1159–E1166, 2002) of the insulin secretory response (by C-peptide deconvolution) to oral glucose.

Results

In comparison with NGT, IGT were modestly insulin resistant (M=29±2 vs 35±2 µmol·min−1·kgFFM −1, p=0.01); insulin sensitivity of glucose production also was reduced, in approximate proportion to M. Despite higher baseline insulin secretion rates, IGT was characterized by a 50% reduction in glucose sensitivity [53 (36) vs 102 (123) pmol·min−1·m–2·mM–1, median (interquartile range), p=0.001] and impaired potentiation [1.6 (0.8) vs 2.0 (1.5) units, p<0.04] of insulin release, whereas rate sensitivity [1.15 (1.15) vs 1.38 (1.28) nmol·m–2·mM–1] was not significantly reduced. Glucose sensitivity made the single largest contribution (~50%) to the observed variability of glucose tolerance.

Conclusion/interpretation

In IGT the defect in glucose sensitivity of insulin release quantitatively predominates over insulin resistance in the genesis of the reduced tolerance to oral glucose.

Keywords

IGT beta-cell function insulin secretion insulin resistance mathematical modelling