scholarly journals Mice with Type 2 Diabetes Present Significant Alterations in Their Tissue Biomechanical Properties and Histological Features

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 57
Author(s):  
Tânia B. Cruz ◽  
Filomena A. Carvalho ◽  
Paulo N. Matafome ◽  
Raquel A. Soares ◽  
Nuno C. Santos ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Biomechanical Properties ◽  
Diabetic Mice ◽  
Force Microscopy ◽  
Chronic Hyperglycemia ◽  
Biomimetic Scaffolds ◽  
Patient Morbidity

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease often associated with severe complications that may result in patient morbidity or death. One T2DM etiological agent is chronic hyperglycemia, a condition that induces damaging biological processes, including impactful extracellular matrix (ECM) modifications, such as matrix components accumulation. The latter alters ECM stiffness, triggering fibrosis, inflammation, and pathological angiogenesis. Hence, studying ECM biochemistry and biomechanics in the context of T2DM, or obesity, is highly relevant. With this in mind, we examined both native and decellularized tissues of obese B6.Cg-Lepob/J (ob/ob) and diabetic BKS.Cg-Dock7m+/+LeprdbJ (db/db) mice models, and extensively investigated their histological and biomechanical properties. The tissues analyzed herein were those strongly affected by diabetes—skin, kidney, adipose tissue, liver, and heart. The referred organs and tissues were collected from 8-week-old animals and submitted to classical histological staining, immunofluorescence, scanning electron microscopy, rheology, and atomic force microscopy. Altogether, this systematic characterization has identified significant differences in the architecture of both ob/ob and db/db tissues, namely db/db skin presents loose epidermis and altered dermis structure, the kidneys have clear glomerulopathy traits, and the liver exhibits severe steatosis. The distribution of ECM proteins also pinpoints important differences, such as laminin accumulation in db/db kidneys and decreased hyaluronic acid in hepatocyte cytoplasm in both obese and diabetic mice. In addition, we gathered a significant set of data showing that ECM features are maintained after decellularization, making these matrices excellent biomimetic scaffolds for 3D in vitro approaches. Importantly, mechanical studies revealed striking differences between tissue ECM stiffness of control (C57BL/6J), obese, and diabetic mice. Notably, we have unveiled that the intraperitoneal adipose tissue of diabetic animals is significantly stiffer (G* ≈ 10,000 Pa) than that of ob/ob or C57BL/6J mice (G* ≈ 3000–5000 Pa). Importantly, this study demonstrates that diabetes and obesity selectively potentiate severe histological and biomechanical alterations in different matrices that may impact vital processes, such as angiogenesis, wound healing, and inflammation.

scholarly journals Elevated circulating follistatin associates with an increased risk of type 2 diabetes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chuanyan Wu ◽  
Yan Borné ◽  
Rui Gao ◽  
Maykel López Rodriguez ◽  
William C. Roell ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Genome Wide Association Study ◽  
Regulatory Protein ◽  
Alcoholic Fatty Liver ◽  
Increased Risk

AbstractThe hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04–1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09–1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.

Reduction of Insulin Signaling Upregulates Angiopoietin-like Protein 4 Through Elevated Free Fatty Acids in Diabetic Mice

2011 ◽  
Vol 120 (03) ◽  
pp. 139-144 ◽  
Author(s):  
N. Mizutani ◽  
N. Ozaki ◽  
Y. Seino ◽  
A. Fukami ◽  
E. Sakamoto ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Fatty Acids ◽  
Adipose Tissue ◽  
Mrna Expression ◽  
High Fat Diet ◽  
Serum Triglyceride ◽  
Diabetic Mice ◽  
Brown Adipose

