Mutation of the 5' untranslated region stem-loop mRNA structure reduces type I collagen deposition and arterial stiffness in male obese mice

2021 ◽  
Author(s):  
Francisco I. Ramirez-Perez ◽  
Makenzie L. Woodford ◽  
Mariana Morales-Quinones ◽  
Zachary I. Grunewald ◽  
Francisco J Cabral-Amador ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Arterial Stiffness ◽  
Type I Collagen ◽  
Type I ◽  
Collagen Deposition ◽  
Wild Type ◽  
Stem Loop ◽  
Arterial Stiffening

Arterial stiffening, a characteristic feature of obesity and type 2 diabetes, contributes to the development and progression of cardiovascular diseases (CVD). Currently, no effective prophylaxis or therapeutics is available to prevent or treat arterial stiffening. A better understanding of the molecular mechanisms underlying arterial stiffening is vital to identify newer targets and strategies to reduce CVD burden. A major contributor to arterial stiffening is increased collagen deposition. In the 5' untranslated regions of mRNAs encoding for type I collagen, an evolutionally conserved stem-loop (SL) structure plays an essential role in its stability and post-transcriptional regulation. Here, we show that feeding a high fat/high sucrose (HFHS) diet for 28 weeks increases adiposity, insulin resistance, and blood pressure in male wild-type littermates. Moreover, arterial stiffness, assessed in vivo via aortic pulse wave velocity, and ex vivo using atomic force microscopy in aortic explants or pressure myography in isolated femoral and mesenteric arteries, was also increased in those mice. Notably, all these indices of arterial stiffness, along with collagen type I levels in the vasculature, were reduced in HFHS-fed mice harboring a mutation in the 5'SL structure, relative to wild-type littermates. This protective vascular phenotype in 5'SL-mutant mice did not associate with a reduction in insulin resistance or blood pressure. These findings implicate the 5'SL structure as a putative therapeutic target to prevent or reverse arterial stiffening and CVD associated with obesity and type 2 diabetes.

GLUT-1 or GLUT-4 transgenes in obese mice improve glucose tolerance but do not prevent insulin resistance

1999 ◽  
Vol 276 (2) ◽  
pp. E390-E400 ◽  
Author(s):  
Bess Adkins Marshall ◽  
Polly A. Hansen ◽  
Nancy J. Ensor ◽  
M. Allison Ogden ◽  
Mike Mueckler
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Transgenic Mice ◽  
Glucose Utilization ◽  
Wild Type ◽  
High Fat ◽  
Glut 1 ◽  
High Sugar ◽  
Glut 4

Insulin-stimulated glucose uptake is defective in patients with type 2 diabetes. To determine whether transgenic glucose transporter overexpression in muscle can prevent diabetes induced by a high-fat, high-sugar diet, singly (GLUT-1, GLUT-4) and doubly (GLUT-1 and -4) transgenic mice were placed on a high-fat, high-sugar diet or a standard chow diet. On the high-fat, high-sugar diet, wild-type but not transgenic mice developed fasting hyperglycemia and glucose intolerance (peak glucose of 337 ± 19 vs. 185–209 mg/dl in the same groups on the high-fat, high-sugar diet and 293 ± 13 vs. 166–194 mg/dl on standard chow). Hyperinsulinemic clamps showed that transporter overexpression elevated insulin-stimulated glucose utilization on standard chow (49 ± 4 mg ⋅ kg−1 ⋅ min−1in wild-type vs. 61 ± 4, 67 ± 5, and 63 ± 6 mg ⋅ kg−1 ⋅ min−1in GLUT-1, GLUT-4, and GLUT-1 and -4 transgenic mice given 20 mU ⋅ kg−1 ⋅ min−1insulin, and 54 ± 7, 85 ± 4, and 98 ± 11 in wild-type, GLUT-1, and GLUT-4 mice given 60–80 mU ⋅ kg−1 ⋅ min−1insulin). On the high-fat, high-sugar diet, wild-type and GLUT-1 mice developed marked insulin resistance, but GLUT-4 and GLUT-1 and -4 mice were somewhat protected (glucose utilization during hyperinsulinemic clamp of 28.5 ± 3.4 vs. 42.4 ± 5.9, 51.2 ± 8.1, and 55.9 ± 4.9 mg ⋅ kg−1 ⋅ min−1in wild type, GLUT-1, GLUT-4, GLUT-1 and -4 mice). These data demonstrate that overexpression of GLUT-1 and/or GLUT-4 enhances whole body glucose utilization and prevents the development of fasting hyperglycemia and glucose intolerance induced by a high-fat, high-sugar diet. GLUT-4 overexpression improves the insulin resistance induced by the diet. We conclude that upregulation of glucose transporters in skeletal muscle may be an effective therapeutic approach to the treatment of human type 2 diabetes.

