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Beta-cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1alpha mutation carriers.

OBJECTIVE
Patients with diabetes due to hepatocyte nuclear factor (HNF)-1alpha mutations have beta-cell deficiency, insulin sensitivity, altered proinsulin levels, and a low renal threshold for glucose. It is uncertain how many of these features precede the development of diabetes. The aim of our study was to test for these characteristics in young nondiabetic HNF-1alpha mutation carriers.


RESEARCH DESIGN AND METHODS
A total of 47 offspring from 19 extended families underwent genetic testing, a standard oral glucose tolerance test, and urine testing.


RESULTS
HNF-1alpha mutations were found in 20 offspring, 7 with diabetes and 13 without diabetes. The 13 nondiabetic mutation carriers were compared with 27 family control subjects, who were matched for age, sex, and BMI. There was marked beta-cell deficiency with reduced insulinogenic index (53.5 [31.5-90.9] vs. 226.0 [126.0-407.1], SD [range], P < 0.001) and area under the curve for insulin (P < 0.001). Insulin sensitivity was increased in mutation carriers (homeostatic model assessment of insulin sensitivity 144.6 [82.7-252.7] vs. 100 [66.9-149.4], P = 0.025). A total of 38% of mutation carriers had glycosuria at 2 h compared with 0% of control subjects (P = 0.0034). Those with glycosuria had peak glucose values that were higher than the mutations carriers without glycosuria (range 8.1-11.8 vs. 6.2-8.4 mmol/l, P = 0.002). The seven subjects with diabetes all showed glycosuria.


CONCLUSIONS
We conclude that marked beta-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1alpha mutation carriers. The presence of glycosuria post-glucose load could be used to screen children of mutation carriers as it occurs in all mutation carriers with a peak glucose in the oral glucose tolerance test >8.4 mmol/l.