Insulin resistance and atherosclerosis

Insulin resistance characterizes type 2 diabetes and the metabolic syndrome, disorders associated with an increased risk of death due to macrovascular disease. In the past few decades, research from both the basic science and clinical arenas has enabled evidence-based use of therapeutic modalities such as statins and angiotensin-converting enzyme inhibitors to reduce cardiovascular (CV) mortality in insulin-resistant patients. Recently, promising drugs such as the thiazolidinediones have come under scrutiny for possible deleterious CV effects. Ongoing research has broadened our understanding of the pathophysiology of atherosclerosis, implicating detrimental effects of inflammation and the cellular stress response on the vasculature. In this review, we address current thinking that is shaping our molecular understanding of insulin resistance and atherosclerosis.     

Insulin resistance and atherosclerosis in diabetes mellitus

The aim of this study was to test our hypothesis that insulin resistance determines systemic atherosclerosis in type 2 diabetic patients. The design of the study was cross-sectional and included 28 type 2 patients with 48 type 1 patients as controls. The total daily insulin dose required to maintain glycosylated hemoglobin, HbA(1c), at 6.0% for 1 year was used as a measure of long-term insulin resistance. Systemic atherosclerosis was estimated by the toe systolic blood pressure index (TSPI). The results showed that total daily insulin dose was closely and independently associated with TSPI (r =.4652, partial P =.0064) in type 2 diabetic patients with secondary failure, even when adjusted for serum C-peptide (r =.4443, partial P =.00123). The association was absent in type 1 patients. Established risk factors were not associated with TSPI, but the products between individual risk factors and insulin dose were closely associated with TSPI. In conclusion, the daily insulin dose is associated with peripheral atherosclerosis in type 2 diabetic patients with high insulin resistance, but not in type 1 diabetes. The effect is additive to a lesser, underlying effect of established risk factors on atherosclerosis. Longstanding insulin resistance, as estimated by the daily insulin dose, is a determinant of atherogenesis.     

Insulin resistance and angiographical characteristics of coronary atherosclerosis.

Insulin resistance (IR) is frequently observed in patients with coronary heart disease (CHD). The relationship between IR and the angiographical characteristics of coronary atherosclerosis were investigated in 66 patients with coronary artery lesions. Insulin resistance was assessed by a 75-g oral glucose tolerance test and homeostasis model assessment (HOMA). The angiographical characteristics of coronary atherosclerosis (i.e., the severity of CHD) were defined by both Gensini's score (GS) (a higher degree of coronary artery stenosis or a proximal lesion was assigned a higher score than a distal lesion) and the number of significantly stenosed vessels. When GS was examined as a categorical variable classified by tertile values (Group A, n = 22: 1< or =GS< or =14; Group B, n = 22: 15< or =GS< or =32; and Group C, n = 22: 33< or =GS), patients with a high GS (Group C) had significantly (p<0.05) higher values of fasting plasma insulin, insulin response, and HOMA IR than patients with a low GS (Group A) (12.6+/-1.2 microU/ml vs. 6.9+/-1.2 microU/ml, 122.2+/-11.9 microU ml(-1) h(-1) vs. 72.9+/-12.9 microU ml(-1) h(-1), and 2.9+/-0.3 vs. 1.5+/-0.3, respectively).The values in Group B patients (9.4+/-1.2,microU/mI, 108.5+/-12.5 microU ml(-1) h(-1), and 2.1+/-0.3, respectively) were intermediate between those in Groups A and C. The area of insulin/area of glucose ratio was significantly (p<0.05) higher in Groups B and C than in Group A (0.54+/-0.06 microU/mg, 0.54+/-0.06 microU/mg, and 0.32+/-0.06 microU/mg, respectively). However, no significant differences were observed in variables of glucose tolerance, serum lipid, lipoproteins, fibrinogen, uric acid, and blood pressure among the 3 groups. Significant (p<0.05) positive associations were found between GS, the number of diseased coronary arteries, and fasting immunoreactive insulin, insulin response, the area of insulin/area of glucose ratio and HOMA IR by logistic regression analysis. After adjusting for the number of diseased coronary arteries, the association between GS and IR was not significant, suggesting that IR contributed to the severity of coronary atherosclerosis but not to the distribution of lesions. In conclusion, IR was associated with the severity of CHD as measured by both Gensini's score and the number of diseased coronary arteries, and increased the risk of CHD regardless of the location of the lesions.     

