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SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells
Melkam A. Kebede, … , Anjon Audhya, Alan D. Attie
Melkam A. Kebede, … , Anjon Audhya, Alan D. Attie
Published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4240-4256. https://doi.org/10.1172/JCI74072.
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Research Article Endocrinology Article has an altmetric score of 6

SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed β cells

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Abstract

We previously positionally cloned Sorcs1 as a diabetes quantitative trait locus. Sorcs1 belongs to the Vacuolar protein sorting-10 (Vps10) gene family. In yeast, Vps10 transports enzymes from the trans-Golgi network (TGN) to the vacuole. Whole-body Sorcs1 KO mice, when made obese with the leptinob mutation (ob/ob), developed diabetes. β Cells from these mice had a severe deficiency of secretory granules (SGs) and insulin. Interestingly, a single secretagogue challenge failed to consistently elicit an insulin secretory dysfunction. However, multiple challenges of the Sorcs1 KO ob/ob islets consistently revealed an insulin secretion defect. The luminal domain of SORCS1 (Lum-Sorcs1), when expressed in a β cell line, acted as a dominant-negative, leading to SG and insulin deficiency. Using syncollin-dsRed5TIMER adenovirus, we found that the loss of Sorcs1 function greatly impairs the rapid replenishment of SGs following secretagogue challenge. Chronic exposure of islets from lean Sorcs1 KO mice to high glucose and palmitate depleted insulin content and evoked an insulin secretion defect. Thus, in metabolically stressed mice, Sorcs1 is important for SG replenishment, and under chronic challenge by insulin secretagogues, loss of Sorcs1 leads to diabetes. Overexpression of full-length SORCS1 led to a 2-fold increase in SG content, suggesting that SORCS1 is sufficient to promote SG biogenesis.

Authors

Melkam A. Kebede, Angie T. Oler, Trillian Gregg, Allison J. Balloon, Adam Johnson, Kelly Mitok, Mary Rabaglia, Kathryn Schueler, Donald Stapleton, Candice Thorstenson, Lindsay Wrighton, Brendan J. Floyd, Oliver Richards, Summer Raines, Kevin Eliceiri, Nabil G. Seidah, Christopher Rhodes, Mark P. Keller, Joshua L. Coon, Anjon Audhya, Alan D. Attie

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Figure 1

Deletion of Sorcs1 in the leptin-deficient mice leads to diabetes.

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Deletion of Sorcs1 in the leptin-deficient mice leads to diabetes.
(A an...
(A and B) Plasma glucose (A) and insulin (B) levels following a 4-hour fast in female B6 ob/ob (n = 12) and Sorcs1 KO ob/ob (n = 10) mice as a function of age. (C–E) Plasma glucose (C), insulin (D), and insulin-to-glucose ratio (E) during an oral glucose tolerance test (OGTT) in 20-week-old female B6 ob/ob (n = 9) and Sorcs1 KO ob/ob (n = 12) mice. (F) Glucose during an intraperitoneal insulin tolerance test (IP-ITT) in 4-hour-fasted 12-week-old female B6 ob/ob (n = 8) and Sorcs1 KO ob/ob (n = 12) mice. Data are represented as mean ± SEM (*P < 0.05, **P < 0.005, ***P < 0.0001).

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