- Email: [email protected]
Chronic Diabetes Complications: The Need to Move beyond Classical Concepts
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 micro- and macrovascular trees, with target organs considered as the paradigm of large vessel injury also entailing microangiopathic changes. However, complications independent or partially independent from vascular damage are often overlooked. This includes neuronal dysfunction (e.g., retinal neurodegeneration), interstitial injury (e.g., tubulointerstitial disease), metabolic damage (e.g., in the heart and liver), and nonclassical conditions such as cognitive decline, impaired pulmonary function, or increased risk of cancer. In this scenario, researchers, endocrinologists and primary care physicians should have a holistic view of the disease and pay further attention to all organs and all potential clinical repercussions, which would certainly contribute to a more rational and integrated patient health care.
Highlights Diabetes complications include pathological changes beyond the vascular system and classical target organs. Microangiopathy may affect nonclassical target organs. Organs affected by microangiopathy may also show neuronal or structural deficits including: neurodegeneration and neurodysfunction of the retina; structural changes in the kidney tubular interstitium; and nerve fiber dysfunction. Organs affected by macroangiopathy also show microvascular and neuronal deficits including: microangiopathy of the arterial wall; microangiopathy and neuropathic changes adding to ischemic and nonischemic heart disease; metabolic peripheral nerve damage; cerebral small vessel disease; and structural changes leading to cognitive impairment.
Diabetes Is a Multisystemic Disease Traditionally defined, long-term diabetes complications are largely seen as the consequence of vascular damage, categorized as either those affecting large vessels (macrovascular complications or diabetic macroangiopathy) (see Glossary) or those affecting microvessels (microvascular complications or diabetic microangiopathy). Microvascular complications include diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN), whereas macrovascular complications manifest as an increased risk of coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease (CeVD). This classification is convenient at the clinical level because it gives a broad idea of the comorbidity associated with diabetes and can be pragmatically translated into prevention, treatment, and management recommendations. However, microangiopathy (and all the diabetes-specific mechanisms 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 classification (Figure 1). We hereby provide a general view about organs, tissues or cell types not usually 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 damage in these overlooked structures also leads to (or aggravates) diabetes–related damage.
Microvascular Disease in Diabetes Is Not Only Microvascular Retinal Neurodegeneration Diabetic retinopathy (DR) is the prime example of microangiopathy and the most common and well-studied ocular complication of diabetes. However, vascular and neural components (i.e., neurons and glia) of the retinal parenchyma are intimately interconnected at the metabolic and structural levels in the so-called neurovascular unit. Blood vessels feed the neural component of the retina, but they represent less than 5% of the retinal mass. Therefore, it is not surprising that DR encompasses concomitant vascular abnormalities and nonvascular damage, namely Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
Nonclassical chronic complications include abnormal pulmonary function and microangiopathy, metabolic liver and myocardial damage, and increased risk of carcinogenesis.
1
DAP–Cat group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain 2 CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain 3 Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
https://doi.org/10.1016/j.tem.2020.01.007 © 2020 Elsevier Ltd. All rights reserved.
1
Trends in Endocrinology & Metabolism
neurodysfunction and neurodegeneration. Indeed, the recent position statement of the American Diabetes Association on DR states that it is ‘a highly specific neurovascular complication’ [1], which is a more inclusive definition. Moreover, some have proposed that it should be viewed as a sensory neuropathy similar to peripheral neuropathies [2]. Retinal structural neuronal damage in diabetes is demonstrated through dysfunction of the neurosensory 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 electrophysiological activity, dark adaptation, contrast sensitivity, or color vision [3,4]. The relative independence 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].
4
Department of Endocrinology and Nutrition, Health Sciences Research Institute & University Hospital Germans Trias i Pujol, Badalona, Spain
*Correspondence: [email protected] (D. Mauricio).
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.
2
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
Trends in Endocrinology & Metabolism
determined through decreased glomerular filtration and albuminuria. In addition, fibroblasts interconnect vessels with tubular epithelial cells to provide a scaffold-like structure, and therefore besides glomerular structures, diabetes also harms the renal tubules. This is demonstrated through epithelial degeneration, myofibroblast accumulation, nodular or diffuse glomerulosclerosis, tubulointerstitial disease, tubular atrophy, and renal arteriolar hyalinosis [8]. Tubular dysfunction is considered to be closely correlated with glomerular injury, typically found in advanced stages of DN [8]. However, this may be challenged by different observations: firstly, tubulointerstitial fibrosis is better correlated with DN progression than glomerular changes [8]. Secondly, although tubular changes may be more evident at later stages of DN, there is evidence of subtle tubular damage in early DN, with impaired tubular reabsorption and excretion of proteins that originate in the tubular interstitium, which could explain the dissociation between microalbuminuria and glomerular structural changes in early stages of DN [9]. Peripheral Nerves Diabetic neuropathy is traditionally considered a microvascular complication of diabetes in which nerve ischemia leads to motor, sensory, and autonomic neuropathy. However, these conditions cannot be explained by nerve ischemia alone, and diabetic neuropathy is considered to actually arise from a combination of microvascular dysfunction and neuronal deficits [10]. Vasa nervorum damage (i.e., vasoconstriction, capillary basement membrane thickening, and endothelial hyperplasia) leads to endoneurial hypoxemia and nerve hypoperfusion [10]. In addition, damage of the nerve fibers is also the result of the metabolic cellular injury triggered by the deleterious effects of long-term hyperglycemia and dyslipidemia [10]. The confluence of metabolic and vascular disturbances contributes to nerve hypoperfusion and loss of neurotrophic support, further leading to nerve dysfunction and eventually apoptosis of neurons, Schwann cells, and glial cells of the peripheral nerve [10]. The neurovascular dysfunction due to microcirculatory and also metabolic damage in peripheral nerve small fibers has been shown to contribute, for instance, to the development of pain and foot ulceration in T2D irrespective of the presence of macrovascular disease [11,12]. In addition, cardiovascular autonomic neuropathy (CAN) is another often-overlooked clinically relevant complication of diabetes. It refers to the impairment of autonomic nerve fibers that innervate the heart and blood vessels [13]. It starts with increased sympathetic tone and evolves to denervation, which progressively compromises ventricle function, contributing to cardiomyopathy [14], increasing the risk of arrhythmias, silent myocardial infarction and death [15].
