beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations.
Mutations in the beta-cell genes encoding the glycolytic enzyme glucokinase (GCK) and the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the most common causes of maturity-onset diabetes of the young (MODY). Studying patients with mutations in these genes gives insights into the functions of these two critical beta-cell genes in humans. We studied 178 U.K. and French MODY family members, including 45 GCK mutation carriers and 40 HNF-1alpha mutation carriers. Homeostasis model assessment of fasting insulin and glucose showed reduced beta-cell function in both GCK (48% controls, P<0.0001) and HNF-1alpha (42% controls, P<0.0001). Insulin sensitivity was similar to that of control subjects in the GCK subjects (93% controls, P = 0.78) but increased in the HNF-1alpha subjects (134.5% controls, P = 0.005). The GCK patients showed a similar phenotype between and within families with mild lifelong fasting hyperglycemia (fasting plasma glucose [FPG] 5.5-9.2 mmol/l, interquartile [IQ] range 6.6-7.4), which declined slightly with age (0.017 mmol/l per year) and rarely required pharmacological treatment (17% oral hypoglycemic agents, 4% insulin). HNF-1alpha patients showed far greater variation in fasting glucose both between and within families (FPG 4.1-18.5 mmol/l, IQ range 5.45-10.4), with a marked deterioration with age (0.06 mmol/l per year), and 59% of patients required treatment with tablets or insulin. Proinsulin-to-insulin ratios are increased in HNF-1alpha subjects (29.5%) but not in GCK (18.5%) subjects. In an oral glucose tolerance test, the 0- to 120-min glucose increment was small in GCK patients (2.4+/-1.8 mmol/l) but large in HNF-1alpha patients (8.5+/-3.0 mmol/l, P< 0.0001). This comparison shows that the clear clinical differences in these two genetic subgroups of diabetes reflect the quantitative and qualitative differences in beta-cell dysfunction. The defect in GCK is a stable defect of glucose sensing, whereas the HNF-1alpha mutation causes a progressive defect that alters beta-cell insulin secretion directly rather than the sensing of glucose.
Department of Vascular Medicine and Diabetes Research, School of Postgraduate Medicine and Health Sciences, University of Exeter, Devon, UK.
E R
ER
Pearson
G
G
Velho
P
P
Clark
A
A
Stride
M
M
Shepherd
T M
TM
Frayling
M P
MP
Bulman
S
S
Ellard
P
P
Froguel
A T
AT
Hattersley
D000328:Adult; D000367:Age Factors; D001786:Blood Glucose / Q000378:metabolism; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005192:Family Health; D005215:Fasting; D005260:Female; D005796:Genes / Q000235:genetics*; D005941:Glucokinase / Q000235:genetics; D005951:Glucose Tolerance Test; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins; D011384:Proinsulin / Q000097:blood; 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; D011384:Proinsulin; D005941:Glucokinase