AbstractAngiopoietin-like protein 4 (Angptl4) is thought to cause an increase in serum triglyceride levels. In the present study, we elucidated Angptl4 expression in the mouse models of type 1 and type 2 diabetes mellitus, and investigated the possible mechanisms involved.Type 1 diabetes was induced in C57BL/6 J mice by treating them with streptozotocin (STZ). Type 2 diabetes was induced by feeding the mice a high-fat diet (HFD) for 18 weeks.The levels of Angptl4 mRNA expression in liver, white adipose tissue (WAT), and brown adipose tissue (BAT) were found to increase in the STZ diabetic mice relative to control mice. This effect was attenuated by insulin administration. In the HFD diabetic mice, the Angptl4 mRNA expression levels were increased in liver, WAT, and BAT. Treatment with metformin for 4 weeks attenuated the increased levels of Angptl4 mRNA. Fatty acids (FAs) such as palmitate and linoleate induced Angptl4 mRNA expression in H4IIE hepatoma cells and 3T3-L1 adipocytes. Treatment with insulin but not metformin attenuated FA-induced Angptl4 mRNA expression in H4IIE. Both insulin and metformin did not influence the effect of FAs in 3T3-L1 cells.These observations demonstrated that Angptl4 mRNA expression was increased through the elevated free FAs in diabetic mice.

scholarly journals Vitamin D, adipose tissue, and obesity

2013 ◽  
Vol 15 (3) ◽  
Author(s):  
Julie Marcotorchino ◽  
Franck Tourniaire ◽  
Jean-François Landrier
Keyword(s):  
Type 2 Diabetes ◽  
Vitamin D ◽  
Adipose Tissue ◽  
Cardiovascular Diseases ◽  
Vitamin D Deficiency ◽  
Epidemiological Studies ◽  
The Relationship ◽  
Diabetes And Obesity

AbstractEpidemiological studies have shown a link between vitamin D deficiency and numerous pathologies such as cancers, immunity diseases, cardiovascular diseases, hypertension, type 2 diabetes, and obesity. Recent studies in vitro and in animal models demonstrated an impact of vitamin D on adipose tissue and adipocyte biology. Such observations are of particular interest and provide mechanistic explanations on the relationship between vitamin D deficiency and obesity.

Effect of punicalagin on multiple targets in streptozotocin/high-fat diet-induced diabetic mice

2020 ◽  
Vol 11 (12) ◽  
pp. 10617-10634
Author(s):  
Dan Jin ◽  
Baiyu Zhang ◽  
Qiaoling Li ◽  
Jingjing Tu ◽  
Benhong Zhou
Keyword(s):  
Type 2 Diabetes ◽  
High Fat Diet ◽  
Diabetic Mice ◽  
High Fat ◽  
Multiple Targets ◽  
Chronic Hyperglycemia ◽  
P Type

Type 2 diabetes has a series of metabolic aberrations accompanied by chronic hyperglycemia, along with various comorbidities.

scholarly journals Adipose tissue derived bacteria are associated with inflammation in obesity and type 2 diabetes

Gut ◽  
2020 ◽  
Vol 69 (10) ◽  
pp. 1796-1806 ◽  
Author(s):  
Lucas Massier ◽  
Rima Chakaroun ◽  
Shirin Tabei ◽  
Alyce Crane ◽  
Konrad David Didt ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Immune Cell ◽  
In Situ Hybridisation ◽  
Rrna Gene ◽  
Fluorescence In Situ Hybridisation ◽  
Bacterial Dna ◽  
Tissue Specific

ObjectiveBacterial translocation to various organs including human adipose tissue (AT) due to increased intestinal permeability remains poorly understood. We hypothesised that: (1) bacterial presence is highly tissue specific and (2) related in composition and quantity to immune inflammatory and metabolic burden.DesignWe quantified and sequenced the bacterial 16S rRNA gene in blood and AT samples (omental, mesenteric and subcutaneous) of 75 subjects with obesity with or without type 2 diabetes (T2D) and used catalysed reporter deposition (CARD) – fluorescence in situ hybridisation (FISH) to detect bacteria in AT.ResultsUnder stringent experimental and bioinformatic control for contaminants, bacterial DNA was detected in blood and omental, subcutaneous and mesenteric AT samples in the range of 0.1 to 5 pg/µg DNA isolate. Moreover, CARD-FISH allowed the detection of living, AT-borne bacteria. Proteobacteria and Firmicutes were the predominant phyla, and bacterial quantity was associated with immune cell infiltration, inflammatory and metabolic parameters in a tissue-specific manner. Bacterial composition differed between subjects with and without T2D and was associated with related clinical measures, including systemic and tissues-specific inflammatory markers. Finally, treatment of adipocytes with bacterial DNA in vitro stimulated the expression of TNFA and IL6.ConclusionsOur study provides contaminant aware evidence for the presence of bacteria and bacterial DNA in several ATs in obesity and T2D and suggests an important role of bacteria in initiating and sustaining local AT subclinical inflammation and therefore impacting metabolic sequelae of obesity.

