Diabetic Microvascular Disease: An Endocrine Society Scientific Statement

Eugene J. Barrett; Zhenqi Liu; Mogher Khamaisi; George L. King; Ronald Klein; Barbara E. K. Klein; Timothy M. Hughes; Suzanne Craft; Barry I. Freedman; Donald W. Bowden; Aaron I. Vinik; Carolina M. Casellini


J Clin Endocrinol Metab. 2017;102(12):4343-4410. 

In This Article

The Microvasculture in Skeletal and Cardiac Muscle, Adipose, and Skin


Diabetic microvascular disease is usually associated with eye, nerve, and renal injury. However, diabetes is a pervasive microvascular disease with functional consequences in tissues outside of those commonly associated with the disease. In this section, we review microvascular changes in skeletal and cardiac muscle, adipose, and skin, highlighting structural and functional changes that result from chronic hyperglycemia and from other factors that accompany diabetes. The retinal, renal, and neural pathology that accompanies diabetes arises in each case from disease/dysfunction of a very small mass of vessels in critical areas. However, for skeletal and cardiac muscle, adipose, and skin, we are dealing with a larger set of microvascular target vessels that when dysfunctional can impact general metabolic function.

Skeletal Muscle Microvasculature: Structural and Functional Changes That Accompany Diabetes and Insulin Resistance

A study using electron-microscopic methods to examine pathologic changes in tissues from patients with diabetes reported that the BM of the microvasculature within skeletal muscle was thicker in diabetic than in healthy control subjects.[414] The study also suggested that this change might occur early after the onset of diabetes or even precede frank hyperglycemia.[414] However, subsequent work suggested that BM thickening correlated well with diabetes duration and glycemic control.[415] Some initial confusion may have arisen as a result of different fixation methodologies for preparing tissues for electron microscopy,[416] as well as differences related to which muscle group was biopsied (vastus lateralis, gastrocnemius, or neck muscles).[417,418] Most experts now agree that the degree and duration of hyperglycemia appear to be important predictors of BM thickness.[415] Research also indicates that, despite increased thickness of the BM, the peripheral vasculature in individuals with established diabetes appeared to be more leaky compared with nondiabetic controls. Studies most commonly defined leaky as the escape of radiolabeled albumin from the systemic circulation.[419,420] Although these studies used albumin as the tracer, other plasma proteins and lipoproteins also exit plasma at an accelerated rate. In the wall of larger arteries, this leakage from the vasa vasorum may contribute to the increased atherosclerosis that accompanies diabetes.

Over several decades, more has been learned about the composition of the BM[421] and how diabetes affects it. The principal proteins include type 4 collagen, laminin, perlecan, and nidogen/entactin. These proteins include several different isoforms, and the relative abundance and combinations of specific isoforms differ in various vascular beds. There are also a large number of other proteins present in smaller quantities. The biochemical composition of the BM in diabetes suggested that accumulation of glycosylated and cross-linked proteins contributed to the expanded membrane structure and disordered function.[422] The nonenzymatic glycosylation of these proteins (like that of intracellular proteins), as well as cross-linking of the BM structural proteins by reactive carbonyl compounds like methylglyoxal (see Biochemical Pathways of Microvascular Injury), can affect endothelial cell/ECM interactions.[422]

The pericyte is another important support component of the muscle microvasculature. As described elsewhere, pericyte loss is an early finding in the genesis of DR. In the kidney, changes in mesangial cell function (the glomerular cognate of the pericyte) contribute to the glomerular pathology of diabetes. Within skeletal muscle and many other tissues, pericytes and smooth muscle cells line the vessels down to the level of the capillary. Although originally thought to play principally a support and contractile function, it appears more likely that these cells may play a more dynamic role in regulating multiple functional aspects of the microvasculature.[423] For example, although pericytes appear to play an important role in angiogenesis within the microvasculature, they also participate in the formation of the BM that envelops the endothelium. Within skeletal muscle, diabetes decreases the density of pericytes.[417,424] It is not certain whether this is one of the factors leading to muscle capillary rarefaction that is seen in diabetes,[425] as well as in persons with hypertension or with simple obesity.[426] It is of interest that insulin resistance is a common trait among these latter disorders, and impaired insulin action on muscle vascular elements may underlie this loss of capillary numbers. This has also been nicely demonstrated in animal models of obesity and insulin resistance in which decreased NO availability was implicated as potentially causative.[427] In addition to changes in skeletal muscle capillary numbers, diabetes is associated with changes in the capillary architecture, which affect the perfusion pattern within the muscle.[428]

