Insulin resistance: the link between obesity and cardiovascular disease

Insulin-mediated glucose disposal varies at least sixfold in apparently healthy individuals. The adverse effect of decreases in the level of physical fitness on insulin sensitivity is comparable to the untoward impact of excess adiposity, with each accounting for approximately 25% of the variability of insulin action. It is the loss of insulin sensitivity that explains why obese individuals are more likely to develop cardiovascular disease, but not all overweight/obese individuals are insulin resistant. At a clinical level, it is important to identify those overweight individuals who are also insulin resistant and to initiate the most intensive therapeutic effort in this subgroup. Finally, it appears that the adverse impact of overall obesity, as estimated by body mass index, is comparable to that of abdominal obesity, as quantified by waist circumference.     

Adipokines: A link between obesity and cardiovascular disease

Obesity is a risk factor for various cardiovascular diseases including hypertension, atherosclerosis, and myocardial infarction. Recent studies aimed at understanding the microenvironment of adipose tissue and its impact on systemic metabolism have shed light on the pathogenesis of obesity-linked cardiovascular diseases. Adipose tissue functions as an endocrine organ by secreting multiple immune-modulatory proteins known as adipokines. Obesity leads to increased expression of pro-inflammatory adipokines and diminished expression of anti-inflammatory adipokines, resulting in the development of a chronic, low-grade inflammatory state. This adipokine imbalance is thought to be a key event in promoting both systemic metabolic dysfunction and cardiovascular disease. This review will focus on the adipose tissue microenvironment and the role of adipokines in modulating systemic inflammatory responses that contribute to cardiovascular disease.     

M2 and M3-muscarinic acetylcholine receptors remodelling in patients with a dilated atrium

BACKGROUND: Studies have shown that autonomic tone plays an important role in the pathogenesis of atrial fibrillation (AF) and remodelling of I(K, ACh) in chronic AF serves as a compensatory mechanism for the AF. The relation between atrial size and AF has been established. We investigated the remodelling of muscarinic receptors in patients with dilated atrium and assessed the relationship between the muscarinic receptor remodelling and the dilated atrium. METHODS: A small piece of the tip of the right atrial appendage was obtained from 19 patients in sinus rhythm (SR), 28 patients with mitral stenosis and 10 patients with chronic AF (AF > 6 months). Western-blot was used to determine the expression of M2 and M3 receptors. RESULTS: Patients with mitral stenosis and chronic AF had a larger left atrial diameter than patients in SR. The densities of the M2 receptor in patients with mitral stenosis (with AF and with SR) and chronic AF were lower than that in patients with SR (0.54 +/- 0.08 vs. 0.29 +/- 0.06, 0.26 +/- 0.05 and 0.28 +/- 0.06, P < 0.05). However, the densities of the M3 receptor in patients with mitral stenosis and chronic AF were higher than that in patients with SR (0.07 +/- 0.01 vs. 0.18 +/- 0.02, 0.17 +/- 0.01 and 0.15 +/- 0.01, P< 0.05). Furthermore, there was no significant difference in M2 and M3 receptors between AF and SR in patients with mitral stenosis. CONCLUSION: Remodelling of M2 and M3 receptors is not associated with AF, but with the dilated left atrium.     

Insulin resistance--a common link between type 2 diabetes and cardiovascular disease

Evidence suggests that diabetes and cardiovascular disease (CVD) may share an underlying cause(s), a theory known as the 'common soil' hypothesis. Insulin resistance is central both to the progression from normal glucose tolerance to type 2 diabetes and to a constellation of cardiovascular risk factors known as the metabolic syndrome. These risk factors include visceral obesity and dyslipidaemia characterized by low levels of high-density lipoprotein cholesterol, hypertriglyceridaemia and raised small dense low-density lipoprotein particle levels. Changes in adipose tissue mass and metabolism may link insulin resistance and visceral obesity, a condition that is common in type 2 diabetes. Furthermore, weight reduction, increased physical activity, metformin and acarbose have been shown to reduce the development of type 2 diabetes in genetically predisposed subjects and may decrease the high cardiovascular risk of patients with diabetes. Some fatty acid derivatives can affect energy metabolism by activating peroxisome proliferator-activated receptors (PPARs), nuclear receptors that play a key role in energy homeostasis. These receptors represent an ideal therapeutic target for reducing cardiovascular risk, because they are involved in the regulation of both insulin action and lipid metabolism. In addition to lifestyle changes, PPARgamma agonists such as thiazolidinediones are frequently beneficial and have been shown to ameliorate insulin resistance, while activation of PPARalpha (e.g. by fibrates) can lead to improvements in free fatty acid oxidation and lipid profile, and a reduction in cardiovascular events. The development of agents with both PPARalpha and PPARgamma activity promises added benefits with amelioration of insulin resistance, delayed progression to and of type 2 diabetes and a reduction of CVD.     

