beta-cell genes and diabetes: Quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1 alpha and glucokinase mutations

Mutations in the beta -cell genes encoding the glycolytic enzyme glucokinas e (GCK) and the transcription factor hepatocyte nuclear factor (HNF)-1 alph a are the most common causes of maturity-onset diabetes of the young (MODY) , Studying patients with mutations in these genes gives insights into the f unctions 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-1 alpha mutation carriers. Homeostasis model assessment of fasting i nsulin and glucose showed reduced beta -cell function in both GCK (48% cont rols, P < 0.0001) and HNF-1<alpha> (42% controls, P < 0.0001), Insulin sens itivity was similar to that of control subjects in the GCK subjects (93% co ntrols, P = 0.78) but increased in the HNF-1<alpha> subjects (134.5% contro ls, P = 0.005), The GCK patients showed a similar phenotype between and wit hin families with mild lifelong fasting hyperglycemia (fasting plasma gluco se [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 pharmacologic al treatment (17% oral hypoglycemic agents, 4% insulin). HNF-1 alpha patien ts 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 deteriora tion with age (0.06 mmol/l per year), and 59% of patients required treatmen t with tablets or insulin. Proinsulin-to-insulin ratios are increased in HN F-1 alpha subjects (29.5%) but not in GCK (18.5%) subjects. In an oral gluc ose tolerance test, the 0- to 120-min glucose increment was small in GCK pa tients (2.4 +/- 1.8 mmol/l) but large in HNF-1 alpha patients (8.5 +/- 3.0 mmol/l, P < 0.0001), This comparison shows that the clear clinical differen ces in these two genetic subgroups of diabetes reflect the quantitative and qualitative differences in P-cen dysfunction, The defect in GCK is a stabl e defect of glucose sensing, whereas the HNF-1<alpha> mutation causes a pro gressive defect that alters beta -cell insulin secretion directly rather th an the sensing of glucose.