Day 1 :
Keynote Forum
Douglas N Ishii
Colorado State University, USA
Keynote: Why clinical trials that reduce glucose levels fail to prevent complications in diabetic patients: Tests support an alternative hypothesis for pathogenesis
Time : 09:-10:00
Biography:
Douglas N Ishii received his BA in Biochemistry from University of California, Berkeley and PhD in Pharmacology from Stanford University Medical School and conducted Postdoctoral work in Neurobiology at Stanford. He became Assistant then Associate Professor of Pharmacology at Columbia University, New York City. He is a Professor of Biomedical Sciences at Colorado State University. He served on various scientific study sections for National Science Foundation, National Institutes of Health and The Juvenile Diabetes International Foundation. Press coverage on his laboratory’s research on pathogenesis of diabetic neurological complications, and cause of brain atrophy in Alzheimer’s disease, includes articles in Der Spiegel, Hong Kong Standard, NY Times, LA Times, Denver Post, Chicago Tribune, ABC News, Forbes News, USA Today, National Public Radio, and elsewhere. Nineteen patents were awarded based on this research.
Abstract:
Statement of Problem: Meta-analysis of outcomes on 34,533 Type 2 diabetic patients shows that intensive lowering of glucose levels
does not prevent neuropathy, retinopathy, nephropathy, cardiovascular death, nor excess mortality. Nor does lowering of glucose levels prevent complications in approximately 40% of type 1 patients. Exposing patients to adverse effects from unbeneficial drugs is unjustified, yet remains standard therapy. The development of meaningful novel treatments awaits an alternative hypothesis for
pathogenesis of diabetic complications.
Methodology & Theoretical Orientation: Insulin and insulin-like growth factors (IGFs) are neurotrophic factors. The inter-related
hypotheses were developed that diminished insulin and IGF activities is the dominant cause of neurological complications, and that replacement of such activities should ameliorate diabetic complications irrespective of unabated hyperglycemia. These hypotheses were tested by infusing IGFs, insulin, or their combination into diabetic rats to determine whether neuropathy is alleviated under conditions in which hyperglycemia remains unabated.
Conclusion & Significance: IGF mRNA levels are reduced in peripheral nerves, brain and spinal cord in diabetes. Replacement IGF infusion prevented impaired sensory and motor nerve regeneration, hyperalgesia, abnormal ultrastructure in autonomic axons, loss of epidermal nerve fiber density, and poor gastric wound healing despite undiminished hyperglycemia. Tiny doses of insulin
and/or IGF were infused into diabetic rat brains under conditions that did not reduce hyperglycemia. A decrease in total mRNA, protein, and DNA levels was associated with brain atrophy and impaired learning/memory in diabetic rats. Insulin and IGF i.c.v. infusion prevented all such disturbances despite unabated hyperglycemia. Insulin and IGFs are master switches controlling the levels of hundreds of proteins in brain; loss of protein regulation, not hyperglycemia, is proposed as the most likely pathogenic cause for diabetic complications. Governments should manufacture clinical grade IGF (off- patent). Clinical trials are urgently needed to test insulin/IGF therapy.
Keynote Forum
Serge P Bottari
University Grenoble Alpes, France
Keynote: Serum IRAP, a novel direct biomarker of insulin-resistance
Time : 10:00-10:45
Biography:
Serge P. Bottari obtained his MD and his PhD degrees at the Free University Brussels, Belgium. He is specialized in OB/GYN and also obtained a PhD in Biochemistry. He was a Post-Doctoral Fellow and Research Associate at UC San Francisco. After having been a Project Leader at Sandoz and Ciba-Geigy in Basel, Switzerland, he became Professor of Cell Biology at the Medical School and Head of Endocrine Biology at the University Hospital in Grenoble, France, in 1993. He published over 65 articles in premium journals and is a member of several editorial boards. His current work focuses among others on the molecular mechanisms involved in insulin resistance and on the development of novel diagnostic tools.
