Susceptibility to oxidative stress, insulin resistance, and insulin secretory response in the development of diabetes from obesity

Background/Aim. Oxidative stress plays a critical role in the pathogenesis of various diseases. Recent reports indicate that obesity may induce systemic oxidative stress. The aim of the study was to potentiate oxidative stress as a factor which may aggravate peripheral insulin sensitivity and insulinsecretory response in obesity in this way to potentiate development of diabetes. The aim of the study was also to establish whether insulin-secretory response after glucagonstimulated insulin secretion is susceptible to prooxidant/ antioxidant homeostasis status, as well as to determine the extent of these changes. Methods. A mathematical model of glucose/insulin interactions and C-peptide was used to indicate the degree of insulin resistance and to assess their possible relationship with altered antioxidant/prooxidant homeostasis. The study included 24 obese healthy and 16 obese newly diagnozed non-insulin dependent diabetic patients (NIDDM) as well as 20 control healthy subjects, matched in age. Results. Total plasma antioxidative capacity, erythrocyte and plasma reduced glutathione level were significantly decreased in obese diabetic patients, but also in obese healthy subjects, compared to the values in controls. The plasma lipid peroxidation products and protein carbonyl groups were significantly higher in obese diabetics, more than in obese healthy subjects, compared to the control healthy subjects. The increase of erythrocyte lipid peroxidation at basal state was shown to be more pronounced in obese daibetics, but the apparent difference was obtained in both the obese healthy subjects and obese diabetics, compared to the control values, after exposing of erythrocytes to oxidative stress induced by H2O2. Positive correlation was found between the malondialdehyde (MDA) level and index of insulin sensitivity (FIRI). Conclusion. Increased oxidative stress together with the decreased antioxidative defence seems to contribute to decreased insulin sensitivity and impaired insulin secretory response in obese diabetics, and may be hypothesized to favour the development of diabetes during obesity.

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Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients

British Journal Of Nutrition ◽

10.1017/s0007114511000316 ◽

2011 ◽

Vol 106 (3) ◽

pp. 383-389 ◽

Cited By ~ 374

Author(s):

Pál Brasnyó ◽

Gergő A. Molnár ◽

Márton Mohás ◽

Lajos Markó ◽

Boglárka Laczy ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Cell Function ◽

Diabetic Patients ◽

Β Cell ◽

Type 2 Diabetic Patients ◽

Β Cell Function ◽

Type 2 Diabetic

Although resveratrol has widely been studied for its potential health benefits, little is known about its metabolic effects in humans. Our aims were to determine whether the polyphenol resveratrol improves insulin sensitivity in type 2 diabetic patients and to gain some insight into the mechanism of its action. After an initial general examination (including blood chemistry), nineteen patients enrolled in the 4-week-long double-blind study were randomly assigned into two groups: a resveratrol group receiving oral 2 × 5 mg resveratrol and a control group receiving placebo. Before and after the second and fourth weeks of the trial, insulin resistance/sensitivity, creatinine-normalised ortho-tyrosine level in urine samples (as a measure of oxidative stress), incretin levels and phosphorylated protein kinase B (pAkt):protein kinase B (Akt) ratio in platelets were assessed and statistically analysed. After the fourth week, resveratrol significantly decreased insulin resistance (homeostasis model of assessment for insulin resistance) and urinary ortho-tyrosine excretion, while it increased the pAkt:Akt ratio in platelets. On the other hand, it had no effect on parameters that relate to β-cell function (i.e. homeostasis model of assessment of β-cell function). The present study shows for the first time that resveratrol improves insulin sensitivity in humans, which might be due to a resveratrol-induced decrease in oxidative stress that leads to a more efficient insulin signalling via the Akt pathway.

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Novel Interactions of Adiponectin with the Endocrine System and Inflammatory Parameters

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2002-021583 ◽

2003 ◽

Vol 88 (6) ◽

pp. 2714-2718 ◽

Cited By ~ 111

Author(s):

