Next Article in Journal
Gastrointestinal Disorders and Metabolic Syndrome: Dysbiosis as a Key Link and Common Bioactive Dietary Components Useful for their Treatment
Next Article in Special Issue
Cardiovascular Risk in Children: Focus on Pathophysiological Aspects
Previous Article in Journal
Unproductive Effects of ALK Gene Amplification and Copy Number Gain in Non-Small-Cell Lung Cancer. ALK Gene Amplification and Copy Gain in NSCLC
Previous Article in Special Issue
Fructose and Uric Acid: Major Mediators of Cardiovascular Disease Risk Starting at Pediatric Age
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 21
Issue 14
10.3390/ijms21144928
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Impact of Diabetes Mellitus on Cardiovascular Risk Onset in Children and Adolescents

by
Ida Pastore
1,
Andrea Mario Bolla
1,
Laura Montefusco
1,
Maria Elena Lunati
1,
Antonio Rossi
1,
Emma Assi
2,
Gian Vincenzo Zuccotti
3 and
Paolo Fiorina
1,2,4,*
1
Division of Endocrinology, ASST Fatebenefratelli-Sacco, 20157 Milan, Italy
2
International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, Department of Biomedical and Clinical Science L. Sacco, University of Milan, 20157 Milan, Italy
3
Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano and Department of Pediatrics, Buzzi Children’s Hospital, 20157 Milan, Italy
4
Nephrology Division, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(14), 4928; https://doi.org/10.3390/ijms21144928
Submission received: 15 June 2020 / Revised: 7 July 2020 / Accepted: 9 July 2020 / Published: 12 July 2020
(This article belongs to the Special Issue Cardiovascular Risk in Children and Adolescents: Focus on Methodological and Pathophysiological Aspects)
Review Reports Versions Notes

Abstract

:
The prevalence of diabetes mellitus is rising among children and adolescents worldwide. Cardiovascular diseases are the main cause of morbidity and mortality in diabetic patients. We review the impact of diabetes on establishing, during childhood and adolescence, the premises for cardiovascular diseases later in life. Interestingly, it seems that hyperglycemia is not the only factor that establishes an increased cardiovascular risk in adolescence. Other factors have been recognized to play a role in triggering the onset of latent cardiovascular diseases in the pediatric population. Among these cardiovascular risk factors, some are modifiable: glucose variability, hypoglycemia, obesity, insulin resistance, waist circumference, hypertension, dyslipidemia, smoking alcohol, microalbuminuria and smoking. Others are unmodifiable, such as diabetes duration and family history. Among the etiological factors, subclinical endothelial dysfunction represents one of the earliest key players of atherosclerosis and it can be detected during early ages in patients with diabetes. A better assessment of cardiovascular risk in pediatric population still represents a challenge for clinicians, and thus further efforts are required to properly identify and treat pediatric patients who may suffer from cardiovascular disease later in early adulthood.

1. Introduction

The prevalence of the two most common forms of diabetes, type 1 (T1D) and type 2 (T2D) is increasing worldwide, even in the pediatric population, rapidly becoming an urgent public health problem [1,2,3]. The International Diabetes Federation has estimated that T1D affects more than 1,100,000 children and adolescents, with an annual incidence of about 128,900 worldwide [1]. Until the early 1990s, T2D was believed to be almost an exclusive condition of adulthood, but its prevalence in adolescents is increasing in many countries [1]. Even if the estimates are not as precise as for T1D, in the United States, 20,262 adolescents are diagnosed with T2D, and by 2050, a fourfold increase will occur [3,4]. In addition, prediabetes affects nearly 5% of children aged between 6 and 10 years [5]. These growing trends are largely due to the spread of a more western lifestyle. Physical inactivity, increased calorie intake and reduced energy expenditure all facilitate overweight and obesity onset in children [6]. These conditions affect almost all children with T2D, and are common also in the pediatric population, with T1D having a prevalence of up to 34% [7,8,9]. A recent study was conducted in a population of 708 children who were positive for one of the circulating diabetes autoantibodies, but were not diabetic. The study revealed that the children who tested negative for HLA haplotypes predisposing to T1D and had an elevated body mass index (BMI) progressed to multiple autoantibodies positivity and had an increased risk of developing T1D [10]. Younger patients with T2D showed an impaired insulin secretion and detectable circulating autoantibodies [11,12]. Moreover, children and adolescents with T2D, when compared to adults with T2D, showed a higher and faster loss of beta-cells activity, which makes achieving optimal metabolic compensation more difficult [13,14,15].
Childhood and adolescence are crucial stages of life for the onset of cardiovascular (CV) risk factors [16]. There is a large body of evidence that suggests that the prevalence of CV risk factors among diabetic children and adolescents is high and, in most cases, these factors are present already at the time of diagnosis [8]. Diabetes mellitus is associated with a two-fold increase in the risk for cardiovascular disease, with a premature CV mortality and a four-fold increase in mortality for all-cause in young [17,18,19]. Moreover, the coexistence of obesity further increases the risk for specific- and all-cause mortality [20]. Previous studies in T1D and T2D, although not conclusive, suggested an increased risk for ischemic heart, macrovascular diseases and death, particularly in patients with T2D diagnosed between 15 and 30 years of age [21]. A longitudinal cohort of 6.840 patients with T1D, and 1.518 patients with T2D, showed an excess mortality in patients with T2D aged between 15 to 19 when compared to the general population [22]. Moreover, in patients with T1D, CV outcomes and mortality inversely correlate with age at diabetes onset; thus suggesting that the earlier the onset, the greater the risk [18]. The prevalence of two or more CV disease risk factors is higher in younger patients with T2D (92%) than those with T1D (14%), and is increased by 1.4% on an annual basis, over the ten years of the study period, in patients with T2D, but not in those with T1D [23,24]. In line with the aforementioned study, Dabalea et al. demonstrated that 72% of 272 young patients with T2D, contrasting only 32% of 1746 young patients with T1D, developed diabetic complications [25]. The role of hyperglycemia in establishing cardiovascular risk in the short-term might not be as clinically evident in children and adolescents with diabetes when compared to adults with diabetes, partially due to the greater potential regenerative capacity and to the higher number of circulating endothelial progenitor cells in the young [26]. However, in the long-term, evidence suggests a more detrimental role of diabetes when present at a younger age in making patients more vulnerable to cardiovascular CV risks later in life [18].