Abstract:
Insulin resistance (IR) affects more than half of the adult population worldwide. Type 2 diabetes (T2D), which often follows in the absence of treatment, affects more than 400 million people and represents more than 10% of the health budget in industrialized countries. A preventive public health policy is urgently needed in order to stop this constantly progressing epidemic. Indeed, early management of IR does not only strongly reduce its evolution towards T2D but also strongly reduces the appearance of cardiovascular comorbidity as well as that of associated cancers. There is however currently no simple and reliable test available for the diagnosis or screening of IR and it is generally estimated that 20% of diabetics are not diagnosed. We therefore developed an ELISA for the quantitative determination of a novel circulating biomarker of IR, IRAP (Insulin-Regulated Amino Peptidase, EC 3.4.11.3). IRAP is associated with and translocated in a stoechiometric fashion to the plasma membrane together with GLUT4 in response to insulin in skeletal muscle and adipose tissue. Its extracellular domain (IRAPs) is subsequently cleaved and secreted in the blood stream. In T2D, IRAP translocation in response to insulin is strongly decreased. Our patented sandwich ELISA is highly sensitive (≥ 10.000- fold normal fasting concentrations) and specific, robust and very cost-effective. Dispersion of fasting plasma concentration values in a healthy population is very low (101.4±15.9 μg/ml) as compared to insulin and C-peptide. Results of pilot studies indicate an excellent correlation between IRAPs levels and insulin sensitivity. We therefore think that plasma IRAPs is a direct marker of insulin sensitivity and that the quantitative determination of its plasma levels should allow large-scale screening of populations at risk for IR and T2D; thereby allow the enforcement of a preventive health policy aiming at efficiently reducing this epidemic.
Keynote Forum
Yoon-Bong Hahn
Chonbuk National University, South Korea
Keynote: Selective detection of glucose, cholesterol and urea with metal oxide nanostructures based field effect transistors array biosensors
Biography:
Yoon-Bong Hahn is a Fellow of Korea Academy of Science and Technology, Director of BK21 Center for Future Energy Materials and Devices, Director of National Leading Research Lab for Hybrid Green Energy and Head of Semiconductor and Chemical Engineering School, Chonbuk National University (CBNU). He joined CBNU in 1991 prior to which he worked for LG Metals Research Center from 1988-1991 after he received his PhD in Metallurgical Engineering from University of Utah in 1988. His main research interest is the synthesis of metal and metal oxide nano structures and their applications for optoelectronic devices and chemical and biological sensors, resulting in over 280 peer-reviewed SCI papers and 14 patents. He co-authored 6 books including “Metal Oxide Nanostructures and Their Applications” published in March 2010 by American Scientific Publishers. He received Asian Energy Technology Award 2017 by International Association of Advanced materials, Rudolf A Marcus Award for outstanding research work in the field of Chemical Science in 2016, the ACerS Global Ambassador Award 2016 conferred by the American Ceramic Society, the Scientist of the Month Award in 2011 by Korea Ministry of Education, Science and Technology, the CBNU’s Best Research Professor Award consecutively in 2008-2010, and top 100 scientists award four times in 2005, 2011, 2014 and 2015 accredited by International Biographical Center, Cambridge, UK.
Abstract:
Nanotechnology revolution has led to the nano fabrication of sensor devices for rapid and specific identification of chemical/ biological species. However, the development of multiplexed nanoscale biosensor for simultaneous detection of different analytes still remains a major challenge at the nanotechnology frontier. It is well recognized that diabetes mellitus is a metabolic disorder resulting in an abnormal blood glucose level and activation of several metabolic pathways related to inflammation and apoptosis events. Heart disease and stroke due to excess cholesterol in blood is the leading cause of death and disability, and kidney failure due to excess urea is caused by urea cycle disorders. We have developed metal-oxide nanostructures based, integrated field-effect transistors (FETs) array biosensor with simultaneously immobilizing GOx, ChOx and Ur enzymes on three separated FET arrays. In this lecture, we report a novel straight forward approach for simultaneous and highly selective detection of multianalytes (i.e., glucose, cholesterol and urea) with the FETs array biosensor without interference in each sensor response. Compared to analytically measured data, performance of the FETs array biosensor is found to be highly reliable for rapid detection of multianalytes in mice blood, serum and blood smaples of diabetic dogs. The development of an integrated, low-cost FETs array biosensor will produce quick detection under critical patient conditions, early identification of disease/disorder, and also have an enormous impact on the future generations.
