Type 2 diabetes mellitus (T2DM), heart failure(HF), and diabetic kidney disease (DKD) are major pandemics of the twenty first century. T2DM affects more than 400 million persons worldwide. These three conditions often coexist,and each worsens the prognosis of the other two, setting up a series of vicious circles.(Fig. 1) For example, T2DM is a powerful risk factor for the development of HF(Fig.1a);it is associated with a 2 to 4 times greater risk of the development of cardiovascular disease (CVD), which is responsible for about two-thirds of all deaths in patients with T2DM.

The combination of T2DM and left ventricular dysfunction is particularly dangerous, with high incidence of chronic disability and mortality.In addition to the increase in HF attributed to T2DM, there is also evidence for the reverse, i.e. it is a "two-way street."1(Fig. 1b) Thus, HF can play a causal role in the development of T2DM, with advanced HF being associated with the development of marked insulin resistance. Conversely, treatment of advanced HF with implantation of a left ventricular assist device has been shown to result in improved diabetic control.

By definition, diabetes is the cause of DKD(Fig.1c). There is "crosstalk" between the failing heart and the failing kidney. The combination of a lower cardiac output and an elevated renal venous pressure reduces renal blood flow. The upregulation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) in HF causes constriction of afferent glomerular arterioles,reducing glomerular filtration.The failing kidney in DKD may contribute to secondary hypertension and to anemia, thereby placing extra burdens on the failing heart. This bidirectional interaction between the heart and kidneys sets up an important vicious circle.(Fig.1c and d).Both HF(Fig.1f)and DKD (Fig.1g)result in sodium retention which can be responsible for pulmonary congestion, dyspnea, and edema.

Disease mechanisms

The vicious circle between HF and T2DM is shown in Fig. 2, modified from Maack et al. Central to the development of T2DM is insulin resistance (Fig. 2a),which is responsible for insulin hypersecretion(Fig. 2b).With progression, insulin secretion by the pancreas,while greater than normal, is insufficient to prevent hyperglycemia, signifying the presence of T2DM(Fig.2c). Fig. 3 shows the relations between HbA1c and arterial pressure with adverse outcomes in patients with T2DM.These include vascular complications,which can be divided into two major categories:The macrovascular complications include epicardial coronary artery disease, cerebrovascular disease, aortic and peripheral arterial disease (Fig. 2d); the microvascular complications include DKD, neuropathy, retinopathy, and small vessel coronary disease. Many patients, especially those with longstanding T2DM, may have multiple vascular complications. Patients with microvascular complications are at increased risk of developing macrovascular complications,as well.

Increased insulin resistance of cardiomyocytes reduces their glucose utilization and contributes to hyperglycemia. It also increases the uptake and metabolism of free fatty acids, which impairs the efficiency of cardiac contraction. When excessive, this uptake can lead to triglyceride storage in cardiomyocytes, causing lipotoxicity, a contributor to impairment of cardiac contractility.

Figure 1 The vicious circle:an overview.Type 2 diabetes mellitus (T2DM), heart failure (HF), and diabetic kidney disease (DKD). T2DM is a major risk factor forHF(a)and for DKD(c).HF can cause or intensify the severity of T2DM(b).Both T2DM(c)and HF(d)can cause DKD.DKD can intensify HF(e). Both HF(f) and DKD(g) can cause sodium retention(Na+ret),pulmonary congestion,dyspnea and edema.

Figure 2 The vicious circle between T2DM and Heart Failure.AGEs,advanced glycation end products;HFrEF,heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; RAAS, reninangiotensin-aldosterone system;LV,left ventricle.

An important mechanism by which hyperglycemia is responsible for adverse clinical outcomes in T2DM is through the production of advanced glycation end products(AGE) (Fig. 2e), which act upon and activate a specific receptor, RAGE. This causes an accumulation of reactive O2 species (ROS) which, in turn, trigger inflammation (Fig. 2f) in both the myocardium and the microcirculation. Oxidative stress and myocardial inflammation can lead to myocyte apoptosis as well as mitochondrial dysfunction; the latter can reduce myocardial production of ATP, which may reduce the uptake of Ca2+by the sarcoplasmic reticulum of cardiomyocytes and thereby interfere with contraction.AGEs can also lead to cardiac fibrosis, which causes myocardial stiffness and HF with preserved ejection fraction(HFpEF)(Fig.2g).AGEs may also be responsible for endothelial dysfunction and microangiopathy.

The development of HF causes activation of two systems:1)the RAAS(Fig.2h),which causes retention of Na+and H2O; and 2) the sympathetic nervous system(Fig. 2i), causing lipolysis (Fig. 2j), which when combined with a typical Western diet and obesity(Fig.2k), can lead to insulin resistance (Fig. 2a), thereby completing the"vicious circle."

Heart failure

T2DM increases the risk of hospitalization or death secondary to HF both with reduced and with preserved ejection fraction. Hypertension (Fig.3a) and dyslipidemias (Fig. 3b) occur earlier, more frequently,and more severely in patients with T2DM, and play an important role in accelerating atherosclerosis (Fig. 3c),which is characterized by earlier and more extensive development of coronary artery plaques. Moreno et al.compared coronary atherectomy specimens obtained from patients with and without T2DM. The former showed greater contents of lipid,with larger infiltrates of macrophages. Such plaques are at high risk of rupture and have been referred to as"vulnerable"plaques.

