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Association Between Obesity and Microvascular Diseases in Patients With Type 2 Diabetes Mellitus

ABSTRACT: This study aimed to evaluate the association between obesity, evaluated by fat mass index (FMI) with the risk of microvascular diseases in patients with type 2 diabetes mellitus (T2DM) and compare the magnitude of associations of FMI, body mass index (BMI), and waist circumference (WC) with the risk of microvascular diseases. We performed a post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes study. The primary microvascular outcomes of the present study included chronic kidney disease (CKD) progression, retinopathy, and neuropathy. Cox proportional-hazards models were performed to evaluate the association of FMI with microvascular diseases. A discordant analysis was performed to compare the magnitude of associations of FMI, BMI, and WC with the risk of microvascular diseases. Our study included 10,251 T2DM participants with a median of 5 years (interquartile range, 4.2–5.7) of follow-up. A total of 6,184 participants developed CKD progression, 896 participants had retinopathy, and 3,213 participants developed neuropathy (Michigan Neuropathy Screening Instrument, >2.0). After the confounding factors were adjusted for, patients in the highest FMI quartile had a higher risk of CKD progression (HR: 1.26, 95%CI: 1.16–1.36) and neuropathy (HR: 1.93, 95% CI: 1.74–2.15), except for retinopathy (HR: 1.17, 95% CI: 0.96–1.43), than those in the lowest quartile. Discordant analyses found that FMI and WC are better in identifying individuals with obesity-related risk of neuropathy, compared with BMI; neither is better in identifying individuals with obesity-related risk of CKD progression and retinopathy. Obesity is associated with CKD progression and neuropathy in T2DM participants. Further randomized trials are needed to test whether obesity control can improve the outcomes of T2DM participants with CKD or neuropathy. FMI and WC are more useful in identifying obesity-related risk of neuropathy compared with BMI in T2DM patients.

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http://www.clinicaltrials.gov, NCT00000620.

SUBMITTER: Gao S

PROVIDER: S-EPMC8576347 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundType 2 diabetes mellitus (T2DM) is a chronic, metabolic disorder in which concomitant insulin resistance and β-cell impairment lead to hyperglycemia, influenced by genetic and environmental factors. T2DM is associated with long-term complications that have contributed to the burden of morbidity and mortality worldwide. The objective of this manuscript is to conduct an Exome-Wide Association Study (EWAS) on T2DM Emirati individuals to improve our understanding on diabetes-related complications to improve early diagnostic methods and treatment strategies.MethodsThis cross-sectional study recruited 310 Emirati participants that were stratified according to their medically diagnosed diabetes-related complications: diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and cardiovascular complications. The Illumina's Infinium Exome-24 array was used and 39,840 SNPs remained for analysis after quality control.FindingsThe analysis revealed the associations of various genes with each complication category: 1) diabetic retinopathy was associated to SHANK3 gene in locus 22q13.33 (SNP rs9616915; p=5.18 x10-4), ZSCAN5A gene in locus 19q13.43 (SNP rs7252603; p=7.55 x10-4), and DCP1B gene in locus 12p13.33 (SNPs rs715146, rs1044950, rs113147414, rs34730825; p=7.62 x10-4); 2) diabetic neuropathy was associated to ADH4 gene in locus 4q23 (SNP rs4148883; p=1.23 x10-4), SLC11A1 gene in locus 2q35 (SNP rs17235409; p=1.85 x10-4), and MATN4 gene in locus 20q13.12 (SNP rs2072788; p=2.68 x10-4); 3) diabetic nephropathy was associated to PPP1R3A gene in locus 7q31.1 (SNP rs1799999; p=1.91 x10-4), ZNF136 gene in locus 19p13.2 (SNP rs140861589; p=2.80 x10-4), and HSPA12B gene in locus 20p13 (SNP rs6076550; p=2.86 x10-4); and 4) cardiovascular complications was associated to PCNT gene in locus 21q22.3 (SNPs rs7279204, rs6518289, rs2839227, rs2839223; p=2.18 x10-4,3.04 x10-4,4.51 x10-4,5.22 x10-4 respectively), SEPT14 gene in locus 7p11.2 (SNP rs146350220; p=2.77 x10-4), and WDR73 gene in locus 15q25.2 (SNP rs72750868; p=4.47 x10-4).InterpretationWe have identified susceptibility loci associated with each category of T2DM-related complications in the Emirati population. Given that only 16% of the markers from the Illumina's Infinium Exome chip passed quality control assessment, this demonstrates that multiple variants were, either, monomorphic in the Arab population or were not genotyped due to the use of a Euro-centric EWAS array that limits the possibility of including targeted ethnic-specific SNPs. Our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci associated to T2DM complications. Further effort must be conducted to improve the representation of diverse populations in genotyping and sequencing studies.