Macrovascular Disease in Diabetes Is Not Only Macrovascular Arterial Wall as a Target of Diabetes Diabetes is traditionally seen as an accelerated atherosclerosis process in which the disease has a role in the proneness to plaque formation, vulnerability, and rupture. This could be explained by a synergistic effect of mechanisms shown to be different in diabetes: thinner fibrous caps, increased lipid deposition and calcification in the intima, increased plaque intimal neovascularization and inflammation, increased hypercoagulability, increased intraplaque hemorrhage, and impaired endothelial repair [16].
Glossary Cardiovascular autonomic neuropathy: peripheral neuropathy that affects the nerves that control the cardiovascular system. Cerebral small vessel disease: this entity designates different diseases affecting the small arteries, arterioles, venules, and capillaries of the brain, and refers to several pathological processes and etiologies. In this article, we only deal with CSVD in diabetes. Diabetic cardiomyopathy: heart condition that develops as a result of diabetes defined by ventricular dysfunction in the absence of coronary atherosclerosis and hypertension. Diabetic macroangiopathy (or diabetic macrovascular disease): this is the term used to define the complication of diabetes affecting large arterial vessels, usually through an accelerated atherosclerotic process. This is usually classified according to the vascular territories that are affected: PAD, CAD, and cerebrovascular disease. Diabetic microangiopathy (diabetic microvascular disease): this is the term used to define the complication of diabetes affecting small vessels. This is usually classified according to the microvascular beds affected: retinal microcirculation (DR), glomerular microvessels (DN) and peripheral nerves (DPN). Nonalcoholic fatty liver disease: histopathological spectrum of liver conditions ranging from simple liver steatosis (accumulation of liver droplets in N5% of hepatocytes) to steatohepatitis, with varying degree of liver fibrosis, and cirrhosis. Tubulointerstitial disease: condition that results in tubular and interstitial injury of the kidney (in contrast to those conditions resulting in glomerular injury). Vasa nervorum: small vessel that provides blood supply to peripheral nerve. Vasa vasorum: the plexus of microvessels that provide blood supply to the external part of the arterial wall of the arteries.
In atherosclerotic disease, when the intima has proliferated beyond a critical thickness, neovascularization 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 immature 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
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
3
Trends in Endocrinology & Metabolism
[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 perineovascular 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 development 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 plaquefree segments of the common carotid adventitial V V in T2D patients without previous CVD compared 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 patients 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 diabetic patients showed that the density of coronary V V is lower among patients with DM compared 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 atherosclerosis, probably since ICAS is less common. This could be explained by the comparative paucity 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 atherosclerotic 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 popliteal artery VV and calcification of the media layer were more frequent among diabetic than in nondiabetic 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 atherosclerotic 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 involved 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 4
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
Trends in Endocrinology & Metabolism
consider that 90% of the myocardial blood volume corresponds to the microvascular compartment, while the remaining 10% is composed of arteries and veins located in the epicardial surface. 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 reactivity, 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 patients with T2D than in controls, and that DR was a risk factor related to the presence of myocardial 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 coronary atherosclerosis and hypertension [38]. The pathogenesis of DCM involves multiple mechanisms, 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 patients 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, abnormal foot pressures, abnormal joint mobility, and minor trauma [44]. However, impaired skin microvascular 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 diabetes 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 microvasculardriven 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 neurodegenerative condition affecting brain capillaries that leads to vascular occlusion and stroke [49]. Additionally, 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 because 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
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
5
Trends in Endocrinology & Metabolism
others [52,53]. Indeed, CSVD shows radiological ischemic and nonischemic findings such as lacunar infarcts, white matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy [40,49]. These changes share mechanisms with other microvascular complications, 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 similarities between the blood–brain and blood–retinal barriers, and that the retina is, from an anatomical 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 disease 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 microangiopathy, 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 ventilatory 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 function 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 subjects [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 studies 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 6
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
Trends in Endocrinology & Metabolism
the ultrasonographic assessment of NAFLD could be used as a screening tool to assess the degree of diabetic micro- and macrovascular complications [76]. Cancer The evidence for an increased risk of carcinogenesis in both T1D and T2D compared with the 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 compared to normoglycemic individuals [78,79]. Although the risk is higher for overall cancer incidence, 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 understood, but hyperglycemia, insulin resistance, and/or hyperinsulinemia have been suggested 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, decreased antiapoptosis, increased cell migration and invasiveness, and activation of oncogenic pathways [82]. Moreover, hyperglycemia may also influence the development of metastasis and perineural invasion, it is correlated with toxicity to chemotherapy, and may contribute to the ineffectiveness of chemotherapy [81]. Although the mechanisms underlying insulin resistance and/or hyperinsulinemia and cancer remain unclear, some explanations include the oncogenic potential of chronic hyperinsulinemia through the abnormal stimulation of multiple cellular signaling cascades, the direct insulin-induced tumor growth, and the increased mitogenic and antiapoptotic effects exerted by insulin growth factors [83].
Concluding Remarks and Future Perspectives Based on all the pieces of evidence, it is clear that chronic-diabetes-related complications go beyond vascular events, and also that the allocation between macro- and microvascular events is in itself artificial. There is a need to increase awareness that DM is a generalized disorder that encompasses 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 DM, so that, when facing a patient with DM, and also when developing hypotheses and research questions, a broader approach is taken to account for the presence of further concomitant pathological changes in all system organs and potential clinical repercussions. Only from a comprehensive view, investigators and clinicians will be able to accurately diagnose, treat and manage patients with DM.
Outstanding Questions What are the pathophysiologic mechanisms of retinal and central nervous system diabetes-related damage leading to neuronal dysfunction and neurodegeneration? What are the pathogenetic mechanisms of diabetic tubulointerstitial kidney damage? What is the role and contribution of nonglomerular kidney damage in diabetic chronic kidney disease? What is the role of large-vessel-wall microangiopathy in the development of diabetic atherosclerotic disease? What is the contribution of lower-limb microangiopathy in the pathogenesis of DF disease? What is the contribution and pathogenesis of diabetes-related CSVD to CeVD in diabetes? What are the pathogenetic mechanisms of DCM: metabolic damage to cardiomyocytes and myocardial microangiopathy? What is the contribution of these factors to DCM in both T1D and T2D? Further investigation is necessary on lung microangiopathy and its clinical expression in diabetes. Further investigation is needed on the diabetes-specific pathogenesis of NAFLD. What are the mechanisms involved in diabetes-induced carcinogenesis?
Acknowledgments 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.
References 1. 2. 3. 4. 5.
6.
7.
