+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Role of the transcription factor sox4 in insulin secretion and impaired glucose tolerance

Role of the transcription factor sox4 in insulin secretion and impaired glucose tolerance

Diabetes 57(8): 2234-2244

To identify, map, clone, and functionally validate a novel mouse model for impaired glucose tolerance and insulin secretion. Haploinsufficiency of the insulin receptor and associated mild insulin resistance has been used to sensitize an N-ethyl-N-nitrosourea (ENU) screen to identify novel mutations resulting in impaired glucose tolerance and diabetes. The new impaired glucose tolerance 4 (IGT4) model was selected using an intraperitoneal glucose tolerance test and inheritance of the phenotype confirmed by generation of backcross progeny. Segregation of the phenotype was correlated with genotype information to map the location of the gene and candidates sequenced for mutations. The function of the SRY-related high mobility group (HMG)-box 4 (Sox4) gene in insulin secretion was tested using another ENU allele and by small interfering RNA silencing in insulinoma cells. We describe two allelic autosomal dominant mutations in the highly conserved HMG box of the transcription factor Sox4. Previously associated with pancreas development, Sox4 mutations in the adult mouse result in an insulin secretory defect, which exhibits impaired glucose tolerance in association with insulin receptor(+/-)-induced insulin resistance. Elimination of the Sox4 transcript in INS1 and Min6 cells resulted in the abolition of glucose-stimulated insulin release similar to that observed for silencing of the key metabolic enzyme glucokinase. Intracellular calcium measurements in treated cells indicate that this defect lies downstream of the ATP-sensitive K(+) channel (K(ATP) channel) and calcium influx. IGT4 represents a novel digenic model of insulin resistance coupled with an insulin secretory defect. The Sox4 gene has a role in insulin secretion in the adult beta-cell downstream of the K(ATP) channel.

(PDF emailed within 0-6 h: $19.90)

Accession: 055614626

Download citation: RISBibTeXText

PMID: 18477811

DOI: 10.2337/db07-0337

Related references

Insulin secretion and insulin sensitivity pattern is different in isolated impaired glucose tolerance and impaired fasting glucose: the risk factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes study. Diabetes Care 26(3): 868-874, 2003

Natural history of insulin sensitivity and insulin secretion in the progression from normal glucose tolerance to impaired fasting glycemia and impaired glucose tolerance: the Inter99 study. Diabetes Care 32(3): 439-444, 2009

Impaired insulin secretion in subjects with impaired glucose tolerance; role of family history of type 2 diabetes. Diabetes Research & Clinical Practice 50(Suppl 1): S103, September, 2000

Islet dysfunction in insulin resistance involves impaired insulin secretion and increased glucagon secretion in postmenopausal women with impaired glucose tolerance. Diabetes Care 23(5): 650-657, 2000

Evaluation of antioxidative activity, insulin sensitivity and insulin secretion in early glucoregulation disorders-impaired fasting glucose and impaired glucose tolerance. Diabetes & Metabolism 29(Hors serie 2): 4S65, August, 2003

Activation of PPARĪ“ up-regulates the expression of insulin gene transcription factor MafA and ameliorates glucose-induced insulin secretion impaired by palmitate. Molecular and Cellular Biochemistry 366(1-2): 183-189, 2012

Insulin secretion and insulin resistance in impaired fasting glucose and impaired glucose tolerance subjects. Diabetologia 44(Supplement 1): A 56, August, 2001

Variants of transcription factor 7-like 2 (TCF7L2) gene predict conversion to type 2 diabetes in the Finnish Diabetes Prevention Study and are associated with impaired glucose regulation and impaired insulin secretion. Diabetologia 50(6): 1192-1200, 2007

Insulin secretion and action show differences in impaired fasting glucose and in impaired glucose tolerance in Asian Indians. Diabetes/Metabolism Research and Reviews 19(4): 329-332, 2003

Impaired insulin sensitivity, insulin secretion, and glucose effectiveness predict future development of impaired glucose tolerance and type 2 diabetes in pre-diabetic African Americans: implications for primary diabetes prevention. Diabetes Care 27(6): 1439-1446, 2004

The significance of impaired fasting glucose versus impaired glucose tolerance: importance of insulin secretion and resistance. Diabetes Care 26(5): 1333-1337, 2003

Secretion and action of insulin among Han and Uygur subjects with impaired fasting glucose and impaired glucose tolerance from Xinjiang. Zhonghua Liu Xing Bing Xue Za Zhi 33(9): 961-963, 2014

Pancreatic fat is negatively associated with insulin secretion in individuals with impaired fasting glucose and/or impaired glucose tolerance: a nuclear magnetic resonance study. Diabetes/Metabolism Research and Reviews 26(3): 200-205, 2010

Effect of pioglitazone on insulin secretion in patients with both impaired fasting glucose and impaired glucose tolerance. Diabetes Research and Clinical Practice 75(1): 115-118, 2006

Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes 55(5): 1430-1435, 2006