Effect of estrogen on intracellular signaling pathways linked to activation of M(2)- and M(3)-muscarinic acetylcholine receptors in the rat myometrium

The estrogen treatment of adult female rats induces an increase in myometrium sensitivity to cholinergic agonists and in this tissue the presence of M₂- and M₃-muscarinic acetylcholine (mACh) receptor was shown. We now report the effect of estrogen on intracellular signaling pathways linked to activation of M₂- and M₃-mACh receptor subtypes. The intracellular cyclic AMP accumulation and [³H]-inositol phosphates content were measured in myometrium strips from rats in estrus (control) and estradiol-treated rats (12.5 μg/100 g body weight, sc, 24 h before experiments) (the plasma estradiol level was 30.9±3.5 pg/ml and 119.3±14.1 pg/ml from control and estrogen-treated rats, respectively). Estrogen treatment increased 2.5-fold the intracellular cyclic AMP accumulation induced by 10 μM forskolin. The effects of muscarinic agonist and antagonists on cyclic AMP accumulation were tested. Carbachol reduced the forskolin-induced intracellular cyclic AMP content, 3.0 and 10.5-fold, in myometrium from control and estradiol-treated rats, respectively. This inhibitory effect failed to occur when carbachol was incubated in the presence of methoctramine. Carbachol also induced increase on total [³H]-inositol phosphates accumulation in myometrium from estradiol-treated rats when compared with control rats. This effect was reversed by pfHHSiD. These studies suggest the modulation by estrogen of intracellular signaling pathways linked to activation of M₂- and M₃-mACh receptors in the rat myometrium.     

Autoantibodies against M2-muscarinic acetylcholine receptors: new upstream targets in atrial fibrillation in patients with dilated cardiomyopathy.

AIM: To characterise the clinical significance of M2-muscarinic acetylcholine receptor autoantibodies (M2-AAB) in patients with dilated cardiomyopathy (DCM). METHODS AND RESULTS: Sera from 104 patients with DCM, age-matched with 104 patients with idiopathic atrial fibrillation (Af) and 104 healthy control subjects, were screened for M2-AAB by enzyme-linked immunosorbent assay (ELISA). IgG purified by Protein-A column was also used as a primary antibody in ELISA. In DCM, M2-AAB were detected in 40% of patients using whole sera and in 36% of patients using purified IgG. M2-AAB were also found in several patients with idiopathic Af (23%, 23%), and these frequencies were significantly higher than those in healthy subjects (8%, 8%). Af was more common in AAB-positive than in AAB-negative patients with DCM. Multivariable analysis confirmed that M2-AAB were independent predictors of the presence of Af in such patients. We determined electrophysiological changes by adding patient purified M2-AAB to chick embryos. Purified IgG from both Af and DCM patients exhibited negative chronotropic effects and induced supraventricular arrhythmias. CONCLUSION: M2-AAB may play a role in mediating the development of Af in patients with DCM.     