scholarly journals Association of urinary RBP4 with insulin resistance, inflammation, and microalbuminuria

2014 ◽  
Vol 171 (4) ◽  
pp. 443-449 ◽  
Author(s):  
Se Eun Park ◽  
Nam Seok Lee ◽  
Ji Woo Park ◽  
Eun-Jung Rhee ◽  
Won-Young Lee ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Arterial Stiffness ◽  
Glucose Tolerance ◽  
Cardiometabolic Risk ◽  
Urinary Albumin ◽  
Metabolic Parameters ◽  
The Relationship

ObjectiveSerum concentrations of retinol-binding protein 4 (RBP4) are elevated in type 2 diabetes and associated with the severity of insulin resistance; however, there are few data about the relationship between urinary RBP4 levels and metabolic parameters. We assessed urinary RBP4 as a new biomarker by establishing its relationship with clinical parameters associated with insulin resistance and urinary albumin excretion.Design and methodsWe measured RBP4 in the serum and urine of 689 subjects with diverse glucose tolerance status. We also evaluated the relationship between urinary RBP4 and cardiometabolic risk factors, including insulin resistance, high-sensitivity C-reactive protein (hsCRP), arterial stiffness, and microalbuminuria.ResultsUrinary RBP4 levels were higher in insulin-resistant subjects with prediabetes or type 2 diabetes than in subjects with normal glucose tolerance (NGT) (type 2 diabetes>prediabetes>NGT; allP<0.001). Urinary RBP4 correlated strongly with homeostasis model assessments of insulin resistance (HOMA-IR), fasting glucose, triglycerides, blood pressure, hsCRP, arterial stiffness, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio (allP<0.01). HOMA-IR and arterial stiffness were found to be independent determinants of urinary RBP4 concentration. Furthermore, urinary RBP4 was highly predictive of microalbuminuria (odds ratio 2.6, 95% CI 1.6–4.2), even after adjustment for other metabolic parameters. The area under the ROC curve for urinary RBP4 to detect the presence of microalbuminuria was 0.80±0.02 (95% CI 0.76–0.84) and the cut-off value was 157.01 μg/gCr.ConclusionsUrinary RBP4 concentrations were elevated in patients with dysregulation of glucose metabolism and were related to various cardiometabolic risk factors including insulin resistance, inflammation, and microalbuminuria.

scholarly journals SNPs for Genes Encoding the Mitochondrial Proteins Sirtuin3 and Uncoupling Protein 2 Are Associated With Disease Severity, Type 2 Diabetes, and Outcomes in Patients With Pulmonary Arterial Hypertension and This Is Recapitulated in a New Mouse Model Lacking Both Genes

2021 ◽  
Author(s):  
Yongneng Zhang ◽  
Sotirios D. Zervopoulos ◽  
Aristeidis E. Boukouris ◽  
Maria Areli Lorenzana‐Carrillo ◽  
Bruno Saleme ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Pulmonary Arterial Hypertension ◽  
Mouse Model ◽  
Pulmonary Artery ◽  
Uncoupling Protein ◽  
Wild Type ◽  
Double Knockout ◽  
Pulmonary Arterial

