Microvascular and Macrovascuar Complications of Type 2 Diabetes Mellitus: Exome Wide Association Analyses
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE226084 | GEO | 2023/04/12
REPOSITORIES: GEO
Similar Datasets
Project description:In this study, we examined the impact of modulating the TGF-β/PAI-1 axis in CD34+ cells function from diabetic patients and controls. Using gene array studies, we found that diabetics, protected from microvascular complications despite suboptimal glycemic control, had reduced level of TGF- β1 and PAI-1 transcripts in their CD34+ cells compared to age, sex, duration and degree of glycemic control -matched diabetics with microvascular complications. Treatment with neutralizing antibody to TGF- β1 in murine hematopoietic stem cells (HSC) enhanced in vivo repopulation potential of these cells in bone marrow transplantation; reduced the time required for cell division of single cells, increased survival of the progenitor cells and reduced TGF-β1 expression. TGF- β1 phosphorodiamidate morpholino oligomers (PMO) treatment reduced PAI-1 mRNA expression in diabetic (p<0.01) and non-diabetic (p=0.05) CD34+ cells. Inhibition of PAI-1 promoted CD34+ cell proliferation and migration in vitro.Targetting TGFβ-1/PAI-1 system offers a promising therapeutic strategy for restoring vascular reparative function in diabetic CD34+ cells and hematopoietic stem cells, enhancing key functions needed for cell therapy. Peripheral blood from either age matched controls (n=5), diabetics with long standing poorly controlled diabetes and no microvascular complications (n=4), and diabetics with long-standing poorly controlled diabetes with severe microvascular complications (n=5) was obtained and CD34+ cells were isolated. RNA was extracted followed by AffyNugen amplification, and the cDNA was probed to Human RSTA Affymetrix 2.0 chip
2013-02-01 | E-GEOD-43950 | biostudies-arrayexpress
Project description:Diabetes mellitus (DM) is a disorder that disrupts the body from shifting glucose into the cells resulting in hyperglycaemia (1). Insulin dependence or DM that resembles type I diabetes in humans is commonly observed in dogs (2). Canine DM diagnosis is based on fasting hyperglycaemia and glucosuria with clinical presentation of polyuria, polydipsia, polyphagia and weight loss (2). Its treatment goal is blood glucose control, which can be accomplished through insulin therapy, dietary modification and control of concurrent disorders (3). The major complications of DM include diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy and atherosclerosis induced by chronic hyperglycaemia via several pathways (4). The proposed unifying mechanism that mediates the tissue-damaging effects of hyperglycaemia is superoxide overproduction (5). Effective monitoring is required for DM treatment to reduce the risk of progression and complication. Hence, the identification of novel biomarkers is being researched (6, 7). Proteomics has been recognised as an important tool for establishing a diagnosis of disease aetiology and monitoring therapy outcomes (8, 9). Proteomic patterns were applied to detect diabetes and complications, as well as to evaluate treatment effectiveness in humans (10-12). There is limited information on proteomic data in DM dogs (13-15). In a proteomic analysis of serum samples from DM dogs, most upregulated proteins are involved in oxidative state, defence and inflammation (13). Medicinal plants are utilised in DM dogs as an adjunct medicine in combination with standard treatment to prevent the development of long-term diabetes complications and improve overall well-being. Curcumin, the most phytochemically active curcuminoid extracted from Curcuma longa, has gained attention in human and laboratory animals. Curcumin is known to have antioxidant, anti-inflammatory and anticancer properties (16-18). In humans and experimental animals with DM, curcumin has an antioxidant potential of enhanced reduced glutathione (GSH) and reduced malondialdehyde (MDA) levels (19, 20). The anti-inflammatory effects of curcumin in DM were reported via decreased interleukin-1β (IL‐1β), interleukin-6 (IL‐6), interleukin-8 (IL‐8) and tumour necrosis factor-α levels and also diminished monocyte chemoattractant protein-1 and C-reactive protein levels (19-21). There has been no published evidence of the impact, safety and proteomic profiles of curcuminoids, particularly curcumin, in client-own DM dogs. Accordingly, the aims of the present study were (1) to evaluate the effects of curcuminoid supplementation on canine DM-associated oxidative stress and inflammation, (2) to determine the safety of curcuminoid supplementation in canine diabetes and (3) to determine whether curcuminoid has an impact on proteins implicated in DM-associated complications by a proteomic analysis.