血清淀粉样蛋白A--联系肥胖及其代谢合并症的促炎性脂肪细胞因子

肥胖常伴胰岛素抵抗(IR)、2型糖尿病(T2DM)、高血压、内皮功能紊乱、血脂异常和高凝状态,这些与心血管疾病(CVD)相关的代谢危险因素在一个个体内集结的情况称为代谢综合征(MS)。迄今为止,MS的具体发病机制仍不明确,但中心性肥胖和IR是被公认的重要的致病因素。长期以来,脂肪组织一直被视作惰性的能量储存器官。近十几年来研究发现,脂肪组织还是一活跃的内分泌器官,具有多种内分泌、自分泌和旁分泌功能,通过分泌瘦素、脂源性肿瘤坏死因子-α(TNF-α)、脂联素、抵抗素、白细胞介素(IL)-6和内脏脂肪素(visfatin)等脂肪细胞因子,与中枢…     

Chemerin: a potential endocrine link between obesity and type 2 diabetes

Obesity and type 2 diabetes have reached epidemic levels and account for a substantial portion of the annual health expenditures of developed nations. While there is an abundance of epidemiological evidence demonstrating that obesity is a primary risk factor for developing type 2 diabetes, the mechanism(s) underlying this linkage are not completely understood. Given the enormous impact of these disorders on global health, considerable research effort has been devoted to elucidate the pathophysiological relationship between these two disorders. Two factors believed to contribute to the causal link between obesity and type 2 diabetes are chronic inflammation and altered secretion of adipose-derived signaling molecules (adipokines). Independent lines of investigation have implicated the novel adipokine chemerin as a regulator of adipogenesis, inflammation, and glucose metabolism through interactions with the cognate cell surface receptor chemokine-like receptor 1. Increased levels of chemerin that occur with obesity are hypothesized to be a causal factor in the development of type 2 diabetes as a consequence of dysregulation of the key physiological processes regulated by this adipokine. This review summarizes current research on the biological roles of chemerin and chemokine-like receptor 1, and highlights key questions to guide future research on the role of this adipokine in mediating obesity and the development of type 2 diabetes.     

Overexpressed A(1) adenosine receptors reduce activation of acetylcholine-sensitive K(+) current by native muscarinic M(2) receptors in rat atrial myocytes

In adult rat atrial myocytes, muscarinic acetylcholine (ACh)-sensitive K(+) current activated by a saturating concentration of adenosine (I(K(ACh),(Ado))) via A(1) receptors (A(1)Rs) amounts to only 30% of the current activated by a saturating concentration of ACh (I(K(ACh),(ACh))) via muscarinic M(2) receptors. The half-time of activation of I(K(ACh),(Ado)) on a rapid exposure to agonist was approximately 4-fold longer than that of I(K(ACh),(ACh)). Furthermore, I(K(ACh),(Ado)) never showed fast desensitization. To study the importance of receptor density for A(1)R-I(K(ACh),(Ado)) signaling, adult atrial myocytes in vitro were transfected with cDNA encoding for rat brain A(1)R and enhanced green fluorescent protein (EGFP) as a reporter. Whole-cell current was measured on days 3 and 4 after transfection. Time-matched cells transfected with only the EGFP vector served as controls. In approximately 30% of EGFP-positive cells (group I), the density of I(K(ACh),(Ado)) was increased by 72%, and its half-time of activation was reduced. Density and kinetic properties of I(K(ACh),(ACh)) were not affected in this fraction. In approximately 70% of transfection-positive myocytes (group II), the density of I(K(ACh),(ACh)) was significantly reduced, its activation was slowed, and the fast desensitizing component was lost. Adenosine-induced currents were larger in group II than in group I, their activation rate was further increased, and a fast desensitizing component developed. These data indicate that in native myocytes the amplitude and activation kinetics of I(K(ACh),(Ado)) are limited by the expression of A(1)R. Overexpression of A(1)R negatively interferes with signal transduction via the muscarinic M(2) receptor-linked pathway, which might reflect a competition of receptors with a common pool of G proteins. Negative interference of an overexpressed receptor with physiological regulation of a target protein by a different receptor should be considered in attempts to use receptor overexpression for gene therapy.     

