The Injurious Effects of Hyperinsulinism on Blood Vessels

Insulin resistance (IR) is a common feature of hypertension, Type II diabetes, coronary heart disease, Syndrome X, and other vascular diseases. It refers to a state in which a certain concentration of insulin produces less biologic effect than expected in human body. When IR develops, the response of human body to insulin decreases accordingly, thus inducing the compensatory hyper-secretion of insulin and consequently hyperinsulinism. Many clinical and epidemiologic studies have demonstrated that IR and iatrogenic hyperinsulinism induced consequently play an essential role in the pathogenesis of hypertension and atherosclerotic cardiovascular diseases. Therefore, more and more attention should be paid to the mechanism of IR in order to explore more therapeutic basis and prospective for the treatment of atherosclerosis and other cardiovascular diseases. In this review, we provided a general overview on the known molecular mechanisms of IR and summarized the recent findings on the injurious effects of hyperinsulinism in vitro and in vivo, which might be important for researchers and clinicians to better understand the etiology and clinical significance of IR.     

Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance

Hypertension commonly occurs in conjunction with insulin resistance and other components of the cardiometabolic syndrome. Insulin resistance plays a significant role in the relationship between hypertension, Type 2 diabetes mellitus, chronic kidney disease, and cardiovascular disease. There is accumulating evidence that insulin resistance occurs in cardiovascular and renal tissue as well as in classical metabolic tissues (i.e., skeletal muscle, liver, and adipose tissue). Activation of the renin-angiotensin-aldosterone system and subsequent elevations in angiotensin II and aldosterone, as seen in cardiometabolic syndrome, contribute to altered insulin/IGF-1 signaling pathways and reactive oxygen species formation to induce endothelial dysfunction and cardiovascular disease. This review examines currently understood mechanisms underlying the development of resistance to the metabolic actions of insulin in cardiovascular as well as skeletal muscle tissue.     

Diagnosis of the metabolic syndrome in children

PURPOSE OF REVIEW: The metabolic syndrome, a cluster of potent risk factors for atherosclerotic cardiovascular disease and type 2 diabetes mellitus in adults, is composed of insulin resistance, obesity, hypertension and hyperlipidemia. Of significant impact in the adult population, atherosclerotic cardiovascular disease and death are rarely seen in the young, but the pathologic processes and risk factors associated with its development have been shown to begin during childhood. The current review summarizes the work published during the past year in the following areas: childhood obesity, insulin resistance, dyslipidemia, hypertension and type 2 diabetes mellitus. RECENT FINDINGS: Recent studies have revealed the presence of components of the metabolic syndrome in children and adolescents. Obesity has a central role in the syndrome. There is an increasing amount of data to show that being overweight during childhood and adolescence is significantly associated with insulin resistance, abnormal lipids, and elevated blood pressure in young adulthood. Weight loss in these situations results in a decrease in insulin concentration and an increase in insulin sensitivity toward normalcy. With cardiovascular disease, obesity, and type 2 diabetes reaching epidemic proportions, it is of great importance to understand and control the risk factors at an early age. SUMMARY: The information obtained during the past year has improved our understanding of the pathogenesis, diagnosis and treatment of components of the metabolic syndrome in children, and potentially could improve the risk profiles for cardiovascular disease as children make the transition toward adolescence and young adulthood.     

Early reduction of circulating homocysteine levels in Goto-Kakizaki rat, a spontaneous nonobese model of type 2 diabetes

Diabetes mellitus is associated with increased risk for cardiovascular disorders, which are major causes of mortality in this disease. Hyperhomocysteinemia, defined by high plasma homocysteine levels, is an independent risk factor for the development of cardiovascular diseases. Type 2 diabetic patients have higher circulating homocysteine levels than healthy subjects and these levels are even higher in plasma of obese than nonobese diabetic patients. Homocysteine metabolism that has been studied in 2 animal models of type 2 diabetes with obesity led to conflicting data. The aim of the present study was to analyze homocysteine metabolism in a spontaneous nonobese model of type 2 diabetes, the Goto-Kakizaki rats at various successive and well characterized stages of the disease: during early postnatal normoglycemia, at the onset of hyperglycemia (around weaning), and during chronic mild hyperglycemia with progressive insulin resistance. Compared to age-matched Wistar controls, Goto-Kakizaki rats showed lower plasma levels of homocysteine and a falling trend in its major byproduct antioxidant, glutathione, from the prediabetic stage onwards. Concomitantly, Goto-Kakizaki rats exhibited increased liver activity of cystathionine beta synthase, which catalyzes the condensation of homocysteine with serine in the first step of the transsulfuration pathway. These results emphasize a strong association between homocysteine metabolism and insulin via the first step of the hepatic transsulfuration pathway in Goto-Kakizaki rats.     

