Vascular dysfunction and insulin stimulated blood flow : impact of physical inactivity and type 2 diabetes

2014 ◽  
Author(s):  
◽  
Leryn J. Boyle
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Blood Flow ◽  
Insulin Sensitivity ◽  
Endothelial Function ◽  
Physical Inactivity ◽  
Vascular Dysfunction ◽  
Insulin Stimulation

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Individuals with type 2 diabetes (T2D) have blunted femoral artery insulin mediated blood flow which is critical for the delivery and uptake of glucose into skeletal muscle. However, it is unclear in humans the precise mechanisms by which insulin resistance impairs insulin stimulated blood flow. Further, chronic physical inactivity is a powerful stimulus for reduced insulin sensitivity and vascular dysfunction; however, the effects of short term, modest reductions in physical activity are limited. Thus, we examined 1) if inactivity for 5 days would impair endothelial function in healthy individuals (study one) 2) if reducing whole body insulin sensitivity, via 5 days of inactivity, would impair the blood flow response to insulin stimulation in parallel with glycemic control (study two) and 3) phosphorylation of endothelial nitric oxide (eNOS) and endothelin-1 (ET-1) production to insulin stimulation would be decreased and increased, respectively, in insulin resistant individuals (study three). We demonstrated significant reductions in endothelial function with only 5 days of reduced daily steps while blood flow to glucose ingestion was unaltered. Further, in obese humans with type 2 diabetes it does not appear that that the reduction in blood flow to 1 hr of insulin stimulation is due to altered peNOS or ET-1. Collectively, these data suggest that reduced daily physical activity and chronic insulin resistance mediate negative impacts on vascular function and insulin stimulated blood flow and signaling.

scholarly journals Endothelial Dysfunction: Is There a Hyperglycemia-Induced Imbalance of NOX and NOS?

2019 ◽  
Vol 20 (15) ◽  
pp. 3775 ◽  
Author(s):  
Cesar A. Meza ◽  
Justin D. La Favor ◽  
Do-Houn Kim ◽  
Robert C. Hickner
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Blood Flow ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Dysfunction ◽  
Vascular Complications ◽  
Enzymatic Production

NADPH oxidases (NOX) are enzyme complexes that have received much attention as key molecules in the development of vascular dysfunction. NOX have the primary function of generating reactive oxygen species (ROS), and are considered the main source of ROS production in endothelial cells. The endothelium is a thin monolayer that lines the inner surface of blood vessels, acting as a secretory organ to maintain homeostasis of blood flow. The enzymatic production of nitric oxide (NO) by endothelial NO synthase (eNOS) is critical in mediating endothelial function, and oxidative stress can cause dysregulation of eNOS and endothelial dysfunction. Insulin is a stimulus for increases in blood flow and endothelium-dependent vasodilation. However, cardiovascular disease and type 2 diabetes are characterized by poor control of the endothelial cell redox environment, with a shift toward overproduction of ROS by NOX. Studies in models of type 2 diabetes demonstrate that aberrant NOX activation contributes to uncoupling of eNOS and endothelial dysfunction. It is well-established that endothelial dysfunction precedes the onset of cardiovascular disease, therefore NOX are important molecular links between type 2 diabetes and vascular complications. The aim of the current review is to describe the normal, healthy physiological mechanisms involved in endothelial function, and highlight the central role of NOX in mediating endothelial dysfunction when glucose homeostasis is impaired.

scholarly journals The effects of two-week program of individually measured physical activity on insulin resistance in obese non-insulin-dependent diabetes mellitus

2003 ◽  
Vol 60 (6) ◽  
pp. 683-690
Author(s):  
Milica Cizmic ◽  
Mirjana Zivotic-Vanovic ◽  
Slobodan Zivanic ◽  
Radosav Dragojevic
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Aerobic Capacity ◽  
Aerobic Training ◽  
Age Group ◽  
Vo2 Max ◽  
Diabetes Patients

