Abstract
SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1β and FOXA2, which are known to regulate postnatal β cell function. Given this, we investigated the role of SOX17 in the developing and postnatal pancreas and found a novel role for SOX17 in regulating insulin secretion. Deletion of the Sox17 gene in the pancreas (Sox17-paLOF) had no observable impact on pancreas development. However, Sox17-paLOF mice had higher islet proinsulin protein content, abnormal trafficking of proinsulin, and dilated secretory organelles suggesting that Sox17-paLOF adult mice are prediabetic. Consistant with this, Sox17-paLOF mice were more susceptible to aged-related and high fat diet-induced hyperglycemia and diabetes. Overexpression of Sox17 in mature β cells using Ins2-rtTA driver mice resulted in precocious secretion of proinsulin. Transcriptionally, SOX17 appears to broadly regulate secretory networks since a 24-hour pulse of SOX17 expression resulted in global transcriptional changes in factors that regulate hormone transport and secretion. Lastly, transient SOX17 overexpression was able to reverse the insulin secretory defects observed in MODY4 animals and restored euglycemia. Together, these data demonstrate a critical new role for SOX17 in regulating insulin trafficking and secretion and that modulation of Sox17-regulated pathways might be used therapeutically to improve cell function in the context of diabetes.
Highlights
Secretion of insulin by pancreatic b cells in response to glucose is central for glucose homeostasis, and dysregulation of this process is a hallmark of the early stages of diabetes
Sox17 is not required for b cell development During the formation of the embryonic endoderm, SOX17 regulates several key transcription factors and signaling pathways that are known to play a central role in pancreas development and adult b cell homeostasis
Pancreatic loss of Sox17 resulted in trafficking defects of proinsulin through the endoplasmic reticulum (ER), dilated and distended secretory organelles, and a trend of increased secretion of proinsulin (Figure S10C), all of which are hallmarks of prediabetes [7,8,9,10,11,12,13,14,15,16,17]
Summary
Secretion of insulin by pancreatic b cells in response to glucose is central for glucose homeostasis, and dysregulation of this process is a hallmark of the early stages of diabetes. At 12 weeks of age, the pancreas of Sox17-paLOF (Sox17fl/fl;Pdx1-Cre) animals appeared normal and gross islet architecture was no different from control animals as observed by the distribution of insulin, glucagon, and somatostatin expressing cells (Figure S1C–D).
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