2. CV Risk Factors in Children and Adolescents with Diabetes

There are several old and new CV risk factors that appear to be relevant for pediatric patients with diabetes and that can be targeted. We classify them as modifiable and unmodifiable factors (Table 1). Among those unmodifiable factors are the age at onset and the disease duration [18,21,24,27]. A large longitudinal study comprising 27,195 patients with T1D and 135,178 controls, proved that mortality for CV disease and for all-cause inversely correlates with the onset age of T1D [18]. Moreover, patients diagnosed before 10 years of age showed a reduced life expectancy of nearly 18 years for women and 14 years for men [18]. Similarly, an early onset of T2D worsens CV risk, and younger patients with T2D are exposed to higher rates of diabetic micro- and macro-vascular complications [21,25]. As the duration of the disease increases, the prevalence of CV risk factors, CV disease death, myocardial infarction, revascularization, angina and stroke rises as well [24,27]. Contrary to what has been reported for the adult population whereby the female gender is associated with a lower CV risk in pre-menopausal period, data from recent literature reported similar CV risk rates in males and females [27,28,29]. Several modifiable CV risk factors are related to anthropometric measurements and metabolic control [30]. Increased BMI and waist circumference are described in children and adolescents with diabetes, while elevated levels of HbA1c are positively correlated with increased macrovascular complications [1,24,27,31]. Recently, increased glucose variability, which refers to the number and the amplitude of blood glucose fluctuations, more than the mean glycemia or the HbA1c, has been suggested to be a novel CV risk factor [32,33]. A reduction in glucose variability in young patients, with T1D by using continuous subcutaneous insulin infusion and real time continuous glucose monitoring, ameliorates endothelial function by increasing the flow-mediated dilatation of the brachial artery [34]. Another modifiable risk factor is hypoglycemia. Indeed, Fahrmann et al. showed that severe hypoglycemia positively correlates, regardless of age, with coronary artery calcification in the sub-cohort of patients enrolled in DCCT/EDIC study [35]. Insulin resistance is common to both T1D and T2D, although its pathophysiology seems to be different in youth with T1D, as compared to those with T2D [36]. The simultaneous presence of insulin resistance and T1D has been defined as “hybrid or double diabetes” and patients with T1D and insulin resistance own a more elevated CV risk among patients with T1D [37]. The control of other abnormalities associated with diabetes is of paramount importance. For instance, the importance of assessing blood pressure is supported by the observation that children with T1D with elevated systolic blood pressure had increased carotid intima-media thickness [38]. The prevalence of microalbuminuria, another modifiable risk factor, increases proportionally in youth with T2D, together with the disease duration [39], while in youth with T1D, this mainly correlates with elevated arterial stiffness [40]. In youth with diabetes, a more atherogenic lipid profile directly correlates with glycated hemoglobin, fasting glucose, age, disease duration and the presence of insulin resistance. Many of the aforementioned factors may be associated with a reduced nitric oxide availability [30,41,42,43,44]. Finally, the role of smoking and alcohol as CV risk factors in adulthood is well known, even if their long-term effects in adolescents have not been clarified yet [45].

3. Inflammation in Children and Adolescents with Diabetes

An early appearance of a pro-inflammatory state may be a key player in conditioning the onset of CV disease later in life [46]. Central obesity and physical inactivity are both associated with a pro-inflammatory state and are very common in young patients with obesity, with T2D and with T1D [9,11,13,42,47]. Obesity and T2D are characterized by a state of systemic chronic low-grade inflammation, that triggers a vicious circle involving insulin resistance, oxidative stress and endothelial dysfunction and lays the basis for early and accelerated atherosclerosis [46]. A low-grade inflammation is also observed in lean children with T1D, while increased levels of pro-inflammatory cytokines are described, either in T1D or T2D [48,49]. Continuous systemic chronic inflammation from childhood accelerates plaque formation and contributes to its growth [48]. Nearly 700 adolescents aged between 10 and 17 years who had a recent diagnosis of T2D were studied, and a detrimental inflammatory profile that worsened over time was shown [50]. Indeed, the inflammatory state was only partially reverted by pharmacological therapy [50]. In children and adolescents with diabetes, pro-inflammatory abnormalities may play a prognostic role for the development of diabetic complications and may represent novel pharmacological targets [51]. Previous studies, although not conclusive, demonstrated increased levels of C-reactive protein, interleukin-6, tumor necrosis factor-α, leptin, and decreased levels of adiponectin in children and adolescents with diabetes [52,53,54,55,56,57]. Interestingly, pro-inflammatory marker levels seem to also be elevated in lean adolescents with diabetes and good glycemic control [58,59]. Interestingly, the role of diet in modifying the inflammatory profile in children with diabetes is still debated; while in children with obesity, it only seems to be more evident [60,61]. More recently, a putative role for microbiome in the activation of gut and systemic inflammation was suggested in children and adolescents with diabetes [62]. This is of particular interest, especially in children and adolescents in which a pro-inflammatory state may persist over time, and may exert a detrimental effect on the CV system [46]. Interventional studies on the effect of prebiotics on gut microbiota are needed to elucidate their role in improving inflammatory state, insulin resistance and glycemic control.