Insulin resistance: cellular and clinical concepts

Insulin resistance is defined as a clinical state in which a normal or elevated insulin level produces an attenuated biologic response. Specifically, the biologic response most studied is insulin-stimulated glucose disposal, yet the precise cellular mechanism responsible is not yet known. However, the presence of insulin resistance is observed many years before the onset of clinical hyperglycemia and the diagnosis of Type 2 diabetes. Insulin resistance at this stage appears to be significantly associated with a clustering of cardiovascular risk factors predisposing the individual to accelerated cardiovascular disease. An overview of insulin resistance and the associated clinical insulin resistant state will be discussed.     

Impact of insulin resistance on enhanced monocyte adhesion to endothelial cells and atherosclerogenesis independent of LDL cholesterol level

Epidemiological studies suggest that insulin resistance is an independent risk factor for cardiovascular disease. However, there is little information on the role of insulin resistance in atherosclerogenesis independent of LDL cholesterol level. The aim of this study was to investigate the impact of systemic insulin resistance on monocyte adhesion to endothelial cells and atherosclerotic lesions independent of LDL cholesterol level. KKAy mice are obese mice with spontaneous diabetes and insulin resistance, and normal levels of LDL cholesterol. In parallel with systemic insulin resistance, decreased insulin signal, and the increased expression of monocyte chemoattractant protein-1 (MCP-1) were noted in macrophages isolated from KKAy mice. These mice showed enhanced monocyte adhesion to the endothelial cells of the thoracic artery. Furthermore, these mice showed expanded atherosclerotic lesions when fed high cholesterol diet. Our data indicate that insulin resistance promotes the atherosclerogenesis independent of LDL cholesterol level. Decreased insulin signaling in macrophages associated with systemic insulin resistance could be involved, at least in part, in this pathological process.     

Regulating insulin signaling and beta-cell function through IRS proteins

Diabetes mellitus is a complex disorder that arises from various causes, including dysregulated glucose sensing and impaired insulin secretion (maturity onset diabetes of youth, MODY), autoimmune-mediated beta-cell destruction (type 1), or insufficient compensation for peripheral insulin resistance (type 2). Type 2 diabetes is the most prevalent form that usually occurs at middle age; it afflicts more than 30 million people over the age of 65, but is appearing with greater frequency in children and adolescents. Dysregulated insulin signaling exacerbated by chronic hyperglycemia promotes a cohort of systemic disorders--including dyslipidemia, hypertension, cardiovascular disease, and female infertility. Understanding the molecular basis of insulin resistance can prevent these disorders and their inevitable progression to type 2 diabetes.     

Type 2 diabetes as an inflammatory cardiovascular disorder

Type 2 diabetes carries a 2-6-fold increased risk of cardiovascular disease (CVD) and death. Indeed, the risk of major cardiovascular events in Type 2 diabetic patients without history of coronary heart disease (CHD) is equivalent to that observed in non-diabetic subjects with CHD. However, atherosclerosis may also precede the development of diabetes, suggesting that both disorders share common genetic and environmental antecedent factors ("common soil" hypothesis). One such a possible ancestor is insulin resistance which constitutes both a major feature of Type 2 diabetes and an independent risk factor for CHD. It is well documented that inflammatory processes play an important role in the causation of atherosclerotic CVD. Inflammatory mediators play a paramount role in the initiation, progression, and rupture of atherosclerotic plaques. Thus, markers of inflammation and endothelial dysfunction may provide additional information about a patient's risk of developing CVD and may become new targets for treatment. On the other hand, evidence has emerged suggesting that inflammation is also involved in the development of Type 2 diabetes. Prospective studies have demonstrated that increased levels of pro-inflammatory markers such as CRP or reduced levels of anti-inflammatory markers such as adiponectin predict the development of Type 2 diabetes. Thus, there is accumulating evidence suggesting that inflammation is the bridging link between atherosclerosis and the metabolic syndrome. Interventions by lifestyle modification or agents with anti-inflammatory properties may reduce the risk of both conditions. Drugs exerting anti-inflammatory and vascular effects have future potential to be used within an array of interventions aimed at reducing the enormous cardiovascular burden associated with Type 2 diabetes.     