One study reported that muscle-specific VEGFdeficient mice have capillary rarefaction in both skeletal and cardiac muscle, and this is accompanied by decreased insulin action on skeletal muscle glucose uptake during a euglycemic clamp.[429] Glucose uptake in response to insulin was normal when these muscles were excised and studied in vitro, suggesting that the capillary rarefaction was responsible for at least a significant fraction of the metabolic insulin resistance observed. Likewise, a second study reported that mice deficient in insulin receptor substrate 2, specifically in the endothelium, have in vivo metabolic insulin resistance during the euglycemic clamp.[430] This appears to be secondary to impaired insulin signaling to activate NOS and increase NO production. Interestingly, the study also reported that endothelial cells from control mice placed on a high-fat diet demonstrated decreased IRS-2 protein content, as well as impaired insulin-mediated glucose disposal. The study did not examine microvascular rarefaction. However, it did report that in control mice, insulin increased capillary recruitment (a process by which insulin, exercise, and other factors increase the fraction of capillaries within muscle that are perfused at any point in time); this did not occur in high fat–fed or endothelial cell–specific IRS-2 knockout mice.

These last two studies begin to probe the relationship between microvascular perfusion, capillary density, andmetabolic function in muscle. Preceding that work, there are several decades of publications indicating a clear relationship between insulin's metabolic actions in muscle and insulin's action on vasculatures (both large conduit vessels, resistance vessels, and the microvasculature) that supply skeletal muscle. By the mid-1990s, it was reasonably established that changes in insulin concentrations (using the insulin clamp technique) could modify total blood flow to muscle, and that states of insulin resistance, including obesity,[431] T1DM,[432] and T2DM,[433] blunted this effect. Presumably, this effect was principally mediated by actions on resistance arterioles, which (along with the microvasculature) regulate total blood flow to muscle. With the development of several methods to specifically measure muscle microvascular blood flow[434,435] and the distribution of blood flow within the muscle, it became apparent that insulin also significantly enhanced the recruitment of capillaries that were relatively less perfused or unperfused within resting skeletal muscle. Both insulin's effect on resistance arterioles and insulin's effect on the smaller fourth- or fifth-order arterioles that regulate muscle flow distribution require intact signaling to NOS.[436,437] Insulin's microvascular effect (like its effect on resistance arterioles) was impaired in states of insulin resistance (including diabetes) and correlated strongly with insulin's metabolic effects within skeletal muscle in both experimental animals[438–440] and humans.[441–445]

Even very modest exercise recruits capillaries within human skeletal muscle,[446] and the effect appears stronger than that of insulin. Furthermore, the effect of exercise persists unabated in insulin-resistant states. The fact that expanding capillary surface enhances insulin (and nutrient) delivery to muscle[67] may, in part, explain the insulin-sensitizing effect of exercise.

Two aspects related to impaired skeletal muscle microvascular insulin action and its metabolic consequences are of particular interest. First, although this impairment is quite evident in individuals with diabetes, it is also apparent in other states of insulin resistance, like metabolic syndrome or simple obesity. As such, this microvascular dysfunction affects even a larger segment of the general population. This is of significant concern because both obesity alone and metabolic syndrome increase CVD risk.[447] Second, clearly different mechanisms are most likely involved. Diabetes microvascular injury appears to be provoked (in many tissues) by excess glucose metabolism by the endothelial cell, which results in enhanced glycolytic activity, greater AGE formation, mitochondrial ROS production, and increased PKC activity.[64] Because endothelial cell glucose metabolism occurs in an insulin-independent fashion, but is proportional to the degree of glycemia, it clearly involves a separate mechanism from that seen in normo-glycemic insulin-resistant obese or metabolic syndrome subjects. The latter may involve nutrient overload by FAs or other nutrients,[448] although the relationship between obesity (or even T2DM) and increases in circulating concentrations of nonesterified FAs is not without controversy.[449]

The Myocardial Microcirculation in Diabetes

The coronary microvasculature plays a dynamic role in the regulation of coronary blood flow to meet the oxygen and nutrient demands of the myocardium. Because the heart's microvascular bed provides endothelial surface area to facilitate the delivery of oxygen, nutrients, and hormones and the removal of metabolic end products from the myocardium, changes in the cardiac microvascular blood volume and flow could profoundly affect myocardial metabolism, function, and health.