4. Endothelial Dysfunction in Children and Adolescents with Diabetes

Even if not entirely well elucidated in their mechanisms, vascular complications are the results of direct action of hyperglycemia, but also of abnormalities of other mediators such as proinflammatory cytokines, growth factors, advanced glycation end-products (AGEs) and cell adhesion molecules [63,64]. Endothelial injury may represent the earlier phenomenon of vascular dysfunction, and hyperglycemia is probably the main driver of endothelial injury in children [65]. Hyperglycemia increases the production of reactive oxygen species and of AGEs, activates the protein kinase C, hexosamine and polyol pathways and affects the function of endothelial progenitor cells [51,66,67]. A growing number of studies showed increased inflammation and endothelial dysfunction in children and adolescents with diabetes, which was then associated with an increased CV risk (Table 2).
Children and adolescents with T1D showed elevated levels of the highly sensitive C-reactive protein when compared to healthy subjects [53,68]. In children and adolescents with diabetes, an increased level of serum intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was observed [47,55,69,70,71]. Levels of E-selectin are augmented in children and adolescents with T1D and are associated with systolic and diastolic blood pressure abnormalities [69,72]. Furthermore, high levels of circulating endothelial cells in children and adolescents with T1D positively correlated with HbA1c levels [53]. Increased levels of tumor necrosis factor-α were observed in young patients with T1D and T2D, and high interleukin-6 levels were observed in those with T1D [54,55,70,73]. Unfortunately, the clinical significance of these biomarkers must still be proven, and their use in epidemiological studies still needs to be explored. In this view, the early detection of endothelial dysfunction in children and adolescents with diabetes might be useful to prevent, or at least delay, cardiovascular complications [74].

5. Cardiac Dysfunction in Children and Adolescents with Diabetes

Diabetic cardiomyopathy comprises both functional and structural changes of the myocardium, regardless of hypertension, ischemic or valvular heart disease, and it can occur either as a systolic or diastolic dysfunction [75]. Hyperglycemia leads to the increased tissue deposition of AGEs that crosslink with proteins of the extracellular matrix, resulting in fibrosis and myocardial tissue remodeling [76]. The role of hyperglycemia in initiating and maintaining left ventricular diastolic dysfunction is supported by the observation that, in patients undergoing combined kidney and pancreas transplantation, no longer requiring insulin administration, a reversal of diastolic dysfunction was observed [77]. Endothelial dysfunction and vascular stiffness precede diastolic dysfunction, and their early recognition and treatment may prevent or delay diastolic dysfunction [78]. As left ventricular diastolic dysfunction represents the earliest manifestation of the diabetic cardiomyopathy that anticipates systolic dysfunction, several studies revealed diastolic dysfunction still in the presence of a normal left ventricular ejection fraction [77,79]. Children and adolescents with diabetes manifested subclinical ventricular abnormalities, when studied with both conventional or novel tissue Doppler echocardiography, and compared with healthy controls [80,81,82]. Moreover, concentric left ventricular hypertrophy is common among adolescents with diabetes, especially in those with obesity, identified by the increase of left ventricular wall thickness over time [82].
Children and adolescents with a recent onset of T1D showed the same cardiac function of healthy peers [83]. In a prospective cross-sectional study, it has been demonstrated that effectively controlled children and adolescents with long-term T1D showed diastolic dysfunction and subclinical systolic dysfunction, regardless of a normal left ventricular ejection fraction, and both of these abnormalities are associated with disease duration [81]. Cardiac functional abnormalities are associated with BMI in children and adolescents with and without diabetes, suggesting that the control of obesity is mandatory to prevent cardiac disease, especially in those with diabetes in which the progression of cardiac abnormalities seems accelerated [82,84,85]. In children with T1D, cardiac dysfunction seems to be influenced by disease duration, poor glycemic control, microalbuminuria, retinopathy and increased blood pressure [83,86,87]. Left ventricular performance has also been studied during physical activity sessions in adolescents with and without diabetes and, as expected, those with T1D or T2D showed a lower exercise tolerance compared to healthy controls [88,89]. Interestingly, a structured physical activity program over time is able to ameliorate physical training tolerance in adolescents with and without diabetes, but the level of cardiac performance remains lower in those with diabetes [89,90]. Nevertheless, these observations confirm the essential role of physical exercise in a necessarily modified lifestyle, adapted for the prevention of CV disease, especially in the high-risk CV population [89].

6. Vascular Tests to Unveil Early CV Risk in Children and Adolescents with Diabetes

Several surrogate indices are used in clinical practice to assess early vascular abnormalities (Table 3). Young patients with T1D showed delayed or reduced brachial artery flow mediated dilatation (FMD) reactivity and higher carotid femoral pulse wave velocity (PWV), as compared to healthy controls [53,54,59,68,78,91,92,93,94,95,96]. On the other hand, Bradley et al. demonstrated that carotid-radial PWV, but not carotid-femoral PWV, is higher in adolescents with T1D than in healthy controls [93]. In young patients with T1D, arterial stiffness is positively associated with glycated hemoglobin levels, disease duration and insulin resistance [97]. When it comes to carotid intima-media thickness (cIMT), an early marker of atherosclerosis, the SEARCH CVD study by analyzing data from 298 adolescents with diabetes, showed that BMI is a strong predictor of cIMT over time [45], and that cIMT increases in young patients with the worst glycometabolic control [98,99]. The mean cIMT correlates positively with hypertension, retinopathy, microalbuminuria, and in males with HDL cholesterol too [100].