Background Isolated loss‐of‐function single nucleotide polymorphisms (SNPs) for SIRT3 (a mitochondrial deacetylase) and UCP2 (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with both pulmonary arterial hypertension (PAH) and insulin resistance, but their collective role in animal models and patients is unknown. Methods and Results In a prospective cohort of patients with PAH (n=60), we measured SNPs for both SIRT3 and UCP2, along with several clinical features (including invasive hemodynamic data) and outcomes. We found SIRT3 and UCP2 SNPs often both in the same patient in a homozygous or heterozygous manner, correlating positively with PAH severity and associated with the presence of type 2 diabetes and 10‐year outcomes (death and transplantation). To explore this mechanistically, we generated double knockout mice for Sirt3 and Ucp2 and found increasing severity of PAH (mean pulmonary artery pressure, right ventricular hypertrophy/dilatation and extensive vascular remodeling, including inflammatory plexogenic lesions, in a gene dose‐dependent manner), along with insulin resistance, compared with wild‐type mice. The suppressed mitochondrial function (decreased respiration, increased mitochondrial membrane potential) in the double knockout pulmonary artery smooth muscle cells was associated with apoptosis resistance and increased proliferation, compared with wild‐type mice. Conclusions Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PAH (without environmental or chemical triggers) that mimics human PAH and may explain the findings in our patient cohort. Our study offers a new mouse model of PAH, with several features of human disease that are typically absent in other PAH mouse models.

scholarly journals Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus

2012 ◽  
Vol 166 (4) ◽  
pp. 711-716 ◽  
Author(s):  
A H van Lierop ◽  
N A T Hamdy ◽  
R W van der Meer ◽  
J T Jonker ◽  
H J Lamb ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Type I Collagen ◽  
Negative Regulator ◽  
Type I ◽  
Healthy Controls ◽  
Amino Terminal ◽  
Increased Risk

ObjectivePatients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures and thiazolidinediones (TZDs) increase this risk. TZDs stimulate the expression of sclerostin, a negative regulator of bone formation, in vitro. Abnormal sclerostin production may, therefore, be involved in the pathogenesis of increased bone fragility in patients with T2DM treated with TZDs.MethodsWe measured serum sclerostin, procollagen type 1 amino-terminal propeptide (P1NP), and carboxy-terminal cross-linking telopeptide of type I collagen (CTX) in 71 men with T2DM treated with either pioglitazone (PIO) (30 mg once daily) or metformin (MET) (1000 mg twice daily). Baseline values of sclerostin and P1NP were compared with those of 30 healthy male controls.ResultsCompared with healthy controls, patients with T2DM had significantly higher serum sclerostin levels (59.9 vs 45.2 pg/ml, P<0.001) but similar serum P1NP levels (33.6 vs 36.0 ng/ml, P=0.39). After 24 weeks of treatment, serum sclerostin levels increased by 11% in PIO-treated patients and decreased by 1.8% in MET-treated patients (P=0.018). Changes in serum sclerostin were significantly correlated with changes in serum CTX in all patients (r=0.36, P=0.002) and in PIO-treated patients (r=0.39, P=0.020), but not in MET-treated patients (r=0.17, P=0.31).ConclusionsMen with T2DM have higher serum sclerostin levels than healthy controls, and these levels further increase after treatment with PIO, which is also associated with increased serum CTX. These findings suggest that increased sclerostin production may be involved in the pathogenesis of increased skeletal fragility in patients with T2DM in general and may specifically contribute to the detrimental effect of TZDs on bone.

scholarly journals Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance

2016 ◽  
Vol 36 (23) ◽  
pp. 2956-2966 ◽  
Author(s):  
Sezin Dagdeviren ◽  
Dae Young Jung ◽  
Eunjung Lee ◽  
Randall H. Friedline ◽  
Hye Lim Noh ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Underlying Mechanism ◽  
Interleukin 10 ◽  
Glucose Turnover ◽  
Wild Type ◽  
Beneficial Effects

