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Sox17 regulates insulin secretion in the normal and pathologic mouse ? cell.

ABSTRACT: SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1? and FOXA2, which are known to regulate postnatal ? 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 ? 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.

SUBMITTER: Jonatan D

PROVIDER: S-EPMC4140688 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe increase in diabetes worldwide is alarming. Decreased acute insulin response to intravenous glucose tolerance test (IVGTT) during first-phase insulin secretion (FPIS) is a characteristic of diabetes. However, knowledge of the insulin secretion characteristics identified by different time to glucose peak in subjects with different metabolic state is sparse.AimsThis study aimed to find different patterns of FPIS in subjects with normal glucose tolerance (NGT) and analyzed the relationship between insulin secretion patterns and the risk for development of type 2 diabetes mellitus (T2DM).MethodsA total of 126 subjects were divided into three groups during a 10-min IVGTT, including NGT with time to glucose peak after 3 min (G1, n = 21), NGT with time to glucose peak at 3 min (G2, n = 95), and prediabetes or diabetes with time to glucose peak at 3 min (G3, n = 10). Glucose, insulin, and C-peptide concentrations at 0, 3, 5, 7, and 10 min during the IVGTT were tested. IVGTT-based indices were calculated to evaluate the insulin secretion and insulin sensitivity.ResultsAge, body mass index (BMI), waist-to-hip ratio, triglyceride (TG), and hemoglobin A1c (HbA1c) of subjects were gradually higher, while high-density lipoprotein cholesterol (HDL-C) was gradually lower from G1 to G3 (p for linear trend <0.05), and the differences between G1 and G2 were also statistically significant (p < 0.05). Glucose peak of most participants in G1 converged at 5 min, and the curves shape of insulin and C-peptide in G2 were the sharpest among three groups. There was no significant difference in all IVGTT-based indices between G1 and G2, but AUCIns, AUCIns/AUCGlu, and △Ins3/△Glu3 in G2 were the highest, and the p-value for linear trend of those indices among three groups were statistically significant (p < 0.05).ConclusionsTwo patterns of FPIS were in subjects with NGT, while subjects with later time to glucose peak during FPIS might be less likely to develop T2DM in the future.

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Sox17 regulates insulin secretion in the normal and pathologic mouse ? cell.

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