Can J Diabetes 37 (2013) 351e358

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Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.com

Review

The Genetic and Metabolic Determinants of Cardiovascular Complications in Type 2 Diabetes: Recent Insights from Animal Models and Clinical Investigations Rita Kohen Avramoglu PhD a, Marc-André Laplante PhD a, Khai Le Quang PhD a, Yves Deshaies PhD a, Jean-Pierre Després PhD, FACC, FAHA a, Eric Larose DVM, MD, FRCPC, FAHA a, Patrick Mathieu MD a, Paul Poirier MD, PhD, FRCPC, FAHA, FACC a, e, Louis Pérusse PhD b, Marie-Claude Vohl PhD b, Gary Sweeney PhD c, Seppo Ylä-Herttuala MD d, Markku Laakso MD d, Matti Uusitupa MD d, André Marette PhD a, b, * a

Centre de recherche de l’Institut Universitaire de Cardiologie et Pneumologie de Québec, Pavillon Marguerite d’Youville, Ste-Foy, Canada Institute of Nutrition and Functional Foods, 2440, boul. Hochelaga, Québec City, Québec, Canada Department of Biology, York University, Toronto, Ontario, Canada d A.I.Virtanen Institute, University of Eastern Finland, Kuopio, Finland e Faculty of Pharmacy, Université Laval, Québec, Canada b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 27 May 2013 Received in revised form 9 August 2013 Accepted 12 August 2013

Cardiovascular complications (CVC) are the most common causes of death in patients with type 2 diabetes (T2D). However the pathophysiological determinants and molecular mechanisms involved in the progression of CVC in T2D are poorly understood. We have undertaken the challenging task of identifying some of the genetic and clinical determinants of CVC through a unique multidisciplinary approach involving Canadian and Finnish investigators. We are studying novel animal models combining atherosclerosis, diet-induced obesity and T2D to understand the molecular basis of CVC in obesity-linked T2D. We are also conducting clinical studies to identify key determinants of CVC in T2D patients and to determine whether a lifestyle modification program targeting loss of visceral adipose tissue/ectopic fat could be associated with clinical benefits in these patients. Together, we strongly believe that we can fill some gaps in our understanding of the CVC pathogenesis in T2D and identify novel therapeutic targets and hope that this new knowledge may be translated into the design of effective clinical interventions to optimally reduce cardiovascular risk in T2D subjects. Ó 2013 Canadian Diabetes Association

Keywords: animal models cardiovascular disease clinical studies heart obesity type 2 diabetes

r é s u m é Mots clés : modèles animaux maladie cardiovasculaire études cliniques cœur obésité diabète de type 2

Les complications cardiovasculaires (CCV) sont les causes les plus fréquentes de mortalité chez les patients ayant le diabète de type 2 (DT2). Cependant, les déterminants physiopathologiques et les mécanismes moléculaires impliqués dans la progression des CCV liées au DT2 sont mal compris. Nous avons entrepris de cerner quelques déterminants génétiques et cliniques des CCV par une approche multidisciplinaire unique impliquant des investigateurs canadiens et finlandais. Nous étudions les nouveaux modèles animaux combinant l’athérosclérose, l’obésité induite par l’alimentation et le DT2 pour comprendre les bases moléculaires des CCV du DT2 lié à l’obésité. Nous menons également des études cliniques pour cerner les principaux déterminants des CCV chez les patients ayant le DT2 et pour déterminer si un programme de modification du mode de vie ciblant la perte de tissu adipeux viscéral et de graisse ectopique pourrait être associée à des avantages cliniques chez ces patients. Ensemble, nous croyons fermement que nous pourrons combler certaines lacunes en matière de compréhension de la pathogenèse des CCV liées au DT2 et trouver de nouvelles cibles thérapeutiques, et nous espérons que ces nouvelles connaissances pourront mener à l’élaboration d’interventions cliniques efficaces destinées à réduire de manière optimale le risque cardiovasculaire chez les sujets ayant le DT2. Ó 2013 Canadian Diabetes Association

Introduction * Address for correspondence: André Marette, PhD, Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Québec City, Québec G1V 4G5, Canada. E-mail address: [email protected]. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2013.08.262

It has long been established that type 2 diabetes (T2D) is associated with a myriad of metabolic disorders and with preferential accumulation of adipose tissue in the abdominal region (1e3).