Skeletal muscle insulin resistance is a major characteristic of obesity and type 2 diabetes. Although obesity-mediated inflammation is causally associated with insulin resistance, the underlying mechanism is unclear. Here, we examined the effects of chronic obesity in mice with muscle-specific overexpression of interleukin-10 (M IL10 ). After 16 weeks of a high-fat diet (HFD), M IL10 mice became markedly obese but showed improved insulin action compared to that of wild-type mice, which was largely due to increased glucose metabolism and reduced inflammation in skeletal muscle. Since leptin regulates inflammation, the beneficial effects of interleukin-10 (IL-10) were further examined in leptin-deficient ob / ob mice. Muscle-specific overexpression of IL-10 in ob / ob mice (MCK-IL10 ob / ob ) did not affect spontaneous obesity, but MCK-IL10 ob / ob mice showed increased glucose turnover compared to that in ob / ob mice. Last, mice with muscle-specific ablation of IL-10 receptor (M-IL10R −/− ) were generated to determine whether IL-10 signaling in skeletal muscle is involved in IL-10 effects on glucose metabolism. After an HFD, M-IL10R −/− mice developed insulin resistance with reduced glucose metabolism compared to that in wild-type mice. Overall, these results demonstrate IL-10 effects to attenuate obesity-mediated inflammation and improve insulin sensitivity in skeletal muscle, and our findings implicate a potential therapeutic role of anti-inflammatory cytokines in treating insulin resistance and type 2 diabetes.

Intramyocellular lipid content in type 2 diabetes patients compared with overweight sedentary men and highly trained endurance athletes

2004 ◽  
Vol 287 (3) ◽  
pp. E558-E565 ◽  
Author(s):  
Luc J. C. van Loon ◽  
René Koopman ◽  
Ralph Manders ◽  
Walter van der Weegen ◽  
Gerrit P. van Kranenburg ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Lipid Content ◽  
Endurance Athletes ◽  
Type I ◽  
Fiber Types ◽  
Intramyocellular Lipid ◽  
Muscle Lipid ◽  
Diabetes Patients

Recent evidence suggests that intramyocellular lipid (IMCL) accretion is associated with obesity and the development of insulin resistance and/or type 2 diabetes. However, trained endurance athletes are markedly insulin sensitive, despite an elevated mixed muscle lipid content. In an effort to explain this metabolic paradox, we compared muscle fiber type-specific IMCL storage between populations known to have elevated IMCL deposits. Immunofluorescence microscopy was performed on muscle biopsies obtained from eight highly trained endurance athletes, eight type 2 diabetes patients, and eight overweight, sedentary men after an overnight fast. Mixed muscle lipid content was substantially greater in the endurance athletes (4.0 ± 0.4% area lipid stained) compared with the diabetes patients and the overweight men (2.3 ± 0.4 and 2.2 ± 0.5%, respectively). More than 40% of the greater mixed muscle lipid content was attributed to a higher proportion type I muscle fibers (62 ± 8 vs. 38 ± 3 and 33 ± 7%, respectively), which contained 2.8 ± 0.3-fold more lipid than the type II fibers. The remaining difference was explained by a significantly greater IMCL content in the type I muscle fibers of the trained athletes. Differences in IMCL content between groups or fiber types were accounted for by differences in lipid droplet density, not lipid droplet size. IMCL distribution showed an exponential increase in lipid content from the central region toward the sarcolemma, which was similar between groups and fiber types. In conclusion, IMCL contents can be substantially greater in trained endurance athletes compared with overweight and/or type 2 diabetes patients. Because structural characteristics and intramyocellular distribution of lipid aggregates seem to be similar between groups, we conclude that elevated IMCL deposits are unlikely to be directly responsible for inducing insulin resistance.