- Diabetes Melitus Type 1| Diabetes Melitus Type 2 | Diabetes Research | Diabetic Disorders and Treatment | Diabetic Neuropathy
Location: Olimpica 2
Chair
Douglas N. Ishii
Colorado State University | USA
Co-Chair
Serge P. Bottari
University Grenoble Alpes | France
Session Introduction
Sara Lasker
Madison T1D Coach LLC | USA
Title: Type 1 Diabetes: Seeing the whole person
Time : 14:15-14:40
Biography:
Sara Lasker is one of the first MCHES, CDE's in the world! As a Certified Diabetes Educator (CDE) and Master Certified Health Education Specialist (MCHES) she works with people to become the diabetes expert of their type 1 diabetes by discovering the Occupational, Social, Spiritual, Intellectual, Physical, Emotional, and Environmental
balance.
Abstract:
There is a mind shift that needs to occur in the clinical world of diabetes management to stay relative. The shift is to listen to the patient; what they were wanting out of their life with diabetes, and what/who can help motivate them; patients want to be more involved, motivated, and guided to find solutions to manage their diabetes. The management of type 1 diabetes goes beyond the basics and dives into the balance of the occupational, social, spiritual, intellectual, physical, emotional, and environmental (OSSIPEE) factors to live happy, healthful lives with diabetes. To stay relevant in your practice, you must come explore OSSIPEE.
Anna Archvadze
Tbilisi State Medical University | Georgia
Title: Clinical and Pharmacological basis for the use of drugs inhibiting of the RAAS in patients with Diabetic Neuropathy
Time : 14:40-15:05
Biography:
Archvadze Anna S H has Over 8 years’ experience as a Medical Doctor working in different medical institutions. She has Over 15 years’ experience as a Trainer/Teacher of Medical Sciences. Over 11 years’ experience in health and Social project/program development, execution, monitoring and completion, Over 7 years’ experience in International Project Management working for the world bank financed health projects, Over 5 years’ experience in an assessment of training needs, design and elaboration of training programs, provision of trainings for emergency care medical staff and for healthcare service providers, Over 10 years of experience in supervision of the contract performance with medical institutions, pharmaceutical firms, governmental and non-governmental organizations.
Abstract:
Introduction: The incidence of diabetes and its complications is increasing to staggering proportions. In 2014 the WHO estimated an overall prevalence of 422 million (8.5%) individuals with diabetes mellitus (DM). The diabetic neuropathy (DNP) which is one of complication of DM (50%) comprises a heterogeneous group of disorders that can cause neuronal dysfunction
throughout the human body. The optimal therapy involves: blood glucose level control, anticonvulsants, antidepressants and opioid administration, though it does not change pathogenic pattern. The recent studies suggest that the renin angiotensin aldosterone system (RAAS) plays a vital role in regulating glucose metabolism and blood pressure. In the same time the metabolic abnormalities associated with diabetes lead to activation RAAS, which might promote the formation of reactive oxygen species to lead the neuronal dysfunctions. Furthermore, TNFα is part of the response of the organism to hypertension and is originally described as one of the central mediators of inflammation trough the activation of transcription factor NFκB.
Methodology: The study is going on in parallel groups. The patients (enrolled on randomized principle) with DNP will be investigated. Group I with DNP was treated by aliskiren and group II with the same pathology, proceeding with the treatment without aliskiren but given telmisartan, for certainty of aliskiren efficacy. At the start of the trial and on completion of the six weeks period TNFα level and C-peptide are determined.
