Untitled Document
Diabetes mellitus (DM) and its complications pose a serious threat to human health and have become a global public health issue. Over 90% of patients with diabetes have type 2 DM (T2DM). Diabetic complications can be classified according to the involvement of cardiopathy and encephalopathy, nephropathy, retinopathy, and peripheral vasculopathy. DM increases the risk of all these complications, and multiple vasculopathy is associated with a poorer prognosis. Recent intensive investigations into diabetic complications have significantly promoted the understanding of the pathogenesis of this disease. However, the increasing division of medical science into various subspecialties, has resulted in a tendency to focus on localized lesions instead of integrating overall evidence. Thus, a holistic investigation of diabetic complications involving multiple systems and different angiopathies is needed.
The pathology of diabetic complications has a high degree of commonality at the vascular level; that is, complications manifest mostly as endothelial dysfunction and atherosclerosis (AS). DM being a risk factor for vascular disease, the several vascular comorbidities seriously affect the prognosis and treatment of patients, leading to the concept of “panvascular disease”. Since the late 20th century, the concept of a “vessel tree” has been proposed and “polyvascular atherosclerotic disease” has been defined considering coronary and non-coronary AS, mainly peripheral arterial and cerebrovascular diseases (peripheral vascular disease and cerebrovascular disease respectively). This definition indicates that comprehensive management of the multivessel disease is clinically essential for improving outcomes and prognoses. However, this definition does not consider either microvascular disease (especially in vital organs) or multidisciplinary fusion. To improve this definition, we propose the concept of diabetic panvascular disease (DPD). This is a clinical syndrome in which AS is a common pathology between macrovessels and microvessels in the cardiac, cerebral, renal, ophthalmic, and peripheral systems in patients with diabetes. The main outcomes would be cardiovascular and cerebrovascular events, and the prognosis could be improved through aggressive intervention against metabolic abnormalities.
Diabetic complications are usually classified in two dimensions: macro/microvascular disease, or complications classified by target organs. DPDs synthesize these concepts. This article systematically reviews general pathological manifestations of vascular lesions and differences in the etiology of macro/microvascular lesions; pathological manifestations and molecular mechanisms of different target organs in DPDs; common molecular mechanisms and therapeutic targets in DPDs; time course characteristics of pathological changes in organs and mutual predictive effects among DPDs to provide clues for early diagnosis. Our findings should promote the establishment of a multidisciplinary DPD management system.
Diabetes and panvasculopathy
The vasculature comprises endothelial cells (EC), smooth muscle cells (SMC), pericytes, fibroblasts, and various other types of cells. AS, endothelial barrier damage, loss of pericytes, capillary thinning, and angiogenic disorders are common pathologies of systemic vascular disease. Blood vessels, together with nerves and lymphatic vessels, are wrapped in connective tissue membranes to form vascular nerve bundles. Differences in perivascular tissues, vascular nerve bundles, and intravascular structures result in altered vascular function. When imbalanced homeostasis is characterized by abnormal glucose and lipid metabolism, activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) directly or indirectly causes widespread vascular damage throughout the body, leading to the development of panvascular complications of DM. SNS dominates vasoconstriction and RAAS regulates of blood volume, vascular tone, and blood pressure. The vascular system in target organs is tightly regulated by surrounding tissues that regulate microvascular units through physical and signal transduction. As DM progresses, patients are more likely to develop various vascular complications and experience many pathological changes, such as endothelial dysfunction, AS, and microcirculatory disorders that interact with each other, consequently leading to the development of DPD.
Diabetic vasculopathy is classified as macroangiopathy and microangiopathy. Macroangiopathy includes AS of large and medium arteries (aorta, coronary, renal, basilar, and peripheral arteries), whereas microangiopathy includes endothelial damage to vessels between primary arterioles and venules, vascular basement membrane thickening, microthrombosis, platelet and red blood cell adhesion aggregation, and microcirculatory disorders. Due to differences in hemodynamics, vascular structure, and the affected cells, macro/microangiopathy present with different pathological manifestations. AS often occurs in sites of hemodynamic disturbances (preferably in elastic arteries). It manifests as macrophage foaming and EC lesions as well as mesangial SMC lesions. Microvessels are more hemodynamically stable, with a few cell layers, accompanying abundant plexus. On the other hand, differences in energy metabolic status, and organ-specific growth factors or cytokines in different target organs are also important components of the differences. Most target organs (heart, brain, peripheral vasculature) are affected by both diabetic macrovasculopathy and microvasculopathy; the retina and kidney are mainly affected by microvasculopathy.