7. Early Treatment of Children and Adolescents with Diabetes

In pediatric patients with diabetes, CV risk begins early and grows over time, and thus maintaining an optimal glycometabolic control in the long term is mandatory [101,102]. In the management of children and adolescents with diabetes, a pivotal role is played by health education [101]. The identification of a nutritional educational plan, with the aim of managing the intake of nutrients is essential [101]. Regular physical activity improves glycemic control, insulin sensitivity, lipid profile, body composition, wellbeing and cardiovascular health [103]. Therapeutic strategies used in the treatment of young patients with T1D and T2D partially differ from those used in adults [101]. Indeed, insulin therapy is recommended in children and adolescents with T1D, while metformin, insulin and liraglutide are approved for clinical use in children and adolescents with T2D [101]. Intensive insulin therapy allows one to achieve glycemic control, while it can facilitate weight gain, central adiposity, rises in blood pressure, and a more atherogenic lipoprotein profile [104,105]. In young patients with T2D, a more aggressive treatment with metformin and rosiglitazone results in a better durability, with beneficial consequences also on the development of micro- and macro- complications [106,107]. Recently, a secondary analysis of the same population demonstrated that metformin ameliorates lipoprotein profile, glycemic control, blood pressure and BMI, suggesting the role of metformin in improving CV parameters [108]. Data from a pediatric diabetes consortium registry analyzing young patients with T2D demonstrated the durability of metformin monotherapy in those with lower HbA1c and a more recent onset of the disease [109]. A growing number of studies showed that metformin enhances insulin sensitivity and reduces insulin dose in youth with T1D, but also improves vascular markers [105,110].
The sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are two classes of anti-diabetic drugs that have demonstrated to exert cardioprotective effects in multiple cardiovascular and renal outcomes trials in adults with T2D, on primary and secondary prevention [111,112,113,114]. Moreover, their effectiveness and safety are also being tested in the treatment of patients with T1D [115,116,117]. Recently, Tamborlane et al. demonstrated the efficacy of liraglutide in children and adolescents with diabetes aged between 10 to 17, but they also observed an increased number of gastrointestinal adverse effects [118].
In line with these observations, novel antidiabetic therapies should be tested as a treatment of young patients, either with T1D or T2D, with the aim not only of optimizing glycemic control, but also of mitigating their CV risk (Table 4). Further studies are needed to evaluate SGLT2i and GLP1RA efficacy and safety in large cohorts of young patients with diabetes. Current guidelines recommend the use of drugs to control hypertension and dyslipidemia after changes in lifestyle in children and adolescents with diabetes [102,119]. However, there is concern about the use of statins and antihypertensive drugs in this population, for the lack of large intervention trials in the young and their teratogenic effect. More recently, regenerative therapy has proven to be a useful and innovative strategy in preventing and treating vascular complications in diabetes. Even further clinical trials are required; these therapies might be of particular interest in the young, who have a higher cellular regenerative capacity than adults [51,120].

8. Conclusions

CV disease still remains the leading cause of mortality in diabetes, and the onset of diabetes in pediatric age results in an increased risk for lifelong CV disease. The prevention, or at least the delay, of diabetic complications still represents a challenge for clinicians and caregivers of pediatric patients. If targeted early, cardiovascular complications may be potentially reversible, so interventions should be initiated as soon as possible to avoid the establishment of potentially untreatable CV disease. The CV risk in children and adolescents not only results from the deleterious effects of hyperglycemia, but also can be mediated by others CV risk factors, such as dyslipidemia, hypertension, albuminuria, overweight or obesity. Efforts are needed to better understand the pathophysiology of CV risk in children and adolescents with T1D and T2D, to avoid CV diseases in patients with diabetes.

Funding

Paolo Fiorina is supported by the Italian Ministry of Health grant RF-2016-02362512 and by the Linea-2 2019 funding from Università di Milano. We thank the “Fondazione Romeo e Enrica Invernizzi” for extraordinary support.

Conflicts of Interest

The authors declare no conflict of interest. This study was performed without the support or involvement of any external funding source or study sponsor in any phase of the investigation, or in the writing or submission of the manuscript.

Abbreviations

CVCardiovascular
T1DType 1 diabetes
T2DType 2 diabetes
FMDFlow mediated dilatation
cIMTCarotid intima-media thickness
PWVPulse wave velocity
AGEsAdvanced glycation end-products
BMIBody mass index

