Discovery of coding genetic variants influencing diabetes-related serum biomarkers and their impact on risk of type 2 diabetes.
Ahluwalia Tarunveer Singh,Allin Kristine Højgaard,Sandholt Camilla Helene,Sparsø Thomas Hempel,Jørgensen Marit Eika,Rowe Michael,Christensen Cramer,Brandslund Ivan,Lauritzen Torsten,Linneberg Allan,Husemoen Lise Lotte,Jørgensen Torben,Hansen Torben,Grarup Niels,Pedersen Oluf
The Journal of clinical endocrinology and metabolism
CONTEXT:Type 2 diabetes (T2D) prevalence is spiraling globally, and knowledge of its pathophysiological signatures is crucial for a better understanding and treatment of the disease. OBJECTIVE:We aimed to discover underlying coding genetic variants influencing fasting serum levels of nine biomarkers associated with T2D: adiponectin, C-reactive protein, ferritin, heat shock 70-kDa protein 1B, IGF binding protein 1 and IGF binding protein 2, IL-18, IL-2 receptor-α, and leptin. DESIGN AND PARTICIPANTS:A population-based sample of 6215 adult Danes was genotyped for 16 340 coding single-nucleotide polymorphisms and were tested for association with each biomarker. Identified loci were tested for association with T2D through a large-scale meta-analysis involving up to 17 024 T2D cases and up to 64 186 controls. RESULTS:We discovered 11 associations between single-nucleotide polymorphisms and five distinct biomarkers at a study-wide P < 3.4 × 10(-7). Nine associations were novel: IL18: BIRC6, RAD17, MARVELD2; ferritin: F5; IGF binding protein 1: SERPING1, KLKB, GCKR, CELSR2, and heat shock 70-kDa protein 1B: CFH. Three of the identified loci (CELSR2, HNF1A, and GCKR) were significantly associated with T2D, of which the association with the CELSR2 locus has not been shown previously. CONCLUSION:The identified loci influence processes related to insulin signaling, cell communication, immune function, apoptosis, DNA repair, and oxidative stress, all of which could provide a rationale for novel diabetes therapeutic strategies.
10.1210/jc.2014-3677
Differential Promoter Methylation of Macrophage Genes Is Associated With Impaired Vascular Growth in Ischemic Muscles of Hyperlipidemic and Type 2 Diabetic Mice: Genome-Wide Promoter Methylation Study.
Babu Mohan,Durga Devi Thota,Mäkinen Petri,Kaikkonen Minna,Lesch Hanna P,Junttila Sini,Laiho Asta,Ghimire Bishwa,Gyenesei Attila,Ylä-Herttuala Seppo
Circulation research
RATIONALE:Hyperlipidemia and type 2 diabetes mellitus (T2DM) severely impair adaptive vascular growth responses in ischemic muscles. This is largely attributed to dysregulated gene expression, although details of the changes are unknown. OBJECTIVE:To define the role of promoter methylation in adaptive vascular growth in hyperlipidemia (LDLR(-/-)ApoB(100/100)) and T2DM (IGF-II/LDLR(-/-)ApoB(100/100)) mouse models of hindlimb ischemia. METHODS AND RESULTS:Unilateral hindlimb ischemia was induced by ligating femoral artery. Perfusion was assessed using ultrasound, and capillary and arteriole parameters were assessed using immunohistochemistry. Genome-wide methylated DNA sequencing was performed with DNA isolated from ischemic muscle, tissue macrophages (Mϕs), and endothelial cells. Compared with the controls, hyperlipidemia and T2DM mice showed impaired perfusion recovery, which was associated with impaired angiogenesis and arteriogenesis. Genome-wide proximal promoter DNA methylation analysis suggested differential patterns of methylation in Mϕ genes in ischemic muscles. Classically activated M1-Mϕ gene promoters, including Cfb, Serping1, and Tnfsf15, were significantly hypomethylated, whereas alternatively activated M2-Mϕ gene promoters, including Nrp1, Cxcr4, Plxnd1, Arg1, Cdk18, and Fes, were significantly hypermethylated in Mϕs isolated from hyperlipidemia and T2DM ischemic muscles compared with controls. These results combined with mRNA expression and immunohistochemistry showed the predominance of proinflammatory M1-Mϕs, compared with anti-inflammatory and proangiogenic M2-Mϕs in hyperlipidemia and T2DM ischemic muscles. CONCLUSIONS:We found significant promoter hypomethylation of genes typical for proinflammatory M1-Mϕs and hypermethylation of anti-inflammatory, proangiogenic M2-Mϕ genes in hyperlipidemia and T2DM ischemic muscles. Epigenetic alterations modify Mϕ phenotype toward proinflammatory M1 as opposed to anti-inflammatory, proangiogenic, and tissue repair M2 phenotype, which may contribute to the impaired adaptive vascular growth under these pathological conditions.
10.1161/CIRCRESAHA.115.306424
Genetic Investigation of Complement Pathway Genes in Type 2 Diabetic Retinopathy: An Inflammatory Perspective.
Yang Ming Ming,Wang Jun,Ren Hong,Sun Yun Duan,Fan Jiao Jie,Teng Yan,Li Yan Bo
Mediators of inflammation
Diabetic retinopathy (DR) has complex multifactorial pathogenesis. This study aimed to investigate the association of complement pathway genes with susceptibility to DR. Eight haplotype-tagging SNPs of SERPING1 and C5 were genotyped in 570 subjects with type 2 diabetes: 295 DR patients (138 nonproliferative DR [NPDR] and 157 proliferative DR [PDR]) and 275 diabetic controls. Among the six C5 SNPs, a marginal association was first detected between rs17611 and total DR patients (P = 0.009, OR = 0.53 for recessive model). In stratification analysis, a significant decrease in the frequencies of G allele and GG homozygosity for rs17611 was observed in PDR patients compared with diabetic controls (Pcorr = 0.032, OR = 0.65 and Pcorr = 0.016, OR = 0.37, resp.); it was linked with a disease progression. A haplotype AA defined by the major alleles of rs17611 and rs1548782 was significantly predisposed to PDR with increased risk of 1.54 (Pcorr = 0.023). Regarding other variants in C5 and SERPING1, none of the tagging SNPs had a significant association with DR and its subgroups (all P > 0.05). Our study revealed an association between DR and C5 polymorphisms with clinical significance, whereas SERPING1 is not a major genetic component of DR. Our data suggest a link of complement pathway with DR pathogenesis.
10.1155/2016/1313027
Identification of core genes and pathways in type 2 diabetes mellitus by bioinformatics analysis.