José Manuel Fernández-Real ◽

Abel López-Bermejo ◽

Roser Casamitjana ◽

Wifredo Ricart

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Healthy Subjects ◽

Density Lipoprotein ◽

Endocrine System ◽

Insulin Resistance Syndrome ◽

Diabetic Patients ◽

Free T4 ◽

Type 2 Diabetic Patients ◽

Waist To Hip Ratio

Several markers of chronic immune activation have been found in association with obesity and insulin resistance. We aimed to study the interaction of adiponectin with chronic inflammation and known components of the insulin resistance syndrome. Insulin sensitivity (minimal model analysis) and plasma soluble fractions of TNF-α receptor 1 (sTNFR1) and 2 (sTNFR2), adrenal and thyroid function, and adiponectin were evaluated in 68 apparently healthy subjects. An additional group of type 2 diabetic patients (n = 19) similarly studied, except for insulin sensitivity, were also included in the analysis. As reported by others, serum adiponectin concentrations were higher in women than in men (13.55 ± 9.79 vs. 8.64 ± 7.83 mg/liter; P = 0.018). They were also higher in healthy subjects compared with diabetic patients (10.35 ± 8.48 vs. 7.41 ± 8.31 mg/liter; P = 0.021). As expected also, circulating adiponectin was significantly associated with waist to hip ratio (r = −0.28; P = 0.013), diastolic blood pressure (r = −0.25; P = 0.027), fasting plasma high-density lipoprotein cholesterol (r = 0.35; P = 0.001), triglycerides (r = −0.37; P = 0.001), and insulin sensitivity (r = 0.30; P = 0.011). Additionally, subjects in the higher quartile of circulating adiponectin had lower sTNFR2 concentrations (3.05 vs. 4.37 μg/liter; P = 0.012), a trend to lower sTNFR1 concentrations (1.76 vs. 2.20 μg/liter; P = 0.055), higher concentration of serum morning cortisol (16.86 vs. 13.52 μg/dl; P = 0.027), and higher serum free T4 levels (1.31 vs. 1.20 ng/dl; P = 0.038). Multiple regression analysis models were constructed to predict adiponectin concentrations. Predictive variables in these models included insulin sensitivity, waist to hip ratio and free T4, contributing to 17%, 10%, and 8% of adiponectin variance, respectively, These findings suggest that circulating adiponectin differentially modulates insulin action and that thyroid-axis, inflammatory cytokines, and the adrenal cortex might intervene in this modulation.

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Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00046.2004 ◽

2004 ◽

Vol 287 (5) ◽

pp. E919-E925 ◽

Cited By ~ 40

Author(s):

Thomas Nyström ◽

Arne Nygren ◽

Åke Sjöholm

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Endothelial Function ◽

Healthy Subjects ◽

Diabetic Patients ◽

Sensitivity Index ◽

Type 2 Diabetic Patients ◽

Brachial Artery Diameter ◽

Type 2 Diabetic

Tetrahydrobiopterin (BH4) is an essential cofactor of nitric oxide synthase that improves endothelial function in diabetics, smokers, and patients with hypercholesterolemia. Insulin resistance has been suggested as a contributing factor in the development of endothelial dysfunction via an abnormal pteridine metabolism. We hypothesized that BH4 would restore flow-mediated vasodilation (FMD, endothelial-dependent vasodilation), which may affect insulin resistance in type 2 diabetic patients. Thirty-two subjects (12 type 2 diabetic subjects, 10 matched nondiabetic subjects, and 10 healthy unmatched subjects) underwent infusion of BH4 or saline in a random crossover study. Insulin sensitivity index (SI) was measured by hyperinsulinemic isoglycemic clamp. FMD was measured using ultrasonography. BH4 significantly increased SI in the type 2 diabetics [3.6 ± 0.6 vs. 4.9 ± 0.7 × 10−4 dl·kg−1·min−1/(μU/ml), P < 0.05], while having no effects in nondiabetics [8.9 ± 1.1 vs. 9.0 ± 0.9 × 10−4 dl·kg−1·min−1/(μU/ml), P = 0.92] or in healthy subjects [17.5 ± 1.6 vs. 18 ± 1.8 × 10−4 dl·kg−1·min−1/(μU/ml), P = 0.87]. BH4 did not affect the relative changes in brachial artery diameter from baseline FMD (%) in type 2 diabetic subjects (2.3 ± 0.8 vs. 1.8 ± 1.0%, P = 0.42), nondiabetic subjects (5.3 ± 1.1 vs. 6.6 ± 0.9%, P = 0.32), or healthy subjects (11.9 ± 0.6 vs. 11.0 ± 1.0%, P = 0.48). In conclusion, BH4 significantly increases insulin sensitivity in type 2 diabetic patients without any discernible improvement in endothelial function.