Solomon, S.D. et al. (2017) Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care 40, 412–418 Gardner, T.W. et al. (2011) An integrated approach to diabetic retinopathy research. Arch. Ophthalmol. 129, 230–235 Lynch, S.K. and Abramoff, M.D. (2017) Diabetic retinopathy is a neurodegenerative disorder. Vis. Res. 139, 101–107 Simo, R. et al. (2018) Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia 61, 1902–1912 Tavares Ferreira, J. et al. (2016) Retinal neurodegeneration in diabetic patients without diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 57, 6455–6460 Carbonell, M. et al. (2019) Assessment of inner retinal layers and choroidal thickness in Type 1 diabetes mellitus: a crosssectional study. J. Clin. Med. Published online September 8, 2019. https://doi.org/10.3390/jcm8091412 Santos, A.R. et al. (2017) Functional and structural findings of neurodegeneration in early stages of diabetic retinopathy: cross-
8. 9. 10. 11.
12.
13.
sectional analyses of baseline data of the EUROCONDOR Project. Diabetes 66, 2503–2510 Thomas, M.C. et al. (2015) Diabetic kidney disease. Nat. Rev. Dis. Primers 1, 15018 Ziyadeh, F.N. and Goldfarb, S. (1991) The renal tubulointerstitium in diabetes mellitus. Kidney Int. 39, 464–475 Vincent, A.M. et al. (2011) Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat. Rev. Neurol. 7, 573–583 Korei, A.E. et al. (2016) Small-fiber neuropathy: a diabetic microvascular complication of special clinical, diagnostic, and prognostic importance. Angiology 67, 49–57 Eleftheriadou, I. et al. (2019) The association of diabetic microvascular and macrovascular disease with cutaneous circulation in patients with type 2 diabetes mellitus. J. Diabetes Complicat. 33, 165–170 Tesfaye, S. et al. (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33, 2285–2293
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
7
Trends in Endocrinology & Metabolism
14. Verrotti, A. et al. (2014) Autonomic neuropathy in diabetes mellitus. Front. Endocrinol. (Lausanne) 5, 205 15. Maser, R.E. et al. (2003) The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 26, 1895–1901 16. Rai, V. and Agrawal, D.K. (2017) Pathogenesis of the plaque vulnerability in diabetes mellitus. In Mechanisms of Vascular Defects in Diabetes Mellitus (Kartha, C.C. et al., eds), pp. 95–107, Springer Nature 17. Moulton, K.S. (2006) Angiogenesis in atherosclerosis: gathering evidence beyond speculation. Curr. Opin. Lipidol. 17, 548–555 18. Chistiakov, D.A. et al. (2015) Contribution of neovascularization and intraplaque haemorrhage to atherosclerotic plaque progression and instability. Acta Physiol. 213, 539–553 19. Carter, A. et al. (2007) Intimal neovascularisation is a prominent feature of atherosclerotic plaques in diabetic patients with critical limb ischaemia. Eur. J. Vasc. Endovasc. Surg. 33, 319–324 20. Hayden, M.R. and Tyagi, S.C. (2004) Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: a malignant transformation. Cardiovasc. Diabetol. 3, 1 21. Purushothaman, K.R. et al. (2007) Inflammation and neovascularization in diabetic atherosclerosis. Indian J. Exp. Biol. 45, 93–102 22. Purushothaman, K.R. et al. (2011) Inflammation, neovascularization and intra-plaque hemorrhage are associated with increased reparative collagen content: implication for plaque progression in diabetic atherosclerosis. Vasc. Med. 16, 103–108 23. Arcidiacono, M.V. et al. (2013) Microangiopathy of large artery wall: a neglected complication of diabetes mellitus. Atherosclerosis 228, 142–147 24. Angervall, L. et al. (1966) The aortic vasa vasorum in juvenile diabetes. Pathol. Microbiol. (Basel) 29, 431–437 25. Rubinat, E. et al. (2015) Microangiopathy of common carotid vasa vasorum in type 1 diabetes mellitus. Atherosclerosis 241, 334–338 26. Sampson, U.K. et al. (2015) Carotid adventitial vasa vasorum and intima-media thickness in a primary prevention population. Echocardiography 32, 264–270 27. Gerstein, H.C. et al. (2019) Dysglycemia and the density of the coronary vasa vasorum. Diabetes Care 42, 980–982 28. Portanova, A. et al. (2013) Intracranial vasa vasorum: insights and implications for imaging. Radiology 267, 667–679 29. Uehara, T. et al. (2005) Risk factors for occlusive lesions of intracranial arteries in stroke-free Japanese. Eur. J. Neurol. 12, 218–222 30. Bae, H.J. et al. (2007) Risk factors of intracranial cerebral atherosclerosis among asymptomatics. Cerebrovasc. Dis. 24, 355–360 31. Santos, V.P. et al. (2008) Comparative histological study of atherosclerotic lesions and microvascular changes in amputated lower limbs of diabetic and non-diabetic patients. Arq. Bras. Endocrinol. Metabol. 52, 1115–1123 32. Orrico, C. et al. (2010) Dysfunctional vasa vasorum in diabetic peripheral artery obstructive disease with critical lower limb ischaemia. Eur. J. Vasc. Endovasc. Surg. 40, 365–374 33. Ostlund Papadogeorgos, N. et al. (2016) Severely impaired microvascular reactivity in diabetic patients with an acute coronary syndrome. Cardiovasc. Diabetol. 15, 66 34. Hernandez, C. et al. (2011) Prevalence and risk factors accounting for true silent myocardial ischemia: a pilot case-control study comparing type 2 diabetic with non-diabetic control subjects. Cardiovasc. Diabetol. 10, 9 35. Gottsater, A. et al. (2003) Cardiovascular autonomic neuropathy associated with carotid atherosclerosis in Type 2 diabetic patients. Diabet. Med. 20, 495–499 36. Gottsater, A. et al. (2006) Decreased heart rate variability may predict the progression of carotid atherosclerosis in type 2 diabetes. Clin. Auton. Res. 16, 228–234 37. Pereira Jr., V.L. et al. (2017) Association between carotid intima media thickness and heart rate variability in adults at increased cardiovascular risk. Front. Physiol. 8, 248 38. Authors/Task Force, M et al. (2013) ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes,
8
39.
40.
41. 42.
43.
44.
45.
46.
47.
48.
49.
50.
51. 52. 53.
54.
55.
56. 57. 58. 59.
60.
61. 62. 63.
64.
