TEM 1482 No.

of Pages 9

Trends in Endocrinology & Metabolism

Opinion

Chronic Diabetes Complications: The Need to

Move beyond Classical Concepts
Dídac Mauricio ,1,2,3,* Núria Alonso,2,4 and Mònica Gratacòs1

Chronic-diabetes-related complications simultaneously compromise both the Highlights

micro- and macrovascular trees, with target organs considered as the paradigm Diabetes complications include patho-
of large vessel injury also entailing microangiopathic changes. However, compli- logical changes beyond the vascular sys-
tem and classical target organs.
cations independent or partially independent from vascular damage are often
overlooked. This includes neuronal dysfunction (e.g., retinal neurodegeneration), Microangiopathy may affect nonclassical
interstitial injury (e.g., tubulointerstitial disease), metabolic damage (e.g., in the target organs.
heart and liver), and nonclassical conditions such as cognitive decline, impaired
Organs affected by microangiopathy
pulmonary function, or increased risk of cancer. In this scenario, researchers,
may also show neuronal or structural
endocrinologists and primary care physicians should have a holistic view of the deficits including: neurodegeneration
disease and pay further attention to all organs and all potential clinical repercus- and neurodysfunction of the retina;
sions, which would certainly contribute to a more rational and integrated patient structural changes in the kidney tubular
interstitium; and nerve fiber dysfunction.
health care.
Organs affected by macroangiopathy
Diabetes Is a Multisystemic Disease also show microvascular and neuronal
Traditionally defined, long-term diabetes complications are largely seen as the consequence of deficits including: microangiopathy of
vascular damage, categorized as either those affecting large vessels (macrovascular complica- the arterial wall; microangiopathy and
neuropathic changes adding to ischemic
tions or diabetic macroangiopathy) (see Glossary) or those affecting microvessels (microvas- and nonischemic heart disease; meta-
cular complications or diabetic microangiopathy). Microvascular complications include bolic peripheral nerve damage; cerebral
diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy small vessel disease; and structural
(DPN), whereas macrovascular complications manifest as an increased risk of coronary artery changes leading to cognitive impairment.

disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease (CeVD). This classi- Nonclassical chronic complications in-
fication is convenient at the clinical level because it gives a broad idea of the comorbidity associ- clude abnormal pulmonary function and
ated with diabetes and can be pragmatically translated into prevention, treatment, and microangiopathy, metabolic liver and
management recommendations. However, microangiopathy (and all the diabetes-specific mech- myocardial damage, and increased risk
of carcinogenesis.
anisms of action of diabetic complications) is not only present in the retina, kidneys, and nerves,
but it is ubiquitous and is the cause of the increased severity of diabetes-related complications.
Moreover, diabetes affects almost every organ system beyond the vascular beds, with damage
and further complications that do not strictly fall into the artificial micro- and macrovascular clas-
sification (Figure 1). We hereby provide a general view about organs, tissues or cell types not usu-
ally perceived as prime targets of diabetes and hence not always receiving due attention. We
show that it is pivotal to have a holistic view of the disease because structural and functional dam-
1
age in these overlooked structures also leads to (or aggravates) diabetes–related damage. DAP–Cat group, Unitat de Suport a la
Recerca Barcelona, Fundació Institut
Universitari per a la recerca a l’Atenció
Microvascular Disease in Diabetes Is Not Only Microvascular Primària de Salut Jordi Gol i Gurina
Retinal Neurodegeneration (IDIAPJGol), Barcelona, Spain
2
Diabetic retinopathy (DR) is the prime example of microangiopathy and the most common and CIBER of Diabetes and Associated
Metabolic Diseases (CIBERDEM),
well-studied ocular complication of diabetes. However, vascular and neural components Instituto de Salud Carlos III (ISCIII),
(i.e., neurons and glia) of the retinal parenchyma are intimately interconnected at the metabolic Barcelona, Spain
3
and structural levels in the so-called neurovascular unit. Blood vessels feed the neural component Department of Endocrinology and
Nutrition, Hospital de la Santa Creu i
of the retina, but they represent less than 5% of the retinal mass. Therefore, it is not surprising that Sant Pau, Autonomous University of
DR encompasses concomitant vascular abnormalities and nonvascular damage, namely Barcelona, Barcelona, Spain

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© 2020 Elsevier Ltd. All rights reserved.
Trends in Endocrinology & Metabolism

4
neurodysfunction and neurodegeneration. Indeed, the recent position statement of the American Department of Endocrinology and
Nutrition, Health Sciences Research
Diabetes Association on DR states that it is ‘a highly specific neurovascular complication’ [1], Institute & University Hospital Germans
which is a more inclusive definition. Moreover, some have proposed that it should be viewed as Trias i Pujol, Badalona, Spain
a sensory neuropathy similar to peripheral neuropathies [2].