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SAT0111 THE RELATIONSHIP BETWEEN THE ADMINISTRATION OF IL-6 INHIBITORS AND INSULIN RESISTANCE IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6509 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 989.3-989

Author(s):

A. Jitaru ◽

C. Pomirleanu ◽

M. M. Leon-Constantin ◽

F. Mitu ◽

C. Ancuta

Keyword(s):

Rheumatoid Arthritis ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Beneficial Effect ◽

Disease Activity ◽

Interleukin 6 ◽

Normal Weight ◽

Diabetic Patients ◽

Model Assessment ◽

Inflammatory Status

Background:Rheumatoid arthritis (RA) is associated with an increased cardiovascular (CV) risk, due not only to the traditional risk factors (hypertension, insulin resistance/diabetes, obesity, smoking), but to the inflammatory status as well. The blockade of interleukin-6 (IL-6) can regulate the glucose metabolism, reducing the glucose level and insulin resistance (IR). This beneficial effect is seen more in patients with normal values of body mass index (BMI), compared to the obese population.Objectives:Given the mentioned existing data, we aim to demonstrate the positive effect of IL-6 inhibitors in active RA patients with normal or increased BMI.Methods:We recruited 56 consecutive patients with definite and active RA, non-responders/partial responders to conventional synthetic Drug Modifying Anti-Rheumatic Drugs (csDMARDs)/biological therapy. For a period of 52 weeks, patients received subcutaneous Tocilizumab (TCZ) in a dose of 162mg once a week, according to European League Anti Rheumatism (EULAR) recommendation and National Protocol. We assessed demographics, RA-related parameters (clinical, inflammatory and immune) and metabolic markers, as well as the peripheral response to insulin, quantified by Homeostasis Model Assessment for insulin resistance (HOMA-IR) and the Quantitative Insulin Sensitivity Check Index (QUICKI). We did not include in the study the patients known with diabetes mellitus (DM) and those undergoing glucocorticoids.Results:After 52 weeks of treatment, most of the patients showed a statistically significant reduction of HOMA-IR (3.61 ± 1.21 at the onset vs. 2.45 ± 1.46 at the end of the study, p<0.001), while QUICKI registered a slight increase (0.32 ± 0.01 at the onset vs. 0.33 ± 0.01 at the end of the study, p<0.001). Also, the decrease in insulin and glucose levels were more obvious in patients with normal BMI, strictly related to disease activity.Conclusion:Long-term administration of TCZ in active RA is associated with a significant reduction of disease activity and IR, especially in normal weight patients. This confirms that obesity, as a CV risk factor, represents one of the main causes of IR.References:[1]Castañeda S, Remuzgo-Martínez S, López-Mejías R et al. Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis.Clin Exp Rheumatol. 2019; 37(3):465-473.[2]Lehrskov LL, Christensen RH. The role of interleukin-6 in glucose homeostasis and lipid metabolism.Semin Immunopathol. 2019; 41(4):491-499.[3]Ursini F, Russo E, Ruscitti P, Giacomelli R, De Sarro G. The effect of non-TNF-targeted biologics and small molecules on insulin resistance in inflammatory arthritis.Autoimmun Rev. 2018 Apr;17(4):399-404.Disclosure of Interests:Alexandra Jitaru: None declared, Cristina Pomirleanu: None declared, Maria-Magdalena Leon-Constantin: None declared, Florin Mitu: None declared, CODRINA ANCUTA Consultant of: AbbVie, Pfizer, Roche, Novartis, UCB, Ewopharma, Merck Sharpe and Dohme, and Eli Lilly, Speakers bureau: AbbVie, Pfizer, Roche, Novartis, UCB, Ewopharma, Merck Sharpe and Dohme, and Eli Lilly

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Effect of carvedilol versus nebivolol on insulin resistance among non-diabetic, non-ischemic cardiomyopathy with heart failure

The Egyptian Heart Journal ◽

10.1186/s43044-020-00099-5 ◽

2020 ◽

Vol 72 (1) ◽

Author(s):