Findings: Telmisartan has less TNFα modulatory effects than aliskiren, namely, the symptoms of neuropathy as well as blood TNFα level and C-peptide level are not changed significantly.
Conclusion & Significance: TNFα is involved in DNP pathogenesis formation and clinical manifestation. Aliskiren amelioratessymptoms in DNP patients by modulatory impact on TNFα, so we have results for clinical and pharmacological analysis ofaliskiren application in DNP. The involvements of RAAS system in developments of DNP need further clinical analysis.
Kyunglim Lee
Ewha Womans University | Korea
Title: Use of transnationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin
Time : 15:05-15:30
Biography:
Kyunglim Lee received PhD degrees from Tufts University, MA, USA. She had Postdoctoral research training in Molecular and Cellular Biology, Harvard University. Since 1995, she has been with the College of Pharmacy, Ewha Womans University, where she is currently a Full Professor. Her main areas of research interest are pathophysiology of hypertension, allergy, and tumorigenesis caused by translationally controlled tumor protein. Currently, she serves as an Editorial Board Member of Scientific Reports and SM Journal of Nephrology and Therapeutics. She is a Member of the American Society for Biochemistry and Molecular Biology, Korean Society of Biochemistry and Molecular Biology, Korean Society for Molecular and Cellular Biology, Pharmaceutical Society of Korea.
Abstract:
Statement of the Problem: Insulin is given to patients with diabetes by subcutaneous injection. However, noninvasive intranasal administration is easier for patients requiring daily treatment. Protein transduction domains (PTDs) are recognized as promising vehicles for the delivery of macromolecular drugs. We have previously shown that a region in the N-terminus (residues 1–10) of translationally controlled tumor protein (TCTP) contains aPTD (TCTP-PTD), MIIYRDLISH, which can serve as a vehicle for the delivery of macromolecules into the cells and tissues. In the current study, we evaluated the potential and safety of TCTP-PTD and its mutant analogs as nasal absorption enhancers for delivery of insulin. The goal of the current study was to examine whether the co administration of a drug with TCTP-PTD or its mutant analogs, can efficiently deliver insulin into the nasal mucosal membranes of animals.
Methodology & Theoretical Orientation: We examined the degree to which insulin was absorbed in nasal mucosa and also if any mucosal damage occurs following such nasal delivery of insulin using TCTP-PTDs as a vehicle. The systemic delivery of insulin was assessed by measuring the changes in blood glucose levels after nasal co administration insulin and TCTP-PTDs.
Findings: Of the 4 TCTP-PTD analogs examined, TCTP-PTD 13 significantly enhanced the nasal absorption of insulin in normal mice as well as alloxan induced diabetic rats. The binding between the TCTP-PTD analog and insulin may enable the penetration of insulin through the nasal mucosa. Histological examination of mice and rat nasal mucosa 7 days after repeated nasal administration showed no evidence of toxicity at the site of nasal administration.
Conclusion & Significance: In this study using insulin as a test system we demonstrate that the TCTP-PTD analog offers a promising approach for nasal peptides and protein-drugs delivery.
Yoshihisa Sugimura
Fujita Health University | Japan
Title: Rabphilin-3A as a targeted autoantigen in lymphocytic infundibuloneurohypophysitis
Time : 15:30-15:55
Biography:
Yoshihisa Sugimura is currently working as Professor in the Division of Endocrinology and Metabolism, Department of Internal Medicine at Fujita Health University, Japan. He did his PhD at Nagoya University Graduate School of Medicine, Japan and he joined as an Assistant Professor in the same university. His main research interest is in endocrinology, diabetes, neuroendocrinology, water, sodium metabolism and hypernatremia vasopressin.