Project description:BackgroundSchizophrenia (SCZ) and type 2 diabetes mellitus (T2D) are both complex diseases. Accumulated studies indicate that schizophrenia patients are prone to present the type 2 diabetes symptoms, but the potential mechanisms behind their association remain unknown. Here we explored the pathogenetic association between SCZ and T2D based on pathway analysis and protein-protein interaction.ResultsWith sets of prioritized susceptibility genes for SCZ and T2D, we identified significant pathways (with adjusted p-value < 0.05) specific for SCZ or T2D and for both diseases based on pathway enrichment analysis. We also constructed a network to explore the crosstalk among those significant pathways. Our results revealed that some pathways are shared by both SCZ and T2D diseases through a number of susceptibility genes. With 382 unique susceptibility proteins for SCZ and T2D, we further built a protein-protein interaction network by extracting their nearest interacting neighbours. Among 2,104 retrieved proteins, 364 of them were found simultaneously interacted with susceptibility proteins of both SCZ and T2D, and proposed as new candidate risk factors for both diseases. Literature mining supported the potential association of partial new candidate proteins with both SCZ and T2D. Moreover, some proteins were hub proteins with high connectivity and interacted with multiple proteins involved in both diseases, implying their pleiotropic effects for the pathogenic association. Some of these hub proteins are the components of our identified enriched pathways, including calcium signaling, g-secretase mediated ErbB4 signaling, adipocytokine signaling, insulin signaling, AKT signaling and type II diabetes mellitus pathways. Through the integration of multiple lines of information, we proposed that those signaling pathways, which contain susceptibility genes for both diseases, could be the key pathways to bridge SCZ and T2D. AKT could be one of the important shared components and may play a pivotal role to link both of the pathogenetic processes.ConclusionsOur study is the first network and pathway-based systematic analysis for SCZ and T2D, and provides the general pathway-based view of pathogenetic association between two diseases. Moreover, we identified a set of candidate genes potentially contributing to the linkage between these two diseases. This research offers new insights into the potential mechanisms underlying the co-occurrence of SCZ and T2D, and thus, could facilitate the inference of novel hypotheses for the co-morbidity of the two diseases. Some etiological factors that exert pleiotropic effects shared by the significant pathways of two diseases may have important implications for the diseases and could be therapeutic intervention targets.

Project description:We will explore the genetic (including APC, k-ras, p53, MSI, etc.) and environmental (including family history, life style, diet, nutritional status, DM, serum IGF-I, IGFBP-3, etc.) risk factors of colorectal tumorigenesis. We will accrue approximately 1000 patients as experimental group. The control group consists of 2000 individuals who were confirmed without colorectal cancer or polyps by colonoscopy. We estimated the statistical power of this study will reach more than 90%. In the second year, we will explore the association between various environmental risk factors with the epigenetic changes of various oncogenes and tumor suppressor genes. Firstly, we will study the correlation between hypermethylation of promoter region of hMLH1 gene with various environmental factors. Next, we will explore the genetic polymorphisms of promoter of E-cadherin gene. Recently, it has been reported that the C→A genetic polymorphism in the promoter region of E-cadherin gene in prostate cancer. Since this phenomenon has not been reported in colorectal cancer, it is mandatory for us to extend our research to the E-cadherin polymorphisms of colorectal cancer. Moreover, this project will focus on exploration of the association between the genetic polymorphisms of promoter of TS gene with chemosensitivity to 5-Fu-based therapy. We speculated that the better prognosis in colorectal tumors with MSI is related to their expression of TS gene. In summary, the second year of this project will extend our accumulated experience in the study of genetic polymorphisms to further clarify the association between genetic polymorphisms of TS gene with the prognosis of colorectal cancers after chemotherapy. We believe that this project will facilitate: (1) the further clarification of colorectal cancer tumorigenesis; (2) the establishment of domestic epidemiological data of colorectal cancer of Taiwan, and (3) the improvement of the quality of clinical management of patients with colorectal cancer.

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Association Between Obesity and Microvascular Diseases in Patients With Type 2 Diabetes Mellitus

Clinical Trial Registration

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