Glycemia and Cardiova Scular Disease in Type 1 Diabetes Mellitus

ObjectiveTo evaluate the role of glycemic control in the development of cardiovascular disease (CVD) in type 1 diabetes mellitus (DM).MethodsWe review the literature regarding coronary atherosclerosis, coronary artery calcification, and the epidemiologic studies related to the role of glycemia and the classic risk factors for coronary artery disease (CAD) in type 1 DM.ResultsFour prospective studies (Wisconsin Epidemiologic Study of Diabetic Retinopathy, EURODIAB, Steno Diabetes Center Study of Adults With Type 1 DM, and Pittsburgh Epidemiology of Diabetes Complications study) do not show that glycemic control predicts CAD occurrence. Findings from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study show that compared with conventional insulin therapy, intensive insulin therapy reduces CVD among patients with type 1 DM and is associated with lower prevalence of coronary artery calcification. The discrepancies between the findings from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study and the Pittsburgh Epidemiology of Diabetes Complication study are likely due to differences between the study populations and the lower prevalence of renal disease in the former study. Besides duration of DM and albuminuria/overt nephropathy, insulin resistance is a major determinant of CAD associated with type 1 DM.ConclusionsDiscrepant study results regarding the relationship between glycemia and CAD/coronary artery calcification may be related to the prevalence of renal disease and the presence of the metabolic syndrome. Published data suggest that addressing traditional risk factors including albuminuria, the metabolic syndrome, and inflammatory markers is better for preventing and treating CAD than focusing exclusively on glycemic control, which is still necessary for preventing microvascular complications. Furthermore, there is a synergistic effect of glycemic control and albuminuria on the development of CVD. (Endocr Pract. 2008;14:912-923)     

Dorothy Hodgkin Lecture 2012* Non-alcoholic fatty liver disease, insulin resistance and ectopic fat: a new problem in diabetes management

Diabet. Med. 29, 1098-1107 (2012) ABSTRACT: Non-alcoholic fatty liver disease is now recognized as the hepatic component of the metabolic syndrome. Non-alcoholic fatty liver disease is a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in non-alcoholic fatty liver disease and may progress to non-alcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. Prevalence estimates for non-alcoholic fatty liver disease range from 17 to 33% in the general populations and it has been estimated that non-alcoholic fatty liver disease exists in up to 70% of people with Type?2 diabetes. Non-alcoholic fatty liver disease increases risk of Type?2 diabetes and cardiovascular disease. In people with Type?2 diabetes, non-alcoholic fatty liver disease is the most frequent cause (～80%) of fatty liver diagnosed by ultrasound. As non-alcoholic fatty liver disease is strongly associated with insulin resistance, the presence of non-alcoholic fatty liver disease with diabetes often contributes to poor glycaemic control. Consequently, strategies that decrease liver fat and improve whole-body insulin sensitivity may both contribute to prevention of Type?2 diabetes and to better glycaemic control in people who already have developed diabetes. This review summarizes the Dorothy Hodgkin lecture given by the author at the 2012 Diabetes UK annual scientific conference, proposing that fatty acid fluxes through the liver are crucial for the pathogenesis of non-alcoholic fatty liver disease and for increasing insulin resistance.     

Renal Lipotoxicity-Associated Inflammation and Insulin Resistance Affects Actin Cytoskeleton Organization in Podocytes

In the last few decades a change in lifestyle has led to an alarming increase in the prevalence of obesity and obesity-associated complications. Obese patients are at increased risk of developing hypertension, heart disease, insulin resistance (IR), dyslipidemia, type 2 diabetes and renal disease. The excess calories are stored as triglycerides in adipose tissue, but also may accumulate ectopically in other organs, including the kidney, which contributes to the damage through a toxic process named lipotoxicity. Recently, the evidence suggests that renal lipid accumulation leads to glomerular damage and, more specifically, produces dysfunction in podocytes, key cells that compose and maintain the glomerular filtration barrier. Our aim was to analyze the early mechanisms underlying the development of renal disease associated with the process of lipotoxicity in podocytes. Our results show that treatment of podocytes with palmitic acid produced intracellular accumulation of lipid droplets and abnormal glucose and lipid metabolism. This was accompanied by the development of inflammation, oxidative stress and endoplasmic reticulum stress and insulin resistance. We found specific rearrangements of the actin cytoskeleton and slit diaphragm proteins (Nephrin, P-Cadherin, Vimentin) associated with this insulin resistance in palmitic-treated podocytes. We conclude that lipotoxicity accelerates glomerular disease through lipid accumulation and inflammation. Moreover, saturated fatty acids specifically promote insulin resistance by disturbing the cytoarchitecture of podocytes. These data suggest that renal lipid metabolism and cytoskeleton rearrangements may serve as a target for specific therapies aimed at slowing the progression of podocyte failure during metabolic syndrome.     