Tissue-specific patterns of Gap junctions in adult rat atrial and ventricular cardiomyocytes in vivo and in vitro

To verify the hypothesis that tissue-specific patterns of gap junctions (GJs) are determined by intrinsic factors within myocytes forming different cardiac tissues, we have compared by quantitative transmission electron microscopy (TEM) the structural features of GJs in adult rat atrial myocytes (AMs) and ventricular myocytes (VMs) in vivo with those in developing GJs in cultured AMs and VMs in vitro. Quantitative TEM data revealed a 3-fold increase in the number of developing GJs per intercalated disk in both AMs and VMs from 6 to 15 days in culture. However, at days 12 and 15, the percentage of GJ length per intercalated disk and mean GJ length were 2-fold higher in VMs than in AMS: Measurements of connexin43 GJs by confocal microscopy confirmed TEM data and demonstrated respectively 2- and 4.5-fold greater mean values of GJ length and area in VMs than in AMS: These differences are attributable to the development of large GJs (>3 micrometer) in VMs, closely resembling those observed in VMs in vivo. Although large GJs in cultured VMs comprised approximately 14% of the total number of GJs, their contribution to total GJ length and area constituted >60% and 85%, respectively. In marked contrast, the number of large GJs in AMs both in vitro and in vivo was <1% from the total number of GJS: These data confirm our hypothesis and provide the first evidence that tissue-specific patterns of GJs in AMs and VMs are determined primarily by intrinsic factors within cardiac myocytes and are developmentally regulated.     

Inflammation as a link between obesity,metabolic syndrome and type 2 diabetes

It is recognized that a chronic low-grade inflammation and an activation of the immune system are involved in the pathogenesis of obesity-related insulin resistance and type 2 diabetes. Systemic inflammatory markers are risk factors for the development of type 2 diabetes and its macrovascular complications. Adipose tissue, liver, muscle and pancreas are themselves sites of inflammation in presence of obesity. An infiltration of macrophages and other immune cells is observed in these tissues associated with a cell population shift from an anti-inflammatory to a pro-inflammatory profile. These cells are crucial for the production of pro-inflammatory cytokines, which act in an autocrine and paracrine manner to interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency. Particularly, the pro-inflammatory interleukin-1β is implicated in the pathogenesis of type 2 diabetes through the activation of the NLRP3 inflammasome. The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship. If type 2 diabetes is an inflammatory disease, anti-inflammatory therapies could have a place in prevention and treatment of type 2 diabetes.     

Transfection with 5-HT1A receptor gene and antisense directed against muscarinic M2 receptors reveal a mutual influence between Gi/o-coupled receptors in rat atrial myocytes

A recently described reduction in sensitivity of G protein-activated inward-rectifying K(+) (GIRK) channels to stimulation of muscarinic M(2) receptors (M(2)AChR) in atrial myocytes overexpressing purinergic A(1) receptors (A(1)AdoR) was further investigated by heterologous expression of a 5-HT(1A) receptor (5-HT(1A)R) and by reducing the expression level of endogenous M(2)AChR receptors using antisense. In 5-HT(1A)R-expressing myocytes, in line with previous studies, sizable GIRK currents could be activated by 5-HT. In these cells, the mean current density and activation rate of M(2)AChR-activated current were significantly reduced, supporting the notion that signalling via this receptor is negatively regulated by other G protein-coupled receptors (GPCR) coupling to the same class (G(i/o)) of G proteins. To study if reducing M(2)AChR expression affects sensitivity of GIRK current to stimulation of A(1)AdoR, antisense oligodinucleotides (AsODN) against the M(2)AChR were used. Incubation of myocytes with M(2)AChR-specific AsODN resulted in a significant reduction in mean amplitude and activation rate of ACh-induced currents. This was paralleled by an increase in mean amplitude and activation rate of current activated by stimulation of A(1)AdoR. Plotting amplitudes of 5-HT- or Ado-induced currents from individual manipulated cells against the amplitude of ACh-induced current yielded a positive correlation between these data. Although difficult to interpret in mechanistic terms, this argues against a competition of receptors for a common pool of G(i/o). The mutual interaction between G(i/o)-coupled receptors depends on manipulation of the expression level, since long-term desensitization or down regulation of M(2)AChR by treatment with carbachol did not affect sensitivity of GIRK current to A(1)AdoR stimulation, despite a substantial reduction in amplitude and activation rate of M(2)AChR-activated currents. These data suggest a novel crosstalk between parallel receptors converging on the same class of G proteins.     