Abstract:
Central diabetes insipidus (CDI) can be caused by several diseases, but in about half of the patients the etiological diagnosis remains unknown. Lymphocytic infundibulo-neurohypophysitis (LINH) is an increasingly recognized entity among idiopathic CDI; however, the differential diagnosis from other pituitary diseases including tumors can be difficult due to similar clinical manifestations. The definite diagnosis of LINH requires invasive pituitary biopsy. The study was designed to identify the autoantigen(s) in LINH and thus develop a diagnostic test based on serum autoantibodies. Rabphilin-3A proved the most
diagnostically useful autoantigen. Anti-rabphilin-3A antibodies were detected in 22 of the 29 (76%) patients (including 4 of the 4 biopsy-proven samples) with LINH. In contrast, these antibodies were absent in patients with biopsy-proven sellar/ suprasellar masses without lymphocytic hypophysitis (n=34), including 18 patients with CDI. Rabphilin-3A was expressed in posterior pituitary and hypothalamic vasopressin neurons but not anterior pituitary. In conclusion, these results suggest that rabphilin-3A is a major autoantigen in LINH. Autoantibodies to rabphilin-3A may serve as a biomarker for the diagnosis of LINH, and be useful for the differential diagnosis in patients with CDI.
Sungmun Lee
Khalifa University of Science and Technology | UAE
Title: Inhibition of amylin aggregation and cytotoxicity to β-cells by acids
Time : 16:10-16:35
Biography:
Sungmun Lee is currently working as an Assistant Professor in Khalifa University. He completed his Ph.D. in Texas A&M University, USA. His main research interest is in Development of Novel Drug Delivery System, Cardiovascular Diseases, Diabetes, Alzheimer's disease and Inflammatory Diseases. He has focused on the development of novel drugs and drug delivery systems for treating inflammatory diseases such as diabetes, Alzheimer’s disease, and cardiovascular diseases.
Abstract:
Statement of the Problem: Protein aggregation is associated with more than 20 degenerative diseases. Fibrillar aggregates of Aβ, α-synuclein, and amylin are pathological features in Alzheimer’s disease, Parkinson’s disease, and type II diabetes respectively. Aggregation of amylin causes cytotoxicity to pancreatic β-cells. The purpose of this study is to investigate the effect of different types of acids on the aggregation of amylin and cytotoxicity of aggregates to β-cells.
Methodology & Theoretical Orientation: Amylin-(1-37) was purchased from Sigma-Aldrich. Amylin (15 μM) with or without different types of acids were incubated at 37oC and the amylin fibrils were measured by the thioflavin T (ThT) binding assay at indicated time points. For cytotoxicity test, RIN-m5f, pancreatic β-cells, was incubated in a amylin (15 μM) with or without different types of acids. After 24 h, Thiazolyl blue tetrazolium bromide (MTT) was added to cells and the absorbance of live cells was measured at 570 nm.
Findings: Six acidic small molecules were screened in terms of their ability to inhibit amylin aggregation using ThT assay. Among six acids, two acids, lipoic acid and ascorbic acid, showed highest attenuation in ThT fluorescence intensity of 57.9±17.2% and 57.1±12.8%, compared to amylin (15μM) only. To further assess the cytotoxicity of amylin aggregates with or without two acids, MTT assay was performed using pancreatic RIN-m5f β-cells. Pre-formed fibrillar amylin only caused the cytotoxicity of 67% as compared to freshly prepared monomeric amylin. The addition of two acids to amylin decreased the
cytotoxicity to 44% and 49% respectively. Molecular modeling demonstrated that lipoic acid and ascorbic acid interact with amylin via hydrophobic interactions.
Conclusion & Significance: Lipoic acid and ascorbic acid can bind to amylin via hydrophobic interaction, which inhibits orslows down the aggregation of amylin and the toxicity of amylin aggregates to RIN-m5f, pancreatic β-cells.