Peroxisome proliferator-activated receptor-gamma agonists in atherosclerosis: current evidence and future directions

PURPOSE OF REVIEW: The prevalence of type 2 diabetes globally is reaching epidemic proportions. Type 2 diabetes is strongly associated with increased risk of cardiovascular disease. Atherosclerosis is thought to arise as a result of a chronic inflammatory process within the arterial wall. Insulin resistance is central to the pathogenesis of type 2 diabetes and may contribute to atherogenesis, either directly or through associated risk factors. The peroxisome proliferator-activated receptor-gamma agonists, the thiazolidinediones, pioglitazone and rosiglitazone, are insulin sensitizing agents, that are licensed for the management of hyperglycaemia. Growing evidence supports an array of additional effects of thiazolidinedione therapy, both immunomodulatory and antiinflammatory, which may attenuate atherogenesis in type 2 diabetes. RECENT FINDINGS: Studies have shown that thiazolidinedione therapy may lead to risk factor modulation in type 2 diabetes. Thiazolidinediones treatment has been shown to reduce blood pressure, modify the atherogenic lipid profile associated with type 2 diabetes, reduce microalbuminuria and ameliorate the prothrombotic diathesis. Further evidence suggests that thiazolidinediones therapy inhibits the inflammatory processes which may be involved in atherosclerotic plaque initiation, propagation and destabilization. SUMMARY: Modification of insulin resistance by thiazolidinedione therapy in type 2 diabetes and the range of pleiotropic effects may not only impact on incident type 2 diabetes, but also on associated cardiovascular disease. Numerous large clinical endpoint studies are under way to investigate these issues.     

尿酸代谢失衡与心血管疾病及药物干预

尿酸是体内嘌呤代谢的终末产物,与各类心血管疾病的发生发展密切相关,是心血管疾病的重要危险因子之一。综述尿酸的代谢及生理病理意义,尿酸代谢失衡与急性心肌梗死、高血压、胰岛素抵抗、肥胖症等心血管疾病的关联以及尿酸代谢失衡的药物干预与心血管保护作用。     

Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin-resistant mice and adipocytes

BACKGROUND: Although the association between insulin resistance and cardiovascular risk is well established, the underlying molecular mechanisms are poorly understood. The antifibrinolytic molecule plasminogen activator inhibitor 1 (PAI-1) is a cardiovascular risk factor that is consistently elevated in insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). The strong positive correlation between this elevated PAI-1 and the degree of hyperinsulinemia not only implicates insulin itself in this increase, but also suggests that PAI-1 is regulated by a pathway that does not become insulin resistant. The data in this report supports this hypothesis. MATERIALS AND METHODS: We show that insulin stimulates PAI-1 gene expression in metabolically insulin-resistant ob/ob mice and in insulin-resistant 3T3-L1 adipocytes. Moreover, we provide evidence that glucose transport and PAI-1 gene expression are mediated by different insulin signaling pathways. These observations suggest that the compensatory hyperinsulinemia that is frequently associated with insulin-resistant states, directly contribute to the elevated PAI-1. CONCLUSIONS: These results provide a potential mechanism for the abnormal increases in cardiovascular risk genes in obesity, NIDDM, and polycystic ovary disease.     

Gout. Epidemiology of gout

Gout is the most prevalent form of inflammatory arthropathy. Several studies suggest that its prevalence and incidence have risen in recent decades. Numerous risk factors for the development of gout have been established, including hyperuricaemia, genetic factors, dietary factors, alcohol consumption, metabolic syndrome, hypertension, obesity, diuretic use and chronic renal disease. Osteoarthritis predisposes to local crystal deposition. Gout appears to be an independent risk factor for all-cause mortality and cardiovascular mortality and morbidity, additional to the risk conferred by its association with traditional cardiovascular risk factors.     

