Age-related obesity and type 2 diabetes dysregulate neuronal associated genes and proteins in humans.
Despite numerous developed drugs based on glucose metabolism interventions for treatment of age-related diseases such as diabetes neuropathies (DNs), DNs are still increasing in patients with type 1 or type 2 diabetes (T1D, T2D). We aimed to identify novel candidates in adipose tissue (AT) and pancreas with T2D for targeting to develop new drugs for DNs therapy. AT-T2D displayed 15 (e.g. SYT4 up-regulated and VGF down-regulated) and pancreas-T2D showed 10 (e.g. BAG3 up-regulated, VAV3 and APOA1 down-regulated) highly differentially expressed genes with neuronal functions as compared to control tissues. ELISA was blindly performed to measure proteins of 5 most differentially expressed genes in 41 human subjects. SYT4 protein was upregulated, VAV3 and APOA1 were down-regulated, and BAG3 remained unchanged in 1- Obese and 2- Obese-T2D without insulin, VGF protein was higher in these two groups as well as in group 3- Obese-T2D receiving insulin than 4-lean subjects. Interaction networks analysis of these 5 genes showed several metabolic pathways (e.g. lipid metabolism and insulin signaling). Pancreas is a novel site for APOA1 synthesis. VGF is synthesized in AT and could be considered as good diagnostic, and even prognostic, marker for age-induced diseases obesity and T2D. This study provides new targets for rational drugs development for the therapy of age-related DNs.
Faculty of Medical Science, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Mehran
M
Rahimi
Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, UK.|Gastroenterology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Manlio
M
Vinciguerra
Department of Biomedical Engineering, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Mojtaba
M
Daghighi
Department of Endocrinology, Erasmus Medical Center, Rotterdam, The Netherlands.
Behiye
B
Özcan
Institute Center-45, Medical Center, University of Amsterdam, The Netherlands.
Vishtaseb
V
Akbarkhanzadeh
Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Fareeba
F
Sheedfar
Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Marzyeh
M
Amini
Bioinformatics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Tommaso
T
Mazza
Gastroenterology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Valerio
V
Pazienza
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
Mahdi M
MM
Motazacker
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, United States.|Department of Nanotechnology and Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Morteza
M
Mahmoudi
Department of Cardiovascular Genetics, Metabolism, Erasmus Medical Center, Rotterdam, The Netherlands.
Felix W M
FW
De Rooij
Department of Cardiovascular Genetics, Metabolism, Erasmus Medical Center, Rotterdam, The Netherlands.
Eric
E
Sijbrands
Department of Gastroenterology and Hepatology, Erasmus Medical Center, University of Rotterdam, Rotterdam, The Netherlands.
Maikel P
MP
Peppelenbosch
Department of Gastroenterology and Hepatology, Erasmus Medical Center, University of Rotterdam, Rotterdam, The Netherlands.|Department of Cell Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Farhad
F
Rezaee
D048868:Adaptor Proteins, Signal Transducing / Q000097:blood / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000097:blood / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000503:physiopathology*; D010179:Pancreas / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000097:blood / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050857:Synaptotagmins / Q000097:blood / Q000235:genetics / Q000378:metabolism
C505693:APOA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016632:Apolipoprotein A-I; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D007004:Hypoglycemic Agents; D007328:Insulin; D009414:Nerve Growth Factors; D051567:Proto-Oncogene Proteins c-vav; C494292:SYT4 protein, human; C496621:VAV3 protein, human; C510637:VGF protein, human; D050857:Synaptotagmins
age-related diabetes neuropathy; aging; diabetes; obesity; pancreas