Evidence for Impaired Gluconeogenesis in Very Long-chain Acyl-CoA Dehydrogenase-deficient Mice (original) (raw)

Horm Metab Res 2006; 38(10): 625-630
DOI: 10.1055/s-2006-954581

Original Basic

U. Spiekerkoetter 1 , 2 , 3 , J. Ruiter 2 , C. Tokunaga 3 , U. Wendel 1 , E. Mayatepek 1 , F. A. Wijburg 2 , A. W. Strauss 3 , R. J. A. Wanders 2

1Department of General Pediatrics, University Children's Hospital, 40225 Düsseldorf, Germany
2University of Amsterdam, Academic Medical Centre, Departments of Pediatrics and Clinical Chemistry, 1105 AZ Amsterdam, The Netherlands
3Department of Pediatrics and Vanderbilt Children's Hospital, Vanderbilt University, Nashville, TN, 37232, USA

Further Information

Publication History

Received 16 February 2006

Accepted after revision 3 July 2006

Publication Date:
30 October 2006 (online)

Abstract

Hypoketotic hypoglycaemia is a characteristic feature of fatty acid oxidation (FAO) defects. Although the underlying pathogenic mechanism is unknown, one hypothesis points to an impairment in gluconeogenesis. To study hepatic glucose production in FAO defects, we used the knockout mouse model of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency presenting with stress-induced hypoglycaemia. We analysed metabolites of hepatic glucose production under non-stressed conditions and after stress in comparison to wildtype controls. Analysis included glycogen, glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), glycerol-3-phosphate (G3P) and dihydroxyacetone-phosphate (DHAP). We also measured the activity of the key enzyme glucose-6-phosphatase. Blood and liver glucose were found to be low after stress, and liver glycogen was depleted. In addition, hepatic G6P and F6P were significantly reduced, especially during hypoglycaemia. Importantly, the activity of the enzyme converting G6P into glucose was not impaired. These data indicate a reduced rate of gluconeogenesis. The levels of DHAP and G3P were significantly lower suggesting decreased availability of glucose precursors from glycerol. This study gives biochemical evidence of impaired gluconeogenesis as one of the causes for hypoglycaemia observed in VLCAD deficiency. Whether this is due to lack of a substrate, inhibitory effects on other gluconeogenic enzymes or impaired transcription of gluconeogenic enzymes needs to be resolved in the future.

Key words

Fatty acid β-oxidation - hypoketotic hypoglycaemia - glycerol - hepatic glucose production

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Correspondence

Ute Spiekerkoetter

Department of General Pediatrics·University Children's Hospital

Moorenstr. 5· 40225 Düsseldorf

Germany

Phone: +49/211/811 76 87

Fax: +49/211/811 95 12

Email: ute.spiekerkoetter@uni-duesseldorf.de