A Model of Insulin Resistance in Mice, Born to Diabetic Pregnancy, Is Associated with Alterations of Transcription-Related Genes in Pancreas and Epididymal Adipose Tissue

Objective. This study is conducted on a model of insulin-resistant (IR) mice born to dams which were rendered diabetic by the administration of streptozotocin.Methods. Adult IR and control offspring were selected and we determined the mRNA expression of transcription factors known to modulate pancreatic and adipose tissue activities and inflammation.Results. We observed that serum insulin increased, and the mRNA of insulin gene transcription factors, Pdx-1, Nkx6.1 and Maf-A, were upregulated in IR mice pancreas. Besides, their pancreatic functional capacity seemed to be exhausted as evidenced by low expression of pancreatic Glut2 and glucokinase mRNA. Though IR offspring exhibited reduced epididymal adipose tissue, their adipocytes seemed to be differentiated into macrophage-like cells, as they exhibited upregulated CD14 and CD68 antigens, generally expressed by macrophages. However, there was no peripheral macrophages infiltration into epididymal adipose tissue, as the expression of F4/80, a true macrophage marker, was undetectable. Furthermore, the expression of IL-6, TNF-α and TLR-2, key players of insulin resistance, was upregulated in the adipose tissue of IR offspring.Conclusion. Insulin resistant state in mice, born to diabetic pregnancy, alters the expression of function-related genes in pancreas and epididymal adipose tissue and these offspring are prone to develop metabolic syndrome.

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Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00664.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. E1433-E1440 ◽

Cited By ~ 48

Author(s):

Jinhui Zhang ◽

Wendy Wright ◽

David A. Bernlohr ◽

Samuel W. Cushman ◽

Xiaoli Chen

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Epididymal Adipose Tissue ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Insulin Resistant ◽

Obese Rats ◽

Initial Activation ◽

Adipose Cells ◽

Classic Pathway

Adipose tissue inflammation has recently been linked to the pathogenesis of obesity and insulin resistance. C1 complex comprising three distinct proteins, C1q, C1r, and C1s, involves the key initial activation of the classic pathway of complement and plays an important role in the initiation of inflammatory process. In this study, we investigated adipose expression and regulation of C1 complement subcomponents and C1 activation regulator decorin in obesity and insulin resistance. Expression of C1q in epididymal adipose tissue was increased consistently in ob/ob mice, Zucker obese rats, and high fat-diet-induced obese (HF-DIO) mice. Decorin was found to increase in expression in Zucker obese rats and HF-DIO mice but decrease in ob/ob mice. After TZD administration, C1q and decorin expression was reversed in Zucker obese rats and HF-DIO mice. Increased expression of C1 complement and decorin was observed in both primary adipose and stromal vascular cells isolated from Zucker obese rats. Upregulation of C1r and C1s expression was also perceived in adipose cells from insulin-resistant humans. Furthermore, expression of C1 complement and decorin is dysregulated in TNF-α-induced insulin resistance in 3T3-L1 adipocytes and cultured rat adipose cells as they become insulin resistant after 24-h culture. These data suggests that both adipose and immune cells are the sources for abnormal adipose tissue production of C1 complement and decorin in obesity. Our findings also demonstrate that excessive activation of the classic pathway of complement commonly occurs in obesity, suggesting its possible role in adipose tissue inflammation and insulin resistance.

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Visfatin levels in non-obese, obese, and insulin resistant adolescents

Paediatrica Indonesiana ◽

10.14238/pi56.5.2016.291-6 ◽

2017 ◽

Vol 56 (5) ◽

pp. 291

Author(s):