Yasser Gaber Metwally ◽

Heba Kamal Sedrak ◽

Inass Fahiem Shaltout

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Ischemic Cardiomyopathy ◽

Diabetic Patients ◽

Promising Strategy ◽

Improve Insulin Resistance ◽

First Choice ◽

The Difference

Abstract Background Although B-blockers provide unequivocal benefits in heart failure (HF) management, some B-blockers worsen insulin resistance. It will be a promising strategy to recruit such a B blocker that did not worsen or can even improve insulin resistance (IR). So, this study aimed to assess the effect of two of the third-generation B-blockers (carvedilol versus nebivolol) on insulin sensitivity state in non-diabetic patients with non-ischemic cardiomyopathy with heart failure. Results Out of 43 patients enrolled, 58.1% represented the carvedilol group while 41.9% represented the nebivolol group. Nebivolol improves insulin resistance-related variables (fasting glucose, fasting insulin, and HOMA-IR; P < 0.001, 0.01, and 0.01 respectively). The percentage of change at homeostasis model of assessment (HOMA-IR), indicative of insulin sensitivity status, between baseline versus at 3-months follow-up level of intra-group comparison was increased by 4.58% in the carvedilol arm whereas it was decreased by 11.67% in the nebivolol arm, and the difference on the intragroup level of comparison was significant (P < 0.001 and 0.01 respectively). Conclusion Nebivolol improves insulin resistance-related variables .Nebivolol may be recommended as the B blocker of the first choice for those with non-ischemic cardiomyopathy heart failure with evident insulin resistance; however, larger scaled prospective multicenter randomized trials are needed for confirming our favorable results.

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

Healthcare ◽

10.3390/healthcare9081010 ◽

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.

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Insulin secretory response in Japanese type 2 (non-insulin-dependent) diabetic patients

Diabetes Research and Clinical Practice ◽

10.1016/0168-8227(94)90235-6 ◽

1994 ◽

Vol 24 ◽

pp. S101-S110 ◽

Cited By ~ 16

Author(s):

Kinori Kosaka ◽

Takeshi Kuzuya ◽

Ryoko Hagura

Keyword(s):

Secretory Response ◽

Diabetic Patients ◽

Insulin Dependent ◽

Insulin Dependent Diabetic ◽

Insulin Secretory Response

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Lack of relationship between 11β-hydroxysteroid dehydrogenase setpoint and insulin sensitivity in the basal state and after 24h of insulin infusion in healthy subjects and type 2 diabetic patients*

Clinical Endocrinology ◽

10.1046/j.1365-2265.2000.00975.x ◽

2000 ◽

Vol 52 (4) ◽

pp. 403-411 ◽

Cited By ~ 30

Author(s):

M. N. Kerstens ◽

S. C. Riemens ◽

W. J. Sluiter ◽

J. J. Pratt ◽

B. G. Wolthers ◽

...

Keyword(s):

Insulin Sensitivity ◽

Healthy Subjects ◽

Insulin Infusion ◽

Hydroxysteroid Dehydrogenase ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Type 2 Diabetic

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Selenoprotein W deficiency does not affect oxidative stress and insulin sensitivity in the skeletal muscle of high-fat diet-fed obese mice

AJP Cell Physiology ◽

10.1152/ajpcell.00064.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. C1172-C1182 ◽

Cited By ~ 3

Author(s):

Min-Gyeong Shin ◽

Hye-Na Cha ◽

Soyoung Park ◽

Yong-Woon Kim ◽

Jong-Yeon Kim ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

High Fat Diet ◽

Control Diet ◽

In Vivo Studies ◽

Selenoprotein W ◽

Obese Mice ◽

High Fat

Selenoprotein W (SelW) is a selenium-containing protein with a redox motif found abundantly in the skeletal muscle of rodents. Previous in vitro studies suggest that SelW plays an antioxidant role; however, relatively few in vivo studies have addressed the antioxidant role of SelW. Since oxidative stress is a causative factor for the development of insulin resistance in obese subjects, we hypothesized that if SelW plays a role as an antioxidant, SelW deficiency could aggravate the oxidative stress and insulin resistance caused by a high-fat diet. SelW deficiency did not affect insulin sensitivity and H2O2 levels in the skeletal muscle of control diet-fed mice. SelW levels in the skeletal muscle were decreased by high-fat diet feeding for 12 wk. High-fat diet induced obesity and insulin resistance and increased the levels of H2O2 and oxidative stress makers, which were not affected by SelW deficiency. High-fat diet feeding increased the expression of antioxidant enzymes; however, SelW deficiency did not affect the expression levels of antioxidants. These results suggest that SelW does not play a protective role against oxidative stress and insulin resistance in the skeletal muscle of high-fat diet-fed obese mice.

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