scholarly journals Huntingtin-associated protein 1 plays an essential role in the pathogenesis of type 2 diabetes by regulating the translocation of GLUT4 in mouse adipocytes

2020 ◽  
Vol 8 (1) ◽  
pp. e001199
Author(s):  
Yan-Ju Gong ◽  
Ying Feng ◽  
Yuan-Yuan Cao ◽  
Jia Zhao ◽  
Wei Wu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Body Weight ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Hek293 Cells ◽  
Diabetic Mice ◽  
Glut4 Translocation ◽  
Mouse Adipocytes

ObjectiveGlucose disposal by insulin-responsive tissues maintains the body glucose homeostasis and insulin resistance leads to a risk of developing type 2 diabetes (T2DM). Insulin stimulates the translocation of glucose transporter isoform 4 (GLUT4) vesicles from intracellular compartments to the plasma membrane to facilitate glucose uptake. However, the underlying mechanisms of GLUT4 vesicle translocation are not well defined. Here we show the role of huntingtin-associated protein 1 (HAP1) in GLUT4 translocation in adipocytes and the pathogenesis of T2DM.Research design and methodsThe parameters for glucose metabolism including body weight, glucose tolerance and insulin tolerance were assessed in wild-type (WT) and Hap1+/- mice. HAP1 protein expression was verified in adipose tissue. Hap1 mRNA and protein expression was monitored in adipose tissue of high-fat diet (HFD)-induced diabetic mice. Insulin-stimulated GLUT4 vesicle translocation and glucose uptake were detected using immunofluorescence techniques and quantified in primary adipocytes from Hap1-/- mice. The interaction between HAP1 and GLUT4 was assessed by immunofluorescence colocalization and co-immunoprecipitation in HEK293 cells and adipose tissue. The role of sortilin in HAP1 and GLUT4 interaction was approved by co-immunoprecipitation and RNA interference.ResultsThe expression of Hap1 mRNA and protein was detected in WT mouse adipose tissue and downregulated in adipose tissue of HFD-induced diabetic mice. Hap1+/- mice exhibited increased body weight, pronounced glucose tolerance and significant insulin intolerance compared with the WT mice. HAP1 colocalized with GLUT4 in mouse adipocytes and cotransfected HEK293 cells. Furthermore, the insulin-stimulated GLUT4 vesicle translocation and glucose uptake were defective in Hap1-/- adipocytes. Finally, sortilin mediated the interaction of HAP1 and GLUT4.ConclusionsOur study showed that HAP1 formed a protein complex with GLUT4 and sortilin, and played a critical role in insulin-stimulated GLUT4 translocation in adipocytes. Its downregulation may contribute to the pathogenesis of diabetes.

scholarly journals High Norepinephrine Status Induced Growth of Colorectal Cancer With Type 2 Diabetes Mellitus Benefited From ADP-Ribosyltransferase 1

2020 ◽  
Author(s):  
Wenwen Chen ◽  
Yanping Yang ◽  
Jiale Duan ◽  
Ming Li ◽  
Yi Tang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Colorectal Cancer ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Diabetic Mice ◽  
Transplanted Tumors ◽  
Norepinephrine Level ◽  
Adp Ribosyltransferase