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur. Heart J. 34, 3035–3087 Alonso, N. et al. (2018) Pathogenesis, clinical features and treatment of diabetic cardiomyopathy. Adv. Exp. Med. Biol. 1067, 197–217 Barrett, E.J. et al. (2017) Diabetic microvascular disease: an Endocrine Society Scientific statement. J. Clin. Endocrinol. Metab. 102, 4343–4410 Shome, J.S. et al. (2017) Current perspectives in coronary microvascular dysfunction. Microcirculation 24, e12340 American Diabetes Association (ADA) (2003) Peripheral arterial disease in people with diabetes. Diabetes Care 26, 3333–3341 Thiruvoipati, T. et al. (2015) Peripheral artery disease in patients with diabetes: Epidemiology, mechanisms, and outcomes. World J. Diabetes 6, 961–969 Reiber, G.E. et al. (1999) Causal pathways for incident lowerextremity ulcers in patients with diabetes from two settings. Diabetes Care 22, 157–162 Jorneskog, G. et al. (1995) Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications. Diabetologia 38, 474–480 Jorneskog, G. et al. (1995) Skin capillary circulation is more impaired in the toes of diabetic than non-diabetic patients with peripheral vascular disease. Diabet. Med. 12, 36–41 Jorneskog, G. et al. (1998) Pronounced skin capillary ischemia in the feet of diabetic patients with bad metabolic control. Diabetologia 41, 410–415 Sutherland, G.T. et al. (2017) Epidemiological approaches to understanding the link between type 2 diabetes and dementia. J. Alzheimers Dis. 59, 393–403 Funnell, C. et al. (2017) What is the relationship between type 2 diabetes mellitus status and the neuroradiological correlates of cerebral small vessel disease in adults? Protocol for a systematic review. Syst. Rev. 6, 7 Hatzitolios, A.I. et al. (2009) Diabetes mellitus and cerebrovascular disease: which are the actual data? J. Diabetes Complicat. 23, 283–296 Prasad, S. et al. (2014) Diabetes mellitus and blood-brain barrier dysfunction: an overview. J. Pharmacovigil. 2, 125 Mayeda, E.R. et al. (2015) Diabetes and cognition. Clin. Geriatr. Med. 31, 101–115, ix Simo, R. et al. (2017) Cognitive impairment and dementia: a new emerging complication of type 2 diabetes – the diabetologist’s perspective. Acta Diabetol. 54, 417–424 Sanahuja, J. et al. (2016) Increased burden of cerebral small vessel disease in patients with type 2 diabetes and retinopathy. Diabetes Care 39, 1614–1620 Umemura, T. et al. (2017) Pathogenesis and neuroimaging of cerebral large and small vessel disease in type 2 diabetes: a possible link between cerebral and retinal microvascular abnormalities. J. Diabetes Investig. 8, 134–148 London, A. et al. (2013) The retina as a window to the brain-from eye research to CNS disorders. Nat. Rev. Neurol. 9, 44–53 Hsia, C.C. and Raskin, P. (2008) Lung involvement in diabetes: does it matter? Diabetes Care 31, 828–829 Pitocco, D. et al. (2012) The diabetic lung – a new target organ? Rev. Diabet. Stud. 9, 23–35 Lecube, A. et al. (2017) Pulmonary function and sleep breathing: two new targets for type 2 diabetes care. Endocr. Rev. 38, 550–573 Vracko, R. et al. (1979) Basal lamina of alveolar epithelium and capillaries: quantitative changes with aging and in diabetes mellitus. Am. Rev. Respir. Dis. 120, 973–983 Kodolova, I.M. et al. (1982) Changes in the lungs in diabetes mellitus. Arkh. Patol. 44, 35–40 Weynand, B. et al. (1999) Diabetes mellitus induces a thickening of the pulmonary basal lamina. Respiration 66, 14–19 Klein, O.L. et al. (2010) Systematic review of the association between lung function and Type 2 diabetes mellitus. Diabet. Med. 27, 977–987 Sandler, M. (1990) Is the lung a ‘target organ’ in diabetes mellitus? Arch. Intern. Med. 150, 1385–1388
Trends in Endocrinology & Metabolism
65. Kaparianos, A. et al. (2008) Pulmonary complications in diabetes mellitus. Chron. Respir. Dis. 5, 101–108 66. Klein, O.L. et al. (2012) Lung spirometry parameters and diffusion capacity are decreased in patients with Type 2 diabetes. Diabet. Med. 29, 212–219 67. Martin-Frias, M. et al. (2015) Pulmonary function in children with type 1 diabetes mellitus. J. Pediatr. Endocrinol. Metab. 28, 163–169 68. Roberts, T.J. et al. (2018) Diagnosis and significance of pulmonary microvascular disease in diabetes. Diabetes Care 41, 854–861 69. Gutierrez-Carrasquilla, L. et al. (2019) Effect of glucose improvement on spirometric maneuvers in patients with type 2 diabetes: the Sweet Breath Study. Diabetes Care 42, 617–624 70. Mikolasevic, I. et al. (2016) Nonalcoholic fatty liver disease – a multisystem disease? World J. Gastroenterol. 22, 9488–9505 71. Byrne, C.D. and Targher, G. (2015) NAFLD: a multisystem disease. J. Hepatol. 62, S47–S64 72. McGavock, J.M. et al. (2007) Cardiac steatosis in diabetes mellitus: a 1 H-magnetic resonance spectroscopy study. Circulation 116, 1170–1175 73. Rijzewijk, L.J. et al. (2008) Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 52, 1793–1799 74. Bonapace, S. et al. (2012) Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 35, 389–395
75. Lautamaki, R. et al. (2006) Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 291, E282–E290 76. Suresh, E. et al. (2018) Association of microvascular and macrovascular complications with non alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus – a comparative cross sectional study. IOSR-JDMS 17, 10–17 77. Wojciechowska, J. et al. (2016) Diabetes and cancer: a review of current knowledge. Exp. Clin. Endocrinol. Diabetes 124, 263–275 78. Barone, B.B. et al. (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300, 2754–2764 79. Harding, J.L. et al. (2015) Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation. Diabetes Care 38, 734–735 80. Vigneri, P. et al. (2009) Diabetes and cancer. Endocr. Relat. Cancer 16, 1103–1123 81. Duan, W. et al. (2014) Hyperglycemia, a neglected factor during cancer progression. Biomed. Res. Int. 2014, 461917 82. Ryu, T.Y. et al. (2014) Hyperglycemia as a risk factor for cancer progression. Diabetes Metab. J. 38, 330–336 83. Arcidiacono, B. et al. (2012) Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp. Diabetes Res. 2012, 789174
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
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 micro- and macrovascular trees, with target organs considered as the paradigm of large vessel injury also entailing microangiopathic changes. However, complications independent or partially independent from vascular damage are often overlooked. This includes neuronal dysfunction (e.g., retinal neurodegeneration), interstitial injury (e.g., tubulointerstitial disease), metabolic damage (e.g., in the heart and liver), and nonclassical conditions such as cognitive decline, impaired pulmonary function, or increased risk of cancer. In this scenario, researchers, endocrinologists and primary care physicians should have a holistic view of the disease and pay further attention to all organs and all potential clinical repercussions, which would certainly contribute to a more rational and integrated patient health care.