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Today, despite several decades having passed since these seminal observations, what are the key drivers of increased cardiovascular disease (CVD) in obese T2D patients still largely remains an unanswered question. The constellation of complications that are considered as features of the MetS that accompanies T2D are now well characterized and include insulin resistance, hyperinsulinemia, hypertension, obesity, hypertriglyceridemia and low HDL (4). It is also well recognized that the low-grade chronic inflammation found among patients with T2D subjects likely contributes to their elevated cardiometabolic risk (5,6). Moreover, whereas T2D correlates positively with an increased risk of cardiovascular disease, careful analysis of clinical data suggests there is no single clear disease profile (7). In addition, despite recent advances in therapy that have resulted in a reduction in cardiovascular mortality, this decrease is not evident in individuals with T2D (8e11). However, we now have at our disposal advanced resources in biochemical, genetic and clinical research that have provided us with most powerful tools to help us identify novel therapeutic targets, customizing treatments and personalized medicine approaches. This narrative review will present convergent findings from these diverse research approaches. Cardiovascular complications of type 2 diabetic animal models Tissue-specific genetic manipulation of the insulin receptor itself has provided only limited information and not necessarily reflect a true state of T2D with its constellation of pathologies and secondary health effects. In addition, while hepatic disruption of the insulin receptor alone is sufficient to produce a diabetic state, disruption in other tissues have generated mixed phenotypes. The use of genetically modified or diet-induced animal models of diabetes (summarized in Table 1) has undoubtedly provided some of the most important findings in the field of metabolic diseases. However, it has been difficult to find an adequate model combining both insulin resistance and cardiovascular pathologies in which detailed studies of the CVC of T2D could be carried out. One of the more commonly used models, the db/db mouse results from a

genetic disruption of the leptin receptor and exhibits severe obesity and diabetes that gets progressively worse with aging (12). Yet this model, which also exhibits an altered inflammatory profile, dyslipidemia and left ventricular cardiac hypertrophy, remains limited. Because of its extreme nature, it is difficult to identify the effects of these different mechanisms on any single phenotype. Other models of T2D, brought about by dietary intervention usually on a C57BL/6 background, have also been extensively used and provide a very useful alternative (13). However, the literature remains highly controversial as to the precise phenotype of these animals since even small variations in diet or study conditions have resulted in a wide range of phenotypes (14). In addition, because of the very different way rodent models handle lipids, extrapolating back to human dyslipidemic profiles can be problematic. Some general conclusions common to most study models can nevertheless be drawn. On the C57BL/6 background, diets very high in fat, both with and without the addition of cholesterol, have generally been shown to bring about obesity and at least a modest hyperglycemia. The addition of a large amount of sucrose or fructose to a high fat content diet further exacerbates the phenotype to full blown insulin resistance (15). Nevertheless, atherosclerosis does not develop easily from dietary intervention alone in these models and modest plaque formation can only be seen after the animals have been fed a cholesterol and cholate-supplemented Paigen diet for extended periods of time (16). Another important limitation of common murine models for the study of atherosclerosis is the different way in which they handle dietary lipids, secreting the bulk of cholesterol in a nonatherogenic HDL fraction. True atherosclerosis in the mouse thus often requires some degree of genetic manipulation. Both the apoE-/- and the LDL receptor (LDLr)-/- mouse models exhibit severe atherosclerosis and CVC; but this is not usually accompanied by progression toward a full blown diabetic state unless dietary intervention is also applied (17,18). In addition, the apoE-/- model is complicated by the fact that whole body knockout occurs in bone marrow-derived macrophages that may affect atherosclerosis progression (19). Thus, despite these models being readily available and having the

Table 1 Some well-established mouse models used for the study of type 2 diabetes Mouse model

Reference(s)