Abstract BackgroundIt is known that type 2 diabetes mellitus patients have higher susceptibility to colorectal cancer and poorer prognosis, but the mechanism is quite unknown. Here, we investigated effect of ADP-Ribosyltransferase 1 on growth of colorectal cancer combined diabetes in high norepinephrine status and the potential mechanism. MethodsWe evaluated size and weight of transplanted tumors with different ADP-Ribosyltransferase 1 level of CT26 cells or different norepinephrine level on diabetic mice model and observed their survival time as well. Consistently, CCK8 and flow cytometry were applied for detecting growth of CT26 cells in vitro. Western blot was performed for analyzing differentially expressed proteins of proliferatic profiles to determine ADP-Ribosyltransferase 1-modulated pathway.ResultsAccording to our data, high level of norepinephrine and ADP-Ribosyltransferase 1 both facilitated proliferation of CT26 cells in vitro and in vivo, besides, inhibition of norepinephrinee-depended-proliferation was observed in ADP-Ribosyltransferase 1 silencing CT26 cells in vitro compared with CT26 cells with ADP-Ribosyltransferase 1 expression. However, we discovered after reducing norepinephrine level of serum by surgery, size and weight of the transplanted tumors were significantly reduced compared with non-operated group and sham-operated group. Further, expression of ADP-Ribosyltransferase 1, mTOR, STAT3, p-AKT protein in tumor tissues of diabetic mice was increased rather than non-diabetes mice, while after depleting norepinephrine level by renal denervation operation, expression of proliferation-relative proteins mTOR, STAT3, p-AKT protein was decreased, but no change was discovered in ADP-Ribosyltransferase 1 expression. While under the same concentration of norepinephrine environment, ADP-Ribosyltransferase 1 boosts expression of p-AKT, mTOR, STAT3, CyclinD1 and c-myc in CT26 cells in vitro. ConclusionsThis study proposed a hypothesis that high-norepinephrine-induced proliferation of colorectal cancer required expression of ADP-Ribosyltransferase 1, and raise ADP-Ribosyltransferase 1 might be a candidate target for treatment of diabetes-associated colorectal cancer.

scholarly journals Dysregulation of Leukocyte Trafficking in Type 2 Diabetes: Mechanisms and Potential Therapeutic Avenues

2021 ◽  
Vol 9 ◽  
Author(s):  
Laleh Pezhman ◽  
Abd Tahrani ◽  
Myriam Chimen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Beta Cell ◽  
Beta Cell Dysfunction ◽  
Low Grade ◽  
Leukocyte Trafficking ◽  
Cell Dysfunction ◽  
Chronic Hyperglycemia

Type 2 Diabetes Mellitus (T2DM) is a chronic inflammatory disorder that is characterized by chronic hyperglycemia and impaired insulin signaling which in addition to be caused by common metabolic dysregulations, have also been associated to changes in various immune cell number, function and activation phenotype. Obesity plays a central role in the development of T2DM. The inflammation originating from obese adipose tissue develops systemically and contributes to insulin resistance, beta cell dysfunction and hyperglycemia. Hyperglycemia can also contribute to chronic, low-grade inflammation resulting in compromised immune function. In this review, we explore how the trafficking of innate and adaptive immune cells under inflammatory condition is dysregulated in T2DM. We particularly highlight the obesity-related accumulation of leukocytes in the adipose tissue leading to insulin resistance and beta-cell dysfunction and resulting in hyperglycemia and consequent changes of adhesion and migratory behavior of leukocytes in different vascular beds. Thus, here we discuss how potential therapeutic targeting of leukocyte trafficking could be an efficient way to control inflammation as well as diabetes and its vascular complications.

scholarly journals RGC32 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

2014 ◽  
Vol 224 (2) ◽  
pp. 127-137 ◽  
Author(s):  
Xiao-Bing Cui ◽  
Jun-Na Luan ◽  
Jianping Ye ◽  
Shi-You Chen
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Tolerance Test ◽  
High Fat ◽  
Diet Induced Obesity

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases and many other chronic diseases. Adipose tissue inflammation is a critical link between obesity and insulin resistance and type 2 diabetes and a contributor to disease susceptibility and progression. The objective of this study was to determine the role of response gene to complement 32 (RGC32) in the development of obesity and insulin resistance. WT and RGC32 knockout (Rgc32−/− (Rgcc)) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical, and histologic analyses were performed. 3T3-L1 preadipocytes were used to study the role of RGC32 in adipocytes in vitro. Rgc32−/− mice fed with HFD exhibited a lean phenotype with reduced epididymal fat weight compared with WT controls. Blood biochemical analysis and insulin tolerance test showed that RGC32 deficiency improved HFD-induced dyslipidemia and insulin resistance. Although it had no effect on adipocyte differentiation, RGC32 deficiency ameliorated adipose tissue and systemic inflammation. Moreover, Rgc32−/− induced browning of adipose tissues and increased energy expenditure. Our data indicated that RGC32 plays an important role in diet-induced obesity and insulin resistance, and thus it may serve as a potential novel drug target for developing therapeutics to treat obesity and metabolic disorders.

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