Insulin sensitizers and atherosclerosis

It is surprising that only about ten years after the concept of insulin resistance in diabetes mellitus was established, the role of insulin resistance in the development of atherosclerosis has been discussed and clarified. Insulin resistance predisposes the development of glucose intolerance, hyperlipidemia, and hypertension; the cluster of these abnormalities is referred to as multiple risk factor syndrome and it increases the risk of atherosclerosis. A few insulin sensitizers have recently begun to be used in the therapy for diabetic patients. However, the inhibitory effects of these insulin sensitizers against atherosclerosis have not been studied in large-scale clinical trials because these drugs were approved for clinical treatment only several years ago. Accordingly, this review presents a summary of the previous studies on the anti-atherogenic effects of insulin sensitizers by different strategies and provides information on why it is expected that insulin sensitizers will be used as anti-atherogenic drugs.     

Insulin resistance,diabetes, and atherosclerosis: thiazolidinediones as therapeutic interventions

The insulin resistance syndrome, a cluster of metabolic abnormalities involving dyslipidemia, hypertension, diabetes, impaired glucose tolerance, and hypercoagulability, carries an increased risk of atherosclerosis. Although interventions targeting elements of this syndrome have dramatically reduced cardiovascular risk, the impact of glucose-lowering has been more disappointing. Thiazolidinediones (TZDs) are a new class of insulin-sensitizing agents that activate the nuclear receptor peroxisome proliferators-activated receptor-γ. TZDs may improve not only glucose levels but also other metabolic parameters associated with insulin resistance. The TZD data are reviewed, with a focus on their potential cardiovascular effects.     

Insulin resistance as a risk factor for subclinical atherosclerosis in rheumatoid arthritis

BackgroundInsulin resistance (IR) is strongly associated with systemic inflammation. Insulin resistance is known to be increased in patients with rheumatoid arthritis (RA) and has been shown to be a risk factor for both clinical cardiovascular disease and subclinical atherosclerosis.Aim of the workTo study the relationship between insulin resistance, disease activity and subclinical atherosclerosis in RA patients.Patients and methodsForty RA patients and twenty age and sex matched healthy individuals as controls were included. Patients with diabetes mellitus, obesity and hypertension were excluded. Fasting plasma sugar and serum insulin were done, RA disease activity was assessed using the disease activity score (DAS28) and IR was evaluated by the homeostasis model assessment (HOMA2). Carotid artery intima media thickness (IMT) was evaluated using ultrasound.ResultsRA patients had significantly higher erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) positivity, fasting plasma sugar and fasting serum insulin, HOMA2-IR levels than the controls. IR was present in 33 (82.5%) RA patients while it was present in only one (10%) of the controls (p = 0.001). RA patients with IR had significantly longer disease duration (p = 0.003), higher disease activity (p = 0.000), greater carotid IMT (p = 0.000), and more carotid plaques (p = 0.043) than those without insulin resistance. RA patients with increased IMT had significantly longer disease duration (p = 0.002), higher DAS28 score (p = 0.000) and higher HOMA2-IR (p = 0.000) than those with normal IMT.ConclusionsIn RA patients, IR significantly correlated with both disease activity and disease duration. Our study pointed out a significant association between IR and subclinical atherosclerosis in RA.     

非酒精性脂肪性肝病肝硬化患者胰岛素抵抗水平与颈动脉硬化程度和左心室功能研究*

目的 调查非酒精性脂肪性肝病（NAFLD）所致肝硬化患者与胰岛素抵抗（IR）有关的指标及颈动脉硬化程度和左心室功能变化。方法 2016年6月~2018年6月我院诊治的64例NAFLD所致肝硬化患者,其中Child-Pugh A级26例、B级21例和C级17例,另选择30例健康志愿者。检测空腹血糖（FPG）、空腹胰岛素（FINS）水平,并计算胰岛素敏感指数（ISI）,使用超声检查颈动脉内膜中层厚度（IMT）、颈动脉局部血管收缩末期脉搏波（PWV）传导速度（PWVES）和左心室Tei指数。结果 Child A级、B级和C级肝硬化患者FPG水平分别为（5.5±1.1） mmol/L、（5.6±1.2） mmol/L和（5.8±1.4） mmol/L,均显著高于健康人的[（4.8±0.8） mmol/L,P<0.05];FINS水平分别为（8.7±1.7） mIU/L、（10.9±2.2） mIU/L和（15.1±3.1） mIU/L, 均显著高于健康人的 [（6.5±1.3）mIU/L,P<0.05]; ISI水平分别为（-4.5±0.4）、（-4.8±0.5）和（-5.1±0.7）,均显著低于对照组的[（-4.0±0.3）,P<0.05];Child A级、B级和C级肝硬化患者颈动脉IMT分别为（0.8±0.1） mm、（1.1±0.2） mm和（1.3±0.3） mm,均显著大于对照组[（0.5±0.1） mm,P<0.05];颈动脉PWVES分别为（8.1±1.3） m/s、（8.5±1.6） m/s和（8.7±1.8） m/s,均显著大于健康人[（7.4±1.1） m/s,P<0.05];左心室Tei指数分别为（0.38±0.08）、（0.44±0.09）和（0.52±0.12）, 均显著高于健康人[（0.32±0.05）,P<0.05]。结论 NAFLD所致的肝硬化患者存在IR、颈动脉硬化和左心室功能损害,它们存在发病基础上的某种关联,需要进行综合预防和控制,才能改变疾病的发展轨迹。     