2022-12-15 | PXD037667 | Pride
Project description:The main cause of morbidity and mortality in diabetes mellitus (DM) are cardiovascular complications. Diabetic cardiomyopathy (DCM) remains incompletely understood. Animal models have been crucial in exploring DCM pathophysiology while identifying potential therapeutic targets. Streptozotocin (STZ) has been widely used to produce experimental models of both type 1 and type 2 DM (T1DM and T2DM). Here we compared these two models for their effects on cardiac structure, function, and transcriptome. Different doses of STZ and different diet chows were used to generate T1DM and T2DM in C57BL/6J mice. Normal euglycemic and non-obese sex and age-matched mice served as controls (CTRL). Immunohistochemistry, RT-PCR, and RNA-Seq were employed to compare hearts from the three animal groups. STZ-induced T1DM and T2DM differently affect left ventricular function and myocardial performance. T1DM displays an exaggerated apoptotic cardiomyocyte (CM) death and reactive hypertrophy and fibrosis along with increased cardiac oxidative stress, CM DNA damage and senescence when compared to T2DM mice. T1DM and T2DM differently affect whole cardiac transcriptome. In conclusion, STZ-induced T1DM and T2DM mouse models show significant differences in cardiac remodeling, function and whole transcriptome. These differences could be of key relevance when choosing an animal model to study specific features of DCM.
2023-02-20 | E-MTAB-12558 | biostudies-arrayexpress
Project description:BACKGROUND: Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, non-invasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. METHODS: A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case-control design. RESULTS: Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without (testing set: AUC = 0.85, 95%CI, 0.73-0.96), outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84, 95%CI, 0.68-0.99), showing superiority over conventional clinical variables. CONCLUSIONS: The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, non-invasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.
2020-01-31 | GSE125929 | GEO
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM. Total RNA from L-Δprkar1a KO mice compared to control D-glucose mice
2014-04-01 | E-GEOD-48815 | biostudies-arrayexpress
Project description:Glucagon and insulin are counter-regulatory pancreatic hormones that precisely control blood glucose homeostasis1. Type 2 diabetes mellitus (T2DM) is characterized by inappropriately elevated blood glucagon2-5 levels as well as insufficient glucose stimulated insulin secretion (GSIS) by pancreatic ß-cells6. Early in the pathogenesis of T2DM, hyperglucagonemia is observable antecedent to ß-cell dysfunction7-9; and in mice, liver-specific activation of glucagon receptor-dependent signaling results in impaired GSIS10. However, the mechanistic relationship between hyperglucagonemia, hepatic glucagon action, and ß-cell dysfunction remains poorly understood. Here we show that glucagon action stimulates hepatic production of the neuropeptide kisspeptin1, which acts in an endocrine manner on ß-cells to suppress GSIS. In vivo glucagon administration acutely stimulates hepatic kisspeptin1 production, and kisspeptin1 is increased in livers from humans with T2DM and from mouse models of diabetes mellitus. Synthetic kisspeptin1 potently suppresses GSIS in vivo and in vitro from normal isolated islets, which express the kisspeptin1 receptor Kiss1R. Administration of a Kiss1R antagonist in diabetic Leprdb/db mice potently augments GSIS and reduces glycemia. Our observations indicate in the pathogenesis of T2DM an endocrine mechanism sequentially linking hyperglucagonemia via hepatic kisspeptin1 production to impaired insulin secretion. In addition, our findings suggest Kiss1R antagonism as a therapeutic avenue to improve ß-cell function in T2DM.
2014-04-01 | GSE48815 | GEO
Project description:DR, DPN and DN are common complications in diabetes, and the differentially expressed mRNAs and lncRNAs in these diabetic complications may help to identify the molecular markers for the onset and progression of diseases. In our study, high-throughput sequencing technique was used to analyze the expression profile of mRNA and lncRNA in the peripheral blood of health control, T2DM, DR, DPN and DN patients, in order to determine the differentially expressed transcriptomic profiles changes in diabetic complications and identify the shared and specific biological signaling pathways related to DR, DPN and DN.
2022-08-31 | GSE185011 | GEO
Project description:Studies of Diabetes Mellitus and its Complications in American Indians
| PRJNA744590 | ENA
Project description:Studies of Diabetes Mellitus and its Complications in American Indians
| PRJNA744591 | ENA
Project description:In this study, we examined the impact of modulating the TGF-β/PAI-1 axis in CD34+ cells function from diabetic patients and controls. Using gene array studies, we found that diabetics, protected from microvascular complications despite suboptimal glycemic control, had reduced level of TGF- β1 and PAI-1 transcripts in their CD34+ cells compared to age, sex, duration and degree of glycemic control -matched diabetics with microvascular complications. Treatment with neutralizing antibody to TGF- β1 in murine hematopoietic stem cells (HSC) enhanced in vivo repopulation potential of these cells in bone marrow transplantation; reduced the time required for cell division of single cells, increased survival of the progenitor cells and reduced TGF-β1 expression. TGF- β1 phosphorodiamidate morpholino oligomers (PMO) treatment reduced PAI-1 mRNA expression in diabetic (p<0.01) and non-diabetic (p=0.05) CD34+ cells. Inhibition of PAI-1 promoted CD34+ cell proliferation and migration in vitro.Targetting TGFβ-1/PAI-1 system offers a promising therapeutic strategy for restoring vascular reparative function in diabetic CD34+ cells and hematopoietic stem cells, enhancing key functions needed for cell therapy.
2013-02-01 | GSE43950 | GEO