Indra Ihsan ◽

Eka Agustia Rini ◽

Rismawati Yaswir

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Serum Insulin ◽

Enzyme Linked Immunosorbent Assay ◽

Model Assessment ◽

Fasting Serum ◽

Obese Adolescents ◽

Insulin Resistant ◽

Resistant Group ◽

Visfatin Level

Background Adipose tissue is not merely a site for energy storage, but is also the largest endocrine organ, secreting various adipocytokines. Plasma visfatin, an adipocytokine predominantly secreted from visceral adipose tissue, has insulin-mimetic effects, and has been closely linked to insulin resistance.Objective To compare plasma visfatin levels between obese and non-obese adolescents, as well as between obese adolecents with and without insulin resistance.Methods This cross-sectional study was conducted in students who attended three senior high schools in Padang. Subjects comprised 28 obese and 28 non-obese adolescents. The age of the subjects ranged from 14-18 years. Obesity criteria were based on body mass index (BMI) measurements. Fasting serum glucose level was measured by glucose hexokinase photometry and serum insulin was measured by chemiluminesence immunoassay. Plasma visfatin was measured by enzyme-linked immunosorbent assay (ELISA). The insulin resistance index was estimated from fasting serum insulin and glucose levels using the homeostatic model assessment for insulin resistance (HOMA-IR). Differences in the variables were tested using independent T-test and Mann-Whitney test, depending on the distribution of the variables.Results The mean plasma visfatin level was significantly higher in the obese than in the control group [2.55 (SD 1.54) vs. 1.61 (SD 0.64) ng/mL, respectively; (P=0.005)]. The insulin resistant group had significantly higher mean plasma visfatin level than the non-resistant group [3.61 (SD 1.59) vs. 1.96 (SD 1.18) ng/mL, respectively; (P=0.004)].Conclusion Obese adolescents with insulin resistance have signifcantly higher plasma visfatin levels compared to those without insulin resistance.

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Maternal Protein Restriction Altered Insulin Resistance and Inflammation-Associated Gene Expression in Adipose Tissue of Young Adult Mouse Offspring in Response to a High-Fat Diet

Nutrients ◽

10.3390/nu12041103 ◽

2020 ◽

Vol 12 (4) ◽

pp. 1103 ◽

Cited By ~ 2

Author(s):

Juhae Kim ◽

Alee Choi ◽

Young Hye Kwon

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Serum Insulin ◽

Protein Restriction ◽

Epididymal Adipose Tissue ◽

Model Assessment ◽

High Fat ◽

Maternal Protein Restriction ◽

Increased Risk

Maternal protein restriction is associated with increased risk of insulin resistance and inflammation in adulthood offspring. Here, we investigated whether maternal protein restriction could alter the risk of metabolic syndrome in postweaning high-fat (HF)-diet-challenged offspring, with focus on epididymal adipose tissue gene expression profile. Female ICR mice were fed a control (C) or a low-protein (LP) diet for two weeks before mating and throughout gestation and lactation, and their male offspring were fed an HF diet for 22 weeks (C/HF and LP/HF groups). A subset of offspring of control dams was fed a low-fat control diet (C/C group). In response to postweaning HF diet, serum insulin level and the homeostasis model assessment of insulin resistance (HOMA-IR) were increased in control offspring. Maternal LP diet decreased HOMA-IR and adipose tissue inflammation, and increased serum adiponectin level in the HF-diet-challenged offspring. Accordingly, functional analysis revealed that differentially expressed genes (DEGs) enriched in cytokine production were downregulated in the LP/HF group compared to the C/HF group. We also observed the several annotated gene ontology terms associated with innate immunity and phagocytosis in down-regulated DEGs between LP/HF and C/C groups. In conclusion, maternal protein restriction alleviated insulin resistance and inflammation in young offspring mice fed a HF diet but may impair development of immune system in offspring.

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Investigation of the Association Between Carotid Artery Intima-Media Thickness (IMT) and Cardiac Risk Factors in Patients with Systemic Lupus Erythematosus

Current Rheumatology Reviews ◽

10.2174/1573397116666191217122030 ◽

2020 ◽

Vol 16 (2) ◽

pp. 125-133

Author(s):

Zahra Rezaieyazdi ◽

Sima Sedighi ◽

Masoumeh Salari ◽

Mohammadreza H. Fard ◽

Mahmoud R. Azarpazhooh ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Lupus Erythematosus ◽