Phenotype

Drawbacks

db/db

(12)

Extreme nature, dependent on leptin receptor mutation, difficult to identify the effects of these different mechanisms on any single phenotype

C57BL/6 with high-fat diets

(13)

C57BL/6 with high fat, high sucrose/fructose diets

(15)

C57BL/6 with high-cholesterol or Paigen diet

(16)

Severe obesity and diabetes that becomes progressively worse with aging; altered inflammatory profile dyslipidemia and left ventricular cardiac hypertrophy More coherence with normal physiology of the development of diabetes Development of insulin resistance is dependent on experimental conditions More coherence with normal physiology of the development of diabetes Obesity and insulin resistance Atherosclerosis model

ApoE-/-

(17)

Develop vascular lesions

LDL receptor knockout LDLr-/-

(18)

LDLr-/-ApoB100/100

(20)

LDLr-/-ApoB100/100 X IGF-II

(20)

Develop vascular lesions if combined with dietary intervention. Lipid profile different than human Develop vascular lesions Circulating lipid profile closer to human Develop vascular lesions Circulating lipid profile closer to human Develop diabetes Develop aortic calcification Develop cardiac hypertrophy

No or modest hyperglycemia, pre-diabetic model, wide range of phenotypes caused by variable experimental conditions Moderate hyperglycemia, wide range of phenotypes caused by variable experimental conditions No or modest hyperglycemia. Dietary cholesterol varied metabolic effects depending on experimental context. Only long-term intake can lead to significant lesion development. Does not develop diabetes ApoE is expressed in many cell types and affect macrophage functions Does not develop diabetes Less prone to diet-induced obesity than wild-type animals Does not develop diabetes Less prone to diet-induced obesity than wild-type animals Less prone to diet-induced obesity than wild-type animals

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potential to develop advanced diabetes and cardiovascular pathologies, an ideal model combining diabetes, atherosclerosis, cardiomyopathy, obesity and inflammation remains elusive. In recent years, a new model has emerged that may add yet another key to this puzzle. The LDLr-/-ApoB100/100 X IGF-II mouse was generated by crossing the LDLr-/-ApoB100/100 mouse encoding genetic deletions for the LDL receptor and apoB48 with a mouse overexpressing IGF-II in pancreatic beta cells. This model exhibits severe hypercholesterolemia, hyperglycemia and insulin resistance (20). Not surprisingly, this model also shows advanced atherosclerosis and vascular calcification; however, when compared to an LDLr-/-ApoB100/100 mouse, the only parameter that was further deteriorated in the LDLr-/- ApoB100/100 X IGF-II mouse was the vascular calcification, suggesting that the addition of severe insulin resistance on top of the atherogenic phenotype did not worsen other aspects of cardiovascular pathology. This represents a very useful new model of aortic or valvular calcification, which has been previously limited to using very old animals (21). More recently, Heinonen et al (22) showed that in an atherosclerotic LDLR-/-ApoB100/100 mouse there was rapid development of left ventricular dysfunction; but again, this was not further exacerbated in a diabetic mouse on the same genetic background. On the other hand, we recently found that LDLr-/- ApoB100/100 X IGF-II mice, but not their nondiabetic LDLr-/-ApoB100/100 counterparts, develop aortic stenosis within only 6 months of a high-fat diet (23), suggesting that the diabetic state may be a key pathogenic determinant of calcific aortic valve disease (CAVD), a condition that was recently found to be a common cardiovascular complication of the MetS (see below). What remains to be investigated is whether LDLr-/ApoB100/100 X IGF-II mouse model can also reproduce plaque rupture, a fundamental step of the human atherosclerosis pathology and a major cause of stroke, myocardial infarction and mortality. Adiponectin and cardiovascular protection in T2D Genetic manipulation of adiponectin action has provided useful models to bring insight into the role of adiponectin in cardiovascular disease (24). Most studies in adiponectin knockout mice indicated that adiponectin has beneficial effects in the cardiovascular system, as the lack of adiponectin conferred higher susceptibility to heart failure and atherosclerosis (25). This conclusion that adiponectin is cardioprotective is supported by most, but not all, clinical studies that found inverse correlations between circulating adiponectin and occurrence or severity of CVD (24). Adiponectin receptors (AdipoRs) have been found to be decreased in failing human hearts or in various animal models of heart failure (26e28) and mice lacking one or both adiponectin receptor (AdipoR) isoforms have also been generated. Using cardiomyocytes isolated from AdipoR1-KO mice, adiponectin no longer protected against hypoxia reoxygenation induced oxidative stress and cell death (29). The regulation of cardiovascular events by adiponectin is likely to reflect both direct effects on the heart and vasculature as well as systemic influences of improved peripheral metabolism and reduced levels of inflammation (30). Adiponectin has been shown to regulate substrate metabolism, oxidative/nitrative stress and apoptosis amongst other effects in the heart. In the vasculature, the anti-atherosclerotic effects of adiponectin include attenuation of proliferation and migration of smooth muscle cells, endothelial dysfunction and macrophage to foam cell transition (24,25). Adiponectin has also been shown to mobilize and increase function of endothelial progenitor cells (31,32). The heart as a key whole-body metabolic regulator Particularly intriguing is the very recent discovery that the heart itself may act as a metabolic tissue to regulate whole body energy