*Correspondence:
Retinal structural neuronal damage in diabetes is demonstrated through dysfunction of the neu-
dmauricio@santpau.cat (D. Mauricio).
rosensory retina, with loss of synaptic activity and dendrites, neural apoptosis, ganglion cell loss,
thinning of the inner retina, and reactive microglial activation [3,4]. Moreover, functional changes in
neurodegeneration independent of vascular retinopathy include deficits in the retina’s electro-
physiological activity, dark adaptation, contrast sensitivity, or color vision [3,4]. The relative inde-
pendence of damage to the neural components from damage to the vascular components is
exemplified by several studies showing that functional neurogenic changes and thinning of the
neuroretina layers in DM can even be present with minimal or an absence of characteristic
microvascular DR changes [5,6]. However, another study reported that this might not apply to
all subjects with type 2 diabetes (T2D), since in 61% of those without visible microvascular
disease there were functional or structural abnormalities related to neurodegeneration, but in
32% of those with visible early microvascular retinal impairment there were not [7].

Tubulointerstitial Disease
DN or chronic kidney disease attributable to diabetes is caused by altered renal microcirculation
that leads to structural and functional glomerular damage, with functional damage objectively

Trends in Endocrinology & Metabolism

Figure 1. Schematic Figure of the Traditional Classification of Chronic Diabetes–Related Complications between Micro- and Macrovascular Events
(black font), Although Vascular Damage Is Only One Part of the Myriad of Possible Complications; Many of Them Often Overlooked (Grey Font).
Abbreviation; DM, diabetes mellitus.

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Trends in Endocrinology & Metabolism