References

  1. Saeedi, P.; Petersohn, I.; Salpea, P.; Malanda, B.; Karuranga, S.; Unwin, N.; Colagiuri, S.; Guariguata, L.; Motala, A.A.; Ogurtsova, K.; et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 2019, 157, 107843. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Williams, R.; Karuranga, S.; Malanda, B.; Saeedi, P.; Basit, A.; Besancon, S.; Bommer, C.; Esteghamati, A.; Ogurtsova, K.; Zhang, P.; et al. Global and regional estimates and projections of diabetes-related health expenditure: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 2020, 162, 108072. [Google Scholar] [CrossRef] [Green Version]
  3. Pettitt, D.J.; Talton, J.; Dabelea, D.; Divers, J.; Imperatore, G.; Lawrence, J.M.; Liese, A.D.; Linder, B.; Mayer-Davis, E.J.; Pihoker, C.; et al. Prevalence of diabetes in U.S. youth in 2009: The SEARCH for diabetes in youth study. Diabetes Care 2014, 37, 402–408. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Jensen, E.T.; Dabelea, D. Type 2 Diabetes in Youth: New Lessons from the SEARCH Study. Curr. Diab. Rep. 2018, 18, 36. [Google Scholar] [CrossRef] [PubMed]
  5. Breyer, M.K.; Ofenheimer, A.; Altziebler, J.; Hartl, S.; Burghuber, O.C.; Studnicka, M.; Purin, D.; Heinzle, C.; Drexel, H.; Franssen, F.M.E.; et al. Marked differences in prediabetes- and diabetes-associated comorbidities between men and women-Epidemiological results from a general population-based cohort aged 6–80 years-The LEAD (Lung, hEart, sociAl, boDy) study. Eur. J. Clin. Investig. 2020, 50, e13207. [Google Scholar] [CrossRef] [PubMed]
  6. Lobstein, T.; Jackson-Leach, R. Planning for the worst: Estimates of obesity and comorbidities in school-age children in 2025. Pediatr. Obes. 2016, 11, 321–325. [Google Scholar] [CrossRef]
  7. Xu, Z.R.; Zhang, M.Y.; Ni, J.W.; Cheng, R.Q.; Zheng, Z.Q.; Xi, L.; Luo, F.H. Clinical characteristics and beta-cell function of Chinese children and adolescents with type 2 diabetes from 2009 to 2018. World J. Pediatr. 2019, 15, 405–411. [Google Scholar] [CrossRef]
  8. Jones, S.; Khanolkar, A.R.; Gevers, E.; Stephenson, T.; Amin, R. Cardiovascular risk factors from diagnosis in children with type 1 diabetes mellitus: A longitudinal cohort study. BMJ Open Diabetes Res. Care 2019, 7, e000625. [Google Scholar] [CrossRef] [Green Version]
  9. Maffeis, C.; Birkebaek, N.H.; Konstantinova, M.; Schwandt, A.; Vazeou, A.; Casteels, K.; Jali, S.; Limbert, C.; Pundziute-Lycka, A.; Toth-Heyn, P.; et al. Prevalence of underweight, overweight, and obesity in children and adolescents with type 1 diabetes: Data from the international SWEET registry. Pediatr. Diabetes 2018, 19, 1211–1220. [Google Scholar] [CrossRef]
  10. Ferrara-Cook, C.; Geyer, S.M.; Evans-Molina, C.; Libman, I.M.; Becker, D.J.; Gitelman, S.E.; Redondo, M.J.; Type 1 Diabetes TrialNet Study Group. Excess BMI Accelerates Islet Autoimmunity in Older Children and Adolescents. Diabetes Care 2020, 43, 580–587. [Google Scholar] [CrossRef] [PubMed]
  11. Bacha, F.; Gungor, N.; Lee, S.; Arslanian, S.A. Progressive deterioration of beta-cell function in obese youth with type 2 diabetes. Pediatr. Diabetes 2013, 14, 106–111. [Google Scholar] [CrossRef] [PubMed]
  12. Klingensmith, G.J.; Pyle, L.; Arslanian, S.; Copeland, K.C.; Cuttler, L.; Kaufman, F.; Laffel, L.; Marcovina, S.; Tollefsen, S.E.; Weinstock, R.S.; et al. The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: Results from the TODAY study. Diabetes Care 2010, 33, 1970–1975. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Elder, D.A.; Hornung, L.N.; Khoury, J.C.; D’Alessio, D.A. beta-Cell Function Over Time in Adolescents With New Type 2 Diabetes and Obese Adolescents Without Diabetes. J. Adolesc. Health 2017, 61, 703–708. [Google Scholar] [CrossRef] [PubMed]
  14. Dabelea, D.; Mayer-Davis, E.J.; Andrews, J.S.; Dolan, L.M.; Pihoker, C.; Hamman, R.F.; Greenbaum, C.; Marcovina, S.; Fujimoto, W.; Linder, B.; et al. Clinical evolution of beta cell function in youth with diabetes: The SEARCH for Diabetes in Youth study. Diabetologia 2012, 55, 3359–3368. [Google Scholar] [CrossRef] [PubMed]
  15. Steinarsson, A.O.; Rawshani, A.; Gudbjornsdottir, S.; Franzen, S.; Svensson, A.M.; Sattar, N. Short-term progression of cardiometabolic risk factors in relation to age at type 2 diabetes diagnosis: A longitudinal observational study of 100,606 individuals from the Swedish National Diabetes Register. Diabetologia 2018, 61, 599–606. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Tanrikulu, M.A.; Agirbasli, M.; Berenson, G. Primordial Prevention of Cardiometabolic Risk in Childhood. Adv. Exp. Med. Biol. 2017, 956, 489–496. [Google Scholar]
  17. Sarwar, N.; Gao, P.; Seshasai, S.R.; Gobin, R.; Kaptoge, S.; Di Angelantonio, E.; Ingelsson, E.; Lawlor, D.A.; Selvin, E.; Emerging Risk Factors Collaboration; et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: A collaborative meta-analysis of 102 prospective studies. Lancet 2010, 375, 2215–2222. [Google Scholar]
  18. Rawshani, A.; Sattar, N.; Franzen, S.; Rawshani, A.; Hattersley, A.T.; Svensson, A.M.; Eliasson, B.; Gudbjornsdottir, S. Excess mortality and cardiovascular disease in young adults with type 1 diabetes in relation to age at onset: A nationwide, register-based cohort study. Lancet 2018, 392, 477–486. [Google Scholar] [CrossRef] [Green Version]
  19. Svane, J.; Lynge, T.H.; Pedersen-Bjergaard, U.; Jespersen, T.; Gislason, G.H.; Risgaard, B.; Winkel, B.G.; Tfelt-Hansen, J. Cause-specific mortality in children and young adults with diabetes mellitus: A Danish nationwide cohort study. Eur. J. Prev. Cardiol. 2019, in press. [Google Scholar] [CrossRef]
