New insulin sensitivity adjusted beta cell indices: validation according to a genetic study.
OBJECTIVE
The role of hepatocyte nuclear factor-1alpha (HNF1alpha) in the maturity-onset diabetes of the young 3 (MODY3) is well established. A common polymorphism, I27L that is not linked to MODY3, has been demonstrated to affect beta cell function. To facilitate the identification of subjects with a low beta cell reserve, we developed beta cell indices and validated according to a genetic study.


METHODS
Insulin sensitivity index (ISI), 1st phase insulin response (1stIR), and 2nd phase insulin response (2ndIR) were assessed in 60 glucose tolerant subjects using hyperglycemic clamps. Delta1stIR and delta2ndIR were defined as differences between 1stIR (or 2ndIR) and the ISI-adjusted 1stIR (or 2ndIR). The genotypes were determined from genomic DNA.


RESULTS
Delta1stIR (P = 0.0130) and delta2ndIR (P = 0.0482) differed among the 3 genotypic groups. Multivariate analysis confirmed the independent influence of the I27L polymorphism on delta1stIR (P = 0.0130) and delta2ndIR (P = 0.0369). Within the LL group, 75% and 63% of the subjects were within the lowest quartile of delta1stIR (P = 0.0011) and delta2ndIR (P = 0.0277), respectively.


CONCLUSIONS
With new beta cell indices, we demonstrated the independent impact of the I27L polymorphism on beta cell function. The new beta cell indices will facilitate the identification of glucose tolerant subjects with reduced beta cell reserve.
Chiu
Ken C
KC
Division of Endocrinology, Diabetes, and Hypertension, University of California, Los Angeles, School of Medicine, Los Angeles, California, USA. kchiu@mednet.ucla.edu
Martinez
Dorothy S
DS
Lee
Nancy P
NP
Saad
Mohammed F
MF
D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D004268:DNA-Binding Proteins; D005215:Fasting; D005260:Female; D005838:Genotype; D005947:Glucose / Q000008:administration & dosage; D015309:Glucose Clamp Technique; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D008297:Male; D015999:Multivariate Analysis; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*
D001786:Blood Glucose; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D007328:Insulin; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005947:Glucose