It is well known that under the influence of regular, individually measured aerobic physical activity, it is possible to raise the biological efficiency of insulin by several mechanisms: by increasing the number of insulin receptors, their sensitivity and efficiency, as well as by increasing glucose transporters GLUT-4 on the level of cell membrane. The aim of this research was to examine whether decreased insulin resistance could be achieved under the influence of the program of individually measured aerobic physical activity in the 2-week period, in the obese type 2 diabetes patients with the increased aerobic capacity (VO2)max. In 10 type 2 diabetes patients 47.6 ? 4.6 years of age (group E), in the 14-days period, program of aerobic training was applied (10 sessions - 35 min session of walking on treadmill, intensity 60.8 ? 5.7% (VO2)max, frequency 5 times a week ), as well as 1 600 kcal diet. At the same time, other 10 type 2 diabetes patients 45.9 ? 5.5 years of age (group C) were on 1 600 kcal diet. Before and after this period the following was measured in both groups: insulin sensitivity (M/I) by the method of hyperinsulin euglycemic clamp, and (VO2)max by Astrand test on ergocycle. In contrast to the group C, in the second testing of E group subjects a significant increase was obtained in M/I (1.23 ? 0.78 vs. 2.42 ? 0.95 mg/kg/min/mU p<0.001, 96.75%) as well as the increase of (VO2)max (26.34 ? 4.26 vs. 29.16 ? 5.01 ml/kg/min p<0.05, 10.7%). The results had shown that 2-week program of aerobic training had had significant influence on the increased aerobic capacity and insulin sensitivity in the tested patients.

Strategies to enhance compliance to physical activity for patients with insulin resistance

2007 ◽  
Vol 32 (3) ◽  
pp. 549-556 ◽  
Author(s):  
Alison Kirk ◽  
Pierpaolo De Feo
Keyword(s):  
Physical Activity ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Wearable Sensors ◽  
Physical Activity Promotion ◽  
Physical Activity Behaviour ◽  
Future Research ◽  
Evidence Based ◽  
Activity Promotion

The evidence that physical activity is an effective therapeutic tool in the management of insulin resistance and type 2 diabetes is well documented. Limited research has addressed how best to promote and maintain physical activity in these individuals. This paper explores strategies to enhance compliance to physical activity for patients with insulin resistance. Several evidence-based guidelines and reviews recommend that physical activity interventions are based on a valid theoretical framework. However, there is no evidence-based consensus on the best theory or the combination of theories to use. Motivational tools such as pedometers, wearable sensors measuring energy expenditure, and point of choice prompts appear to be effective at stimulating short-term substantial increases in physical activity, but further strategies to maintain physical activity behaviour change are required. Physical activity consultation has demonstrated effective physical activity promotion over periods of up to 2 years in people with type 2 diabetes. Future research should identify the longer term effects of this intervention and the effectiveness of different methods of delivery. Overall, there needs to be a lot more focus on this area of research. Without this, the abundance of research investigating the effects of physical activity on people with insulin resistance and type 2 diabetes is essentially redundant.

scholarly journals Physical activity versus metformin for increasing insulin sensitivity in children and adolescents at-risk for type 2 diabetes

2016 ◽  
Vol 85 (2) ◽  
pp. 26-28
Author(s):  
Andrew D Hanna ◽  
Natalie V Scime
Keyword(s):  
Physical Activity ◽  
Type 2 Diabetes ◽  
At Risk ◽  
Insulin Sensitivity ◽  
Children And Adolescents ◽  
Pediatric Population ◽  
Current Evidence ◽  
Beneficial Effects ◽  
Pediatric Populations