右心耳M2和M3受体重构与左心房扩张和心房颤动关系的比较研究

目的探讨M受体重构与左房扩张和心房颤动的关系。方法取57例开胸手术患者的右心耳组织（19例窦性心律、28例风湿性二尖瓣狭窄、10例慢性房颤），Western—blot技术检测M2和M3受体的表达。结果风湿性二尖瓣狭窄和慢性房颤患者明显比窦性心律患者的左心房大（P〈0．05）；M2受体在风湿性二尖瓣狭窄引起的左心房扩张和慢性房颤患者心耳的表达明显低于窦性心律患者（0．54±0．08和0．29±0．06，0．26±0．05和0．28±0．06，P〈0．05），而M3受体在风湿性二尖瓣狭窄引起的左心房扩张和慢性房颤患者心耳的表达明显高于窦性心律患者（0．07±0．01和0．18±0．02，0．17±0．01和0．15±0．01，P〈0．05）。在风湿性二尖瓣狭窄患者中，M2和M3受体在窦性心律和房颤患者之间没有明显差别。结论M2和M3受体重构与左心房扩张有关，而与房颤无关。     

Aliskiren prevents cardiovascular complications and pancreatic injury in a mouse model of obesity and type 2 diabetes

Aims/hypothesis  

The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes.     

Impaired atrial M(2)-cholinoceptor function in obesity-related hypertension

The aim of this study was to investigate the activity of the parasympathetic limb of the baroreflex arch in a canine model of obesity-related hypertension. Twelve male beagle dogs were randomized into 2 groups. Six dogs were fed with normal canine food and 6 were submitted to a 10-week high-fat diet (HFD). We have evaluated the consequences of HFD on heart rate (HR) and blood pressure (BP) circadian cycles and methylscopolamine dose-response curves. Binding of [(3)H]-AF-DX 384 and adenylyl cyclase activity were investigated to determine the density and functionality of M(2)-cholinoceptors on right atrial membranes from control and HFD dogs. HFD induced a significant increase in body weight (15+/-1 vs 12+/-1 kg), systolic BP (161+/-5 vs 145+/-4 mm Hg), diastolic BP (92+/-3 vs 79+/-2 mm Hg), and HR (96+/-4 vs 81+/-3 bpm). Circadian rhythms of HR and BP observed in the baseline period were abolished after 9 weeks of HFD. After propranolol (1 mg/kg) pretreatment, the dose of methylscopolamine able to induce 50% maximum tachycardia was significantly increased after 9 weeks of HFD (7.4+/-0.3 vs 4.7+/-0.1 microg/kg). In the control group, the experimental period failed to modify these parameters. The numbers of M(2)-cholinoceptors measured in right atrial membranes were significantly lower in HFD than in control groups (54+/-6 vs 27+/-6 fmol/mg protein). The ability of carbachol to inhibit isoproterenol-stimulated adenylyl cyclase activity was significantly lower in HFD than in control groups (IC(50)=47+/-12 vs 6.4+/-1.4 micromol/L). However, the basal activity of adenylyl cyclase was unchanged by HFD. HFD decreases M(2)-cholinoceptor number and function in cardiomyocytes. This could explain the abolition of circadian rhythm of HR and the changes in chronotropic effect brought about by methylscopolamine.     

The renin-angiotensin system: a link between obesity, inflammation and insulin resistance

The renin-angiotensin system (RAS) is classically known for its role in regulation of blood pressure, fluid and electrolyte balance. Recently, several local RASs in organs such as brain, heart, pancreas and adipose tissue have also been identified. Evidence from clinical trials suggests that in addition to anti-hypertensive effects, pharmacological inhibition of RAS also provides protection against the development of type-2 diabetes. Moreover, animal models with targeted inactivation of RAS genes exhibit improved insulin sensitivity and are protected from high-fat diet-induced obesity and insulin resistance. Because there is evidence for RAS overactivation in obesity, it is possible that RAS is a link between obesity and insulin resistance. This review summarizes the evidence and mechanistic insights on the associations between RAS, obesity and insulin resistance, with special emphasis on the role of adipose tissue RAS in the pathogenesis of metabolic derangements in obesity.