Ding Linchao,Fan Lei,Xu Xiaodong,Fu Jianfei,Xue Yadong
Molecular medicine reports
Type 2 diabetes mellitus (T2DM) is a metabolic disorder. Numerous proteins have been identified that are associated with the occurrence and development of T2DM. This study aimed to identify potential core genes and pathways involved in T2DM, through exhaustive bioinformatic analyses using GSE20966 microarray profiles of pancreatic β‑cells obtained from healthy controls and patients with T2DM. The original microarray data were downloaded from the Gene Expression Omnibus database. Data were processed by the limma package in R software and the differentially expressed genes (DEGs) were identified. Gene Ontology functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out to identify potential biological functions and pathways of the DEGs. Key transcription factors were identified using the WEB‑based GEne SeT AnaLysis Toolkit (WebGestalt) and Enrichr. The Search Tool for the Retrieval of Interacting Genes (STRING) database was used to establish a protein‑protein interaction (PPI) network for the DEGs. In total, 329 DEGs were involved in T2DM, with 208 upregulated genes enriched in pancreatic secretion and the complement and coagulation cascades, and 121 downregulated genes enriched in insulin secretion, carbohydrate digestion and absorption, and the Toll‑like receptor pathway. Furthermore, hepatocyte nuclear factor 1‑alpha (HNF1A), signal transducer and activator of transcription 3 (STAT3) and glucocorticoid receptor (GR) were key transcription factors in T2DM. Twenty important nodes were detected in the PPI network. Finally, two core genes, serpin family G member 1 (SERPING1) and alanyl aminopeptidase, membrane (ANPEP), were shown to be associated with the development of T2DM. On the whole, the findings of this study enhance our understanding of the potential molecular mechanisms of T2DM and provide potential targets for further research.
10.3892/mmr.2019.10522
Systemic Proteome Alterations Linked to Early Stage Pancreatic Cancer in Diabetic Patients.
Cancers
BACKGROUND:Diabetes is a risk factor associated with pancreatic ductal adenocarcinoma (PDAC), and new adult-onset diabetes can be an early sign of pancreatic malignancy. Development of blood-based biomarkers to identify diabetic patients who warrant imaging tests for cancer detection may represent a realistic approach to facilitate earlier diagnosis of PDAC in a risk population. METHODS:A spectral library-based proteomic platform was applied to interrogate biomarker candidates in plasma samples from clinically well-defined diabetic cohorts with and without PDAC. Random forest algorithm was used for prediction model building and receiver operating characteristic (ROC) curve analysis was applied to evaluate the prediction probability of potential biomarker panels. RESULTS:Several biomarker panels were cross-validated in the context of detection of PDAC within a diabetic background. In combination with carbohydrate antigen 19-9 (CA19-9), the panel, which consisted of apolipoprotein A-IV (APOA4), monocyte differentiation antigen CD14 (CD14), tetranectin (CLEC3B), gelsolin (GSN), histidine-rich glycoprotein (HRG), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), plasma kallikrein (KLKB1), leucine-rich alpha-2-glycoprotein (LRG1), pigment epithelium-derived factor (SERPINF1), plasma protease C1 inhibitor (SERPING1), and metalloproteinase inhibitor 1 (TIMP1), demonstrated an area under curve (AUC) of 0.85 and a two-fold increase in detection accuracy compared to CA19-9 alone. The study further evaluated the correlations of protein candidates and their influences on the performance of biomarker panels. CONCLUSIONS:Proteomics-based multiplex biomarker panels improved the detection accuracy for diagnosis of early stage PDAC in diabetic patients.
10.3390/cancers12061534
Nonsocial functions of hypothalamic oxytocin.
Yang Hai-Peng,Wang Liwei,Han Liqun,Wang Stephani C
ISRN neuroscience
Oxytocin (OXT) is a hypothalamic neuropeptide composed of nine amino acids. The functions of OXT cover a variety of social and nonsocial activity/behaviors. Therapeutic effects of OXT on aberrant social behaviors are attracting more attention, such as social memory, attachment, sexual behavior, maternal behavior, aggression, pair bonding, and trust. The nonsocial behaviors/functions of brain OXT have also received renewed attention, which covers brain development, reproduction, sex, endocrine, immune regulation, learning and memory, pain perception, energy balance, and almost all the functions of peripheral organ systems. Coordinating with brain OXT, locally produced OXT also involves the central and peripheral actions of OXT. Disorders in OXT secretion and functions can cause a series of aberrant social behaviors, such as depression, autism, and schizophrenia as well as disturbance of nonsocial behaviors/functions, such as anorexia, obesity, lactation failure, osteoporosis, diabetes, and carcinogenesis. As more and more OXT functions are identified, it is essential to provide a general view of OXT functions in order to explore the therapeutic potentials of OXT. In this review, we will focus on roles of hypothalamic OXT on central and peripheral nonsocial functions.
10.1155/2013/179272
Oxytocin and diabetes mellitus: a strong biochemical relation. Review.
Kontoangelos K,Papageorgiou C C,Raptis A E,Rabavilas A D,Papadimitriou G N
Current diabetes reviews
Oxytocin (OXT) is a neurohypophysial hormone which is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. OXT is currently attracting considerable attention because it has been discovered that it regulates various functions of behavior especially in the context of social interactions. OXT is a key component in bone formation, glycemia, male sexuality, cardiac differentiation and pregnancy and thus it is important to be further explored. The authors review various aspects of gestational diabetes, including definition, screening, diagnostic procedures, complications, clinical evaluation, indications of delivery and neonatal aspects. Not only the relation among diabetes mellitus, oxytocin and neurophysiology concerning erectile dysfunction, but also the role of OXT in the activity of arginine and vasopressin is investigated. It is imperative to develop technological and experimental methods that will be able to reveal the oxytocin and its potential.
10.2174/15733998113096660079
The CD38 genotype (rs1800561 (4693C>T): R140W) is associated with an increased risk of admission to the neonatal intensive care unit.
Enami Nobuko,Itaya-Hironaka Asako,Yamauchi Akiyo,Sakuramoto-Tsuchida Sumiyo,Takasawa Shin,Takahashi Yukihiro
Early human development
BACKGROUNDS:Preterm birth (PTB)/admission to the neonatal intensive care unit (NICU) is a complex disorder associated with significant neonatal mortality and morbidity and long-term adverse health consequences. Multiple lines of evidence suggest that genetic factors play an important role in its etiology. AIM:Given the role of CD38 in term delivery through oxytocin (OXT) release, we hypothesized that OXT signaling may play a role in the etiology of PTB/admission to the NICU. This study was designed to identify genetic variation in the CD38-oxytocin pathway associated with PTB/admission to the NICU. METHODS:To identify common genetic variants predisposing individuals to PTB/admission to the NICU, we genotyped two single nucleotide polymorphisms (SNPs) in the CD38-oxytocin pathway in 63 case mothers, 55 control mothers, and 188 female volunteers in Nara Medical University Hospital, Japan. RESULTS:Maternal genetic effect analysis of the SNP genotype data revealed a significant association between an SNP in CD38 (rs1800561 (4693C>T): R140W), which was reported to be correlated with diabetes and autism, and the risk of NICU admission. On the other hand, an SNP in the oxytocin receptor (OXTR) (rs2254298) showed no correlation with the risk of NICU admission. CONCLUSION:Our study points to an association between maternal common polymorphisms in the CD38 (rs1800561) gene in Japanese women and susceptibility to PTB/admission to the NICU. Future studies with larger sample sizes are needed to confirm the findings of this study.
10.1016/j.earlhumdev.2015.05.002
Oxytocin Protects against Stress-Induced Cell Death in Murine Pancreatic β-Cells.