Epidemiology of gout

Gout is the most prevalent form of inflammatory arthropathy. Several studies suggest that its prevalence and incidence have risen in recent decades. Numerous risk factors for the development of gout have been established, including hyperuricaemia, genetic factors, dietary factors, alcohol consumption, metabolic syndrome, hypertension, obesity, diuretic use and chronic renal disease. Osteoarthritis predisposes to local crystal deposition. Gout appears to be an independent risk factor for all-cause mortality and cardiovascular mortality and morbidity, additional to the risk conferred by its association with traditional cardiovascular risk factors.     

Macroangiopathy in adults and children with diabetes: from molecular mechanisms to vascular damage (part 1).

Type 2 diabetes mellitus (T2DM) is an increasing problem in childhood; however type 1 diabetes mellitus (T1DM) remains by far the most common type of diabetes in this age group. In this review we will focus on T1DM, because this will have the greatest implication for patients diagnosed in childhood. During the atherosclerotic process, several molecular, receptorial and cellular factors provide a continous mechanism of vascular damage. In diabetic children this state seems to be enhanced and facilitated so that accelerated atherosclerosis is associated with an increased risk of cardiovascular events in respect to the non diabetic population. Hyperglycemia PER SE and associated with diabetes is an important risk factor for atherosclerosis. At present a substantial part of children with diabetes do not reach satisfactory glycemic control. Other risk factors for the development and progression of atherosclerosis may be inherited or develop in the course of the disease: hypertension, dyslipidemia, insulin resistance, obesity, cigarette smoking, physical inactivity, disturbance of platelet function, coagulation and fibrinolysis. The development and progression of atherosclerosis should be blocked at an early age, if possible. Primary prevention to all risk factors for cardiovascular disease is important and intervention is indicated if necessary. At the moment the best therapeutic strategy is to maintain metabolic control at a physiologic level and perform screening and early intervention for vascular complications.     

Sleep apnea: epidemiology, pathophysiology, and relation to cardiovascular risk

Several studies have shown the occurrence of an independent association between obstructive sleep apnea syndrome (OSAS) and cardiovascular disease, including arterial hypertension, ischemic heart disease, and stroke. The pathogenesis of the cardiovascular complications of OSAS is still poorly understood, however. Several mechanisms are likely to be involved, including sympathetic overactivity, selective activation of inflammatory molecular pathways, endothelial dysfunction, abnormality in the process of coagulation, and metabolic dysregulation. The latter may involve insulin resistance and disorders of lipid metabolism. The aim of this review, which reports the data presented at a workshop jointly endorsed by the European Society of Hypertension and by the European Union COST action on OSAS (COST B26), is to critically summarize the evidence available to support an independent association between OSAS and cardiovascular disease.     

高血压患者胰岛素抵抗与代谢综合征及心血管事件的发生情况的相关性分析

目的:分析高血压患者胰岛素抵抗与代谢综合征及心血管事件的发生情况及其影响因素。方法:选择2014年6月至2017年9月解放军113医院及河南大学附属医院收治的382例高血压患者,根据是否存在胰岛素抵抗将其分为单纯高血压(对照组,n=212)和高血压伴胰岛素抵抗(实验组,n=170)。根据国际糖尿病联盟代谢综合征的相关定义将患者分为A组(代谢综合征,n=202)和B组(非代谢综合征,n=180)。比较患者的身高、体质量并计算其体质量指数(BMI)、收缩压(SBP)、舒张压(DBP),检测两组受试者空腹血糖(FPG)、三酰甘油(TG)、总胆固醇(TC)、肌酐(SCr)、血尿素氮(BUN)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)、采用酶联免疫法测定高敏C反应蛋白(hs-CRP)、脂联素(APN)、空腹胰岛素(FINS)水平。随访1年并记录患者心血管事件发生情况。结果:实验组血清APN、FPG、FINS、HOMA-IR、hs-CRP水平与对照组比较,差异具有统计学意义(P0.05)。A组患者SBP、DBP、BUN、APN、FPG、HOMA-IR、hs-CRP水平明显高于B组,HDL-C水平明显低于B组,差异具有统计学意义(P0.05)。BUN、HDL-C、HOMA-IR、hs-CRP水平升高为高血压患者发生代谢综合征独立危险因素(P0.05)。随访1年后,对照组患者发生心血管事件72例,实验组144例。进一步采用多因素Logistic回归分析显示,血清TG、HDL-C、HOMA-IR、hs-CRP水平升高为高血压患者发生心血管事件的危险因素(P0.05)。结论:高血压伴胰岛素抵抗患者其胰岛素抵抗程度高于单纯高血压患者;胰岛素抵抗与代谢综合征显著相关,为高血压患者发生心血管事件的危险因素。