determined through decreased glomerular filtration and albuminuria. In addition, fibroblasts Glossary
interconnect vessels with tubular epithelial cells to provide a scaffold-like structure, and therefore Cardiovascular autonomic
besides glomerular structures, diabetes also harms the renal tubules. This is demonstrated neuropathy: peripheral neuropathy
through epithelial degeneration, myofibroblast accumulation, nodular or diffuse glomerulosclerosis, that affects the nerves that control the
cardiovascular system.
tubulointerstitial disease, tubular atrophy, and renal arteriolar hyalinosis [8]. Tubular dysfunction
Cerebral small vessel disease: this
is considered to be closely correlated with glomerular injury, typically found in advanced stages of entity designates different diseases
DN [8]. However, this may be challenged by different observations: firstly, tubulointerstitial fibrosis is affecting the small arteries, arterioles,
better correlated with DN progression than glomerular changes [8]. Secondly, although tubular venules, and capillaries of the brain, and
refers to several pathological processes
changes may be more evident at later stages of DN, there is evidence of subtle tubular damage and etiologies. In this article, we only deal
in early DN, with impaired tubular reabsorption and excretion of proteins that originate in the tubular with CSVD in diabetes.
interstitium, which could explain the dissociation between microalbuminuria and glomerular struc- Diabetic cardiomyopathy: heart
tural changes in early stages of DN [9]. condition that develops as a result of
diabetes defined by ventricular
dysfunction in the absence of coronary
Peripheral Nerves atherosclerosis and hypertension.
Diabetic neuropathy is traditionally considered a microvascular complication of diabetes in which Diabetic macroangiopathy (or
nerve ischemia leads to motor, sensory, and autonomic neuropathy. However, these conditions diabetic macrovascular disease):
this is the term used to define the
cannot be explained by nerve ischemia alone, and diabetic neuropathy is considered to actually
complication of diabetes affecting large
arise from a combination of microvascular dysfunction and neuronal deficits [10]. Vasa arterial vessels, usually through an
nervorum damage (i.e., vasoconstriction, capillary basement membrane thickening, and endo- accelerated atherosclerotic process.
thelial hyperplasia) leads to endoneurial hypoxemia and nerve hypoperfusion [10]. In addition, This is usually classified according to the
vascular territories that are affected:
damage of the nerve fibers is also the result of the metabolic cellular injury triggered by the dele- PAD, CAD, and cerebrovascular
terious effects of long-term hyperglycemia and dyslipidemia [10]. The confluence of metabolic disease.
and vascular disturbances contributes to nerve hypoperfusion and loss of neurotrophic support, Diabetic microangiopathy (diabetic
further leading to nerve dysfunction and eventually apoptosis of neurons, Schwann cells, and glial microvascular disease): this is the
term used to define the complication of
cells of the peripheral nerve [10]. diabetes affecting small vessels. This is
usually classified according to the
The neurovascular dysfunction due to microcirculatory and also metabolic damage in peripheral microvascular beds affected: retinal
microcirculation (DR), glomerular
nerve small fibers has been shown to contribute, for instance, to the development of pain and foot
microvessels (DN) and peripheral nerves
ulceration in T2D irrespective of the presence of macrovascular disease [11,12]. In addition, (DPN).
cardiovascular autonomic neuropathy (CAN) is another often-overlooked clinically relevant Nonalcoholic fatty liver disease:
complication of diabetes. It refers to the impairment of autonomic nerve fibers that innervate histopathological spectrum of liver
conditions ranging from simple liver
the heart and blood vessels [13]. It starts with increased sympathetic tone and evolves to
steatosis (accumulation of liver droplets
denervation, which progressively compromises ventricle function, contributing to cardiomyopathy in N5% of hepatocytes) to
[14], increasing the risk of arrhythmias, silent myocardial infarction and death [15]. steatohepatitis, with varying degree of
liver fibrosis, and cirrhosis.
Tubulointerstitial disease: condition
Macrovascular Disease in Diabetes Is Not Only Macrovascular that results in tubular and interstitial injury
Arterial Wall as a Target of Diabetes of the kidney (in contrast to those
Diabetes is traditionally seen as an accelerated atherosclerosis process in which the disease has conditions resulting in glomerular injury).
a role in the proneness to plaque formation, vulnerability, and rupture. This could be explained by Vasa nervorum: small vessel that
provides blood supply to peripheral
a synergistic effect of mechanisms shown to be different in diabetes: thinner fibrous caps, in- nerve.
creased lipid deposition and calcification in the intima, increased plaque intimal neovasculariza- Vasa vasorum: the plexus of
tion and inflammation, increased hypercoagulability, increased intraplaque hemorrhage, and microvessels that provide blood supply
impaired endothelial repair [16]. to the external part of the arterial wall of
the arteries.

In atherosclerotic disease, when the intima has proliferated beyond a critical thickness, neovas-
cularization develops, arising from large artery microvessels (vasa vasorum; V V) as a response
to hypoxia and inflammation [17]. These neomicrovessels penetrate from the adventitia to the
media and reach the intima within the matrix of mature atheroma plaques, but as they are imma-
ture and weak, they are prone to leakage/rupture and can lead to intraplaque hemorrhage, which
is in turn associated with plaque progression and rupture, and the occurrence of ischemic events

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[18]. The degree of adventitially derived intimal–medial neovascularization and inflammation has
been reported to be greater in atherosclerotic lesions of subjects with DM than those without
DM [19,20]. Moreover, neovessels in aortic atherosclerotic plaques of subjects with DM have a
different morphology, namely a complex branched/sprouting appearance associated with peri-
neovascular inflammation, which points to a microangiopathic process in the context of diabetic
vasculopathy [21,22].

Besides the increased plaque intimal neovascularization as a compensatory response to hypoxia,

large-vessel-wall microcirculation could also be an independent/additional target site for diabetic
microangiopathy, and lesions in the intima V V have been proposed as a substrate for the devel-
opment and progression of macroangiopathic changes and diabetic atherosclerosis [20,23]. In
this line, there was an initial observation that the V V of the abdominal aorta in type 1 diabetes
(T1D) patients was thicker than in nondiabetic controls with or without severe atherosclerosis of
the aorta and coronary arteries [24]. The significance of this has not been studied at large since
then, but a further report using ultrasound imaging showed increased angiogenesis in plaque-
free segments of the common carotid adventitial V V in T2D patients without previous CVD com-
pared to nondiabetic controls; an increase that was also associated with DR [23]. In a subsequent
study, a greater carotid V V thickness was corroborated in carotid plaque-free segments of pa-
tients with T1D [25]. Finally, an independent study also observed a greater V V thickness
among T2D patients with minimal carotid atherosclerotic plaques compared to subjects without
DM [26]. Of note, and aside from the increased V V thickness, a recent postmortem study in dia-
betic patients showed that the density of coronary V V is lower among patients with DM com-
pared to those without DM, and that there is a direct relationship between the glycemic level
and the density of V V in the adventitia and in the entire vessel wall [27]. These results demonstrate
the disruptive effects of dysglycemia on the microvasculature of the V V.

