MOH Key Laboratory of Endocrine and Metabolic Diseases has a hormone assay laboratory for all patients with endocrine and metabolic disorders in the hospital and in the other medical and research institutes as well. The center also has a research laboratory occupying a space of nearly 1000 m2 and well equipped with DDPCR, real-time PCR, 2-D gel, LICOR sequencer, CEQ8800 genetics analysis system, patch-clamp, and FISH, etc. for the research in endocrinology and metabolism. The senior endocrinologists in the center have earned a great reputation for their contributions in building up the discipline of endocrinology in China and academic achievements. With their instruction, teaching and support, a bunch of young endocrinologists have grown up. Those young people have also been trained in Western countries, have a good master of English and French and have publications in peer-reviewed journals. They have taken over the heavy task for the further development of the discipline. We study key genes and signaling pathways which regulate β-cell replication and functions for Diabetes treatments. Multiple endocrine neoplasia type 1 (MEN1) gene encodes menin, which plays a crucial role in β-cell proliferation. Our group had demonstrated that menin regulates Wnt/β-catenin signaling (MCB, 2009). In this study, we will focus on the functions of menin and Wnt/β-catenin signaling in pancreatic development and β-cell proliferation. We will establish β-cell specific Men1 knockout mice and Men1/β-catenin double knockout mice. Based on the studies on these models and clinical samples, we will explore the precise regulation of beta-cell proliferation in different developmental stages and in pregnant and obesity. Men1 and Wnt signaling related new targets for diagnosis and treatment of diabetes will be revealed.
Candidate genes on chromosomal region near D9S171 which has been shown to be linked with type 2 diabetes in our previous study have been screened and 2 missense mutations on ADFP gene were shown to be co-segregated with type 2 diabetes in 2 diabetic pedigrees. Both mutations caused amino acid substitution with change of polarity. These kinds of mutations are generally considered to result in the structural and functional modification of the protein, thus causing the disorder of glucose and lipid metabolism.
Besides positional cloning, we also screened genes involved in glucose and lipid metabolism, insulin signal transduction and insulin secretion. Our results showed that ACCB is associated with type 2 diabetes while GLP1R is associated with type 2 diabetes in patients with major pathogenic defect of insulin secretion.
We have developed a rat model of type 2 diabetes associated cardiovascular pathology. Using this model, we have screened differentially expressed genes in the heart tissue of diabetic rat. 63 sequences have been identified by DDPCR, including 32 known genes, ten known EST and 21 unknown EST, from which a new gene have been cloned by RACE and sequencing, with the full length of 1594 bp, and was named as 2ass-bnip3 (AY095482). Structural analysis of the encoded protein showed that it may play an important role in the regulation of Ca concentration and cell apoptosis.
Using 2D electrophoresis, we have screened proteins that are differentially expressed in the vascular tissue of diabetic patients. More than 100 spots have been identified, and 20 of them have been further analyzed with tandem mass spectrometry. One of the identified protein, t-Ror1 has been further confirmed with Western-blot. Tissue distribution analysis showed that it mainly expressed in the adventitia connective tissue and smooth muscle layer of blood vessels.
In adipose tissue, seven proteins have been identified to be differentially expressed in obese and normal weight subjects, amd these proteins included aminopeptidase, cathepsin K, IGFBP-3, FGF receptor, lipin and two unknown proteins. Functional analysis of the catepsin K showed that its expression is steadily increased during the induced differentiation of preadipocyte, implicating its important role in adipocyte differentiation.
We have launched a population study with 20,000 subjects in Baoshan District, Shanghai at the age 40 or above. The cohort of 500 subjects with normal glucose tolerance, pre-diabetes and type 2 diabetes, respectively has been formed. The baseline investigation included a questionnaire, physical examination, vessel function, fasting and 2-h postprandial plasma glucose and serum lipid levels. DNA samples have been obtained and extracted. The trans-sectional data showed the prevalence of type 2 diabetes is 15.6%. The micro- and macrovascular diseases were significantly increased in type 2 diabetic patients.
We have actively engaged in global cooperation and communication. Since 2004, Rui-Jin International Forum of Endocrinology has been held every two years with hundreds of principle investigators in the basic and clinical research field of endocrinology and metabolism coming from different countries and regions all over the world. We have also launched several research projects cooperating with Roche R&D Center, Free University of Brussels, Université de Paris 5, Joslin Diabetes Center, Southwestern University and Baylor College of Medicine, financing young scientists for latest technologies on molecular biology, cell biology and proteomics. There have been three young doctors from our department studying in Free University for M.D. and PH.D. Cooperation in islet transplantation was widely carried out and doctors were sent out to islet transplantation centers in Europe for further learning. Investigations on treatment of ACTH syndrome were performed with IPSEN Corporation from France. Research technologies, platforms and concepts have been greatly enhanced through the afore-mentioned cooperation globally.