Watanabe Sayaka,Wei Fan-Yan,Matsunaga Tomomi,Matsunaga Nanami,Kaitsuka Taku,Tomizawa Kazuhito
Scientific reports
Oxytocin (Oxt) is a key neuropeptide that regulates maternal behaviors as well as social behaviors in mammals. Interestingly, recent studies have shown that the impairment of Oxt signaling is associated with the disturbance of metabolic homeostasis, resulting in obesity and diabetes. However, the molecular mechanism by which Oxt signaling controls metabolic responses is largely unknown. Here, we report that Oxt signaling attenuates the death of pancreatic beta cells in islets exposed to cytotoxic stresses. The protective effect of Oxt was diminished in islets isolated from oxytocin receptor knockout (Oxtr(-/-)) mice. Oxtr(-/-) mice developed normally, but exhibited impaired insulin secretion and showed glucose intolerance under a high-fat diet. Mechanistically, the deficiency of Oxtr impaired MAPK/ERK-CREB signaling, which exaggerated the endoplasmic reticulum stress response and ultimately increased the death of beta cells in pancreatic islets under stressed conditions. These results reveal that Oxt protects pancreatic beta cells against death caused by metabolic stress, and Oxt signaling may be a potential therapeutic target.
10.1038/srep25185
The correlation between plasma levels of oxytocin and betatrophin in non-diabetic and diabetic metabolic syndrome patients: A cross sectional study from Jordan.
Al-Rawashdeh Amani,Kasabri Violet,Bulatova Nailya,Akour Amal,Zayed Ayman,Momani Munther,Khawaja Nahla,Bustanji Haider,Hyasat Dana
Diabetes & metabolic syndrome
BACKGROUND:Oxytocin (OXT) is a neurohypophyseal hormone that has been recently shown to possess a number of beneficial effects in diabetes and obesity. Betatrophin is a protein expressed in fat and liver that regulates lipid metabolism and promotes pancreatic β-cell proliferation. It is not investigated yet whether OXT and betatrophin levels correlate in metabolic syndrome (MS) or diabetes patients. METHODS:The aim was to assess correlations between plasma betatrophin and OXT levels in MS-diabetic or prediabetic (N=89) as compared to MS-non-diabetic (N=69) patients. Competitive binding ELISA was used to evaluate betatrophin and OXT plasma concentrations. Correlations of the above biomarkers and patient clinical characteristics were also detected. RESULTS:As compared to the control MS participants (0.32±0.25ng/mL); betatrophin plasma levels were increased (P<0.001) in the MS-pre/T2DM patients (1.23±0.68ng/mL). On the contrary, OXT concentrations were decreased (P<0.001) in the MS-pre/T2DM patients (1222.46±514.55pg/mL) as compared to the MS control subjects (2323.42±848.68pg/mL). OXT concentration correlated negatively (r=-0.492, P<0.001), while HbA1c and FPG correlated positively with betatrophin plasma levels (P<0.001), but were inversely correlated with OXT levels (P<0.001) in the total sample. CONCLUSION:Betatrophin levels are increased, while OXT levels are decreased in MS-pre/T2DM. We found an inverse correlation between the levels of the two biomarkers in addition to correlation between their levels and the degree of glycemic control.
10.1016/j.dsx.2016.08.008
Levels of metabolic markers in drug-naive prediabetic and type 2 diabetic patients.
Akour Amal,Kasabri Violet,Boulatova Nailya,Bustanji Yasser,Naffa Randa,Hyasat Dana,Khawaja Nahla,Bustanji Haidar,Zayed Ayman,Momani Munther
Acta diabetologica
AIMS:Type 2 diabetes mellitus (T2DM) and prediabetes (pre-DM) are associated with changes in levels of metabolic markers. The main aim of this study is to compare the levels of omentin, irisin, endothelin-1, nesfatin, hepatocyte growth factor (HGF), fibroblast growth factor, and oxytocin (OXT) between normoglycemic and pre-DM/T2DM obese Jordanian patients. METHODS:One hundred and ninety-eight adult Jordanian subjects were recruited. Demographic data and clinical parameters were collected. The serum levels of biomarkers were measured by enzymatic assay procedure. RESULTS:Compared to normoglycemic (95 subjects), pre-DM/T2DM (103 subjects) displayed higher HGF (ng/ml) = 78.8 (71.4-104) versus 55.9 (45.3-66.6), p < 0.0001; and nesfatin (ng/ml) = 0.5 (0.4-0.7) versus 0.2 (0.1-0.4), p < 0.0001; betatrophin (ng/ml) = 1.2 (0.8-1.6) versus 0.22 (0.15-0.41), p < 0.0001. On the other hand, they had lower levels of omentin (ng/ml) = 2.1 (0.9-3.3) versus 3.6 (2.0-6.4), p < 0.0001, irisin (ng/ml) = 113.7 (88.9-142.9) versus 132.6 (110.7-147.8), p < 0.0001; and oxytocin (pg/ml) = 1077.9 (667.3-1506.0) versus 2180.1 (1464.5-2795.6), p < 0.0001; respectively. In comparison, FGF-21 (ng/ml) = 0.3 (0.2-0.5) versus 0.2 (0.1-0.4), and endothelin (pg/ml) = 2.7 (1.3-5.2) versus 2.8 (1.6-5.6) did not differ between the two groups (p > 0.05). CONCLUSIONS:In the present study, patients with pre-DM and T2DM have higher serum levels of metabolic HGF, nesfatin, and betatrophin and lower levels of omentin, irisin, and OXT. Future longitudinal and interventional studies are required to confirm the utility of these markers as novel progression or therapeutic targets in the pharmacotherapy of diabetes.
10.1007/s00592-016-0926-1
Cross-sectional correlates of increased IL-18 but reduced fetuin-A and oxytocin with adiposity and blood indices in metabolic syndrome patients with and without prediabetes.
Kasabri Violet,Shawakri Esraa,Akour Amal,Naffa Randa,Khawaja Nahla,Al-Sarraf Ibrahim,Bzour Jameel
Therapeutic advances in endocrinology and metabolism
BACKGROUND:Oxytocin (OXT), fetuin-A and interleukin-18 (IL-18) are involved in the development and progression of metabolic syndrome (MetS) and prediabetes (pre/T2DM). AIMS PARTICIPANTS AND METHODS:This study aimed to compare and correlate the plasma levels of OXT, fetuin-A and IL-18 with clinical parameters, haematological indices and adiposity indices in Jordanian MetS subjects. In a cross-sectional study, 30 normoglycaemic lean study participants (control), 30 MetS study participants, and 29 MetS pre/T2DM study participants were recruited. RESULTS:Median circulating levels of both OXT and fetuin-A were lower in MetS and MetS pre/T2DM control group. OXT (pg/ml; median interquartile range): MetS 1975.4 and MetS pre/T2DM 1403 control 4176.6 ( = 0.009 and = 0.001, respectively). For fetuin-A (ng/ml), MetS (5784) and MetS pre/T2DM (2154) were lower control (6756.3) ( 0.040 and = 0.007, respectively). Neither biomarker was described as substantially different in MetS MetS pre/T2DM ( = 0.071 and = 0.155, respectively). Conversely, a non-significant increase in IL-18 was observed in the MetS and MetS pre/T2DM groups compared to normoglycaemic lean controls (232 and 287.5, > 0.05 versus 108 for both). In addition, conicity index (C-index), atherogenicity index (TG-HDL-C), waist to hip ratio, mean platelet volume (MPV; fl) and red cell distribution width (RDW-CV%) in both MetS and MetS pre/T2DM were significantly higher ( < 0.001) controls. However all above MetS-related indices were not ascribed any statistically marked variation in the MetS group when compared to the MetS pre/T2DM group. Both total study pool of recruits' fetuin-A (Spearman = 2.66, 0.049) as well as MetS pre/T2DM group IL-18 (Spearman = 0.380, 0.046) were inversely correlated with RDW-CV%. OXT in MetS inversely correlated with waist circumference/hip circumference ratio (Spearman = -0.387, 0.038). No other pronounced associations between biomarkers could be detected in any study arm. CONCLUSION:These findings substantiate the clinical relevance and significance of OXT, fetuin-A and IL-18 as surrogate screening/prognostic tools and therapeutic targets to predict/prevent metabolic dysregularities and anomalies.