Insulin resistance and hepatocarcinogenesis

Hepatocellular carcinoma (HCC) accounts for 85–90% of liver cancers and is one of the most frequent carcinomas in the world. HCCs classically develop against the background of chronic liver diseases. Common causes of such liver diseases are viral hepatitis, alcoholic hepatitis, or immune-related diseases; however, 15–50% of patients with HCCs have none of these classic antecedents, especially in developed countries. In this context, obesity and diabetes mellitus have been found to exhibit an increased risk of HCC. Both conditions are associated with insulin resistance. The tumorigenic effects of insulin resistance and complementary hyperinsulinemia could be mediated directly by insulin signaling, or indirectly related to changes in endogeneous hormone metabolism, particularly insulin-like growth factor I. Conversely, insulin resistance may be a consequence of obesity and hepatic inflammation, both of which can themselves promote tumorigenesis, mainly through cytokine production and/or generation of oxidative stress. Because the prevalence of obesity is now increasing throughout the world, insulin resistance is sure to be emphasized as a major factor in hepatocarcinogenesis in the foreseeable future.     

Insulin resistance and diabetes

Metabolic complications associated with HIV disease and its treatment--including insulin resistance and diabetes, abnormal cholesterol and triglyceride levels (dyslipidemia), and body fat gain or loss--remain a medical mystery and a topic of intense interest for AIDS researchers and people with HIV alike. While these complications sometimes have been collectively referred to as "lipodystrophy syndrome," it remains unclear whether or how they are related and what causes them. Scientists are urgently trying to better understand these conditions, which may have a negative impact on quality of life, interfere with adherence to antiretroviral therapy, and lead to long-term health problems. High blood glucose levels (hyperglycemia) and dyslipidemia are a particular concern because in the population at large they have been linked with increased risk of heart disease. Much research is underway and new clues are steadily emerging, but Daniel Kuritzkes, MD, of Boston's Brigham and Women's Hospital predicts, "We'll need several more years of follow-up to get a better perspective."     

Insulin resistance and hypertension

A common mechanism which may be involved in the development of hypertension in both type I and type II diabetes mellitus is a deficiency of insulin at the cellular level. Observations from a number of laboratories suggest that impaired cellular response to insulin rather than hyperinsulinemia predisposes to increased vascular smooth muscle tone (the hallmark of hypertension in the diabetic state). This review presents some of the data which suggest that there is a relationship between impaired cellular action of insulin, altered cellular calcium metabolism and the development of hypertension.     

Insulin resistance and hypertension

The author has reviewed the development of the concept that insulin resistance is related not only to the hypertensive state but potentially to the initiation and maintenance of high blood pressure. Potential sequelae of insulin resistance and hyperinsulinemia, as they apply to atherogenesis, are also discussed. The impact of present antihypertensive pharmacologic therapy on insulin resistance is addressed, as are future directions in pharmacologic and nonpharmacologic management of hypertension. In addition, the author speculates on possible mechanisms leading to insulin resistance in hypertension.     

Insulin resistance: a multifaceted syndrome responsible for NIDDM,obesity, hypertension,dyslipidaemia and atherosclerosis

Insulin resistance syndrome (IRS) has the potential to explain a large group of common metabolic and cardiovascular disorders [e.g., obesity, non-insulin-dependent diabetes mellitus (NIDDM), hypertension, hyperlipidaemia, hypercoagulability] which are all in themselves cardiovascular risk factors. This contribution firstly reviews the convincing evidence from glucose-clamp studies that all of these conditions are characterised by the presence of combined insulin resistance and hyperinsulinaemia, and secondly examines the relationships of the components of this syndrome to coronary artery disease and to the rational choice of antihypertensive therapy.     

Insulin resistance and blood pressure

Insulin resistance, cardiometabolic syndrome, and hypertension are common health problems with significant consequences for individuals and society. The pathogenesis of these disorders is complex and not fully understood. In this article we review the current knowledge about the effects of lifestyle modification and pharmacologic antihypertensive agents on insulin resistance and hypertension.