TY - JOUR
T1 - β-cell genes and diabetes
T2 - quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1α and glucokinase mutations
AU - Pearson, Ewan R.
AU - Velho, Gilberto
AU - Clark, Penny
AU - Stride, Amanda
AU - Shepherd, Maggie
AU - Frayling, Timothy M.
AU - Bulman, Michael P.
AU - Ellard, Sian
AU - Froguel, Phillipe
AU - Hattersley, Andrew T.
PY - 2001/2/22
Y1 - 2001/2/22
N2 - Mutations in the β-cell genes encoding the glycolytic enzyme glucokinase (GCK) and the transcription factor hepatocyte nuclear factor (HNF)-1α 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 β-cell genes in humans. We studied 178 U.K. and French MODY family members, including 45 GCK mutation carriers and 40 HNF-1α mutation carriers. Homeostasis model assessment of fasting insulin and glucose showed reduced β-cell function in both GCK (48% controls, P < 0.0001) and HNF-1α (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-1α 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-1α 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-1α 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-1α 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 β-cell dysfunction. The defect in GCK is a stable defect of glucose sensing, whereas the HNF-1α mutation causes a progressive defect that alters β-cell insulin secretion directly rather than the sensing of glucose.
AB - Mutations in the β-cell genes encoding the glycolytic enzyme glucokinase (GCK) and the transcription factor hepatocyte nuclear factor (HNF)-1α 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 β-cell genes in humans. We studied 178 U.K. and French MODY family members, including 45 GCK mutation carriers and 40 HNF-1α mutation carriers. Homeostasis model assessment of fasting insulin and glucose showed reduced β-cell function in both GCK (48% controls, P < 0.0001) and HNF-1α (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-1α 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-1α 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-1α 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-1α 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 β-cell dysfunction. The defect in GCK is a stable defect of glucose sensing, whereas the HNF-1α mutation causes a progressive defect that alters β-cell insulin secretion directly rather than the sensing of glucose.
UR - http://www.scopus.com/inward/record.url?scp=0035122350&partnerID=8YFLogxK
U2 - 10.2337/diabetes.50.2007.S101
DO - 10.2337/diabetes.50.2007.S101
M3 - Article
C2 - 11272165
AN - SCOPUS:0035122350
SN - 0012-1797
VL - 50
SP - S101-S107
JO - Diabetes
JF - Diabetes
IS - SUPPL. 1
ER -