Abstract
BackgroundThere is a significant clinical overlap between patients with hepatocyte nuclear factor (HNF)-1A and HNF4A maturity-onset diabetes of the young (MODY), two forms of monogenic diabetes. HNF1A and HNF4A are transcription factors that control common and partly overlapping sets of target genes. We have previously shown that elevated serum pancreatic stone protein / regenerating protein A (PSP/reg1A) levels can be detected in subjects with HNF1A-MODY. In this study, we investigated whether PSP/reg is differentially regulated by HNF1A and HNF4A.MethodsQuantitative real-time PCR (qPCR) and Western blotting were used to validate gene and protein expression in cellular models of HNF1A- and HNF4A-MODY. Serum PSP/reg1A levels and high-sensitivity C-reactive protein (hsCRP) were measured by ELISA in 31 HNF1A- and 9 HNF4A-MODY subjects. The two groups were matched for age, body mass index, diabetes duration, blood pressure, lipid profile and aspirin and statin use.ResultsInducible repression of HNF1A and HNF4A function in INS-1 cells suggested that PSP/reg induction required HNF4A, but not HNF1A. In contrast, crp gene expression was significantly reduced by repression of HNF1A, but not HNF4A function. PSP/reg levels were significantly lower in HNF4A subjects when compared to HNF1A subjects [9.25 (7.85-12.85) ng/ml vs. 12.5 (10.61-17.87) ng/ml, U-test P = 0.025]. hsCRP levels were significantly lower in HNF1A-MODY [0.22 (0.17-0.35) mg/L] compared to HNF4A-MODY group [0.81 (0.38-1.41) mg/L, U-test P = 0.002], Parallel measurements of serum PSP/reg1A and hsCRP levels were able to discriminate HNF1A- and HNF4A-MODY subjects.ConclusionOur study demonstrates that two distinct target genes, PSP/reg and crp, are differentially regulated by HNF1A and HNF4A, and provides clinical proof-of-concept that serum PSP/reg1A and hsCRP levels may distinguish HNF1A-MODY from HNF4A-MODY subjects.
Highlights
There is a significant clinical overlap between patients with hepatocyte nuclear factor (HNF)-1A and Hepatocyte nuclear factor4alpha (HNF4A) maturity-onset diabetes of the young (MODY), two forms of monogenic diabetes
Serum Pancreatic stone protein / regenerating protein (PSP/reg) levels may discriminate Hepatocyte nuclear factor-1alpha (HNF1A)-MODY from HNF4A-MODY subjects In a previous study, we have shown that serum levels of the regenerative protein, PSP/reg1A, were elevated in subjects with HNF1A-MODY when compared to MODYnegative body mass index (BMI), sex, and age-matched family members [24]
We have previously shown that PSP/reg1A levels did not correlate with Haemoglobin A1c (HbA1c) in HNF1A-MODY [25]
Summary
There is a significant clinical overlap between patients with hepatocyte nuclear factor (HNF)-1A and HNF4A maturity-onset diabetes of the young (MODY), two forms of monogenic diabetes. HNF1A and HNF4A are transcription factors that control common and partly overlapping sets of target genes. Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of non-ketotic, non-insulin dependent diabetes that is typically diagnosed before 25 years of age. The majority of MODY subjects are defined by mutations in six specific MODY-related genes, including the nuclear transcription factors hepatocyte nuclear factor (HNF)-1A and HNF-4A [1,2,3]. Features of HNF1A and HNF4A mutation carriers tend to overlap with type 1 diabetes, type 2 diabetes and other monogenic forms of diabetes [12,13]. Sequencing is expensive and not immediately available in many hospitals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