Intracranial cerebral atherosclerosis (ICAS) has not been studied as much as coronary athero-
sclerosis, probably since ICAS is less common. This could be explained by the comparative pau-
city in intracranial V V compared with extracranial arteries, as intracranial V Vs do not exist at birth
but develop in adulthood to respond to the aging-related increase in nutritive demands and the
development of atherosclerosis [28]. However, there is increasing evidence that intracranial ath-
erosclerotic plaques have a role in stroke and that they are in turn strongly associated with the
presence of intracranial V Vs [28]. Finally, diabetes has been reported as an independent predictor
of ICAS among asymptomatic patients [29,30].

Dysfunctional angiogenesis has also been described among DM patients with atherosclerotic PAD
[31,32]. In infrapopliteal arteries with atherosclerotic lesions, PAS-positive thickening of the popli-
teal artery VV and calcification of the media layer were more frequent among diabetic than in non-
diabetic patients [31]. In an immunohistochemistry study, endothelial markers of angiogenesis in
the adventitial VV of femoral arteries were increased compared to healthy controls with similar ath-
erosclerotic lesions, while there was a decreased neoangiogenesis in the media; all of which could
be contributing to reduced artery wall perfusion and impairment of atherosclerosis [32].

Overall, these results show that adventitial V V angiogenesis, as a form of microangiopathy, is in-
volved in the development of the diabetic macroangiopathic disease, and raises the question of
whether V V proliferation is, in fact, a manifestation of the generalized diabetic microangiopathy.

Coronary Artery Disease and Nonischemic Diabetic Cardiomyopathy

It has increasingly been recognized that microangiopathy has a role in the pathogenic process
leading to ischemic heart disease. Microvascular involvement in the heart is not surprising if we

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Trends in Endocrinology & Metabolism

consider that 90% of the myocardial blood volume corresponds to the microvascular compart-
ment, while the remaining 10% is composed of arteries and veins located in the epicardial sur-
face. In addition, there is a link between microangiopathy and neuropathy that may somehow
contribute to the pathogenesis and progression of CAD. In one report, skin microvascular reac-
tivity, measured as a proxy of microvascular dysfunction, was reported to be more impaired in
T2D patients with myocardial ischemia than in patients without CAD or DM [33]. Another study
found that the prevalence of true silent myocardial ischemia was higher among asymptomatic pa-
tients with T2D than in controls, and that DR was a risk factor related to the presence of myocar-
dial perfusion defects [34]. Furthermore, CAN is associated with the extent and progression of
carotid atherosclerosis plaques in T2D patients [35–37].

Diabetic cardiomyopathy (DCM) is defined as ventricular dysfunction in the absence of coro-

nary atherosclerosis and hypertension [38]. The pathogenesis of DCM involves multiple mecha-
nisms, including metabolic (e.g., glucose and lipid toxicity) and inflammation imbalances,
structural myocardial changes (fibrosis), peripheral neuropathy in the form of CAN, and coronary
microvascular dysfunction [39]. Coronary microvascular dysfunction in DCM encompasses both
structural (periarterial fibrosis, arteriolar thickening, focal constrictions, microvascular tortuosity,
capillary basement membrane thickening, and decreased capillary density) and functional
(reduced blood flow and endothelium-dependent coronary vasodilation) deficits [40,41].

PAD and Diabetic Foot

In PAD, arterial narrowing is attributed to the rapid progression of atherosclerosis. PAD in DM is
frequently concomitant with other diabetes-related microvascular disease, in particular DPN,
which impairs sensory feedback and leads to a minimized pain perception, in turn associated
with later presentation and more severe lesions (e.g., ischemic ulcers or gangrene) than in pa-
tients without DM [42,43]. Diabetic foot (DF), which frequently leads to nonhealing foot ulcers,
is a consequence of a combination of different conditions, PAD and DPN, foot deformity, abnor-
mal foot pressures, abnormal joint mobility, and minor trauma [44]. However, impaired skin micro-
vascular reactivity has been reported in the feet of T1D patients without PAD with or without PN
[45–47]. This indicates that capillary ischemia may not only occur secondary to the classical dia-
betes complications, but that other mechanisms are also involved. For example, as previously
discussed, metabolic damage of peripheral nerves and microcirculatory dysfunction contribute
to the development of DF disease. This indicates that capillary ischemia may not be secondary
to other classical diabetic complications [11,12].