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homeostasis via microRNA. Med13, a subunit of the Mediator complex involved in transcriptional regulation of hormone receptors, is believed to negatively regulate cardiac-specific microRNA 208a which, in turn, regulates energy metabolism (33). Studies in mice overexpressing Med13 showed that they were protected against obesity and, conversely, cardiac-targeted suppression of Med13 caused a loss of this protective effect (34). The discovery of Med13 and its potentially important peripheral functions provides evidence that some target tissues may entertain a “dialogue” with systemic metabolic markers contributing to the development of a vicious cycle exacerbating the cardiometabolic risk profile of patients with T2D. This may be important in light of the relationship between ectopic fat and the presence of obesity or diabetic cardiomyopathy (35,36). This concept is ground breaking and opens up new perspectives for the investigation of these questions. Novel genetic determinants of visceral obesity and cardiometabolic risk Although animal models have provided useful information, they remain limited by fundamental species differences. Recent developments in genomic technologies have given us another invaluable tool for the unprecedented rapid discovery of new genes that may be important in the progression of T2D. This holds true for both animal and human studies. In particular, the advent of GWAS technology correlating SNPs to clinical manifestations of the MetS have recently come to the forefront of T2D research and have highlighted some tantalizing new candidate genes for further study. A recent GWAS analysis of 926 individual samples from the Quebec Family Study cohort has established strong ties between visceral adiposity, inflammation and CVD risk. Furthermore, the same study has identified several SNPs that are modulated in the disease state with particular emphasis being placed on LRRFIP1 polymorphisms that correlate with elevated levels of inflammatory markers (CRP, IL-6) (37). It remains to be documented how this protein, a regulator of toll-like receptor (TLR) pathway signalling, could be implicated in the development of inflammation and diabetes (38). Additional GWAS studies have also been conducted to identify genomic targets associated with elevated risk of hypertension and dyslipidemia (39,40). In a very recent study, it is interesting to note that while inflammatory and lipid traits were shown to be linked to SNPs for coronary artery disease, this was not found to be the case for diabetes traits (41). Metabolic and clinical determinants of CVD risk in T2D: implications for management Clinically, 1 of the features of poor glycemic control accompanying T2D is a potentially atherogenic cardiometabolic risk profile that includes hypertension, atherosclerosis, dysregulation of cardiac metabolism and dilated cardiomyopathy. However, it is becoming increasingly clear that the multifactorial nature of T2D will require a much deeper understanding of intertwined metabolic networks and a much more personalized medical approach toward treatment. This is reflected by the evolving clinical definition of diabetes by the American Diabetes Association (42,43). Although the classical co-morbidities of obesity and hypertension have been accepted for decades, some new parameters are being considered in the assessment of patients with T2D. For instance, diabetes diagnosis is based on markers of glycemic control (fasting glucose, glucose levels measured during an oral glucose tolerance test, HbA1c levels) based on their relationship with microvascular complications (43,44). Despite the fact that the relationship between hyperglycemia (assessed by whichever method) and microvascular damages is well established, it has become clear that the relationship of blood glucose levels to macrovascular disease is