Serum Insulin ◽

Venous Blood ◽

Test Group ◽

Control Groups ◽

Significant Difference ◽

The Mean ◽

And Control

Background: The relationship between SLE and traditional risk factors for cardiovascular events was evaluated. Methods: The data regarding sixty patients with SLE and 30 healthy controls (age and sex matched) were gathered using SLEDAI forms. Venous blood (10mL) from all the participants was examined for hs-CRP, homocysteine, VCAM1, CBC, anti-DNA antibody, C3, C4, low-density lipoprotein (LDL), cholesterol, FBS and triglyceride. : The IMT of carotid arteries was determined bilaterally by ultrasound. Other measurements included insulin levels via Elisa (Linco/Millipore Corp) and the HOMA-IR index for insulin resistance. Results: The mean age (in years) in the test and control groups was 28.8±10.3 (18-52) and 33.8±9.13 (18-48), respectively. Results: The mean age (in years) in the test and control groups was 28.8±10.3 (18-52) and 33.8±9.13 (18-48), respectively. : The average IMT in the test group was directly related to serum levels of VCAM1 (p<0.001), homocysteine (p<0.001), cholesterol (p<0.009), LDL (p<0.001), TG (p<0.001), and FPG (p=0.004). The association between other risk factors, insulin resistance, carotid IMT and SLEDAI, was nonexistent. Mean insulin and insulin resistance levels in all the participants were 0.43±2.06 µU/mL and 0.09±0.44, respectively. There was no significant difference between the test and control groups regarding serum insulin and insulin resistance levels (p=0.42 and p=0.9, respectively). None of the risk factors, such as hsCRP, VCAM1, or homocysteine, were shown to be related to insulin resistance (p=0.6, p=0.6, p=0.09, respectively). Conclusion:: Our findings did not show an increase in the prevalence of atherosclerosis in patients with SLE. There was no association between IMT and insulin resistance. However, the former was associated with FPG, total cholesterol, LDL, TG, homocystein and VCAM1.

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Adiponectin and other Adipocytokines as Predictors of Markers of Triglyceride-Rich Lipoprotein Metabolism

Clinical Chemistry ◽

10.1373/clinchem.2004.045120 ◽

2005 ◽

Vol 51 (3) ◽

pp. 578-585 ◽

Cited By ~ 68

Author(s):

Dick C Chan ◽

Gerald F Watts ◽

Theodore WK Ng ◽

Yoshiaki Uchida ◽

Naohiko Sakai ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Independent Predictor ◽

Lipoprotein Metabolism ◽

Bioelectrical Impedance ◽

Apo B ◽

Nonesterified Fatty Acids ◽

Plasma Adiponectin ◽

Tnf Α ◽

Triglyceride Rich Lipoprotein

Abstract Background: Adipocytokines are bioactive peptides that may play an important role in the regulation of glucose and lipid metabolism. In this study, we investigated the association of plasma adipocytokine concentrations with markers of triglyceride-rich lipoprotein (TRL) metabolism in men. Methods: Fasting adiponectin, leptin, resistin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), apolipoprotein (apo) B-48, apo C-III, and remnant-like particle (RLP)-cholesterol concentrations were measured by immunoassays and insulin resistance by homeostasis assessment (HOMA) score in 41 nondiabetic men with a body mass index of 22–35 kg/m2. Visceral and subcutaneous adipose tissue masses (ATMs) were determined by magnetic resonance imaging and total ATM by bioelectrical impedance. Results: In univariate regression, plasma adiponectin and leptin concentrations were inversely and directly associated with plasma apoB-48, apoC-III, RLP-cholesterol, triglycerides, VLDL-apoB, and VLDL-triglycerides (P <0.05). Resistin, IL-6, and TNF-α were not significantly associated with any of these variables, except for a direct correction between apoC-III and IL-6 (P <0.05). In multivariate regression including HOMA, age, nonesterified fatty acids, and adipose tissue compartment, adiponectin was an independent predictor of plasma apoB-48 (β coefficient = −0.354; P = 0.048), apoC-III (β coefficient = −0.406; P = 0.012), RLP-cholesterol (β coefficient = −0.377; P = 0.016), and triglycerides (β coefficient = −0.374; P = 0.013). By contrast, leptin was not an independent predictor of these TRL markers. Plasma apoB-48, apoC-III, RLP-cholesterol, and triglycerides were all significantly and positively associated with plasma insulin, HOMA, and visceral, subcutaneous, and total ATMs (P <0.05). Conclusions: These data suggest that the plasma adiponectin concentration may not only link abdominal fat, insulin resistance, and dyslipidemia, but may also exert an independent role in regulating TRL metabolism.