  20. Lindberg, L.; Danielsson, P.; Persson, M.; Marcus, C.; Hagman, E. Association of childhood obesity with risk of early all-cause and cause-specific mortality: A Swedish prospective cohort study. PLoS Med. 2020, 17, e1003078. [Google Scholar] [CrossRef] [Green Version]
  21. Constantino, M.I.; Molyneaux, L.; Limacher-Gisler, F.; Al-Saeed, A.; Luo, C.; Wu, T.; Twigg, S.M.; Yue, D.K.; Wong, J. Long-term complications and mortality in young-onset diabetes: Type 2 diabetes is more hazardous and lethal than type 1 diabetes. Diabetes Care 2013, 36, 3863–3869. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Reynolds, K.; Saydah, S.H.; Isom, S.; Divers, J.; Lawrence, J.M.; Dabelea, D.; Mayer-Davis, E.J.; Imperatore, G.; Bell, R.A.; Hamman, R.F. Mortality in youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth study. J. Diabetes Complicat. 2018, 32, 545–549. [Google Scholar] [CrossRef] [PubMed]
  23. Rodriguez, B.L.; Fujimoto, W.Y.; Mayer-Davis, E.J.; Imperatore, G.; Williams, D.E.; Bell, R.A.; Wadwa, R.P.; Palla, S.L.; Liu, L.L.; Kershnar, A.; et al. Prevalence of cardiovascular disease risk factors in U.S. children and adolescents with diabetes: The SEARCH for diabetes in youth study. Diabetes Care 2006, 29, 1891–1896. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Kim, G.; Divers, J.; Fino, N.F.; Dabelea, D.; Lawrence, J.M.; Reynolds, K.; Bell, R.A.; Mayer-Davis, E.; Crume, T.; Pettitt, D.J.; et al. Trends in prevalence of cardiovascular risk factors from 2002 to 2012 among youth early in the course of type 1 and type 2 diabetes. The SEARCH for Diabetes in Youth Study. Pediatr. Diabetes 2019, 20, 693–701. [Google Scholar] [CrossRef]
  25. Dabelea, D.; Stafford, J.M.; Mayer-Davis, E.J.; D’Agostino, R., Jr.; Dolan, L.; Imperatore, G.; Linder, B.; Lawrence, J.M.; Marcovina, S.M.; Mottl, A.K.; et al. Association of Type 1 Diabetes vs Type 2 Diabetes Diagnosed During Childhood and Adolescence With Complications During Teenage Years and Young Adulthood. JAMA 2017, 317, 825–835. [Google Scholar] [CrossRef] [Green Version]
  26. Jie, K.E.; Goossens, M.H.; van Oostrom, O.; Lilien, M.R.; Verhaar, M.C. Circulating endothelial progenitor cell levels are higher during childhood than in adult life. Atherosclerosis 2009, 202, 345–347. [Google Scholar] [CrossRef]
  27. Miller, R.G.; Costacou, T.; Orchard, T.J. Risk Factor Modeling for Cardiovascular Disease in Type 1 Diabetes in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study: A Comparison With the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC). Diabetes 2019, 68, 409–419. [Google Scholar]
  28. Peters, S.A.; Huxley, R.R.; Woodward, M. Diabetes as risk factor for incident coronary heart disease in women compared with men: A systematic review and meta-analysis of 64 cohorts including 858,507 individuals and 28,203 coronary events. Diabetologia 2014, 57, 1542–1551. [Google Scholar] [CrossRef]
  29. Peters, S.A.; Huxley, R.R.; Woodward, M. Diabetes as a risk factor for stroke in women compared with men: A systematic review and meta-analysis of 64 cohorts, including 775,385 individuals and 12,539 strokes. Lancet 2014, 383, 1973–1980. [Google Scholar] [CrossRef]
  30. Stankute, I.; Dobrovolskiene, R.; Danyte, E.; Razanskaite-Virbickiene, D.; Jasinskiene, E.; Mockeviciene, G.; Marciulionyte, D.; Schwitzgebel, V.M.; Verkauskiene, R. Factors Affecting Cardiovascular Risk in Children, Adolescents, and Young Adults with Type 1 Diabetes. J. Diabetes Res. 2019, 2019, 9134280. [Google Scholar] [CrossRef]
  31. Diabetes Control and Complications Trial/Epidemiology of Diabetes I; Complications Study Research G. Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes: The DCCT/EDIC Study 30-Year Follow-up. Diabetes Care 2016, 39, 686–693. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Lu, J.; Ma, X.; Shen, Y.; Wu, Q.; Wang, R.; Zhang, L.; Mo, Y.; Lu, W.; Zhu, W.; Bao, Y.; et al. Time in Range Is Associated with Carotid Intima-Media Thickness in Type 2 Diabetes. Diabetes Technol. Ther. 2020, 22, 72–78. [Google Scholar] [CrossRef] [PubMed]
  33. Kataoka, Y.; Hosoda, K.; Makino, H.; Matsubara, M.; Matsuo, M.; Ohata, Y.; Koezuka, R.; Tamanaha, T.; Tomita, T.; Honda-Kohmo, K.; et al. The efficacy of glycemic control with continuous glucose monitoring on atheroma progression: Rationale and design of the Observation of Coronary Atheroma Progression under Continuous Glucose Monitoring Guidance in Patients with Type 2 Diabetes Mellitus (OPTIMAL). Cardiovasc. Diagn. Ther. 2019, 9, 431–438. [Google Scholar] [PubMed]
  34. Jamiolkowska, M.; Jamiolkowska, I.; Luczynski, W.; Tolwinska, J.; Bossowski, A.; Glowinska Olszewska, B. Impact of Real-Time Continuous Glucose Monitoring Use on Glucose Variability and Endothelial Function in Adolescents with Type 1 Diabetes: New TechnologyߞNew Possibility to Decrease Cardiovascular Risk? J. Diabetes Res. 2016, 2016, 4385312. [Google Scholar] [CrossRef]
  35. Fahrmann, E.R.; Adkins, L.; Loader, C.J.; Han, H.; Rice, K.M.; Denvir, J.; Driscoll, H.K. Severe hypoglycemia and coronary artery calcification during the diabetes control and complications trial/epidemiology of diabetes interventions and complications (DCCT/EDIC) study. Diabetes Res. Clin. Pract. 2015, 107, 280–289. [Google Scholar] [CrossRef]