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less straightforward and can be modulated by several factors (10,45e47). In addition to the effects of smoking, blood pressure and cholesterol levels on CVD risk in T2D patients, there is accumulating evidence that a subgroup of T2D patients with a high triglyceridedlow HDL-cholesterol dyslipidemia are at greater risk of CVD than T2D patients matched for the same hyperglycemic state, but without the features of this atherogenic dyslipidemia (48). This has been documented in randomized trial such as ACCORD (9,10). As such, high TGdlow HDL-cholesterol is the “signature” dyslipidemia of the MetS (49) that has also been associated with visceral obesity and excess ectopic fat deposition (50). Such association suggests that excess visceral adiposity/ectopic fat is one of the key modulator of CVD risk in T2D patients. It is important to point out that this atherogenic dyslipidemia of patients with more visceral obesity/excess ectopic fat is also accompanied by an increased proportion of atherogenic small, dense LDL particles (51) and by a chronic low grade inflammatory state, marked by increased C-reactive protein (CRP) levels (52). Characteristics inherent to visceral adipose tissue, such as adipocyte size and number, lipolytic responsiveness and inflammatory cytokine production have been shown to correlate positively with the features of the MetS and, as a result, may play an important role in enhancing the cardiometabolic risk associated with abdominal obesity (53). Thus, beyond glycemic control, it appears important to manage visceral/ ectopic fat accumulation in patients with T2D. Unfortunately, with the exception of cholesterol lowering and hypertension drugs, treatment of T2D has traditionally been rather “glucocentric” in its therapeutic approach (54) (see Table 2 (55e63)), with little attention given to visceral adiposity/ectopic fat and related additional cardiometabolic risk. In order to provide clinicians with simple tools to further refine CVD risk assessment beyond traditional risk factors and blood glucose control, the hypertriglyceridemic waist (hyperTG-waist) phenotype has been proposed (64). HyperTG-waist, which is

defined by an elevated waist circumference coupled to increased plasma triglyceride concentrations, has been shown to be useful in nondiabetic (65) as well as diabetic (66e68) individuals to identify subjects at increased CVD risk due to the presence of excess visceral adiposity and related features of the MetS. These results suggest that, in addition to the traditionally used body mass index (BMI), this simple clinical phenotype could be as helpful as a clinical diagnosis of the MetS would be (69) to rapidly screen individuals at increased risk of having excess visceral/ectopic fat and related cardiometabolic abnormalities. In addition, studies have shown that there may be a preferential mobilization of visceral adipose tissue and of ectopic fat in response to lifestyle modification programs, with such loss sometimes beyond what could be predicted from the magnitude of weight loss (70,71). Hypertriglyceridemic waist has also been shown to be associated with angiographically assessed coronary artery disease in patients with T2D (66). The mechanisms associated with this phenomenon are currently being examined; however, on that basis, reducing waist circumference and fasting triglyceride levels may represent reasonable targets beyond glucose control and cholesterol/blood pressure lowering for the optimal management of CVD risk in patients with T2D. Furthermore, waist circumference should be clinically assessed in these patients on a regular basis (72). Despite numerous large scale clinical studies, whether there is a direct link between the level of blood glucose control and cardiovascular risk remains controversial (73). For instance, recent clinical data strongly suggest that diabetes treatment may not be as simple as re-establishing proper glycemic control. Several prominent studies such as ACCORD (10,74) and ADVANCE (75) have shown that aggressive glucose lowering therapy does not always lead to reduced cardiovascular mortality, with data suggesting that reduction of hyperglycemia to near normal levels for up to 5 years does not reduce the risk of atherosclerotic macrovascular events (76) but may decrease the occurrence of myocardial infarction while increasing mortality (10).