Highlights Diabetes complications include pathological changes beyond the vascular system and classical target organs. Microangiopathy may affect nonclassical target organs. Organs affected by microangiopathy may also show neuronal or structural deficits including: neurodegeneration and neurodysfunction of the retina; structural changes in the kidney tubular interstitium; and nerve fiber dysfunction. Organs affected by macroangiopathy also show microvascular and neuronal deficits including: microangiopathy of the arterial wall; microangiopathy and neuropathic changes adding to ischemic and nonischemic heart disease; metabolic peripheral nerve damage; cerebral small vessel disease; and structural changes leading to cognitive impairment.
Diabetes Is a Multisystemic Disease Traditionally defined, long-term diabetes complications are largely seen as the consequence of vascular damage, categorized as either those affecting large vessels (macrovascular complications or diabetic macroangiopathy) (see Glossary) or those affecting microvessels (microvascular complications or diabetic microangiopathy). Microvascular complications include diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN), whereas macrovascular complications manifest as an increased risk of coronary artery disease (CAD), peripheral artery disease (PAD), and cerebrovascular disease (CeVD). This classification is convenient at the clinical level because it gives a broad idea of the comorbidity associated with diabetes and can be pragmatically translated into prevention, treatment, and management recommendations. However, microangiopathy (and all the diabetes-specific mechanisms 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 classification (Figure 1). We hereby provide a general view about organs, tissues or cell types not usually 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 damage in these overlooked structures also leads to (or aggravates) diabetes–related damage.
Microvascular Disease in Diabetes Is Not Only Microvascular Retinal Neurodegeneration Diabetic retinopathy (DR) is the prime example of microangiopathy and the most common and well-studied ocular complication of diabetes. However, vascular and neural components (i.e., neurons and glia) of the retinal parenchyma are intimately interconnected at the metabolic and structural levels in the so-called neurovascular unit. Blood vessels feed the neural component of the retina, but they represent less than 5% of the retinal mass. Therefore, it is not surprising that DR encompasses concomitant vascular abnormalities and nonvascular damage, namely Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
Nonclassical chronic complications include abnormal pulmonary function and microangiopathy, metabolic liver and myocardial damage, and increased risk of carcinogenesis.
1
DAP–Cat group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain 2 CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain 3 Department of Endocrinology and Nutrition, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain
https://doi.org/10.1016/j.tem.2020.01.007 © 2020 Elsevier Ltd. All rights reserved.
1
Trends in Endocrinology & Metabolism
neurodysfunction and neurodegeneration. Indeed, the recent position statement of the American Diabetes Association on DR states that it is ‘a highly specific neurovascular complication’ [1], which is a more inclusive definition. Moreover, some have proposed that it should be viewed as a sensory neuropathy similar to peripheral neuropathies [2]. Retinal structural neuronal damage in diabetes is demonstrated through dysfunction of the neurosensory 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 electrophysiological activity, dark adaptation, contrast sensitivity, or color vision [3,4]. The relative independence 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].
4
Department of Endocrinology and Nutrition, Health Sciences Research Institute & University Hospital Germans Trias i Pujol, Badalona, Spain
*Correspondence: [email protected] (D. Mauricio).
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.
2
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
Trends in Endocrinology & Metabolism
determined through decreased glomerular filtration and albuminuria. In addition, fibroblasts interconnect vessels with tubular epithelial cells to provide a scaffold-like structure, and therefore besides glomerular structures, diabetes also harms the renal tubules. This is demonstrated through epithelial degeneration, myofibroblast accumulation, nodular or diffuse glomerulosclerosis, tubulointerstitial disease, tubular atrophy, and renal arteriolar hyalinosis [8]. Tubular dysfunction is considered to be closely correlated with glomerular injury, typically found in advanced stages of DN [8]. However, this may be challenged by different observations: firstly, tubulointerstitial fibrosis is better correlated with DN progression than glomerular changes [8]. Secondly, although tubular changes may be more evident at later stages of DN, there is evidence of subtle tubular damage in early DN, with impaired tubular reabsorption and excretion of proteins that originate in the tubular interstitium, which could explain the dissociation between microalbuminuria and glomerular structural changes in early stages of DN [9]. Peripheral Nerves Diabetic neuropathy is traditionally considered a microvascular complication of diabetes in which nerve ischemia leads to motor, sensory, and autonomic neuropathy. However, these conditions cannot be explained by nerve ischemia alone, and diabetic neuropathy is considered to actually arise from a combination of microvascular dysfunction and neuronal deficits [10]. Vasa nervorum damage (i.e., vasoconstriction, capillary basement membrane thickening, and endothelial hyperplasia) leads to endoneurial hypoxemia and nerve hypoperfusion [10]. In addition, damage of the nerve fibers is also the result of the metabolic cellular injury triggered by the deleterious effects of long-term hyperglycemia and dyslipidemia [10]. The confluence of metabolic and vascular disturbances contributes to nerve hypoperfusion and loss of neurotrophic support, further leading to nerve dysfunction and eventually apoptosis of neurons, Schwann cells, and glial cells of the peripheral nerve [10]. The neurovascular dysfunction due to microcirculatory and also metabolic damage in peripheral nerve small fibers has been shown to contribute, for instance, to the development of pain and foot ulceration in T2D irrespective of the presence of macrovascular disease [11,12]. In addition, cardiovascular autonomic neuropathy (CAN) is another often-overlooked clinically relevant complication of diabetes. It refers to the impairment of autonomic nerve fibers that innervate the heart and blood vessels [13]. It starts with increased sympathetic tone and evolves to denervation, which progressively compromises ventricle function, contributing to cardiomyopathy [14], increasing the risk of arrhythmias, silent myocardial infarction and death [15].
Macrovascular Disease in Diabetes Is Not Only Macrovascular Arterial Wall as a Target of Diabetes Diabetes is traditionally seen as an accelerated atherosclerosis process in which the disease has a role in the proneness to plaque formation, vulnerability, and rupture. This could be explained by a synergistic effect of mechanisms shown to be different in diabetes: thinner fibrous caps, increased lipid deposition and calcification in the intima, increased plaque intimal neovascularization and inflammation, increased hypercoagulability, increased intraplaque hemorrhage, and impaired endothelial repair [16].