The coronary circulation is composed of the arterial (epicardial coronary arteries down to 200 μm arterioles), microcirculatory (arterioles <200 μm, capillaries, and small venules <200 μm), and the venous (200 μm venules to coronary sinus) compartments with a total blood volume of ~12 mL/100 g cardiac muscle, which is distributed near evenly among these three compartments.[450,451] Although most of the arterial and venous blood volumes are located on the epicardial surface of the heart, the microvascular compartment is exclusively located within the myocardium and constitutes ~90% of the myocardial blood volume.[450] Compared with other insulin-sensitive tissues (e.g., skeletal muscle and adipose tissue), myocardium has a much larger endothelial surface area (per gram of tissue). Within the myocardium, endothelial cells outnumber cardiomyocytes by three to one, and each mm2 myocardium contains 3000 to 4000 capillaries, which run parallel to cardiomyocytes.[451,452] At rest, only ~50% of myocardial capillaries are perfused.[453] When myocardial oxygen demand increases, myocardial blood flow velocity and/or volume increase to meet demand.

In addition to providing surface area for endothelial exchange, the myocardial microvasculature also actively regulates capillary hydrostatic pressure, which is critical for maintaining cellular homeostasis and health,[454] resulting in a constant coronary blood flow over a wide range of coronary driving pressures (~45 to 120 mm Hg).[451] The largest drop in pressure from the mean aortic pressure of ~90 mm Hg to the capillary hydrostatic pressure of ~30 mm Hg occurs in the arterioles smaller than 100 mm in diameter. Tone in these vessels responds to autonomic control and to local metabolites.[455] Together, the arterioles confer;60% of total myocardial vascular resistance, whereas capillaries account for ~25% and venules ~15%.[451,453,456] Unlike the arterioles that regulate myocardial blood flow, resistance, and volume by vasodilation or vasoconstriction, capillaries (which lack a smooth muscle component) do so via their recruitment or decruitment driven by arteriolar tone.[453]

Many physiological factors regulate coronary blood flow, including catecholamines, adenosine, exercise, insulin, and glucagon-like peptide 1 (GLP-1). Adenosine is a potent vasodilator, which has been widely used clinically to assess coronary blood flow reserve. Exercise is probably the most important and potent physiological stimulus to increase myocardial blood flow. The increase in oxygen demand of the left ventricle during exercise is mainly met by augmenting coronary perfusion via capillary recruitment and the dilatation of coronary microvessels, as oxygen extraction is nearly maximal at rest (70% to 80%).[457] Insulin also increases coronary blood flowin humans,[458–464] suggesting a vasodilatory action on coronary vasculature. Studies using myocardial contrast echocardiography (a noninvasive technology that employs perfluorocarbon gas–containing microbubbles to assess in vivo perfusion of the cardiac microvasculature)[465–467] have shown that insulin potently increases cardiac microvascular perfusion in healthy humans.[443,468,469] This finding extends a prior report that mixed meal feeding significantly increased cardiac microvascular perfusion in healthy but not in T2DM humans.[470] The postprandial increase in cardiac microvascular perfusion is most likely multifactorial. In addition to stimulating insulin secretion, the mixed meal induces the secretion of incretins, and at least one of these incretins (GLP-1) increases coronary blood flow independent of insulin.[471,472] It is very likely that GLP-1 also regulates coronary microvascular perfusion, as studies recently reported that GLP-1 recruits microvasculature and enhances insulin delivery and glucose use in skeletal muscle.[473,474] Researchers have yet to define the mechanisms underlying myocardial capillary recruitment, and these mechanisms most likely vary based on the particular stimuli. In skeletal muscle, insulin and GLP-1 recruitmuscle microvasculature via a NO-dependent mechanism,[67,473,475,476] whereas exercise-induced muscle microvascular recruitment is largely NO independent.[477] It is possible that in myocardium, both insulin and GLP-1 act via the NO-dependent mechanism, and exercise recruits myocardial capillaries perhaps by increased metabolic responses of the small arterioles.