10.1177/2042018818788802
New Molecular Insights into the Inhibition of Dipeptidyl Peptidase-4 by Natural Cyclic Peptide Oxytocin.
Molecules (Basel, Switzerland)
Protease inhibition has led to treating many diseases and has been successful in producing many commercial drugs by pharmaceutical companies. Among many proteases, serine protease has been attractive in treating metabolic disorder diabetes mellitus (DM). Gliptins have been proven to inhibit dipeptidyl peptidase-4 (DPP4), a serine protease, and are an emerging therapeutic drug target to reduce blood glucose levels, but until now there is no natural cyclic peptide proven to inhibit serine protease DPP4. This study demonstrates the potential mechanism of natural cyclic peptide oxytocin (OXT) as a DPP4 inhibitor. To achieve this, initially, activity atlas and field-based models of DPP4 inhibitors were utilized to predict the possible features of positive and negative electrostatic, hydrophobic, and activity shapes of DPP4 inhibition. Oxytocin binding mode, flexibility, and interacting residues were studied using molecular docking simulations studies. 3D-RISM calculations studies revealed that the stability of water molecules at the binding site are favorable. Finally, an experimental study using fluorescence assay revealed OXT inhibits DPP4 in a concentration-dependent manner in a significant way ( < 0.05) and possess IC of 110.7 nM. These new findings significantly expand the pharmaceutical application of cyclic peptides, and in specific OXT, and implicate further optimization of OXT inhibition capacity to understand the effect of DPP4 inhibition. This work highlights the development of natural cyclic peptides as future therapeutic peptides to reduce glucose levels and treat diabetes mellitus.
10.3390/molecules24213887
Circulating Oxytocin Is Genetically Determined and Associated With Obesity and Impaired Glucose Tolerance.
Weingarten Mark Florian Joachim,Scholz Markus,Wohland Tobias,Horn Katrin,Stumvoll Michael,Kovacs Peter,Tönjes Anke
The Journal of clinical endocrinology and metabolism
CONTEXT:Despite the emerging evidence on the role of oxytocin (OXT) in metabolic diseases, there is a lack of well-powered studies addressing the relationship of circulating OXT with obesity and diabetes. OBJECTIVES AND DESIGN:Here, we measured OXT in a study cohort (n = 721; 396 women, 325 men; mean age ± SD, 47.7 ± 15.2 years) with subphenotypes related to obesity, including anthropometric traits such as body mass index [BMI (mean ± SD), 26.8 ± 4.6 kg/m2], waist-to-hip ratio (WHR; 0.88 ± 0.09), blood parameters (glucose, 5.32 ± 0.50 mmol/L; insulin, 5.3 ± 3.3 µU/mL), and oral glucose tolerance test to clarify the association with OXT. We also tested in a genome-wide association study (GWAS) whether the interindividual variation in OXT serum levels might be explained by genetic variation. RESULTS:The OXT concentration was increased in subjects with elevated BMI and positively correlated with WHR, waist circumference, and triglyceride levels. The OXT concentration in subjects with BMI <25 kg/m2 was significantly lower (n = 256; 78.6 pg/mL) than in subjects with a BMI between 25 and 30 kg/m2 (n = 314; 98.5 pg/mL, P = 6 × 10-6) and with BMI >30 kg/m2 (n = 137; 106.4 pg/mL, P = 8 × 10-6). OXT levels were also positively correlated with plasma glucose and insulin and were elevated in subjects with impaired glucose tolerance (P = 4.6 × 10-3). Heritability of OXT was estimated at 12.8%. In a GWAS, two hits in linkage disequilibrium close (19 kb) to the OXT reached genome-wide significant association (top-hit rs12625893, P = 3.1 × 10-8, explained variance 3%). CONCLUSIONS:Our data show that OXT is genetically affected by a variant near OXT and is associated with obesity and impaired glucose tolerance.
10.1210/jc.2019-00643
Downregulation of sulfotransferase expression and activity in diseased human livers.
Yalcin Emine B,More Vijay,Neira Karissa L,Lu Zhenqiang James,Cherrington Nathan J,Slitt Angela L,King Roberta S
Drug metabolism and disposition: the biological fate of chemicals
Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates. However, it is not well known if sulfotransferase activity changes in metabolic and liver disease, such as diabetes, steatosis, or cirrhosis. Sulfotransferases have significant roles in the regulation of hormones and excretion of xenobiotics. In the present study of normal subjects with nonfatty livers and patients with steatosis, diabetic cirrhosis, and alcoholic cirrhosis, we sought to determine SULT1A1, SULT2A1, SULT1E1, and SULT1A3 activity and mRNA and protein expression in human liver tissue. In general, sulfotransferase activity decreased significantly with severity of liver disease from steatosis to cirrhosis. Specifically, SULT1A1 and SULT1A3 activities were lower in disease states relative to nonfatty tissues. Alcoholic cirrhotic tissues further contained lower SULT1A1 and 1A3 activities than those affected by either of the two other disease states. SULT2A1, on the other hand, was only reduced in alcoholic cirrhotic tissues. SULT1E1 was reduced both in diabetic cirrhosis and in alcoholic cirrhosis tissues, relative to nonfatty liver tissues. In conclusion, the reduced levels of sulfotransferase expression and activity in diseased versus nondiseased liver tissue may alter the metabolism and disposition of xenobiotics and affect homeostasis of endobiotic sulfotransferase substrates.
10.1124/dmd.113.050930
Estrogen sulfotransferase in the metabolism of estrogenic drugs and in the pathogenesis of diseases.
Barbosa Anne Caroline S,Feng Ye,Yu Chaohui,Huang Min,Xie Wen
Expert opinion on drug metabolism & toxicology
INTRODUCTION:Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen sulfotransferase (SULT1E1 or EST) is a phase II conjugating enzyme that belongs to the family of cytosolic sulfotransferases. The expression of SULT1E1 can be detected in many tissues, including the liver. SULT1E1 catalyzes the transfer of a sulfate group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to any available hydroxyl group in estrogenic molecules. The substrates of SULT1E1 include the endogenous and synthetic estrogens. Upon SULT1E1-mediated sulfation, the hydrosolubility of estrogens increases, preventing the binding between the sulfated estrogens and the estrogen receptor (ER). This sulfated state of the estrogens is not irreversible, as the steroid sulfatase (STS) can convert sulfoconjugated estrogens to free estrogens. The expression of SULT1E1 is inducible by several diseases that involve tissue inflammation, such as type 2 diabetes, sepsis, and ischemia-reperfusion injury. Areas covered: This systematic literature review aims to summarize the role of SULT1E1 in the metabolism of estrogenic drugs and xenobiotics, and the role of SULT1E1 in the pathogenesis of several diseases, including cancer, metabolic disease, sepsis, liver injury, and cystic fibrosis. Meanwhile, ablation or pharmacological inhibition of SULT1E1 can affect the outcomes of the aforementioned diseases. Expert opinion: In addition to its role in metabolizing estrogenic drugs, SULT1E1 is unexpectedly being unveiled as a mediator for the disease effect on estrogen metabolism and homeostasis. Meanwhile, because the expression and activity of SULT1E1 can affect the outcome of diseases, the same sulfotransferase and the reversing enzymes STS can be potential therapeutic targets to prevent or manage diseases. Accumulating evidence suggest that the physiological and pathophysiological effects of SULT1E1 can be estrogen-independent and it is necessary to elucidate what other possible substrates may be recognized by the enzyme. Moreover, human studies are paramount to confirm the human relevance of the animal studies.