Glossary Cardiovascular autonomic neuropathy: peripheral neuropathy that affects the nerves that control the cardiovascular system. Cerebral small vessel disease: this entity designates different diseases affecting the small arteries, arterioles, venules, and capillaries of the brain, and refers to several pathological processes and etiologies. In this article, we only deal with CSVD in diabetes. Diabetic cardiomyopathy: heart condition that develops as a result of diabetes defined by ventricular dysfunction in the absence of coronary atherosclerosis and hypertension. Diabetic macroangiopathy (or diabetic macrovascular disease): this is the term used to define the complication of diabetes affecting large arterial vessels, usually through an accelerated atherosclerotic process. This is usually classified according to the vascular territories that are affected: PAD, CAD, and cerebrovascular disease. Diabetic microangiopathy (diabetic microvascular disease): this is the term used to define the complication of diabetes affecting small vessels. This is usually classified according to the microvascular beds affected: retinal microcirculation (DR), glomerular microvessels (DN) and peripheral nerves (DPN). Nonalcoholic fatty liver disease: histopathological spectrum of liver conditions ranging from simple liver steatosis (accumulation of liver droplets in N5% of hepatocytes) to steatohepatitis, with varying degree of liver fibrosis, and cirrhosis. Tubulointerstitial disease: condition that results in tubular and interstitial injury of the kidney (in contrast to those conditions resulting in glomerular injury). Vasa nervorum: small vessel that provides blood supply to peripheral nerve. Vasa vasorum: the plexus of microvessels that provide blood supply to the external part of the arterial wall of the arteries.
In atherosclerotic disease, when the intima has proliferated beyond a critical thickness, neovascularization 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 immature 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
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
3
Trends in Endocrinology & Metabolism
[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 perineovascular 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 development 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 plaquefree segments of the common carotid adventitial V V in T2D patients without previous CVD compared 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 patients 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 diabetic patients showed that the density of coronary V V is lower among patients with DM compared 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 atherosclerosis, probably since ICAS is less common. This could be explained by the comparative paucity 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 atherosclerotic 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 popliteal artery VV and calcification of the media layer were more frequent among diabetic than in nondiabetic 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 atherosclerotic 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 involved 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 4
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
Trends in Endocrinology & Metabolism
consider that 90% of the myocardial blood volume corresponds to the microvascular compartment, while the remaining 10% is composed of arteries and veins located in the epicardial surface. 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 reactivity, 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 patients with T2D than in controls, and that DR was a risk factor related to the presence of myocardial 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 coronary atherosclerosis and hypertension [38]. The pathogenesis of DCM involves multiple mechanisms, 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 patients 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, abnormal foot pressures, abnormal joint mobility, and minor trauma [44]. However, impaired skin microvascular 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 diabetes 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 microvasculardriven 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 neurodegenerative condition affecting brain capillaries that leads to vascular occlusion and stroke [49]. Additionally, 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 because 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
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
5
Trends in Endocrinology & Metabolism
others [52,53]. Indeed, CSVD shows radiological ischemic and nonischemic findings such as lacunar infarcts, white matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy [40,49]. These changes share mechanisms with other microvascular complications, 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 similarities between the blood–brain and blood–retinal barriers, and that the retina is, from an anatomical 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 disease 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 microangiopathy, 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 ventilatory 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 function 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 subjects [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 studies 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 6
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
Trends in Endocrinology & Metabolism
the ultrasonographic assessment of NAFLD could be used as a screening tool to assess the degree of diabetic micro- and macrovascular complications [76]. Cancer The evidence for an increased risk of carcinogenesis in both T1D and T2D compared with the 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 compared to normoglycemic individuals [78,79]. Although the risk is higher for overall cancer incidence, 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 understood, but hyperglycemia, insulin resistance, and/or hyperinsulinemia have been suggested 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, decreased antiapoptosis, increased cell migration and invasiveness, and activation of oncogenic pathways [82]. Moreover, hyperglycemia may also influence the development of metastasis and perineural invasion, it is correlated with toxicity to chemotherapy, and may contribute to the ineffectiveness of chemotherapy [81]. Although the mechanisms underlying insulin resistance and/or hyperinsulinemia and cancer remain unclear, some explanations include the oncogenic potential of chronic hyperinsulinemia through the abnormal stimulation of multiple cellular signaling cascades, the direct insulin-induced tumor growth, and the increased mitogenic and antiapoptotic effects exerted by insulin growth factors [83].
Concluding Remarks and Future Perspectives Based on all the pieces of evidence, it is clear that chronic-diabetes-related complications go beyond vascular events, and also that the allocation between macro- and microvascular events is in itself artificial. There is a need to increase awareness that DM is a generalized disorder that encompasses 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 DM, so that, when facing a patient with DM, and also when developing hypotheses and research questions, a broader approach is taken to account for the presence of further concomitant pathological changes in all system organs and potential clinical repercussions. Only from a comprehensive view, investigators and clinicians will be able to accurately diagnose, treat and manage patients with DM.
Outstanding Questions What are the pathophysiologic mechanisms of retinal and central nervous system diabetes-related damage leading to neuronal dysfunction and neurodegeneration? What are the pathogenetic mechanisms of diabetic tubulointerstitial kidney damage? What is the role and contribution of nonglomerular kidney damage in diabetic chronic kidney disease? What is the role of large-vessel-wall microangiopathy in the development of diabetic atherosclerotic disease? What is the contribution of lower-limb microangiopathy in the pathogenesis of DF disease? What is the contribution and pathogenesis of diabetes-related CSVD to CeVD in diabetes? What are the pathogenetic mechanisms of DCM: metabolic damage to cardiomyocytes and myocardial microangiopathy? What is the contribution of these factors to DCM in both T1D and T2D? Further investigation is necessary on lung microangiopathy and its clinical expression in diabetes. Further investigation is needed on the diabetes-specific pathogenesis of NAFLD. What are the mechanisms involved in diabetes-induced carcinogenesis?
Acknowledgments 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.
References 1. 2. 3. 4. 5.
6.
7.