Table 2 Summary of drugs used in mono- or combination therapy for the treatment of type 2 diabetes Medications

Action

Advantages

Disadvantages/side effects

References

Meglitinides (oral) Repaglinide Nateglinide Sulfonylureas (oral) Glipizide Glimepiride Glyburide Biguanides (oral) Metformin

Bind Kþ ATP channel on pancreatic beta cells; stimulate insulin release

Rapid efficacy

Rapid turnover; hypoglycemia; weight gain

55

Bind Kþ ATP channel on pancreatic beta cells; stimulate insulin release

Rapid efficacy

Hypoglycemia; weight gain

56

Mechanism of improved insulin sensitivity not fully understood; inhibit hepatic glucose release; decrease fasting glycemia Peroxisome proliferator-activated receptor g modulator; improve hepatic and peripheral sensitivity to insulin; inhibit hepatic glucose release Block degradation of GLP-1; stimulate insulin release; inhibit the release of hepatic glucagon

May promote slight weight loss and slight lowering of LDL

May interfere with vitamin B12 absorption; lactic acidosis (rare)

57

May increase HDL slightly

Heart failure; heart attack; stroke; liver disease

58

No weight gain

Upper respiratory tract infection; inflammation of the pancreas (sitagliptin)

59,60

Bind GLP-1 receptor; stimulate insulin secretion; decrease postprandial blood glucose

No hypoglycemia

Gastrointestinal disturbances; some concerns over proliferative effects on pancreatic cells

61

Slows breakdown of polysaccharides; decrease postprandial blood glucose

No hypoglycemia; no weight gain

Gastrointestinal disturbances

62,63

Thiazolidinediones (oral) Rosiglitazone Pioglitazone

Dipeptidy peptidase-4 (DPP-4) inhibitors (oral) Saxagliptin Sitagliptin Linagliptin Glucagon-like peptide-1 (GLP-1) agonists (injected) Exenatide Liraglutide Alpha-glucosidase inhibitors (oral) Acarbose Miglitol

Adapted from information published in: Nathan DM, Buse JB, Davidson MB, et al.; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203.

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T2D being closely associated with obesity, one of the great challenges in the field of diabetes management has been the development of drugs to reduce adiposity that would be safe over years of chronic administration (77). Thus the safest approach for the time being remains lifestyle modification intervention that is generally brought about by reducing caloric intake and increasing the level of physical activity/exercise. Although this approach does not generally lead to spectacular rates of weight loss, it has been shown to produce significant long-term benefits for all features of the MetS (78,79). Thus lifestyle intervention focussing on diet and physical activity and exercise should be combined with optimal pharmacological management of diabetes status and related risk factors following current diabetes guidelines (43). As optimal management of risk factors by pharmacotherapy has been reported to be associated with clinical benefits (80), there is evidence that the excess visceral adiposity/ectopic fat of patients with T2D is a significant contributor to the residual risk of CVD (81), thereby making loss of visceral adipose tissue a potentially important additional target for therapy (70). On the basis of the above observations, it remains to be properly tested whether a lifestyle modification program targeting loss of visceral adipose tissue/ectopic fat rather than magnitude of weight loss per se could be associated with clinical benefits in patients with T2D (82). In order to address this issue, a 1-year lifestyle modification program aiming at improving nutritional quality and increasing physical activity/exercise habits in patients who underwent coronary artery bypass graft (CABG) surgery is currently underway at our institution (83). Several of these patients with documented coronary artery disease have either impaired glucose tolerance or T2D. Preliminary unpublished results suggest that these patients can respond to a lifestyle modification program by improving their cardiorespiratory fitness and by losing visceral ectopic fat, while also improving their cardiometabolic risk profile beyond what can be attributed to their aggressive pharmacotherapy of their diabetes or of their related CVD risk factors. Once all subjects have completed the 1-year lifestyle intervention protocol, we will attempt to sort out the independent and possibly additive contributions of improved fitness versus weight loss or loss of visceral adipose tissue/ectopic fat to the improvement of their cardiometabolic status and glucose control. Church et al (84) have well documented the mortality risk associated with poor cardiorespiratory fitness among overweight/obese patients with T2D. Therefore, identification of the mechanisms by which an improved cardiorespiratory fitness associated with a lifestyle modification program may contribute to reduce CVD risk in patients with T2D beyond what can be achieved by optimal pharmacotherapy remains a very fertile area of investigation. A full discussion of the factors involved in the cardioprotective effects of regular physical activity/exercise in patients with T2D is beyond the scope of this narrative review but improving cardiorespiratory fitness represents a relevant therapeutic target in this patient population. Unfortunately, evidence suggests that physical activity/ exercise is one of the aspects of therapy for which patients with T2D are the least compliant (85), and further resources should be provided to help these patients improve and maintain their physical activity/exercise habits. This is also true in a global scale in individuals with cardiovascular disease (86). Calcific aortic valve disease: an unappreciated CVC of T2D? Calcific aortic valve disease (CAVD) is the most common heart valve disorder and the third cause of cardiovascular death. Some studies have shown diabetes mellitus to be a risk factor for aortic stenosis (87). Although CAVD shares some similarities with atherosclerosis, studies have emphasized that they are distinct disorders. To this effect, the aortic valve has a different structure