Global rates of type 2 diabetes (T2D) among children and adolescents are steadily rising. As such, an increasing amount of attention and research has begun to focus on strategies to prevent this chronic and burdensome disease in pediatric populations. The purpose of this article is to briefly review current evidence pertaining to the effectiveness of physical activity versus metformin in improving insulin sensitivity of children at-risk (ie, obese and/or insulin resistant) for developing T2D. Potential barriers to each preventative intervention will also be discussed. Physical activity, both aerobic and resistance, has demonstrated effectiveness in a moderate number of demographically diverse pediatric studies. However, the pediatric population is already alarmingly sedentary with barriers such as lack of motivation, social stigma and discomfort presenting a challenge. A small number of studies have demonstrated the beneficial effects of metformin in children and adolescents for improved insulin sensitivity. However, longer and larger studies are required to confirm these findings and elucidate upon the long-term safety and efficacy of this pharmaceutical in pediatric populations. While no head-to-head studies examining physical activity and metformin exist in pediatric populations and more research is needed, current evidence seems to favour the use of physical activity given the larger quantity of studies and generalizability of its beneficial effects. Thus, physical activity should be emphasized in clinical and public health practice when targeting at-risk children and adolescents to prevent a T2D diagnosis.

scholarly journals Common Risk Factors in Relatives and Spouses of Patients with Type 2 Diabetes in Developing Prediabetes

Healthcare ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1010
Author(s):  
Wei-Hao Hsu ◽  
Chin-Wei Tseng ◽  
Yu-Ting Huang ◽  
Ching-Chao Liang ◽  
Mei-Yueh Lee ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Diabetic Patients ◽  
Β Cell ◽  
Tyg Index ◽  
Β Cell Function

Prediabetes should be viewed as an increased risk for diabetes and cardiovascular disease. In this study, we investigated its prevalence among the relatives and spouses of patients with type 2 diabetes or risk factors for prediabetes, insulin resistance, and β-cell function. A total of 175 individuals were included and stratified into three groups: controls, and relatives and spouses of type 2 diabetic patients. We compared clinical characteristics consisting of a homeostatic model assessment for insulin resistance (HOMA-IR) and beta cell function (HOMA-β), a quantitative insulin sensitivity check index (QUICKI), and triglyceride glucose (TyG) index. After a multivariable linear regression analysis, the relative group was independently correlated with high fasting glucose, a high TyG index, and low β-cell function; the relatives and spouses were independently associated with a low QUICKI. The relatives and spouses equally had a higher prevalence of prediabetes. These study also indicated that the relatives had multiple factors predicting the development of diabetes mellitus, and that the spouses may share a number of common environmental factors associated with low insulin sensitivity.

Increasing endogenous PPARγ ligands improves insulin sensitivity and protects against diet-induced obesity without side effects of thiazolidinediones

2021 ◽  
Author(s):  
Yu-Hua Tseng ◽  
Lee-Ming Chuang ◽  
Yi-Cheng Chang ◽  
Meng-Lun Hsieh ◽  
Lun Tsou ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Side Effects ◽  
Knockout Mice ◽  
Fasting Glucose ◽  
Binding Mode ◽  
Fluid Retention ◽  
Diet Induced Obesity

Abstract Insulin resistance and obesity are pivotal features of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones are potent synthetic PPARγ ligands and insulin sensitizers with undesirable side effects including increased adiposity, fluid retention, and osteoporosis, which limit their clinical use. We and others have proved that 15-keto-PGE2 is an endogenous natural PPARγ ligand. 15-keto-PGE2 is catalyzed by prostaglandin reductase 2 (PTGR2) to become inactive metabolites. We found that 15-keto-PGE2 level is increased in Ptgr2 knockout mice. Ptgr2 knockout mice were protected from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention nor reduced bone mineral density. Diet-induced obese mice have drastically reduced 15-keto-PGE2 levels compared to lean mice. Administration of 15-keto-PGE2 markedly improved insulin sensitivity and prevented diet-induced obesity in mice. We demonstrated that 15-keto-PGE2 activates PPARγ through covalent binding to its cysteine 285 residue at helix 3, which restrained its binding pocket between helix 3 and β-sheets of the PPARγ ligand binding domain. This binding mode differs from the helix12-dependent binding mode of thiazolidinediones. We further identified a small-molecule PTGR2 inhibitor BPRPT245, which interferes the interaction between the substrate-binding sites of PTGR2 and 15-keto-PGE2. BPRPT245 increased 15-keto-PGE2 concentration, activated PPARγ, and promoted glucose uptake in adipocytes. BPRPT245 also prevented diet-induced obesity, improved insulin sensitivity and glucose tolerance, lowers fasting glucose without fluid retention and osteoporosis. In humans, reduced serum 15-keto-PGE2 levels were observed in patients with type 2 diabetes compared with controls. Furthermore, serum 15-keto-PGE2 levels correlate inversely with insulin resistance and fasting glucose in non-diabetic humans. In conclusion, we identified a new therapeutic approach to improve insulin sensitivity and protect diet-induced obesity through increasing endogenous natural PPARγ ligands without side effects of thiazolidinediones.