Solomon, S.D. et al. (2017) Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care 40, 412–418 Gardner, T.W. et al. (2011) An integrated approach to diabetic retinopathy research. Arch. Ophthalmol. 129, 230–235 Lynch, S.K. and Abramoff, M.D. (2017) Diabetic retinopathy is a neurodegenerative disorder. Vis. Res. 139, 101–107 Simo, R. et al. (2018) Neurodegeneration in diabetic retinopathy: does it really matter? Diabetologia 61, 1902–1912 Tavares Ferreira, J. et al. (2016) Retinal neurodegeneration in diabetic patients without diabetic retinopathy. Invest. Ophthalmol. Vis. Sci. 57, 6455–6460 Carbonell, M. et al. (2019) Assessment of inner retinal layers and choroidal thickness in Type 1 diabetes mellitus: a crosssectional study. J. Clin. Med. Published online September 8, 2019. https://doi.org/10.3390/jcm8091412 Santos, A.R. et al. (2017) Functional and structural findings of neurodegeneration in early stages of diabetic retinopathy: cross-
8. 9. 10. 11.
12.
13.
sectional analyses of baseline data of the EUROCONDOR Project. Diabetes 66, 2503–2510 Thomas, M.C. et al. (2015) Diabetic kidney disease. Nat. Rev. Dis. Primers 1, 15018 Ziyadeh, F.N. and Goldfarb, S. (1991) The renal tubulointerstitium in diabetes mellitus. Kidney Int. 39, 464–475 Vincent, A.M. et al. (2011) Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat. Rev. Neurol. 7, 573–583 Korei, A.E. et al. (2016) Small-fiber neuropathy: a diabetic microvascular complication of special clinical, diagnostic, and prognostic importance. Angiology 67, 49–57 Eleftheriadou, I. et al. (2019) The association of diabetic microvascular and macrovascular disease with cutaneous circulation in patients with type 2 diabetes mellitus. J. Diabetes Complicat. 33, 165–170 Tesfaye, S. et al. (2010) Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 33, 2285–2293
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
7
Trends in Endocrinology & Metabolism
14. Verrotti, A. et al. (2014) Autonomic neuropathy in diabetes mellitus. Front. Endocrinol. (Lausanne) 5, 205 15. Maser, R.E. et al. (2003) The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 26, 1895–1901 16. Rai, V. and Agrawal, D.K. (2017) Pathogenesis of the plaque vulnerability in diabetes mellitus. In Mechanisms of Vascular Defects in Diabetes Mellitus (Kartha, C.C. et al., eds), pp. 95–107, Springer Nature 17. Moulton, K.S. (2006) Angiogenesis in atherosclerosis: gathering evidence beyond speculation. Curr. Opin. Lipidol. 17, 548–555 18. Chistiakov, D.A. et al. (2015) Contribution of neovascularization and intraplaque haemorrhage to atherosclerotic plaque progression and instability. Acta Physiol. 213, 539–553 19. Carter, A. et al. (2007) Intimal neovascularisation is a prominent feature of atherosclerotic plaques in diabetic patients with critical limb ischaemia. Eur. J. Vasc. Endovasc. Surg. 33, 319–324 20. Hayden, M.R. and Tyagi, S.C. (2004) Vasa vasorum in plaque angiogenesis, metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: a malignant transformation. Cardiovasc. Diabetol. 3, 1 21. Purushothaman, K.R. et al. (2007) Inflammation and neovascularization in diabetic atherosclerosis. Indian J. Exp. Biol. 45, 93–102 22. Purushothaman, K.R. et al. (2011) Inflammation, neovascularization and intra-plaque hemorrhage are associated with increased reparative collagen content: implication for plaque progression in diabetic atherosclerosis. Vasc. Med. 16, 103–108 23. Arcidiacono, M.V. et al. (2013) Microangiopathy of large artery wall: a neglected complication of diabetes mellitus. Atherosclerosis 228, 142–147 24. Angervall, L. et al. (1966) The aortic vasa vasorum in juvenile diabetes. Pathol. Microbiol. (Basel) 29, 431–437 25. Rubinat, E. et al. (2015) Microangiopathy of common carotid vasa vasorum in type 1 diabetes mellitus. Atherosclerosis 241, 334–338 26. Sampson, U.K. et al. (2015) Carotid adventitial vasa vasorum and intima-media thickness in a primary prevention population. Echocardiography 32, 264–270 27. Gerstein, H.C. et al. (2019) Dysglycemia and the density of the coronary vasa vasorum. Diabetes Care 42, 980–982 28. Portanova, A. et al. (2013) Intracranial vasa vasorum: insights and implications for imaging. Radiology 267, 667–679 29. Uehara, T. et al. (2005) Risk factors for occlusive lesions of intracranial arteries in stroke-free Japanese. Eur. J. Neurol. 12, 218–222 30. Bae, H.J. et al. (2007) Risk factors of intracranial cerebral atherosclerosis among asymptomatics. Cerebrovasc. Dis. 24, 355–360 31. Santos, V.P. et al. (2008) Comparative histological study of atherosclerotic lesions and microvascular changes in amputated lower limbs of diabetic and non-diabetic patients. Arq. Bras. Endocrinol. Metabol. 52, 1115–1123 32. Orrico, C. et al. (2010) Dysfunctional vasa vasorum in diabetic peripheral artery obstructive disease with critical lower limb ischaemia. Eur. J. Vasc. Endovasc. Surg. 40, 365–374 33. Ostlund Papadogeorgos, N. et al. (2016) Severely impaired microvascular reactivity in diabetic patients with an acute coronary syndrome. Cardiovasc. Diabetol. 15, 66 34. Hernandez, C. et al. (2011) Prevalence and risk factors accounting for true silent myocardial ischemia: a pilot case-control study comparing type 2 diabetic with non-diabetic control subjects. Cardiovasc. Diabetol. 10, 9 35. Gottsater, A. et al. (2003) Cardiovascular autonomic neuropathy associated with carotid atherosclerosis in Type 2 diabetic patients. Diabet. Med. 20, 495–499 36. Gottsater, A. et al. (2006) Decreased heart rate variability may predict the progression of carotid atherosclerosis in type 2 diabetes. Clin. Auton. Res. 16, 228–234 37. Pereira Jr., V.L. et al. (2017) Association between carotid intima media thickness and heart rate variability in adults at increased cardiovascular risk. Front. Physiol. 8, 248 38. Authors/Task Force, M et al. (2013) ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes,
8
39.
40.
41. 42.
43.
44.
45.
46.
47.
48.
49.
50.
51. 52. 53.
54.
55.
56. 57. 58. 59.
60.
61. 62. 63.
64.