  36. Nadeau, K.J.; Regensteiner, J.G.; Bauer, T.A.; Brown, M.S.; Dorosz, J.L.; Hull, A.; Zeitler, P.; Draznin, B.; Reusch, J.E. Insulin resistance in adolescents with type 1 diabetes and its relationship to cardiovascular function. J. Clin. Endocrinol. Metab. 2010, 95, 513–521. [Google Scholar] [CrossRef] [Green Version]
  37. Khawandanah, J. Double or hybrid diabetes: A systematic review on disease prevalence, characteristics and risk factors. Nutr. Diabetes 2019, 9, 33. [Google Scholar] [CrossRef]
  38. Schwab, K.O.; Doerfer, J.; Marg, W.; Schober, E.; Holl, R.W.; DPV Science Initiative; the Competence Network Diabetes mellitus. Characterization of 33,488 children and adolescents with type 1 diabetes based on the gender-specific increase of cardiovascular risk factors. Pediatr. Diabetes 2010, 11, 357–363. [Google Scholar] [CrossRef]
  39. Group, T.S. Rapid rise in hypertension and nephropathy in youth with type 2 diabetes: The TODAY clinical trial. Diabetes Care 2013, 36, 1735–1741. [Google Scholar] [CrossRef] [Green Version]
  40. Shah, A.S.; Wadwa, R.P.; Dabelea, D.; Hamman, R.F.; D’Agostino, R., Jr.; Marcovina, S.; Daniels, S.R.; Dolan, L.M.; Fino, N.F.; Urbina, E.M. Arterial stiffness in adolescents and young adults with and without type 1 diabetes: The SEARCH CVD study. Pediatr. Diabetes 2015, 16, 367–374. [Google Scholar] [CrossRef] [Green Version]
  41. Chiesa, S.T.; Charakida, M.; McLoughlin, E.; Nguyen, H.C.; Georgiopoulos, G.; Motran, L.; Elia, Y.; Marcovecchio, M.L.; Dunger, D.B.; Dalton, R.N.; et al. Elevated high-density lipoprotein in adolescents with Type 1 diabetes is associated with endothelial dysfunction in the presence of systemic inflammation. Eur. Heart J. 2019, 40, 3559–3566. [Google Scholar] [CrossRef] [Green Version]
  42. Flokas, M.E.; Zeymo, A.; Mete, M.; Anhalt, H.; Rother, K.I.; Gourgari, E. Overweight and obese children with optimal control in the T1D Exchange Registry: How are they different from lean children with optimal control? J. Diabetes Complicat. 2020, 34, 107513. [Google Scholar] [CrossRef] [PubMed]
  43. Prado, M.M.; Carrizo, T.; Abregu, A.V.; Merono, T. Non-HDL-cholesterol and C-reactive protein in children and adolescents with type 1 diabetes. J. Pediatr. Endocrinol. Metab. 2017, 30, 285–288. [Google Scholar] [CrossRef] [PubMed]
  44. Cree-Green, M.; Maahs, D.M.; Ferland, A.; Hokanson, J.E.; Wang, H.; Pyle, L.; Kinney, G.L.; King, M.; Eckel, R.H.; Nadeau, K.J. Lipoprotein subfraction cholesterol distribution is more atherogenic in insulin resistant adolescents with type 1 diabetes. Pediatr. Diabetes 2016, 17, 257–265. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Shah, A.S.; Dabelea, D.; Fino, N.F.; Dolan, L.M.; Wadwa, R.P.; D’Agostino, R., Jr.; Hamman, R.; Marcovina, S.; Daniels, S.R.; Urbina, E.M. Predictors of Increased Carotid Intima-Media Thickness in Youth with Type 1 Diabetes: The SEARCH CVD Study. Diabetes Care 2016, 39, 418–425. [Google Scholar] [CrossRef] [Green Version]
  46. Furman, D.; Campisi, J.; Verdin, E.; Carrera-Bastos, P.; Targ, S.; Franceschi, C.; Ferrucci, L.; Gilroy, D.W.; Fasano, A.; Miller, G.W.; et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 2019, 25, 1822–1832. [Google Scholar] [CrossRef]
  47. Marcovecchio, M.L.; de Giorgis, T.; Di Giovanni, I.; Chiavaroli, V.; Chiarelli, F.; Mohn, A. Association between markers of endothelial dysfunction and early signs of renal dysfunction in pediatric obesity and type 1 diabetes. Pediatr. Diabetes 2017, 18, 283–289. [Google Scholar] [CrossRef]
  48. Odermarsky, M.; Pesonen, E.; Sorsa, T.; Lernmark, A.; Pussinen, P.J.; Liuba, P. HLA, infections and inflammation in early stages of atherosclerosis in children with type 1 diabetes. Acta Diabetol. 2018, 55, 41–47. [Google Scholar] [CrossRef] [Green Version]
  49. Heier, M.; Margeirsdottir, H.D.; Brunborg, C.; Hanssen, K.F.; Dahl-Jorgensen, K.; Seljeflot, I. Inflammation in childhood type 1 diabetes; influence of glycemic control. Atherosclerosis 2015, 238, 33–37. [Google Scholar] [CrossRef]
  50. Group, T.S. Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: The TODAY clinical trial. Diabetes Care 2013, 36, 1758–1764. [Google Scholar] [CrossRef] [Green Version]
  51. Petrelli, A.; Di Fenza, R.; Carvello, M.; Gatti, F.; Secchi, A.; Fiorina, P. Strategies to reverse endothelial progenitor cell dysfunction in diabetes. Exp. Diabetes Res. 2012, 2012, 471823. [Google Scholar] [CrossRef] [PubMed]
  52. Schwab, K.O.; Doerfer, J.; Krebs, A.; Krebs, K.; Schorb, E.; Hallermann, K.; Superti-Furga, A.; Zieger, B.; Marz, W.; Schmidt-Trucksass, A.; et al. Early atherosclerosis in childhood type 1 diabetes: Role of raised systolic blood pressure in the absence of dyslipidaemia. Eur. J. Pediatr. 2007, 166, 541–548. [Google Scholar] [CrossRef] [PubMed]
  53. Eltayeb, A.A.; Ahmad, F.A.; Sayed, D.M.; Osama, A.M. Subclinical vascular endothelial dysfunctions and myocardial changes with type 1 diabetes mellitus in children and adolescents. Pediatr. Cardiol. 2014, 35, 965–974. [Google Scholar] [CrossRef] [PubMed]
  54. Zhang, Y.; Zhang, H.; Li, P. Cardiovascular risk factors in children with type 1 diabetes mellitus. J. Pediatr. Endocrinol. Metab. 2019, 32, 699–705. [Google Scholar] [CrossRef] [PubMed]
  55. Machnica, L.; Deja, G.; Polanska, J.; Czupryniak, L.; Szymanska-Garbacz, E.; Loba, J.; Jarosz-Chobot, P. Blood pressure disturbances and endothelial dysfunction markers in children and adolescents with type 1 diabetes. Atherosclerosis 2014, 237, 129–134. [Google Scholar] [CrossRef] [PubMed]