Alla Ovsyannikova
IIPM-ICG SB RAS | Russia
Title: The prevalence of dyslipidemia in patients with different types of MODY diabetes
Time : 16:35-17:00
Biography:
Alla Ovsyannikova finished Novosibirsk Medical University, Russia in 2008 year with Honors. She had two certificates of specialists in Internal Medicine and Endocrinologist. She is a PhD since 2013 with dissertation work "Diabetes mellitus in young people: Some clinical and molecular genetic aspects". Currently, she is working as an Endocrinologist and Scientist in IIPM-Branch of IC&G SB RAS. Her research work is about monogenic types of diabetes mellitus (especially MODY diabetes) in young patients. She investigates the characteristics of the clinical course, treatment and genetic features in Siberian and Russian population. She has published more than 20 abstracts in national refereed journals, 30 abstracts in conference with international participation. She has participated in international conferences.
Abstract:
Aim: The purpose of the research was to determine and compare the prevalence of dyslipidemia in patients with different types of maturity onset diabetes of the young (MODY).
Materials & Methods: Diagnosis of MODY was verified in 37 patients on the basis of direct automatic sequencing and sequencing by Sanger genes, mutations in which lead to the development of MODY 1-13 diabetes. This group consisted of 21 patients with GCK-MODY (MODY2), 9 with HNF1A-MODY (MODY3), 1 with HNF1B-MODY (MODY5), 1 with NEUROD1-MODY (MODY6), 2 with CEL-MODY (MODY8), 3 with ABCC8-MODY (MODY12).
Results: The group of patients with MODY diabetes is comprised by 37 people: 23 females (62.2%), 14 (37.8%) males (p=0.934). The median age of the patients was 29.1 (0; 70) years, the median age of diagnosis of diabetes mellitus was 25 (0; 45) years, the median duration was 3.2 (0; 35) years. All patients had a normal body mass index. The median level of total cholesterol was 4.9 (3.4; 7.1) mmol/L, LDL- 2.9 (1.6; 4.5) mmol/L, HDL - 1.3 (1.0; 2.4) mmol/L, triglycerides - 1.0 (0.5; 3.1) mmol/L. Elevated LDL was diagnosed in 10 patients (27.0%) and hypertriglyceridemia in 6 patients (18.8%). The HNF1A gene (MODY3) encodes one of the transcription factors that regulates the expression of genes associated with lipid and carbohydrate metabolism. Therefore, it is this type of MODY associated with the dyslipidemia which leads to early macrovascular complications. In this study 4 out of 9 (44.4%) patients with HNF1A-MODY had an elevated level of LDL and 2 (22.2%) hypertriglyceridemia. In patients with GCK-MODY, an increase in LDL was detected in 3 patients (14.3%, pMODY2-MODY3 = 0.209), hypertriglyceridemia in 2 (12.5%, pMODY2-MODY3 = 0.533).
Conclusions: Dyslipidemia is determined in 27% in young patients with MODY diabetes with a short duration of diabetes mellitus and a lack of obesity which indicates the need for prescribing therapy to prevent macrovascular complications. There were no significant differences in lipid levels in patients with HNF1A-MODY and GCK-MODY in the Siberian region.
Acknowledgement: The research work was suppotted by RSF project N14-15-00496-P
Alla Ovsyannikova
IIPM-ICG SB RAS | Russia
Title: Description of the clinical case of the patient HNF1A (MODY3) with familial segregation of the disease in five generations
Time : 17:00-17:25
Biography:
Alla Ovsyannikova finished Novosibirsk Medical University, Russia in 2008 year with Honors. She had two certificates of specialists in Internal Medicine and Endocrinologist. She is a PhD since 2013 with dissertation work "Diabetes mellitus in young people: some clinical and molecular genetic aspects". Currently, she is working as an Endocrinologist and Scientist in IIPM-Branch of IC&G SB RAS. Her research work is about monogenic types of diabetes mellitus (especially MODY diabetes) in young patients. She investigates the characteristics of the clinical course, treatment and genetic features in Siberian and Russian population. She has published more than 20 abstracts in national refereed journals, 30 abstracts in conference with international participation. She has participated in international conferences.
Abstract:
Aim: The purpose of the research was to determine family segregation in a proband family with a confirmed mutation in the HNF1A gene (MODY3 diabetes).
