Congenital Hyperinsulinism of Infancy (CHI) is a group of rare, inheritable disorders with persistent hypoglycemia due to hyperinsulinemia. CHI is caused by mutations in genes that affect regulation of insulin secretion in β-cells. One such gene is HADH, which encodes short-chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD), a metabolic enzyme of the fatty acid beta-oxidation pathway. Mutations resulting in SCHAD deficiency cause protein-sensitive CHI and increased systemic levels of some fatty acid oxidation metabolites.

To test the hypothesis that SCHAD-CHI is caused by a specific deficiency of this ubiquitously expressed protein in β-cells we created β-cell-specific SCHAD knock-out (β-SCHADKO) mice by crossing Hadh-floxed animals with mice expressing Cre under the regulation of the Ins1 promoter. Validity of the β-SCHADKO model was confirmed by PCR, Western Blot and immunofluorescence staining of pancreas tissue. Growth and development of β-SCHADKO mice was similar to littermate controls. Plasma glucose in the KOs was significantly reduced in the random fed state (♂ 158 ± 15 vs. 115 ± 28 mg/dL, p=0.0016; ♀ 143 ± 8 vs. 97 ± 19 mg/dL, p<0.0001) and after overnight fasting (♂ 82 ± 14 vs. 56 ± 13 mg/dL, p<0.0002; ♀ 62 ± 7 vs. 42 ± 4 mg/dL, p<0.0001). Insulin and C-peptide levels were elevated in female KOs after overnight fasting (insulin: 0.25 ± 0.15 vs. 0.38 ± 0.21 ng/mL, p=0.0507; C-peptide: 0.15 ± 0.07 vs. 0.26 ± 0.16 ng/mL, p=0.05), but unchanged in the fed state. GSIS and overall glucose homeostasis, as assessed by insulin and glucose tolerance tests, were not significantly altered. Overall, these data indicate that the β-SCHADKO mouse is a suitable model to investigate the hypoglycemic phenotype of underlying SCHAD deficiency.


J. Ludeke: None. K.M. Velasco: None. D.F. De Jesus: None. B.A. Slipp: None. J. Hu: None. S.J. Steine: None. G. Helgeland: None. P. Njølstad: None. R. Kulkarni: None. A. Molven: None.

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