Patients with diabetes have accelerated coronary artery disease and are prone to develop diabetic cardiomyopathy. Among many possible contributors are microvascular abnormalities. The morphological changes of small vessels seen in diabetic myocardium are extensive, including periarterial fibrosis, arteriolar thickening, focal constrictions, microvascular tortuosity, capillary BM thickening, capillary microaneurysms, and decreased capillary density.[478,479] In addition to structural abnormalities, coronary microvascular dysfunction also occurs in diabetes. Indeed, the maximal coronary flow reserve is reduced, and endothelium-dependent coronary vasodilation is clearly impaired in diabetes, even in the presence of angiographically normal coronary arteries and normal left ventricular systolic function.[480,481] The reduction in myocardial blood flow reserve correlates significantly with average fasting glucose concentrations and HbA1c,[482] confirming the importance of glycemic control in the maintenance of cardiac health. In patients with T1DM and normal exercise echocardiography and autonomic nervous function, myocardial blood flow (measured with PET and [15O]H2O) is ~30% lower, and total coronary resistance is 70% higher than normal healthy controls during hyperemia.[483]

Endothelial dysfunction and insulin resistance, two core defects associated with diabetes, are both present in the coronary circulation and are most likely the major early cause of coronary microvascular dysfunction. Quantitative angiographic analysis of epicardial coronary artery responses to stepwise intracoronary acetylcholine infusion clearly demonstrates impairment in endothelium-dependent dilatation in diabetic patients with no significant coronary atherosclerosis.[481] Vasodilation of the coronary microcirculation in response to sympathetic stimulation evoked by the cold pressor test is also impaired in T2DM patients in the absence of significant epicardial coronary artery lesions.[484] Although insulin-mediated increases in coronary blood flow are maintained in young patients with T1DM without microvascular complications or autonomic neuropathy,[459,461] it is blunted in patients with obesity[485] or T2DM.[460] Raising plasma insulin concentrations by ~eightfold by ingesting a mixed meal not only fails to increase cardiac microvascular perfusion, as is seen in healthy humans, but actually induces a paradoxical decrease in many patients with diabetes.[470,486] In the acute insulin-resistant state induced by systemic lipid infusion, the myocardial microvascular response to insulin is clearly blunted.[443] However, pretreatment with salsalate, an anti-inflammatory agent that inhibits the NF-κB pathway, preserves the microvascular response to insulin.[468] These findings are consistent with a prior report that free FAs cause endothelial insulin resistance via NF-κB activation.[487] Another potential contributor to coronary microvascular dysfunction is the increased blood viscosity commonly seen in patients with diabetes. Hypertriglyceridemia, a common feature of insulin resistance and insulin deficiency, increases blood viscosity and decreases coronary blood flow.[488]

In patients with fixed stenoses in major coronary arteries due to coronary atherosclerosis, blood supply to the myocardium is limited. Although resting epicardial coronary blood flow remains normal until >85% of the lumen is obstructed, during hyperemia, total flow is reduced when the stenosis exceeds 50%,[489–491] and both microvascular blood volume and flow velocity are depressed.[490,492] Under this circumstance, expansion of the coronary microvascular blood volume could markedly increase the endothelial exchange surface area. The presence of insulin resistance in the coronary microvasculature could further limit the microvascular blood volume and the capability of cardiac muscle to extract oxygen and nutrients and receive signals from circulating anabolic factors. This may explain partly why patients with diabetes tend to develop cardiac complications, including cardiomyopathy and heart failure. This also suggests that the coronary microvascular endothelial dysfunction and insulin resistance could be important therapeutic targets in reducing cardiac morbidity associated with diabetes.

Microvascular Disease/Dysfunction in the Skin

The skin microvasculature plays an important physiologic role in the body's defenses against thermal and mechanical injury and pathogen entry by maintaining the health of the keratinized epithelium of the epidermis, as well as the supporting dermis and subcutaneous tissues. Diabetes can injure the skin's microvasculature, which could compromise the skin barrier and allow trans-cutaneous microbe migration. Pathologically, thickening of the BM and loss of pericyte coverage for microvessels characterize injury to the skin's microvasculature, similar to responses in other tissues. The vessels leak plasma proteins, and, perhaps as a consequence of this leaking or as a consequence of hyperglycemia, the supporting connective tissue becomes more cross-linked and stiff. Microvascular injury may play a role in the development of the limited joint mobility syndrome[493] that is seen in both T1DM and T2DM and correlates with the progression of microvascular disease in the eye.[494]