scholarly journals The ACAA-insertion/deletion polymorphism at the 3′ UTR of the IGF-II receptor gene is associated with type 2 diabetes and surrogate markers of insulin resistance

2006 ◽  
Vol 155 (2) ◽  
pp. 331-336 ◽  
Author(s):  
Gemma Villuendas ◽  
José I Botella-Carretero ◽  
Abel López-Bermejo ◽  
Carme Gubern ◽  
Wifredo Ricart ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mexican Americans ◽  
Receptor Gene ◽  
Diabetic Patients ◽  
Surrogate Markers ◽  
Wild Type ◽  
Deletion Polymorphism ◽  
Insulin Resistant

Objective: The IGF-II receptor gene (IGFIIR) is located at chromosome 6q26, a region that harbors a genetic marker linked to insulin-resistant traits in Mexican–Americans. In the present study conducted in Spaniards, we tested a common polymorphism in IGFIIR for association with type 2 diabetes and insulin-resistant traits. Design: Case–control association study. Methods: One hundred and forty-five type 2 diabetic patients and 217 non-diabetic controls were genotyped for the ACAA-insertion/deletion polymorphism at the 3′ UTR of IGFIIR. Phenotyping included anthropometrics and a metabolic profile, including serum lipid levels and surrogate indexes of insulin resistance whenever possible. Results: Diabetic patients were more frequently homozygous for the wild type 144 bp allele of IGFIIR compared with controls (diabetic patients 77.2%, controls 51.6%, P<0.001) suggesting a potential protective role against type 2 diabetes for the IGFIIR 140 bp variant. Carrying 140 bp alleles was associated with an odds ratio of having diabetes of 0.290 (95% confidence interval 0.109–0.770), and controls homozygous for the wild type 144 bp allele presented with lower insulin and triglyceride levels, which are proxies for insulin resistance. Conclusions: The ACAA-insertion/deletion polymorphism at the 3′ UTR of IGFIIR is associated with type 2 diabetes and influences surrogate markers of insulin resistance in non-diabetic subjects.

scholarly journals Adipose Tissue-Specific Deletion of 12/15-Lipoxygenase Protects Mice from the Consequences of a High-Fat Diet

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Banumathi K. Cole ◽  
Margaret A. Morris ◽  
Wojciech J. Grzesik ◽  
Kendall A. Leone ◽  
Jerry L. Nadler
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Pancreatic Islets ◽  
High Fat Diet ◽  
Epididymal Adipose Tissue ◽  
Wild Type ◽  
High Fat ◽  
Specific Deletion

Type 2 diabetes is associated with obesity, insulin resistance, and inflammation in adipose tissue. 12/15-Lipoxygenase (12/15-LO) generates proinflammatory lipid mediators, which induce inflammation in adipose tissue. Therefore we investigated the role of 12/15-LO activity in mouse white adipose tissue in promoting obesity-induced local and systemic inflammatory consequences. We generated a mouse model for fat-specific deletion of 12/15-LO,aP2-Cre;12/15-LOloxP/loxP, which we call ad-12/15-LO mice, and placed wild-type controls and ad-12/15-LO mice on a high-fat diet for 16 weeks and examined obesity-induced inflammation and insulin resistance. High-fat diet-fed ad-12/15-LO exhibited improved fasting glucose levels and glucose metabolism, and epididymal adipose tissue from these mice exhibited reduced inflammation and macrophage infiltration compared to wild-type mice. Furthermore, fat-specific deletion of 12/15-LO led to decreased peripheral pancreatic islet inflammation with enlarged pancreatic islets when mice were fed the high-fat diet compared to wild-type mice. These results suggest an interesting crosstalk between 12/15-LO expression in adipose tissue and inflammation in pancreatic islets. Therefore, deletion of 12/15-LO in adipose tissue can offer local and systemic protection from obesity-induced consequences, and blocking 12/15-LO activity in adipose tissue may be a novel therapeutic target in the treatment of type 2 diabetes.

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