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur. Heart J. 34, 3035–3087 Alonso, N. et al. (2018) Pathogenesis, clinical features and treatment of diabetic cardiomyopathy. Adv. Exp. Med. Biol. 1067, 197–217 Barrett, E.J. et al. (2017) Diabetic microvascular disease: an Endocrine Society Scientific statement. J. Clin. Endocrinol. Metab. 102, 4343–4410 Shome, J.S. et al. (2017) Current perspectives in coronary microvascular dysfunction. Microcirculation 24, e12340 American Diabetes Association (ADA) (2003) Peripheral arterial disease in people with diabetes. Diabetes Care 26, 3333–3341 Thiruvoipati, T. et al. (2015) Peripheral artery disease in patients with diabetes: Epidemiology, mechanisms, and outcomes. World J. Diabetes 6, 961–969 Reiber, G.E. et al. (1999) Causal pathways for incident lowerextremity ulcers in patients with diabetes from two settings. Diabetes Care 22, 157–162 Jorneskog, G. et al. (1995) Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications. Diabetologia 38, 474–480 Jorneskog, G. et al. (1995) Skin capillary circulation is more impaired in the toes of diabetic than non-diabetic patients with peripheral vascular disease. Diabet. Med. 12, 36–41 Jorneskog, G. et al. (1998) Pronounced skin capillary ischemia in the feet of diabetic patients with bad metabolic control. Diabetologia 41, 410–415 Sutherland, G.T. et al. (2017) Epidemiological approaches to understanding the link between type 2 diabetes and dementia. J. Alzheimers Dis. 59, 393–403 Funnell, C. et al. (2017) What is the relationship between type 2 diabetes mellitus status and the neuroradiological correlates of cerebral small vessel disease in adults? Protocol for a systematic review. Syst. Rev. 6, 7 Hatzitolios, A.I. et al. (2009) Diabetes mellitus and cerebrovascular disease: which are the actual data? J. Diabetes Complicat. 23, 283–296 Prasad, S. et al. (2014) Diabetes mellitus and blood-brain barrier dysfunction: an overview. J. Pharmacovigil. 2, 125 Mayeda, E.R. et al. (2015) Diabetes and cognition. Clin. Geriatr. Med. 31, 101–115, ix Simo, R. et al. (2017) Cognitive impairment and dementia: a new emerging complication of type 2 diabetes – the diabetologist’s perspective. Acta Diabetol. 54, 417–424 Sanahuja, J. et al. (2016) Increased burden of cerebral small vessel disease in patients with type 2 diabetes and retinopathy. Diabetes Care 39, 1614–1620 Umemura, T. et al. (2017) Pathogenesis and neuroimaging of cerebral large and small vessel disease in type 2 diabetes: a possible link between cerebral and retinal microvascular abnormalities. J. Diabetes Investig. 8, 134–148 London, A. et al. (2013) The retina as a window to the brain-from eye research to CNS disorders. Nat. Rev. Neurol. 9, 44–53 Hsia, C.C. and Raskin, P. (2008) Lung involvement in diabetes: does it matter? Diabetes Care 31, 828–829 Pitocco, D. et al. (2012) The diabetic lung – a new target organ? Rev. Diabet. Stud. 9, 23–35 Lecube, A. et al. (2017) Pulmonary function and sleep breathing: two new targets for type 2 diabetes care. Endocr. Rev. 38, 550–573 Vracko, R. et al. (1979) Basal lamina of alveolar epithelium and capillaries: quantitative changes with aging and in diabetes mellitus. Am. Rev. Respir. Dis. 120, 973–983 Kodolova, I.M. et al. (1982) Changes in the lungs in diabetes mellitus. Arkh. Patol. 44, 35–40 Weynand, B. et al. (1999) Diabetes mellitus induces a thickening of the pulmonary basal lamina. Respiration 66, 14–19 Klein, O.L. et al. (2010) Systematic review of the association between lung function and Type 2 diabetes mellitus. Diabet. Med. 27, 977–987 Sandler, M. (1990) Is the lung a ‘target organ’ in diabetes mellitus? Arch. Intern. Med. 150, 1385–1388
Trends in Endocrinology & Metabolism
65. Kaparianos, A. et al. (2008) Pulmonary complications in diabetes mellitus. Chron. Respir. Dis. 5, 101–108 66. Klein, O.L. et al. (2012) Lung spirometry parameters and diffusion capacity are decreased in patients with Type 2 diabetes. Diabet. Med. 29, 212–219 67. Martin-Frias, M. et al. (2015) Pulmonary function in children with type 1 diabetes mellitus. J. Pediatr. Endocrinol. Metab. 28, 163–169 68. Roberts, T.J. et al. (2018) Diagnosis and significance of pulmonary microvascular disease in diabetes. Diabetes Care 41, 854–861 69. Gutierrez-Carrasquilla, L. et al. (2019) Effect of glucose improvement on spirometric maneuvers in patients with type 2 diabetes: the Sweet Breath Study. Diabetes Care 42, 617–624 70. Mikolasevic, I. et al. (2016) Nonalcoholic fatty liver disease – a multisystem disease? World J. Gastroenterol. 22, 9488–9505 71. Byrne, C.D. and Targher, G. (2015) NAFLD: a multisystem disease. J. Hepatol. 62, S47–S64 72. McGavock, J.M. et al. (2007) Cardiac steatosis in diabetes mellitus: a 1 H-magnetic resonance spectroscopy study. Circulation 116, 1170–1175 73. Rijzewijk, L.J. et al. (2008) Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J. Am. Coll. Cardiol. 52, 1793–1799 74. Bonapace, S. et al. (2012) Nonalcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in patients with type 2 diabetes. Diabetes Care 35, 389–395
75. Lautamaki, R. et al. (2006) Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 291, E282–E290 76. Suresh, E. et al. (2018) Association of microvascular and macrovascular complications with non alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus – a comparative cross sectional study. IOSR-JDMS 17, 10–17 77. Wojciechowska, J. et al. (2016) Diabetes and cancer: a review of current knowledge. Exp. Clin. Endocrinol. Diabetes 124, 263–275 78. Barone, B.B. et al. (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300, 2754–2764 79. Harding, J.L. et al. (2015) Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation. Diabetes Care 38, 734–735 80. Vigneri, P. et al. (2009) Diabetes and cancer. Endocr. Relat. Cancer 16, 1103–1123 81. Duan, W. et al. (2014) Hyperglycemia, a neglected factor during cancer progression. Biomed. Res. Int. 2014, 461917 82. Ryu, T.Y. et al. (2014) Hyperglycemia as a risk factor for cancer progression. Diabetes Metab. J. 38, 330–336 83. Arcidiacono, B. et al. (2012) Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp. Diabetes Res. 2012, 789174
Trends in Endocrinology & Metabolism, Month 2020, Vol. xx, No. xx
9