10.1080/17425255.2019.1588884
Nuclear receptor CAR-ERα signaling regulates the estrogen sulfotransferase gene in the liver.
Yi MyeongJin,Fashe Muluneh,Arakawa Shingo,Moore Rick,Sueyoshi Tatsuya,Negishi Masahiko
Scientific reports
Estrogen sulfotransferase (SULT1E1) inactivates estrogen and regulates its metabolic homeostats. Whereas SULT1E1 is expressed low in the liver of adult mice, it is induced by phenobarbital (PB) treatment or spontaneously in diabetic livers via nuclear receptors. Utilizing constitutive active/androstane receptor (CAR) KO, estrogen receptor α (ERα KO, phosphorylation-blocked ERα S216A KI mice, it is now demonstrated that, after being activated by PB, CAR binds and recruits ERα onto the Sulte1 promoter for subsequent phosphorylation at Ser216. This phosphorylation tightens CAR interacting with ERα and to activates the promoter. Hepatic SULT1E1 mRNA levels are constitutively up-regulated in type 1 diabetic Akita mice; CAR spontaneously accumulates in the nucleus and activates the Sult1e1 promoter by recruiting phosphorylated ERα in the liver as observed with PB-induced livers. Thus, this CAR-phosphorylated ERα signaling enables these two nuclear receptors to communicate, activating the Sult1e1 gene in response to either PB or diabetes in mice. ERα phosphorylation may integrate CAR into estrogen actions, providing insights into understanding drug-hormone interactions in clinical therapy.
10.1038/s41598-020-61767-9
Sex-specific expression mechanism of hepatic estrogen inactivating enzyme and transporters in diabetic women.
Biochemical pharmacology
Circulating estrogens levels significantly decrease in menopause and levels off in postmenopausal women. Accordingly, the liver represses levels of enzymes and membrane transporters, thereby decreasing capability of inactivating and excreting estrogens. Women increasingly develop type 2 diabetes during or after menopause. Estrogens are known to promote liver diseases in these women. Here, we have found that the estrogen inactivating sulfotransferase (SULT1E1) and an ATP-binding cassette subfamily G member 2 (ABCG2), a gene encoding breast cancer resistance protein that exports sulfated estrogens, increased their expression levels in diabetic women but not men. For the sulfotransferase gene, phosphorylated nuclear receptors ERα and RORα, at Ser212 and Ser100, respectively, bind their response elements to activate the SULT1E1 promoter in women. This coordinated increase in estrogen inactivation and excretion, and the phosphorylated nuclear receptor-mediated gene activation could be a defense mechanism against toxicities of estrogens through inactivation and excretion in the livers of women.
10.1016/j.bcp.2021.114662
Changing gears in Nrf1 research, from mechanisms of regulation to its role in disease and prevention.
Bugno Magdalena,Daniel Mary,Chepelev Nikolai L,Willmore William G
Biochimica et biophysica acta
The "cap'n'collar" bZIP transcription factor Nrf1 heterodimerizes with small Maf proteins to bind to the Antioxidant Response Element/Electrophile Response Element to transactivate antioxidant enzyme, phase 2 detoxification enzyme and proteasome subunit gene expression. Nrf1 specifically regulates pathways in lipid metabolism, amino acid metabolism, proteasomal degradation, the citric acid cycle, and the mitochondrial respiratory chain. Nrf1 is maintained in the endoplasmic reticulum (ER) in an inactive glycosylated state. Activation involves retrotranslocation from the ER lumen to the cytoplasm, deglycosylation and partial proteolytic processing to generate the active forms of Nrf1. Recent evidence has revealed how this factor is regulated and its involvement in various metabolic diseases. This review outlines Nrf1 structure, function, regulation and its links to insulin resistance, diabetes and inflammation. The glycosylation/deglycosylation of Nrf1 is controlled by glucose levels. Nrf1 glycosylation affects its control of glucose transport, glycolysis, gluconeogenesis and lipid metabolism.
10.1016/j.bbagrm.2015.08.001
Protein therapy using MafA fused to a polyarginine transduction domain attenuates glucose levels of streptozotocin‑induced diabetic mice.
Lu Jun,Lin Lingjing,Dong Huiyue,Meng Xin,Fang Fang,Wang Qinghua,Huang Lianghu,Tan Jianming
Molecular medicine reports
Ectopic expression of musculo aponeurotic fibrosarcoma BZIP transcription factor (Maf) A, has previously been demonstrated to induce insulin expression in non‑β‑cell lines. Protein transduction domains acting as an alternative delivery strategy may deliver heterogeneous proteins into cells. A sequence of 11 arginine residues (11R) has been demonstrated to act as a particularly efficient vector to introduce proteins into various cell types. The present study constructed 11R‑fused MafA to achieve transduction of the protein into cellular membranes and subsequently examined the therapeutic effect of the MafA‑11R protein in streptozotocin‑induced diabetes. A small animal imaging system was used to demonstrate that 11R introduced proteins into cells. The MafA‑11R protein was then injected into the tale vein of healthy male mice, and western blot analysis and immunofluorescence staining was performed to identify the location of the recombinant protein. Ameliorated hyperglycemia in the MafA‑11R‑treated diabetic mice was demonstrated via the improved intraperitoneal glucose tolerance test (IPGTT) and glucose‑stimulated insulin release. Furthermore, insulin producing cells were detected in the jejunum of the MafA‑11R treated mice. The results of the present study indicated that MafA‑11R delivery may act as a novel and potential therapeutic strategy for the future and will not present adverse effects associated with viral vector‑mediated gene therapies.
10.3892/mmr.2017.6536
Pancreatic endocrine-like cells differentiated from human umbilical cords Wharton's jelly mesenchymal stem cells using small molecules.
Belame Shivakumar Sharath,Bharti Dinesh,Baregundi Subbarao Raghavendra,Park Ju-Mi,Son Young-Bum,Ullah Imran,Choe Yong-Ho,Lee Hyeong-Jeong,Park Bong-Wook,Lee Sung-Lim,Rho Gyu-Jin
Journal of cellular physiology
Following success of pancreatic islet transplantation in the treatment of Type I diabetes mellitus, there is a growing interest in using cell-based treatment approaches. However, severe shortage of donor islets-pancreas impeded the growth, and made researchers to search for an alternative treatment approaches. In this context, recently, stem cell-based therapy has gained more attention. The current study demonstrated that epigenetic modification improves the in vitro differentiation of Wharton's jelly mesenchymal stem cells (WJMSCs) into pancreatic endocrine-like cells. Here we used two histone deacetylase (HDAC) inhibitors namely trichostatin A (TSA) and TMP269. TSA inhibits both class I and II HDACs whereas TMP269 inhibits only class IIa HDACs. WJMSCs were differentiated using a multistep protocol in a serum-free condition with or without TSA pretreatment. A marginal improvement in differentiation was observed after TSA pretreatment though it was not significant. However, exposing endocrine precursor-like cells derived from WJMSCs to TMP269 alone has significantly improved the differentiation toward insulin-producing cells. Further, increase in the expression of paired box 4 (PAX4), insulin, somatostatin, glucose transporter 2 (GLUT2), MAF bZIP transcription factor A (MAFA), pancreatic duodenal homeobox 1 (PDX-1), and NKX6.1 was observed both at messenger RNA and protein levels. Nevertheless, TMP269-treated cells secreted higher insulin upon glucose challenge, and demonstrated increased dithizone staining. These findings suggest that TMP269 may improve the in vitro differentiation of WJMSCs into insulin-producing cells.