Materials & Methods: The diagnosis of HNF1A-MODY was verified by the proband and his relatives on the basis of direct automatic sequencing and sequencing by Sanger.
Results: Proband - a woman of 50 years, gestational diabetes mellitus (DM) is diagnosed at the age of 21 during pregnancy, insulin therapy was done in the basis-bolus regimen. After delivery insulin therapy was canceled, the patient had a strict diet. Decompensation of carbohydrate metabolism was at the age of 28 years on the background of stress, insulin therapy was prescribed in the basal-bolus regimen, which is still preserved. Non proliferative diabetic retinopathy, peripheral neuropathy, dyslipidemia were defined. Antibodies to B-cells and glutamate decarboxylase were negative and the C-peptide was slightly reduced. DM was at the great-grandfather, the grandmother from 65 years, mother of the proband from 45 years, at the son from 21 years. Mother and son of the proband had dyslipidemia with increased cholesterol of low density lipoproteins, in grandmothers and great grandfathers- macrovascular complications (acute cerebrovascular accident) at a late age. A previously unrecognized mutation in the 1 exon of the HNF1A gene in a proband, her mother and her son was revealed according to molecular genetic research. An identical mutation was detected in the granddaughter of a proband at the age of 2 months.
Conclusions: The pedigree of HNF1A-MODY demonstrates the phenomenon of genetic prediction that is the gradual decrease in the age of diagnosis in subsequent generations probably due to increased awareness leading to earlier testing of glucose levels.
The decrease in the age of development of dyslipidemia in patients with a mutation in the HNF1A gene was also determined which may be interrelated characteristics and require further study.
Acknowledgement: The research work was suppotted by RSF project N14-15-00496-P
Jishi Liu
Third Xiangya Hospital of Central South University
Title: Protective effects of Vit D/VDR on renal autophagy in early stage of 12-weeks diabetic mice induced by STZ
Biography:
Jishi Liu is working as an associate professor in Third Xiangya Hospital of Central South University in Changsha City, China. Her main research area is in prevention and treatment of acute and chronic kidney disease, the clinical and basic research of IgA nephrology. She received three funding support. Headed over 1 NSFC of China, 2 Hunan provincial natural science fund subject, and published 24 SCI papers.
Abstract:
Background: Autophagy is an important cause of diabetic nephropathy (DN). We found that the expression of nuclear transcription factor VDR in renal tubule epithelium was down-regulated and negatively correlated with urinary albumin and inflammation in DN patients, while intestinal disease and tumor related studies suggested that vitamin D receptor (VDR) could regulate autophagy. Therefore, we studied the relationship between Vit D/VDR and renal autophagy in early stage of 12 weeks diabetic mice induced by STZ.
Methods: In order to investigate the potential regulation of VDR on autophagy in renal cells, we established streptozotocin (STZ) induced diabetic nephropathy model on VDR knockout mice and wild type mice. Then we used VDR agonist paricalcitol to interfere with wild-type mice induced by STZ. The autophagy related indexes, such as LC3II/I, ATG16L1, P62, inflammation and fibrosis level were measured at 12 weeks in the renal cortex of mice.
Results: Results of immunohistochemistry and western blot showed that the level of LC3II/I, ATG16L1, FN and collage were clearly lower in renal tissue of non-diabetic VDR knockout rats than those of the wild type. Level of those indexes also lower in STZ induced diabetic VDR knockout mice than in wild-type mice. Expression of P62 in diabetic VDR knockout mice induced by STZ was significantly higher than that in wild-type DN mice and VDR knockout mice. Paricalcitol could up-regulate LC3II/I protein and ATG16L1mRNA and inhibit the accumulation of P62 protein in wild-type DN mice, but did not inhibit the expression of P62 mRNA.
Conclusion: VDR is involved in the regulation of autophagy in early stage of diabetic nephropathy. Paricalcitol may play a protective role in renal autophagy activation in early stage of diabetic mice induced by STZ through up-regulating ATG16L1 and promoting the degradation of P62.