Beyond structural changes, there are abundant data regarding vascular dysfunction in the skin in diabetes.[495] The skin (like the retina) is one of the few areas where clinicians can directly observe and functionally test the microvasculature. A significant body of data exists that details the changes in microvascular perfusion that occur as a result of diabetes or insulin resistance or components of metabolic syndrome. Researchers have used various techniques, including laser Doppler fluxmetry[496–498] and nail-bed capillaroscopy,[499,500] to characterize skin microvasculature in diabetes,[500–502] obesity,[503] insulin resistance, and metabolic syndrome.[504] With well-established diabetes, the vascular hyperemic response to skin heating is impaired, as is the response to hypoxemia. There appears to be a clear relationship between impaired microvascular function and tissue metabolism in the feet of individuals with diabetes. Tissue oxygen saturation and high-energy phosphate stores are decreased in lower extremity skin in individuals with diabetes compared with controls, and this appears to be further aggravated when neuropathy is present.[495]

Impaired function of the skin microvasculature is a key component contributing to delayed/deficient wound healing in diabetes. This applies to both postsurgical healing as well as spontaneous wound healing, as is seen with diabetic foot ulcers.[505,506] For the former, glycemic control is an important treatment intervention to improve wound healing. For the latter, which are more chronic wounds, there is a complex interplay between local tissue factors, infection, blood flow, and friction/pressure-related hyperkeratosis, each of which must be addressed to optimize the likelihood of successful treatment. Interestingly, recent work in experimental models has suggested that a defect in endothelial progenitor cell proliferation and subsequent recruitment to sites of injury may be playing a significant role. The generation of EPCs appears to depend on NO generation by eNOS within the bone marrow compartment, and diabetes impairs this.[507] Beyond that, the recruitment of generated cells to the area of inflammation is dependent upon local tissue factors, which diabetes also decreases.[507]

Microvascular Dysfunction/Disease in Adipose Tissue

Adipose tissue possesses an abundant microvasculature, and most adipocytes are within one cell diameter of a capillary. The resting blood flow to adipose tissue is similar to that of resting skeletal muscle (2 to 4 mL/min/100 g), and blood flow to each of these tissues increases following a meal in healthy subjects.[508,509] These changes can be blocked by β-blockade but not by α-blockade or NOS inhibition, suggesting an important role for adrenergic regulation. Inasmuch as adipose tissue is a principal repository for dietary fats that circulate in very LDL particles or chylemicrons, postprandial increases in flow could enhance nutrient delivery and storage. In muscle, meal ingestion increases both total blood flow and capillary recruitment. Similar blood flow and capillary recruitment may likewise occur postprandially in adipose tissue.[510]

Interestingly, basal adipose blood flow is reduced, and postprandial adipose blood flow increases are blunted or absent in obese or T2DM subjects.[510,511] Subcutaneous adipose tissue capillary density (capillaries/mm2) is less in obese subjects,[512] consistent with capillary rarefaction similar to that seen in skeletal muscle in diabetes, obesity, and hypertension. The larger fat cell size in subcutaneous tissue from obese diabetic subjects may, in part, explain this apparent rarefaction, which correlates well with the degree of insulin resistance measured using the euglycemic clamp method.

Whether diminished adipose vascularity might have metabolic consequences has been a topic of very recent interest. Several groups had reported decreased tissue oxygen tension within adipose tissue from obese rodents.[512–514] These groups hypothesized that this decrease results in an oxidative stress within the tissue, which might contribute to the development of inflamed adipose tissues and the resultant release of inflammatory cytokines.

This hypothesis has become more controversial with recent data suggesting that in obese humans, subcutaneous adipose tissue oxygen concentration was either minimally lower[512] or higher[508] than is seen in lean, age- and gender-matched control subjects. In the latter study, which also demonstrated decreased vascularity and reduced blood flow, the seemingly paradoxical adipose tissue hyperoxia appeared secondary to decreased mitochondrial activity and tissue energy expenditure. Whether these differences between rodents and humans represent species differences or differences between the methods used in the human compared with the rodent studies is uncertain. It is clear that the tissue pO2 in obese rodents is substantially lower (~20 mm Hg) compared with obese humans (40 to 70 mm Hg). The levels of oxygen seen in humans would not be expected to trigger the same transcriptional program as seen in mice (e.g., enhanced expression of mRNA for HIF-1a, Glut-1, etc.).