10.1002/jcp.27184
LIM-domain transcription complexes interact with ring-finger ubiquitin ligases and thereby impact islet β-cell function.
The Journal of biological chemistry
Diabetes is characterized by a loss of β-cell mass, and a greater understanding of the transcriptional mechanisms governing β-cell function is required for future therapies. Previously, we reported that a complex of the Islet-1 (Isl1) transcription factor and the co-regulator single-stranded DNA-binding protein 3 (SSBP3) regulates the genes necessary for β-cell function, but few proteins are known to interact with this complex in β-cells. To identify additional components, here we performed SSBP3 reverse-cross-linked immunoprecipitation (ReCLIP)- and MS-based experiments with mouse β-cell extracts and compared the results with those from our previous Isl1 ReCLIP study. Our analysis identified the E3 ubiquitin ligases ring finger protein 20 (RNF20) and RNF40, factors that in nonpancreatic cells regulate transcription through imparting monoubiquitin marks on histone H2B (H2Bub1), a precursor to histone H3 lysine 4 trimethylation (H3K4me3). We hypothesized that RNF20 and RNF40 regulate similar genes as those regulated by Isl1 and SSBP3 and are important for β-cell function. We observed that and depletion reduces β-cell H2Bub1 marks and uncovered several target genes, including glucose transporter 2 (), MAF BZIP transcription factor A (), and uncoupling protein 2 (). Strikingly, we also observed that and depletion reduces H2Bub1 and H3K4me3 marks, suggesting that they have epigenetic roles. We noted that the RNF complex is required for glucose-stimulated insulin secretion and normal mitochondrial reactive oxygen species levels. These findings indicate that RNF20 and RNF40 regulate β-cell gene expression and insulin secretion and establish a link between Isl1 complexes and global cellular epigenetics.
10.1074/jbc.RA118.006985
Pax4 synergistically acts with Pdx1, Ngn3 and MafA to induce HuMSCs to differentiate into functional pancreatic β-cells.
Zhang Ting,Wang Hongwu,Wang Tianyou,Wei Chiju,Jiang Hui,Jiang Shayi,Yang Jingwei,Shao Jingbo,Ma Lian
Experimental and therapeutic medicine
It has been indicated that the combination of pancreatic and duodenal homeobox 1 (Pdx1), MAF bZIP transcription factor A (MafA) and neurogenin 3 (Ngn3) was able to reprogram various cell types towards pancreatic β-like cells (pβLCs). Paired box 4 (Pax4), a transcription factor, has a key role in regulating the maturation of pancreatic β-cells (pβCs). In the present study, it was investigated whether Pax4 is able to synergistically act with Pdx1, Ngn3 and MafA to induce human umbilical cord mesenchymal stem cells (HuMSCs) to differentiate into functional pβCs . HuMSCs were isolated, cultured and separately transfected with adenovirus (Ad) expressing enhanced green fluorescence protein, Pax4 (Ad-Pax4), Pdx1+MafA+Ngn3 (Ad-3F) or Ad-Pxa4 + Ad-3F. The expression of C-peptide, insulin and glucagon was detected by immunofluorescence. The transcription of a panel of genes was determined by reverse transcription-quantitative PCR, including glucagon (GCG), insulin (INS), NK6 homeobox 1 (NKX6-1), solute carrier family 2 member 2 (SLC2A2), glucokinase (GCK), proprotein convertase subtilisin/kexin type 1 (PCSK1), neuronal differentiation 1 (NEUROD1), ISL LIM homeobox 1 (ISL 1), Pax6 and PCSK type 2 (PCSK2). Insulin secretion stimulated by glucose was determined using ELISA. The results suggested that, compared with Ad-3F alone, cells co-transfected with Ad-Pax4 and Ad-3F expressed higher levels of INS and C-peptide, as well as genes expressed in pancreatic β precursor cells, and secreted more insulin in response to high glucose. Furthermore, the expression of GCG in cells transfected with Ad-3F was depressed by Ad-Pax4. The present study demonstrated that Pax4 was able to synergistically act with the transcription factors Pdx1, Ngn3 and MafA to convert HuMSCs to functional pβLCs. HuMSCs may be potential seed cells for generating functional pβLCs in the therapy of diabetes.
10.3892/etm.2019.7854
β-Cell-Specific Deletion of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) Reductase Causes Overt Diabetes due to Reduction of β-Cell Mass and Impaired Insulin Secretion.
Takei Shoko,Nagashima Shuichi,Takei Akihito,Yamamuro Daisuke,Wakabayashi Tetsuji,Murakami Akiko,Isoda Masayo,Yamazaki Hisataka,Ebihara Chihiro,Takahashi Manabu,Ebihara Ken,Dezaki Katsuya,Takayanagi Yuki,Onaka Tatsushi,Fujiwara Ken,Yashiro Takashi,Ishibashi Shun
Diabetes
Inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), statins, which are used to prevent cardiovascular diseases, are associated with a modest increase in the risk of new-onset diabetes. To investigate the role of HMGCR in the development of β-cells and glucose homeostasis, we deleted in a β-cell-specific manner by using the Cre-loxP technique. Mice lacking in β-cells (β-KO) exhibited hypoinsulinemic hyperglycemia as early as postnatal day 9 (P9) due to decreases in both β-cell mass and insulin secretion. Ki67-positive cells were reduced in β-KO mice at P9; thus, β-cell mass reduction was caused by proliferation disorder immediately after birth. The mRNA expression of neurogenin3 (), which is transiently expressed in endocrine progenitors of the embryonic pancreas, was maintained despite a striking reduction in the expression of β-cell-associated genes, such as insulin, pancreatic and duodenal homeobox 1 (), and MAF BZIP transcription factor A () in the islets from β-KO mice. Histological analyses revealed dysmorphic islets with markedly reduced numbers of β-cells, some of which were also positive for glucagon. In conclusion, HMGCR plays critical roles not only in insulin secretion but also in the development of β-cells in mice.
10.2337/db19-0996
Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes.
Eom Young Sil,Gwon A-Ryeong,Kwak Kyung Min,Youn Jin-Young,Park Heekyoung,Kim Kwang-Won,Kim Byung-Joon
Diabetes & metabolism journal
BACKGROUND:Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS). METHODS:Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and β-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion. RESULTS:NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and β-cell masses were decreased in NAS mice. The number of large islets (≥250 µm) decreased while that of small islets (<250 µm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice. CONCLUSION:Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and β-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in β-cell mass determination and diabetes.