Cerebrovascular Disease and Brain Damage

Cerebrovascular diseases (CeVD) observed in DM patients includes macro- and microvascular-
driven mechanisms [48]. The DM-induced macrovascular disease may cause cerebral ischemia
through classical atherosclerotic disease of carotid and brain arteries. However, microcirculation
is also involved in CeVD through so-called cerebral small vessel disease (CSVD); a neurode-
generative condition affecting brain capillaries that leads to vascular occlusion and stroke [49]. Ad-
ditionally, alterations in the sympathetic and parasympathetic innervation of the cerebral arterioles
due to CAN contribute to the pathogenesis of CeVD through inadequate blood flow regulation [50].

At the clinical level, CeVD in diabetes (particularly T2D) has been linked to cognitive decline and
vascular dementia in what is considered accelerated aging, and although a matter of debate be-
cause of inconsistent results, with Alzheimer’s disease in the so-called type 3 diabetes [40,51].
Although the underlying mechanism for these associations remains unknown, structural changes
related to CSVD have been proposed as one of the multiple causes involved in diabetes-related
cognitive impairment, together with macrovascular disease and metabolic disturbances, among

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others [52,53]. Indeed, CSVD shows radiological ischemic and nonischemic findings such as la-
cunar infarcts, white matter hyperintensities, enlarged perivascular spaces, microbleeds, and
brain atrophy [40,49]. These changes share mechanisms with other microvascular complica-
tions, that is, DR, DN, and DPN [40,54] and, as an example, vascular retinal abnormalities are
associated with neuroimaging markers of CSVD [55]. This is reasonable if we consider the simi-
larities between the blood–brain and blood–retinal barriers, and that the retina is, from an anatom-
ical and developmental point of view, an extension and integral part of the central nervous system.
Of note, retinal abnormalities such as reduced blood flow, reduced ganglion cell numbers, and
thinner retinal nerve fiber layer have been correlated with cognitive decline and Alzheimer’s dis-
ease compared with controls [56]. Thus, the retina has been proposed as a research model for
the study of brain processes in both health and disease [56]. Following this line, and since retinal
and brain neurodegeneration also co-occur in DM, the functional assessment of the retina has
been suggested as an indirect method to explore events in the brain in DM [4,55].

Other Nonclassical Chronic Complications of Diabetes

Microvascular Lung Complications
The implications of diabetes in pulmonary function have not been explored at large, and although
results are controversial, the lung has been proposed as yet another disregarded target organ of
diabetes [57–59]. At the histopathological level, postmortem studies have shown pulmonary mi-
croangiopathy, and thickened pulmonary capillary basal laminae and alveolar epithelia, the latter
significantly correlated with the thickness of basal lamina in renal tubules [60–62]. At the functional
level, some studies have reported reduced lung volumes, reduced pulmonary elastic recoil, and
impaired diffusion capacity [63–67]. Moreover, an abnormal bronchomotor tone, decreased ven-
tilatory response to hypoxia, reduced strength of respiratory muscles, and lower peaks of oxygen
uptake in the cardiopulmonary exercise test have also been observed in patients with T1D or T2D
[58,68]. Of note, improvement of glycemic control has been shown to ameliorate pulmonary func-
tion measured by spirometric parameters in patients with T2D [69].

Pulmonary microvascular disease in DM has been assessed using pulmonary transit of agitated
contrast (PTAC) during exercise echocardiography, a noninvasive surrogate of microvascular
function [68]. The results showed that patients with T1D and T2D had lower PTAC than controls
without DM [68]. At the clinical level, reduced PTAC was associated with reduced right ventricular
function, higher pulmonary artery pressure, and reduced exercise capacity [68].