Abstract 16: Economic Cost of Type 2 Diabetes Attributable to Physical Inactivity in the United States in 2012

Circulation ◽  
2016 ◽  
Vol 133 (suppl_1) ◽  
Author(s):  
Priyank P Shah ◽  
Fayez Shamoon ◽  
Mahesh Bikkina ◽  
Harold Kohl
Keyword(s):  
Physical Activity ◽  
Type 2 Diabetes ◽  
Physical Inactivity ◽  
Leisure Time ◽  
Sensitivity Analyses ◽  
Physical Activity Guidelines ◽  
Average Annual Cost ◽  
The Cost ◽  
The U.S

Objective: Type 2 diabetes has grown to epidemic proportions in the U.S. and physical activity levels in the population continues to remain low, although it is a major primary preventive strategy for diabetes. The objectives of this study were to estimate the direct medical costs of type 2 diabetes attributable to not meeting physical activity Guidelines and to physical inactivity in the U.S. in 2012. Methods: This was a cross sectional study that used physical activity prevalence data from the 2012 Behavioral Risk Factor Surveillance System (BRFSS). Estimates of relative risk of type 2 diabetes for subjects not engaging in any leisure time physical activity and those not meeting physical activity guidelines were obtained for multiple studies published in the literature. Using the prevalence of not meeting physical activity guidelines, physical inactivity and the respective relative risks, the population attributable risk percentage (PAR%) for type 2 diabetes was estimated by Levin’s formula. These data were combined with the prevalence and cost data of type 2 diabetes (in 2012) to estimate the cost of type 2 diabetes attributable to not meeting physical activity Guidelines, and to physical inactivity in 2012. Sensitivity analyses were done for i) varying the prevalence of not meeting physical activity guidelines from 30-70%, and ii) varying the average annual cost of type 2 diabetes from $4394 (for person less than 45 years of age) to $11825 (for person greater than 65 years of age). Results: The prevalence of U.S. population meeting physical activity guidelines and engaging in no leisure time activity was 50% and 30% respectively in 2012. The average annual cost attributable to type 2 diabetes in the US, was $7888 per person. The cost of type 2 diabetes in the U.S. in 2012, attributable to not meeting physical activity guidelines was estimated to be $18.6 billion, and that attributable to physical inactivity was estimated to be $5.9 billion. Based on sensitivity analyses, these estimates ranged from $10.36 billion to $27.9 billion for not meeting physical activity guidelines and $3.3 billion to $8.87 billion for physical inactivity in the year 2012. Conclusions: This study shows that billions of dollars could be saved annually just in terms of type 2 diabetes cost in the U.S., if the entire adult population was active enough to meet physical activity guidelines. Physical activity promotion, particularly at the environmental and policy level should be a priority in the population.

scholarly journals Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Denise E. Lackey ◽  
Felipe C. G. Reis ◽  
Roi Isaac ◽  
Rizaldy C. Zapata ◽  
Dalila El Ouarrat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Target Genes ◽  
Obese Mice ◽  
Tissue Macrophage

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

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