Diabetic peripheral vasculopathy (DPVD)
DPVD is often overlooked, yet it is one of the most important and common vascular complications in patients with T2DM. In such patients, DPVD increases the risk of not only coronary atherosclerotic events, but also major adverse limb events such as amputation. DPVD can manifest as diabetic foot syndrome and peripheral arterial disease (PAD), which seriously affect the quality of life of patients with diabetes. Peripheral arterial disease is traditionally considered to be dominated by large artery AS. In fact, PAD is often accompanied by local and systemic microangiopathy. Multivessel endothelial dysfunction can manifest as microangiopathy (either exclusively or with other diseases), such as capillary basement membrane thickening, endothelial hyperplasia, oxygen tension reduction, and hypoxia, affecting peripheral nerve function. Pre-DM can affect blood vessels and accompanying nerves. The chronic course of DM might have further adverse effects under poor glycemic control. An increase in postprandial glucose plays an important role in the development of peripheral vascular disease in DM.
The pathogenesis of DPVD overlaps with that of other AS and microvascular endothelial injuries. IL-6, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and high-molecular-weight lipocalin biomarkers serve as indicators of the risk of cardiovascular disease and peripheral vascular disease. Specific markers for DPVD are unknown, but many biomarkers of vascular injury are available. For example, circulating levels of ICAM and sE-selectin indicate EC activation and vascular inflammation, and thus have potential as diagnostic markers of DPVD.
The molecular mechanisms of AS in DPVD can be found in the section on coronary AS. Microvasculopathy in DPVD is highly concomitant with neuropathy, as microvessels form a neurovascular network with accompanying nerves. Neurons and Schwann cells are highly susceptible to hyperglycemia. Energy and inflammation, oxidative stress, insulin resistance, AGEs, nerve growth factors, activation of the polyol pathway, and activation of the hexosamine and PKC pathways are core pathological factors and processes similar to those of other DM vascular complications. Glucose and fatty acid metabolism, neural metabolism, and exosome regulation have recently attracted attention. Much more is known about peripheral neuropathy than about DPVD. Glucose overload and high fatty acid metabolism lead to decreased ATP production, excessive ROS formation, and impaired mitochondrial function, which further increases oxidative stress, leading to the formation of AGEs from the glycosylation of various proteins. The vicious cycle of these events further promotes ROS formation and ER stress, resulting in DNA damage and apoptosis of various cells. Abnormal neurometabolism in DM manifests as changes in sphingolipid metabolism, wherein sphingolipids are biologically active and important structural components of plasma cell membranes and are important signaling molecules. Abnormal sphingolipid metabolism causes neurotoxicity in patients with hyperglycemia. All of these pathways eventually manifest as increased pro-inflammatory factors that further induce AGEs production, leading to oxidative stress and endothelial dysfunction. These interactive processes simultaneously place EC and neurons in a state of oxidative stress and inflammation.
The endpoint of DPVD is amputation, the occurrence of which is closely associated with infection and trauma. Therefore, care and lifestyle changes play an important role in its treatment, which greatly differs from the preventive measures for other vascular pathologies. Normal or near-normal glycemic control is a primary therapeutic goal. Intensified hypoglycemic therapy reduces the incidence of peripheral neuropathy in patients with T1DM but has a little additional benefit for those with T2DM. Systemic antioxidant and anti-inflammatory therapy might also provide some benefits. New glucose-lowering drugs can reduce blood glucose without increasing the risk of amputation. In a subgroup of patients with T2DM combined with PAD, empagliflozin reduced rates of mortality, hospitalization for HF, and the progression of kidney disease. Patients treated with the new glucose-lowering drugs SGLT-2i, GLP-1RA, and DPP-4i have low risks of amputation with a good safety profile. Some glucose-lowering agents have conferred advantages for patients with DPVD and other multivessel diseases. The results of the LEADER trial suggested that liraglutide could be used in diabetic multivessel diseases. These treatment options could improve the overall quality of life of patients.