T2DM can also produce a prothrombotic state(Fig.3e), with hyperactive platelets, and increases in coagulation factors including thrombin, and impaired fibrinolysis. The combination of vulnerable plaques and the prothrombotic state enhance the risk of development of coronary thrombosis, acute myocardial infarction(Fig.3d and f)and HF with reduced ejection fraction(HFrEF).Other important outcomes of accelerated atherosclerosis include chronic coronary artery disease, peripheral vascular disease,cerebrovascular disease,and stroke.

Figure 3 Mechanism of heart failure development in T2DM,which is frequently associated with hypertension(HT,a)and dyslipidemia (DL,b). These and other risk factors are responsible for accelerated atherosclerosis (AA,c),which in turn is responsible for coronary artery disease.The latter interacts with the prothrombotic state(PTS,e)of T2DM to cause myocardial infarction (MI, d and f),which is responsible for HF with reduced ejection fraction. T2DM can cause diabetic cardiomyopathy(DCM, h), in which microvascular coronary artery disease (MVD, i), contributes to the development of heart failure with preserved ejection fraction.

Diabetic cardiomyopathy(DCM)

T2DM is also responsible for molecular changes in myocardial structure and function that can cause DCM(Fig. 3h), a condition characterized by ventricular dysfunction in patients with T2DM in the absence of hypertension and coronary artery disease. Several mechanisms are believed to play important roles in the genesis of DCM. Seferovic and Paulus have described two phenotypes of HF resulting from DCM. The first,myocyte death, causes left ventricular systolic dysfunction and HFrEF. The second, caused by coronary microvascular disease (Fig. 3i), is a restrictive phenotype characterized by concentric left ventricular remodeling and diastolic dysfunction leading to HFpEF.More recently, depressed function of cardiomyocytes related to impaired mitochondrial Ca2+has been implicated. As pointed out above, the presence of HF intensifies the severity of T2DM(Fig.3j).

Diabetic kidney disease

In 1972, Rubler et al. described a "new type of cardiomyopathy associated with diabetic glomerulosclerosis." This condition, DKD, is a microvascular complication which frequently progresses to the need for dialysis or renal transplantation. Next to CVD, DKD is the most common cause of death in patients with T2DM. Mortality is increased about fourfold in patients with albuminuria and preserved glomerular function, about fivefold in patients with impaired glomerular function without albuminuria, but about ten-fold in patients with the combination of impaired glomerular filtration rate R and albuminuria.

T2DM and arterial hypertension play important roles in the development of DKD by causing glomerular hyperfiltration, glomerular hypertrophy, followed by expansion of the mesangium, and accumulation of extracellular matrix. The latter can lead to a loss of podocytes, disruption of the mesangium(mesangiolysis),and glomerular fibrosis. Thus, another vicious circle is created whereby the combination of T2DM and essential hypertension leads to DKD, which may cause secondary hypertension and further impairment of renal function.

As is the case with other microvascular complications of T2DM, early and effective glycemic control reduces the likelihood of developing DKD.Hyperuricemia,which in some instances is secondary to renal dysfunction, can "feed" into this circle. Uric acid is pro-inflammatory, induces oxidative stress, and activates the RAAS. Hyperuricemia is believed to increase the incidence and severity of DKD,which may,in part,be responsive to uric acid lowering.

词 汇

crosstalk n.串话干扰，交谈，巧妙的回答（或反驳），相声

afferent adj.传入的，向心的

signify v.表示，说明，预示，表达

lipotoxicity n.脂毒性

glycation n.糖化

species n.种，物种，基团，（物）核素

apoptosis n.程序性细胞死亡，细胞凋亡

sarcoplasmic adj. 肌质的，肌浆的

implicate n.&v. 包含的东西；牵涉，涉及（某人），表明（或意指）…是起因

glomerulosclerosis n.肾小球硬化症，小动脉性肾硬化

mesangium n.肾小球环毛细血管膜，肾小球膜

mesangiolysis n.肾小球膜基质溶解，肾小球膜细胞退化

atherectomy n.斑块切除术

注 释1.two-way street 有两种译义，一指“双行道路”，二指“互谅互让”。In most instances the route is a two-way street, as his condition improves or worsens.多数情况下随着他的病情改善或恶化而呈双向途径。Marriage is a two-way street.夫妻之道在于夫妻互谅互让。

参考译文

第100 课 糖尿病、心力衰竭和肾功能不全：恶性循环

2 型糖尿病（T2DM），心力衰竭（HF）和糖尿病性肾病（DKD）是21 世纪的主要流行疾病。全球有4 亿T2DM 患者。这三种疾病经常共存，每一种可以使另外两种进展恶化，形成一系列的恶性循环（图1）。例如，T2DM 是发生HF 的强力危险因素（图1a）；伴发心血管疾病（CVD）的风险2～4 倍，后者约占T2DM 所有死因的2/3。

T2DM 合并左心室功能不全特别危险，伴发的慢性失能和死亡率高。除HF 的增加归因于T2DM 外，也有依据表明可倒过来，即为“双向车道”（图1b）。因此，HF 在T2DM 的发生过程中起因果作用，重度HF 伴随着明显的胰岛素抵抗形成。相反，已表明通过植入左心室辅助装置治疗重度HF 后糖尿病控制得以改善。

基于定义，糖尿病是DKD 的病因（图1c）。衰竭心脏与衰竭肾脏之间存在交叉影响。低心排合并肾静脉压的增高导致肾血流减少。HF 时的交感神经和肾素-血管紧张素-醛固酮系统上调引起入球小动脉收缩，减少肾小球滤过。DKD时的衰竭肾脏导致继发性高血压和贫血，以致衰竭心脏增加额外负担。……