Mutations in the gene encoding glucokinase (GCK) cause maturity-onset diabetes of the young (MODY) 2, characterized by impaired prandial insulin secretion and hepatic glycogen storage. Recently diagnosed patients with type 1 diabetes (T1D) exhibit impairment of both beta cell function and hepatic energy metabolism. Thus, this study aimed at examining the effect of MODY 2 on hepatic insulin sensitivity and energy metabolism. Carriers of one recently described GCK mutation (D124N; c.370, GAC>AAC in exon 4) were compared to controls (CON) with similar sex, age and body mass index (BMI) (female/male: 1/2 vs. 3/6; 36±4 vs. 35±2 years; 20.1±1.6 vs. 25.7±1.5 kg/m2) from the German Diabetes Study ( NCT01409330). Whole body and hepatic insulin sensitivity (IS) were assessed by Botnia-clamp tests with [6,6-2H2]glucose. Beta cell function was determined from incremental AUC(C-peptide)0-60min/δAUC(glucose)0-60min during intravenous glucose tolerance test. Hepatocellular lipid content (HCL), γATP and inorganic phosphate (Pi) were measured with by 1H/31P magnetic resonance spectroscopy. MODY 2 patients had higher hemoglobin A1c (6.1±0.1 vs. 5.2±0.1%, p<0.001) along with approximately 62% lower glucose-stimulated C-peptide secretion than CON (p<0.05). They also had lower hepatic IS (1.8±0.1 vs. 2.3±0.1 mg/(kg*min), p<0.05), but similar whole body IS (12.6±1.9 vs. 13.1±1.5 mg/(kg*min), p=0.87) compared to CON. However, HCL (1.0±0.9 vs. 0.5±0.2%, p=0.46), γATP (3.5±0.3 vs. 3.5±0.6 mmol/l, p=0.99) and Pi (1.9±0.5 vs. 2.9±0.7 mmol/l, p=0.45) in the liver were comparable between both groups.

In conclusion, these data show that lower hepatic IS, but not abnormal hepatic energy metabolism, underlies the previously reported reduction in prandial hepatic glycogen synthesis. Moreover, impairment of hepatic IS is not necessarily associated with hepatic mitochondrial function.


K. Bódis: None. O.P. Zaharia: None. Y. Karusheva: None. P. Bobrov: None. D.F. Markgraf: None. B. Knebel: None. Y. Kupriyanova: None. J. Hwang: None. V. Burkart: None. K. Müssig: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. J. Szendroedi: None.

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