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than the arterial wall and mineralization plays a crucial role in the development of CAVD (88). Work performed in the last decade has contributed to highlight that several cardiometabolic risk factors are clearly associated with the risk to develop CAVD as well as with a faster disease progression rate (89). Briand et al. have shown in a population of patients with CAVD that the MetS was independently associated with a faster hemodynamic progression rate and a higher number of clinical events (90). Furthermore, work from our group next identified that patients with a high proportion of circulating small, dense LDL had a faster disease progression rate and a higher accumulation of oxidized-LDL (ox-LDL) within explanted stenotic aortic valves (91). Furthermore, in a group of patients operated for aortic stenosis, it was found that a low blood plasma level of adiponectin was associated with aortic valve inflammation (92). Hence, accumulation of harmful oxidized lipid species and a dysfunctional secretion of adipokines may promote aortic valve mineralization (93,94). The question that arises is why are statins not efficient in CAVD while providing clinical benefits in patients with vascular atherosclerosis (95)? Although the answer is probably multifactorial, one likely explanation is that statins, although lowering the total amount of circulating LDL, may not alter significantly the lipid particle phenotype, namely the size of LDL. It is thus possible that patients with visceral obesity, who are insulin resistant and have a high proportion of circulating small, dense LDL particles, have a greater retention of lipids within the aortic valve which, in turn, promotes inflammation and the mineralization of the aortic valve. To this effect, mineralization and the remodelling process of the aortic valve are intimately linked to the level of inflammation within the aortic valve (96). It should be pointed out that the small, dense LDLs have a greater ability to infiltrate tissues and to become oxidized. Moreover, several mechanisms exist within the stenotic aortic valve in order to promote the lipid retention process. First, biglycan, a proteoglycan that helps to retain lipid particles, is highly expressed within stenotic aortic valves (97). In addition, biglycan promotes the expression of phospholipid transfer protein (PLTP) through the stimulation of toll receptors (TLRs). In turn, PLTP modifies HDL and may prevent reverse cholesterol transport (RCT). Second, lipoprotein lipase (LPL) is expressed by macrophages, which infiltrate stenotic aortic valves, and may thus contribute to the lipid retention process by locally modifying lipoproteins (98). For instance, LPL interacts with LDL and promotes binding to proteoglycans. Third, the small, dense LDL phenotype, which is one important feature of the viscerally obese subject, has been recently linked to a greater accumulation of oxLDL in stenotic aortic valves. Noteworthy, immunostainings for apoA1 co-localized with amyloid depot in stenotic aortic valves and studies indicate as well that apoA1 is an important component of the amyloid substance found in stenotic aortic valves (99). Taken together, these findings suggest that the small, dense HDLs enter the aortic valve and are modified locally by enzymes, such as PLTP, and hence are prevented to perform RCT. The end result is that insulin-resistant and viscerally obese patients with the so-called “atherogenic dyslipidemia” have many mechanisms in place that favour the lipid retention process within the aortic valve, whereby ectopic mineralization is triggered. Although the dyslipidemia of the insulin-resistant/diabetic patient is undoubtedly linked to the pathobiology of CAVD, other potentially important contributor(s) may also play a role. In this regard, 1 crucial question is whether the association between insulin resistance and ectopic valve mineralization can be explained by 1 unifying process. We recently provided evidence that 3 single nucleotide polymorphisms (SNPs) of the gene encoding for ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) are associated with CAVD (100). Moreover, expression of ENPP1 in CAVD tissues was elevated several-fold. It should be pointed out that the same SNPs found in CAVD (rs7754586, rs9402349,