10.4093/dmj.2019.0160
Protective effects of Acyl-coA thioesterase 1 on diabetic heart via PPARα/PGC1α signaling.
Yang Shenglan,Chen Chen,Wang Hong,Rao Xiaoquan,Wang Feng,Duan Quanlu,Chen Fuqiong,Long Guangwen,Gong Wei,Zou Ming-Hui,Wang Dao Wen
PloS one
BACKGROUND:Using fatty acids (FAs) exclusively for ATP generation was reported to contribute to the development of diabetic cardiomyopathy. We studied the role of substrate metabolism related genes in the heart of the diabetes to find out a novel therapeutic target for diabetic cardiomyopathy. METHODS AND RESULTS:By microarray analysis of metabolic gene expression, acyl-CoA thioesterase 1 (acot1) was clearly upregulated in the myocardia of db/db mice, compared with normal control C57BL/Ks. Therefore, gain-of-function and loss-of-function approaches were employed in db/db mice to investigate the functions of ACOT1 in oxidative stress, mitochondrial dysfunction and heart function. We found that in the hearts of db/db mice which overexpressed ACOT1, H(2)O(2) and malondialdehyde (MDA) were reduced, the activities of ATPases in mitochondria associated with mitochondrial function were promoted, the expression of uncoupling protein 3 (UCP3) contributing to oxygen wastage for noncontractile purposes was decreased, and cardiac dysfunction was attenuated, as determined by both hemodynamic and echocardiographic detections. Consistently, ACOT1 deficiency had opposite effects, which accelerated the cardiac damage induced by diabetes. Notably, by real-time PCR, we found that overexpression of ACOT1 in diabetic heart repressed the peroxisome proliferator-activated receptor alpha/PPARγ coactivator 1α (PPARα/PGC1α) signaling, as shown by decreased expression of PGC1α and the downstream genes involved in FAs use. CONCLUSION:Our results demonstrated that ACOT1 played a crucial protective role in diabetic heart via PPARα/PGC1α signaling.
10.1371/journal.pone.0050376
Expression of phosphoenolpyruvate carboxykinase gene in human adipose tissue: induction by rosiglitazone and genetic analyses of the adipocyte-specific region of the promoter in type 2 diabetes.
Duplus Eric,Benelli Chantal,Reis André F,Fouque Françoise,Velho Gilberto,Forest Claude
Biochimie
Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) is the key enzyme in glyceroneogenesis, an important metabolic pathway in adipocytes for reesterification of fatty acids during fasting. Dysregulation of glyceroneogenesis could play a role in the increase in plasma non-esterified fatty acids that accompanies type 2 diabetes. In rodent adipocyte transcription of the PEPCK-C gene is induced by thiazolidinediones (TZDs) through an element, named PCK2, in its promoter. PCK2 binds a peroxisome proliferator activated receptor gamma (PPARgamma), retinoid X receptor alpha (RXRalpha) heterodimer. We demonstrated that in cultured human subcutaneous adipose tissue explants, PEPCK-C specific activity and mRNA were induced by 1 microM of the TZD rosiglitazone, respectively, about twofold in 8 h and fivefold in 5 h. Using gel shift experiments, we show that this effect is likely to involve the human PCK2 (hPCK2) element, which binds a protein complex that contains PPARgamma and RXRalpha. We analyzed hPCK2 (position -1031 to -1015 base pairs) and nearby sequences in the PEPCK-C promoter in 403 subjects with type 2 diabetes and 123 non-diabetic controls. The sequence of hPCK2 was not polymorphic, but we detected two C/T single nucleotide polymorphisms (SNPs), in complete linkage disequilibrium, at positions -1097 and -967 bp. Allele and genotype frequencies were not significantly different in patients and controls. However, our results suggest co-dominant effects of C and T-alleles on fasting plasma glucose and glycosylated hemoglobin A1c levels in obese type 2 diabetic patients.
PCK1 and PCK2 as candidate diabetes and obesity genes.
Beale Elmus G,Harvey Brandy J,Forest Claude
Cell biochemistry and biophysics
The PCK1 gene (Pck1 in rodents) encodes the cytosolic isozyme of phosphoenolpyruvate carboxykinase (PEPCK-C), which is well-known for its function as a gluconeogenic enzyme in the liver and kidney. Mouse studies involving whole body and tissue-specific Pck1 knockouts as well as tissue-specific over-expression of PEPCK-C have resulted in type 2 diabetes as well as several surprising phenotypes including obesity, lipodystrophy, fatty liver, and death. These phenotypes arise from perturbations not only in gluconeogenesis but in two additional metabolic functions of PEPCK-C: (1) cataplerosis which maintains metabolic flux through the Krebs cycle by removing excess oxaloacetate, and (2) glyceroneogenesis which produces glycerol-3-phosphate as a precursor for fatty acid esterification into triglycerides. PEPCK-C catalyzes the conversion of oxaloacetate + GTP to phosphoenolpyruvate + GDP + CO2. It is in part the tissue-specificity of this simple reaction that results in the variety of phenotypes listed above. Briefly: (1) A 7-fold over-expression of PEPCK-C in the livers of mice causes excessive glucose production. (2) Mice with a whole-body knockout of Pck1 die within 2-3 days of birth, not from hypoglycemia, but probably because the Krebs cycle slows to approximately 10% of normal in the absence of cataplerosis. (3) Mice with a liver-specific knockout have an inability to remove oxaloacetate from the Krebs cycle, which leads to a fatty liver following a fast. (4) An adipose-specific knockout of Pck1 results in a fraction of the mice developing lipodystrophy due to lost glyceroneogenesis and a consequent decrease in fatty acid re-esterification. (5) Finally, disregulated over-expression of PEPCK-C in adipose tissue increases fatty acid re-esterification leading to obesity. These varied experimental phenotypes in mice have led us to postulate that abnormal production of PEPCK isozymes encoded by two PEPCK genes, PCK1 and PCK2, in humans could have similar consequences (Beale, E. G. et al. (2004). Trends in Endocrinology and Metabolism, 15, 129-135). The purpose of this review is to further explore these possibilities.
10.1007/s12013-007-0025-6
Early second-trimester serum miRNA profiling predicts gestational diabetes mellitus.
Zhao Chun,Dong Jing,Jiang Tao,Shi Zhonghua,Yu Bin,Zhu Yunlong,Chen Daozhen,Xu Junrong,Huo Ran,Dai Juncheng,Xia Yankai,Pan Shiyang,Hu Zhibin,Sha Jiahao
PloS one
BACKGROUND:Gestational diabetes mellitus (GDM) is one type of diabetes that presents during pregnancy and significantly increases the risk of a number of adverse consequences for the fetus and mother. The microRNAs (miRNA) have recently been demonstrated to abundantly and stably exist in serum and to be potentially disease-specific. However, no reported study investigates the associations between serum miRNA and GDM. METHODOLOGY/PRINCIPAL FINDINGS:We systematically used the TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays to screen miRNAs in serum collected at 16-19 gestational weeks. The expression levels of three miRNAs (miR-132, miR-29a and miR-222) were significantly decreased in GDM women with respect to the controls in similar gestational weeks in our discovery evaluation and internal validation, and two miRNAs (miR-29a and miR-222) were also consistently validated in two-centric external validation sample sets. In addition, the knockdown of miR-29a could increase Insulin-induced gene 1 (Insig1) expression level and subsequently the level of Phosphoenolpyruvate Carboxy Kinase2 (PCK2) in HepG2 cell lines. CONCLUSIONS/SIGNIFICANCE:Serum miRNAs are differentially expressed between GDM women and controls and could be candidate biomarkers for predicting GDM. The utility of miR-29a, miR-222 and miR-132 as serum-based non-invasive biomarkers warrants further evaluation and optimization.