Nonalcoholic Fatty Liver Disease

Liver steatosis unrelated to significant alcohol consumption or other conditions (nonalcoholic
fatty liver disease; NAFLD) mainly affects hepatic structure and function; it often coexists with
DM, and each can influence the course of the other [70]. NAFLD has been related not only with
increased risk of incident T2D [71], but abnormalities in myocardial function and metabolism
have been described in T2D patients with NAFLD, supporting the role of cardiac lipotoxicity in
DM. Firstly, increased myocardial steatosis has been described in T2D compared to healthy sub-
jects [72,73]. Secondly, in T2D patients without evidence of CVD or microvascular complications,
those with high myocardial triglyceride content also had high intrahepatic fat content, and
myocardial steatosis was associated with an impaired left ventricular diastolic function, reduced
myocardial perfusion, and increased myocardial vascular resistance [73]. Moreover, several stud-
ies have found an association between left ventricular diastolic dysfunction in patients with T2D
and NAFLD without a history of CVD, and independently of the existence of traditional CVD risk
factors [74]. Finally, in T2D patients with CAD, NAFLD was found as an independent indicator
of myocardial insulin resistance and reduced coronary function [75]. Due to its close relationship
with the development of micro- and macrovascular conditions in T2D, it has been proposed that

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the ultrasonographic assessment of NAFLD could be used as a screening tool to assess the de- Outstanding Questions
gree of diabetic micro- and macrovascular complications [76]. What are the pathophysiologic
mechanisms of retinal and central
Cancer nervous system diabetes-related dam-
age leading to neuronal dysfunction
The evidence for an increased risk of carcinogenesis in both T1D and T2D compared with the
and neurodegeneration?
general population was evinced more than 50 years ago [77]. Moreover, an increased all-cause
mortality in patients with all types of cancer and pre-existing diabetes has been reported com- What are the pathogenetic mechanisms
pared to normoglycemic individuals [78,79]. Although the risk is higher for overall cancer inci- of diabetic tubulointerstitial kidney
damage?
dence, the strength of the association depends on the cancer site and differs between the two
main diabetes types and also by sex [79,80]. The reasons for this close association are not well What is the role and contribution of
understood, but hyperglycemia, insulin resistance, and/or hyperinsulinemia have been suggested nonglomerular kidney damage in
diabetic chronic kidney disease?
as risk factor for cancer incidence and tumor progression through multiple indirect and direct
pathways [81–83]. For instance, hyperglycemia can lead to rapid cancer cell progression, de- What is the role of large-vessel-wall mi-
creased antiapoptosis, increased cell migration and invasiveness, and activation of oncogenic croangiopathy in the development of
pathways [82]. Moreover, hyperglycemia may also influence the development of metastasis diabetic atherosclerotic disease?

and perineural invasion, it is correlated with toxicity to chemotherapy, and may contribute to What is the contribution of lower-limb
the ineffectiveness of chemotherapy [81]. Although the mechanisms underlying insulin resistance microangiopathy in the pathogenesis
and/or hyperinsulinemia and cancer remain unclear, some explanations include the oncogenic of DF disease?
potential of chronic hyperinsulinemia through the abnormal stimulation of multiple cellular signal-
What is the contribution and
ing cascades, the direct insulin-induced tumor growth, and the increased mitogenic and pathogenesis of diabetes-related CSVD
antiapoptotic effects exerted by insulin growth factors [83]. to CeVD in diabetes?

What are the pathogenetic

Concluding Remarks and Future Perspectives mechanisms of DCM: metabolic
Based on all the pieces of evidence, it is clear that chronic-diabetes-related complications go be- damage to cardiomyocytes and
yond vascular events, and also that the allocation between macro- and microvascular events is in myocardial microangiopathy? What is
the contribution of these factors to
itself artificial. There is a need to increase awareness that DM is a generalized disorder that en-
DCM in both T1D and T2D?
compasses multiorgan involvement and accordingly leads to a myriad of complications; some
of them often neglected (see Outstanding Questions). We assert the need for a holistic view of Further investigation is necessary on
DM, so that, when facing a patient with DM, and also when developing hypotheses and research lung microangiopathy and its clinical
expression in diabetes.
questions, a broader approach is taken to account for the presence of further concomitant path-
ological changes in all system organs and potential clinical repercussions. Only from a compre- Further investigation is needed on the
hensive view, investigators and clinicians will be able to accurately diagnose, treat and manage diabetes-specific pathogenesis of
NAFLD.
patients with DM.
What are the mechanisms involved in
Acknowledgments diabetes-induced carcinogenesis?
CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM) is an initiative from Instituto de Salud Carlos III, Barcelona,
Spain. The authors acknowledge Amanda Prowse (Lochside Medical Communications Ltd.) for proofreading.

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