Predominant role of reduced beta-cell sensitivity to glucose over insulin resistance in impaired glucose tolerance.
OBJECTIVE
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 x min(-1) x 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 micromol x min(-1) x kg(FFM)(-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 x min(-1) x m(-2) x 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 x m(-2) x mM(-1)] was not significantly reduced. Glucose sensitivity made the single largest contribution (approximately 50%) to the observed variability of glucose tolerance.


CONCLUSIONS
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.
Ferrannini
E
E
Metabolism Unit, C.N.R. Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy. ferranni@ifc.cnr.it
Gastaldelli
A
A
Miyazaki
Y
Y
Matsuda
M
M
Pettiti
M
M
Natali
A
A
Mari
A
A
DeFronzo
R A
RA
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D005215:Fasting; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D018149:Glucose Intolerance / Q000503:physiopathology*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D012016:Reference Values
D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D005947:Glucose