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Endothelial dysfunction precedes hypertension in diet-induced insulin resistance

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.3.r788 ◽

1998 ◽

Vol 275 (3) ◽

pp. R788-R792 ◽

Cited By ~ 34

Author(s):

Prasad V. G. Katakam ◽

Michael R. Ujhelyi ◽

Margarethe E. Hoenig ◽

Allison Winecoff Miller

Keyword(s):

Insulin Resistance ◽

Endothelial Dysfunction ◽

Serum Insulin ◽

Serum Glucose ◽

Mesenteric Arteries ◽

Control Group ◽

Sprague Dawley ◽

Insulin Resistant ◽

Glucose Levels

The insulin-resistant (IR) syndrome may be an impetus for the development of hypertension (HTN). Unfortunately, the mechanism by which this could occur is unclear. Our laboratory and others have described impaired endothelium-mediated relaxation in IR, mildly hypertensive rats. The purpose of the current study is to determine if HTN is most likely a cause or result of impaired endothelial function. Sprague-Dawley rats were randomized to receive a fructose-rich diet for 3, 7, 10, 14, 18, or 28 days or were placed in a control group. The control group received rat chow. After diet treatment, animals were instrumented with arterial cannulas, and while awake and unrestrained, their blood pressure (BP) was measured. Subsequently, endothelium-mediated relaxation to acetylcholine was determined (in vitro) by measuring intraluminal diameter of phenylephrine-preconstricted mesenteric arteries (∼250 μM). Serum insulin levels were significantly elevated in all groups receiving fructose feeding compared with control, whereas there were no differences in serum glucose levels between groups. Impairment of endothelium-mediated relaxation starts by day 14 [mean percent maximal relaxation (Emax): 69 ± 10% of baseline] and becomes significant by day 18 (Emax: 52 ± 11% of baseline; P < 0.01). However, the mean BP (mmHg) does not become significantly elevated until day 28 [BP: 132 ± 1 ( day 28) vs. 116 ± 3 (control); P < 0.05]. These findings demonstrate that both IR and endothelial dysfunction occur before HTN in this model and suggest that endothelial dysfunction may be a mechanism linking insulin resistance and essential HTN.

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Adipose Tissue Steroid Receptor RNA Activator 1 (SRA1) Expression Is Associated with Obesity, Insulin Resistance, and Inflammation

Cells ◽

10.3390/cells10102602 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2602

Author(s):

Shihab Kochumon ◽

Hossein Arefanian ◽

Sardar Sindhu ◽

Steve Shenouda ◽

Reeby Thomas ◽

...

Keyword(s):

Adipose Tissue ◽

Serum Insulin ◽

Subcutaneous Fat ◽

Steroid Receptor ◽

Obese People ◽

Total Study Population ◽

Metabolic Markers ◽

Diabetes Status ◽

Tnf Α ◽

Study Population

Steroid receptor RNA activator 1 (SRA1) is involved in pathophysiological responses of adipose tissue (AT) in obesity. In vitro and animal studies have elucidated its role in meta-inflammation. Since SRA1 AT expression in obesity/type 2 diabetes (T2D) and the relationship with immune-metabolic signatures remains unclear, we assessed AT SRA1 expression and its association with immune–metabolic markers in individuals with obesity/T2D. For this, 55 non-diabetic and 53 T2D individuals classified as normal weight (NW; lean), overweight, and obese were recruited and fasting blood and subcutaneous fat biopsy samples were collected. Plasma metabolic markers were assessed using commercial kits and AT expression of SRA1 and selected immune markers using RT-qPCR. SRA1 expression was significantly higher in non-diabetic obese compared with NW individuals. SRA1 expression associated with BMI, PBF, serum insulin, and HOMA-IR in the total study population and people without diabetes. SRA1 associated with waist circumference in people without diabetes and NW participants, whereas it associated inversely with HbA1c in overweight participants. In most study subgroups AT SRA1 expression associated directly with CXCL9, CXCL10, CXCL11, TNF-α, TGF-β, IL2RA, and IL18, but inversely with CCL19 and CCR2. TGF-β/IL18 independently predicted the SRA1 expression in people without diabetes and in the total study population, while TNF-α/IL-2RA predicted SRA1 only in people with diabetes. TNF-α also predicted SRA1 in both NW and obese people regardless of the diabetes status. In conclusion, AT SRA1 expression is elevated in people with obesity which associates with typical immunometabolic markers of obesity/T2D, implying that SRA1 may have potential as a biomarker of metabolic derangements.

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IL-6 as a Surrogate Biomarker: The IL-6 Clinical Value for the Diagnosis of Insulin Resistance and Type 2 Diabetes.