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rs1800949) are also associated with obesity and diabetes (101). Of interest, ENPP1 is a crucial ecto-enzyme, located at the cell membrane, which intervenes in the regulation of ectopic mineralization and is also physically linked to the insulin receptor (IR) at the cell membrane (102). Studies indicate that interaction of ENPP1 with the IR may interfere with the autophosphorylation process of the IR and, in doing so, hinder insulin signalling. On the other hand, ENPP1, when overexpressed, promotes the mineralization of the aortic valve by several mechanisms. First, along with alkaline phosphatase (ALP), it promotes the production of inorganic phosphate, whereby mineralization is triggered (103,104). Second, ENPP1 uses nucleotide triphosphate as a substrate and thereby contributes to depletion of the extracellular pool of ATP. In turn, a low level of ATP decreases purinegic signalling through the P2Y2 receptor, which normally acts as a survival signal by the PI3K/Akt pathway. Hence, a lower purinergic signalling induces apoptosismediated mineralization of the aortic valve. It is thus likely that ENPP1 may represent an important and novel target, which may explain, at least in part, the association between insulin resistance/ diabetes and the development of CAVD. Emerging evidence now indicates that the “valvulo-metabolic risk” is certainly an important concept in the field of metabolic cardiology (105). Although our understanding of the basic concept linking diabetes with ectopic valve mineralization is not complete, recent work has contributed to shed light on potential important underlying mechanisms. In this regard, targeting the enzyme ENPP1 may provide multiscale benefits and prevent the development/progression of CAVD while having a potential role in insulin signalling. Recently, the administration of an enzyme inhibitor of ENPP1 in a nondiabetic rat model was found to prevent the development of CAVD (106). Current studies are underway to test whether ENPP1 inhibition can also reduce CAVD development in our newly developed obese diabetic LDLr-/-ApoB100/100 x IGFII mouse model. Hence, further studies and development may, in the years to come, lead to the development of novel pharmaceutical therapies in order to prevent and treat CAVD. Conclusions and Perspective Clinical evidence undeniably shows that T2D is often accompanied by CVC. A commonality between all studies regardless of the model used is that a chronic inflammatory state most often accompanies T2D. This inflammatory state is usually the result of increased additional factors, such as visceral obesity and excess ectopic fat, insulin resistance, an atherogenic dyslipidemia and hypertension. Such constellation of additional metabolic abnormalities found in patients with T2D has often contributed to confuse thus complicating the issue. Indeed, once these confounding factors have been properly quantified, the independent contribution of impaired plasma glucose homeostasis to CVD risks remains unclear, to say the least. The identification of novel markers for early diagnosis and targeted therapy should, therefore, remain a primary focus of both basic and clinical research. With the forthcoming advent of genetic therapies and a better mechanistic understanding of CVC in T2D, we are coming closer to more personalized approaches to treatment. Such knowledge is key if we wish to optimally manage CVD risk in this expanding population of patients. References 1. Vague J. [La différenciacion sexuelle, facteur déterminant des formes de l’obésité.]. La Presse Medicale 1947;55:339. 2. Avogaro P, Crepaldi G, Enzi G, Tiengo A. [Metabolic aspects of essential obesity]. Epatologia 1965;11:226e38. 3. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595e607.

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