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ACACB encoding mitochondrial enzyme for carboxylation of acetyl-CoA is a novel disease-causing gene for congenital hyperinsulinemia

Campbell, Teresa, B.S.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592171025208869

Abstract Details

2020, MS, University of Cincinnati, Medicine: Genetic Counseling.
Congenital hyperinsulinemia is a heterogenous group of disorders resulting in improper insulin secretion from the pancreatic beta cells at birth. Elevated insulin leads to persistent hypoglycemia, increasing the patient’s risk for seizure and many long-term disabilities. ACACB codes for Acetyl-CoA Carboxylase 2 (ACC2), an outer mitochondrial membrane enzyme involved in fatty acid synthesis. Global ACACB knockout mice show continuous fatty acid oxidation and lowered plasma insulin levels when fed a high fat, high carbohydrate diet. Despite this, the role of ACC2 in the pancreatic beta cell has yet to be described. In this study, we have identified five individuals with congenital hyperinsulinemia hypoglycemia and developmental delays. Next generation sequencing found all five individuals have variants of unknown significance in the ACACB gene. Fibroblast samples collected from two affected individuals demonstrated impaired ACC2 enzyme activity and abnormal ACACB gene expression. To examine the mechanism of ACC2 in the pancreatic beta-cells, a conditional pancreatic-specific ACACB knockout mouse model was created. We found conditional pancreatic-specific ACACB knockout results in increased body weights and elevated circulating insulin levels. For the underlying molecular mechanism, we found mutant mice had increased expression of uncoupling protein 2 (UCP2) and mild elevated fatty acid receptor 1 (FFAR1). Our data demonstrates the loss of ACC2 causes congenital hyperinsulinemia in humans. This clinical feature is recapitulated in pancreatic specific conditional knockout mouse model. We propose the ACACB gene is a novel disease-causing gene for congenital hyperinsulinemia hypoglycemia through regulation of insulin secretion in the pancreatic beta cells.
Taosheng Huang, M.D. Ph.D. (Committee Chair)
Takahisa Nakamura, Ph.D. (Committee Member)
Arnold Strauss, M.D. (Committee Member)
41 p.
Genetics
ACC2; ACACB; Hyperinsulinemia; Hypoglycemia; Fatty Acid Synthesis; Acetyl-CoA Carboxylase

Recommended Citations

Citations

  • Campbell, T. (2020). ACACB encoding mitochondrial enzyme for carboxylation of acetyl-CoA is a novel disease-causing gene for congenital hyperinsulinemia [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592171025208869

    APA Style (7th edition)

  • Campbell, Teresa. ACACB encoding mitochondrial enzyme for carboxylation of acetyl-CoA is a novel disease-causing gene for congenital hyperinsulinemia. 2020. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592171025208869.

    MLA Style (8th edition)

  • Campbell, Teresa. "ACACB encoding mitochondrial enzyme for carboxylation of acetyl-CoA is a novel disease-causing gene for congenital hyperinsulinemia." Master's thesis, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1592171025208869

    Chicago Manual of Style (17th edition)

ucin1592171025208869
110
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This open access ETD is published by University of Cincinnati and OhioLINK.