10.46940/semrj.02.1007 ◽

2021 ◽

pp. 1-13

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Molecular Mechanisms ◽

Diagnostic Value ◽

Low Grade ◽

Clinical Value ◽

Insulin Resistant ◽

Tnf Α ◽

Low Grade Inflammation

1. Abstract Insulin Resistance is the leading cause of Type 2 diabetes mellitus (T2D). It occurs as a result of lipid disorders and increased levels of circulating free fatty acids (FFAs). FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased levels fatty acid has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes. Among the biomarkers that are accompanying low grade inflammation include IL-1β, IL-6 and TNF-α. The current review point out the importance of measuring the inflammatory biomarkers especially focusing on the conductance and measurement for IL-6 as a screening laboratory test and its diagnostic value in clinical practice.

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Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00302.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. E740-E747 ◽

Cited By ~ 561

Author(s):

S. J. Creely ◽

P. G. McTernan ◽

C. M. Kusminski ◽

ff. M. Fisher ◽

N. F. Da Silva ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Protein Expression ◽

Serum Insulin ◽

Human Adipose Tissue ◽

Innate Immune ◽

System Response ◽

Low Grade ◽

Tnf Α

Type 2 diabetes (T2DM) is associated with chronic low-grade inflammation. Adipose tissue (AT) may represent an important site of inflammation. 3T3-L1 studies have demonstrated that lipopolysaccharide (LPS) activates toll-like receptors (TLRs) to cause inflammation. For this study, we 1) examined activation of TLRs and adipocytokines by LPS in human abdominal subcutaneous (AbdSc) adipocytes, 2) examined blockade of NF-κB in human AbdSc adipocytes, 3) examined the innate immune pathway in AbdSc AT from lean, obese, and T2DM subjects, and 4) examined the association of circulating LPS in T2DM subjects. The findings showed that LPS increased TLR-2 protein expression twofold ( P < 0.05). Treatment of AbdSc adipocytes with LPS caused a significant increase in TNF-α and IL-6 secretion (IL-6, Control: 2.7 ± 0.5 vs. LPS: 4.8 ± 0.3 ng/ml; P < 0.001; TNF-α, Control: 1.0 ± 0.83 vs. LPS: 32.8 ± 6.23 pg/ml; P < 0.001). NF-κB inhibitor reduced IL-6 in AbdSc adipocytes (Control: 2.7 ± 0.5 vs. NF-κB inhibitor: 2.1 ± 0.4 ng/ml; P < 0.001). AbdSc AT protein expression for TLR-2, MyD88, TRAF6, and NF-κB was increased in T2DM patients ( P < 0.05), and TLR-2, TRAF-6, and NF-κB were increased in LPS-treated adipocytes ( P < 0.05). Circulating LPS was 76% higher in T2DM subjects compared with matched controls. LPS correlated with insulin in controls ( r = 0.678, P < 0.0001). Rosiglitazone (RSG) significantly reduced both fasting serum insulin levels (reduced by 51%, P = 0.0395) and serum LPS (reduced by 35%, P = 0.0139) in a subgroup of previously untreated T2DM patients. In summary, our results suggest that T2DM is associated with increased endotoxemia, with AT able to initiate an innate immune response. Thus, increased adiposity may increase proinflammatory cytokines and therefore contribute to the pathogenic risk of T2DM.

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Cardiac Development and Transcription Factors: Insulin Signalling, Insulin Resistance, and Intrauterine Nutritional Programming of Cardiovascular Disease

Journal of Nutrition and Metabolism ◽

10.1155/2018/8547976 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Annelene Govindsamy ◽

Strinivasen Naidoo ◽

Marlon E. Cerf

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Transcription Factors ◽

Cardiac Development ◽

Insulin Signalling ◽

Life Stages ◽

Sequential Process ◽

Insulin Resistant ◽

Sensitive Organ ◽

And Function

Programming with an insult or stimulus during critical developmental life stages shapes metabolic disease through divergent mechanisms. Cardiovascular disease increasingly contributes to global morbidity and mortality, and the heart as an insulin-sensitive organ may become insulin resistant, which manifests as micro- and/or macrovascular complications due to diabetic complications. Cardiogenesis is a sequential process during which the heart develops into a mature organ and is regulated by several cardiac-specific transcription factors. Disrupted cardiac insulin signalling contributes to cardiac insulin resistance. Intrauterine under- or overnutrition alters offspring cardiac structure and function, notably cardiac hypertrophy, systolic and diastolic dysfunction, and hypertension that precede the onset of cardiovascular disease. Optimal intrauterine nutrition and oxygen saturation are required for normal cardiac development in offspring and the maintenance of their cardiovascular physiology.

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