10.1371/journal.pone.0023925
Decreased expression of hepatic glucokinase in type 2 diabetes.
Haeusler Rebecca A,Camastra Stefania,Astiarraga Brenno,Nannipieri Monica,Anselmino Marco,Ferrannini Ele
Molecular metabolism
BACKGROUND/OBJECTIVES:Increased endogenous glucose production is a hallmark of type 2 diabetes. Evidence from animal models has suggested that a likely cause of this is increased mRNA expression of glucose 6-phosphatase and phosphoenolpyruvate carboxykinase (encoded by G6PC, PCK1 and PCK2). But another contributing factor may be decreased liver glucokinase (encoded by GCK). METHODS:We examined expression of these enzymes in liver biopsies from 12 nondiabetic and 28 diabetic individuals. Diabetic patients were further separated into those with HbA1c lower or higher than 7.0. RESULTS:In diabetic subjects with HbA1c > 7.0, we found that gluconeogenic enzymes were expressed normally, but GCK was suppressed more than 60%. Moreover, HbA1c and fasting glucose were negatively correlated with GCK, but showed no correlation with G6PC, PCK1, or PCK2. CONCLUSION:These findings suggest an underlying dysregulation of hepatic GCK expression during frank diabetes, which has implications for the therapeutic use of glucokinase activators in this population.
10.1016/j.molmet.2014.12.007
AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.
Song Chun,Yan Han,Wang Hanming,Zhang Yan,Cao Huiqing,Wan Yiqi,Kong Lingbao,Chen Shenghan,Xu Hong,Pan Bingxing,Zhang Jin,Fan Guohuang,Xin Hongbo,Liang Zicai,Jia Weiping,Tian Xiao-Li
Journal of genetics and genomics = Yi chuan xue bao
Type 2 diabetes mellitus (T2DM) is a common metabolic disease influenced by both genetic and environmental factors. In this study, we performed an in-house genotyping and meta-analysis study using three independent GWAS datasets of T2DM and found that rs3743121, located 1 kb downstream of AQR, was a novel susceptibility SNP associated with T2DM. The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells, similar to that observed in T2DM models. The knockdown of AQR in HepG2 facilitated the glucose uptake, decreased the expression level of PCK2, increased the phosphorylation of GSK-3β, and restored the insulin sensitivity. Furthermore, the suppression of AQR inhibited the mTOR pathway and the protein ubiquitination process. Our study suggests that AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.
10.1016/j.jgg.2017.11.007
Dietary Supplementation of Vine Tea Ameliorates Glucose and Lipid Metabolic Disorder via Akt Signaling Pathway in Diabetic Rats.
Xiang Jiamei,Lv Qiuyue,Yi Fan,Song Yanjun,Le Liang,Jiang Baoping,Xu Lijia,Xiao Peigen
Molecules (Basel, Switzerland)
A traditional Chinese tea with many pharmacological effects, vine tea (VT) is considered a potential dietary supplement to improve type 2 diabetes (T2D). To investigate the effect and mechanism of VT on glucose and lipid metabolic disorders in T2D rats, Wistar rats fed a normal diet served as the normal control, while rats fed a high-fat diet combined with low-dose streptozotocin (STZ)-induced T2D were divided into three groups: The model group (MOD); the positive control group (MET, metformin at 200 mg/kg/d); and the VT-treated group (VT500, allowed to freely drink 500 mg/L VT). After four weeks of intervention, biochemical metrics indicated that VT significantly ameliorated hyperglycemia, hyperlipidemia and hyperinsulinemia in T2D rats. Metabolomics research indicated that VT regulated the levels of metabolites closely related to glucose and lipid metabolism and promoted glycogen synthesis. Furthermore, VT had a significant influence on the expression of key genes involved in the Akt signaling pathway, inhibited gluconeogenesis through the Akt/Foxo1/Pck2 signaling pathway, and reduced fatty acid synthesis via the SREBP1c/Fasn signaling pathways. In conclusion, VT has great potential as a dietary supplement to ameliorate glucose and lipid metabolic disorders via the Akt signaling pathway in T2D rats.
10.3390/molecules24101866
Phosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis.
Yu Shuo,Meng Simin,Xiang Meixiang,Ma Hong
Molecular metabolism
BACKGROUND:Phosphoenolpyruvate carboxykinase (PCK) has been almost exclusively recognized as a critical enzyme in gluconeogenesis, especially in the liver and kidney. Accumulating evidence has shown that the enhanced activity of PCK leads to increased glucose output and exacerbation of diabetes, whereas the defects of PCK result in lethal hypoglycemia. Genetic mutations or polymorphisms are reported to be related to the onset and progression of diabetes in humans. SCOPE OF REVIEW:Recent studies revealed that the PCK pathway is more complex than just gluconeogenesis, depending on the health or disease condition. Dysregulation of PCK may contribute to the development of obesity, cardiac hypertrophy, stroke, and cancer. Moreover, a regulatory network with multiple layers, from epigenetic regulation, transcription regulation, to posttranscription regulation, precisely tunes the expression of PCK. Deciphering the molecular basis that regulates PCK may pave the way for developing practical strategies to treat metabolic dysfunction. MAJOR CONCLUSIONS:In this review, we summarize the metabolic and non-metabolic roles of the PCK enzyme in cells, especially beyond gluconeogenesis. We highlight the distinct functions of PCK isoforms (PCK1 and PCK2), depict a detailed network regulating PCK's expression, and discuss its clinical relevance. We also discuss the therapeutic potential targeting PCK and the future direction that is highly in need to better understand PCK-mediated signaling under diverse conditions.
10.1016/j.molmet.2021.101257
Laser Capture Microdissection Coupled Capillary Immunoassay to Study the Expression of PCK-2 on Spatially-Resolved Islets of Rat Langerhans.
Pandey Shashank,Tuma Zdenek,Smrhova Tereza,Cedikova Miroslava,Macanova Tereza,Chottova Dvorakova Magdalena
Pharmaceutics
The platform for precise proteomic profiling of targeted cell populations from heterogeneous tissue sections is developed. We demonstrate a seamless and systematic integration of LCM with an automated cap-IA for the handling of a very small-sized dissected tissues section from the kidney, liver and pancreatic Langerhans islet of rats. Our analysis reveals that the lowest LCM section area ≥ 0.125 mm with 10 µm thickness can be optimized for the detection of proteins through LCM-cap-IA integration. We detect signals ranging from a highly-abundant protein, β-actin, to a low-abundance protein, LC-3AB, using 0.125 mm LCM section from rat kidney, but, so far, a relatively large section is required for good quality of results. This integration is applicable for a highly-sensitive and accurate assessment of microdissected tissue sections to decipher hidden proteomic information of pure targeted cells. To validate this integration, PCK2 protein expression is studied within Langerhans islets of normal and diabetic rats. Our results show significant overexpression of PCK2 in Langerhans islets of rats with long-term diabetes.
10.3390/pharmaceutics13060883