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General Poster Session

Hyperproinsulinemia in OGlcNAc Transferase Deficient Mice Is Associated with Loss of CPE and eIF4G1, but ß-Cell Deletion of eIF4G1 Induces Glucose Intolerance Independent of CPE Dysregulation

  1. SEOKWON JO,
  2. AMBER D. LOCKRIDGE and
  3. EMILYN ALEJANDRO
  1. Minneapolis, MN, Saint Paul, MN
Diabetes 2018 Jul; 67(Supplement 1): -. https://doi.org/10.2337/db18-2167-P
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Abstract

β cell loss of OGlcNAc transferase (βOGTKO), the sole enzyme that adds OGlcNAc post-translational modification onto target proteins impacting their function and stability, leads to diabetes and islet failure in mice. βOGTKO mice present hyperproinsulinemia, typified by increased serum proinsulin/insulin ratio. Here, we show that βOGTKO islets have reduced carboxypeptidase E protein but not mRNA (CPE, an exopeptidase that converts proinsulin to insulin), independent of sex, age and glucose levels. We identified that CPE is neither the target nor a binding partner of OGT. Eukaryotic initiation factor 4 gamma 1 (eIF4G1), previously shown to regulate CPE in vitro, is reduced at the protein level, but not mRNA, in βOGTKO islets. We identified that eIF4G1 is OGlcNAc-modified in β cells and mutation of the putative OGlcNAc site at serine 61 to alanine led to decreased protein stability, but not on CPE translation. To assess the role of eIF4G1 on CPE regulation in vivo, we generated mice with β cell specific deletion of eIF4G1 (RIPCre; eIF4G1flox/flox (βeIF4G1KO)), in R1207H eIF4G1 (eIF4G1) background. At 6 weeks of age in normal chow diet, glucose intolerance was evident between βeIF4G1KO and littermate control eIF4G1 mice, without alteration in peripheral insulin sensitivity. Surprisingly, no apparent insulin processing deficit was observed between βeIF4G1KO and eIF4G1 mice, consistent with the observed normal level of CPE protein among islets of βeIF4G1 KO, eIF4G1 or wild type mice via immunofluorescence, and comparable serum proinsulin/insulin ratio in βeIF4G1 KO and eIF4G1 mice. Significant reduction in the average β cell size and increased number of α cells was evident in βeIF4G1KO vs. eIF4G1 mice, hinting at loss in β cell mass. Together, these data unveil the regulation of OGT on eIF4G1, and underscore the novel role of eIF4G1 on glucose homeostasis and modulation of β cell size.

Disclosure S. Jo: None. A.D. Lockridge: None. E. Alejandro: None.

  • © 2018 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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July 2018, 67(Supplement 1)
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Hyperproinsulinemia in OGlcNAc Transferase Deficient Mice Is Associated with Loss of CPE and eIF4G1, but ß-Cell Deletion of eIF4G1 Induces Glucose Intolerance Independent of CPE Dysregulation
SEOKWON JO, AMBER D. LOCKRIDGE, EMILYN ALEJANDRO
Diabetes Jul 2018, 67 (Supplement 1) 2167-P; DOI: 10.2337/db18-2167-P

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Hyperproinsulinemia in OGlcNAc Transferase Deficient Mice Is Associated with Loss of CPE and eIF4G1, but ß-Cell Deletion of eIF4G1 Induces Glucose Intolerance Independent of CPE Dysregulation
SEOKWON JO, AMBER D. LOCKRIDGE, EMILYN ALEJANDRO
Diabetes Jul 2018, 67 (Supplement 1) 2167-P; DOI: 10.2337/db18-2167-P
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