The recognition of the close relationship between adipose tissue microvasculature and the adipocyte has recently provoked a number of very interesting investigations into the relationships between expanding fat mass and microvascular angiogenesis or involution and how both relate to body metabolic function. Over a decade ago, Rupnick et al.[515] observed that angiogenesis inhibitors could lead to significant weight loss in ob/ob mice. This was particularly intriguing, as the effect occurred using several different types of angiogenesis inhibitors, and the animals tolerated the treatment quite well. Withdrawal of the inhibitor allowed rapid regain of the lost weight. The animals treated with the angiogenesis inhibitors demonstrated increased apoptosis and decreased angiogenic activity in adipose tissue. The treated animals consumed less food than control animals; however, this did not entirely explain the weight loss, which was greater in the animals treated with the angiogenesis inhibitors compared with pair-fed controls. More recently, several intriguing studies have shown that adipose tissue endothelium specifically targeted with a proapoptotic peptide likewise caused weight loss inmice.[516,517] This treatment affected a decrease in food intake without other apparent toxicity. Importantly, it did not affect appetite or body weight in lean control animals.[518] The mechanism responsible for this obesity-dependent appetite decrease is unclear. It is intriguing that treating mice with proapoptotic peptide, while causing vessel rarefaction in adipose tissue, improved glucose tolerance and insulin resistance.[516] Studies targeting adipose angiogenesis did not assess tissue oxygenation, so it is unclear how this work relates to the hypothesis that adipose hypoxia causes a proinflammatory state and consequent insulin resistance.

Several other groups have reported finding a significant relationship between the microvasculature and the metabolic function of the adipocyte. When the VEGF gene is overexpressed in the adipocyte using an AP2-directed promoter, there is increased microvasculature development, specifically in adipose tissue (both white and brown).[518] These mice did not become obese when placed on a high-fat diet. They also showed decreased M1 macrophage infiltration of fat, increased thermogenesis, and improved glucose tolerance, and maintained greater insulin sensitivity when compared with high-fat–fed control mice. The complexity of this relationship is underscored by the observation that inhibiting VEGF-A expression (whole animal) using an inducible repression system also diminished weight gain on a high-fat diet and led to a browning of white adipose tissue. In addition, VEGF-B expression was increased in these mice, as were downstream FA transport proteins regulated by VEGF-B.[519] This is particularly interesting in light of the report that knockout of VEGF-B (whole body) prevented the development of insulin resistance in db/db mice and improved glucose tolerance.[520] In part, these salutary metabolic effects appeared due to decreased FA transport proteins in the endothelium of muscle and heart, which slowed ectopic lipid deposition at these sites.

Studies probing the relationship between VEGF expression and microvascular development have recently been extended to muscle. Bonner et al.[521] created a muscle-specific VEGF-A knockout mouse using the Cre/lox method. VEGF-A was absent in both cardiac and skeletal muscle, whereas plasma concentrations were decreased ~25%. Accompanying this was nearly a 50% decline in capillary volume in both skeletal and cardiac muscle. Insulin sensitivity (euglycemic clamp) was diminished in the knockout animals due to a decline in insulin-stimulated glucose disposal. However, when muscles were excised and incubated in vitro with insulin and glucose, metabolism appeared normal. This suggests that the impairment in insulin-stimulated muscle glucose uptake was due to poor muscle perfusion.

It could be that there is an entirely different relationship between the microvasculature and adipose within skeletal muscle. This relates to the fact that small arterioles within both skeletal and cardiac muscle have a surrounding envelope of adipocytes, and the volume of this envelope increases with obesity. Nearly a decade ago it was proposed that a local signaling process occurs between perivascular adipose tissue and the microvasculature within skeletal muscle,[522] and that adipokines released by adipose might influence muscle nutritive perfusion in a paracrine fashion. Such a process could provide an important linkage in our understanding of the relationship between adiposity, inflammation, and vascular dysfunction that is prevalent in diabetes. Increases in perivascular adipose tissue are not restricted to skeletal muscle. Indeed, several studies have noted an association between perivascular adipose tissue in the thoracic aorta and both extramural coronary circulation calcification and CVD prevalence.[523,524]


In summary, there is now abundant evidence that microvascular dysfunction/disease is by no means restricted to the traditional target tissues (i.e., retina, kidney, and peripheral nerve). Rather, it is a generalized phenomenon affecting multiple tissues throughout the body. This allows one to appreciate the pleiotropic effects of diabetes on health. In addition, dysfunction of the microvasculature in tissues like skeletal and cardiac muscle, skin, and adipose also occurs in settings related to insulin resistance and contributes to both metabolic and other functional defects in these tissues.