  56. Zorena, K.; Kula, M.; Malinowska, E.; Raczynska, D.; Mysliwiec, M.; Raczynska, K. Threshold serum concentrations of tumour necrosis factor alpha (TNFalpha) as a potential marker of the presence of microangiopathy in children and adolescents with type 1 diabetes mellitus (T1DM). Hum. Immunol. 2013, 74, 75–81. [Google Scholar] [CrossRef]
  57. Morales, A.; Wasserfall, C.; Brusko, T.; Carter, C.; Schatz, D.; Silverstein, J.; Ellis, T.; Atkinson, M. Adiponectin and leptin concentrations may aid in discriminating disease forms in children and adolescents with type 1 and type 2 diabetes. Diabetes Care 2004, 27, 2010–2014. [Google Scholar] [CrossRef] [Green Version]
  58. Snell-Bergeon, J.K.; West, N.A.; Mayer-Davis, E.J.; Liese, A.D.; Marcovina, S.M.; D’Agostino, R.B., Jr.; Hamman, R.F.; Dabelea, D. Inflammatory markers are increased in youth with type 1 diabetes: The SEARCH Case-Control study. J. Clin. Endocrinol. Metab. 2010, 95, 2868–2876. [Google Scholar] [CrossRef]
  59. Alman, A.C.; Talton, J.W.; Wadwa, R.P.; Urbina, E.M.; Dolan, L.M.; Hamman, R.F.; D’Agostino, R.B., Jr.; Marcovina, S.M.; Dabelea, D.M. Inflammation, adiposity, and progression of arterial stiffness in adolescents with type 1 diabetes: The SEARCH CVD Study. J. Diabetes Complicat. 2018, 32, 995–999. [Google Scholar] [CrossRef]
  60. Balagopal, P.; George, D.; Patton, N.; Yarandi, H.; Roberts, W.L.; Bayne, E.; Gidding, S. Lifestyle-only intervention attenuates the inflammatory state associated with obesity: A randomized controlled study in adolescents. J. Pediatr. 2005, 146, 342–348. [Google Scholar] [CrossRef]
  61. Liese, A.D.; Ma, X.; Ma, X.; Mittleman, M.A.; The, N.S.; Standiford, D.A.; Lawrence, J.M.; Pihoker, C.; Marcovina, S.M.; Mayer-Davis, E.J.; et al. Dietary quality and markers of inflammation: No association in youth with type 1 diabetes. J. Diabetes Complicat. 2018, 32, 179–184. [Google Scholar] [CrossRef] [PubMed]
  62. Brar, P.C.; Kohn, B. Use of the microbiome in the management of children with type 2 diabetes mellitus. Curr. Opin. Pediatr. 2019, 31, 524–530. [Google Scholar] [CrossRef] [PubMed]
  63. Wang, P.; Xu, Y.Y.; Lv, T.T.; Guan, S.Y.; Li, X.M.; Li, X.P.; Pan, H.F. Subclinical Atherosclerosis in Patients With Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Angiology 2019, 70, 141–159. [Google Scholar] [CrossRef] [PubMed]
  64. Lanfredini, M.; Fiorina, P.; Peca, M.G.; Veronelli, A.; Mello, A.; Astorri, E.; Dall’Aglio, P.; Craveri, A. Fasting and post-methionine load homocyst(e)ine values are correlated with microalbuminuria and could contribute to worsening vascular damage in non-insulin-dependent diabetes mellitus patients. Metabolism 1998, 47, 915–921. [Google Scholar] [CrossRef]
  65. Jarvisalo, M.J.; Raitakari, M.; Toikka, J.O.; Putto-Laurila, A.; Rontu, R.; Laine, S.; Lehtimaki, T.; Ronnemaa, T.; Viikari, J.; Raitakari, O.T. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 2004, 109, 1750–1755. [Google Scholar] [CrossRef] [Green Version]
  66. King, G.L.; Loeken, M.R. Hyperglycemia-induced oxidative stress in diabetic complications. Histochem. Cell Biol. 2004, 122, 333–338. [Google Scholar] [CrossRef]
  67. Folli, F.; Guzzi, V.; Perego, L.; Coletta, D.K.; Finzi, G.; Placidi, C.; La Rosa, S.; Capella, C.; Socci, C.; Lauro, D.; et al. Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients’ skin which are normalized by kidney-pancreas transplantation. PLoS ONE 2010, 5, e9923. [Google Scholar] [CrossRef]
  68. Babar, G.S.; Zidan, H.; Widlansky, M.E.; Das, E.; Hoffmann, R.G.; Daoud, M.; Alemzadeh, R. Impaired endothelial function in preadolescent children with type 1 diabetes. Diabetes Care 2011, 34, 681–685. [Google Scholar] [CrossRef] [Green Version]
  69. Glowinska, B.; Urban, M.; Peczynska, J.; Florys, B. Soluble adhesion molecules (sICAM-1, sVCAM-1) and selectins (sE selectin, sP selectin, sL selectin) levels in children and adolescents with obesity, hypertension, and diabetes. Metabolism 2005, 54, 1020–1026. [Google Scholar] [CrossRef]
  70. Aburawi, E.H.; AlKaabi, J.; Zoubeidi, T.; Shehab, A.; Lessan, N.; Al Essa, A.; Yasin, J.; Saadi, H.; Souid, A.K. Subclinical Inflammation and Endothelial Dysfunction in Young Patients with Diabetes: A Study from United Arab Emirates. PLoS ONE 2016, 11, e0159808. [Google Scholar] [CrossRef] [PubMed]
  71. Fathollahi, A.; Massoud, A.; Amirzargar, A.A.; Aghili, B.; Nasli Esfahani, E.; Rezaei, N. sICAM-1, sVCAM-1 and sE-Selectin Levels in Type 1 Diabetes. Fetal. Pediatr. Pathol. 2018, 37, 69–73. [Google Scholar] [CrossRef]
  72. Babar, G.; Clements, M.; Dai, H.; Raghuveer, G. Assessment of biomarkers of inflammation and premature atherosclerosis in adolescents with type-1 diabetes mellitus. J. Pediatr. Endocrinol. Metab. 2019, 32, 109–113. [Google Scholar] [CrossRef]
  73. Gidding, S.S.; Bacha, F.; Bjornstad, P.; Levitt Katz, L.E.; Levitsky, L.L.; Lynch, J.; Tryggestad, J.B.; Weinstock, R.S.; El Ghormli, L.; Lima, J.A.C.; et al. Cardiac Biomarkers in Youth with Type 2 Diabetes Mellitus: Results from the TODAY Study. J. Pediatr. 2018, 192, 86–92 e5. [Google Scholar] [CrossRef]
  74. Mameli, C.; Mazzantini, S.; Ben Nasr, M.; Fiorina, P.; Scaramuzza, A.E.; Zuccotti, G.V. Explaining the increased mortality in type 1 diabetes. World J. Diabetes 2015, 6, 889–895. [Google Scholar] [CrossRef]
  75. Aneja, A.; Tang, W.H.; Bansilal, S.; Garcia, M.J.; Farkouh, M.E. Diabetic cardiomyopathy: Insights into pathogenesis, diagnostic challenges, and therapeutic options. Am. J. Med. 2008, 121, 748–757. [Google Scholar] [CrossRef] [PubMed]
  76. Van Heerebeek, L.; Hamdani, N.; Handoko, M.L.; Falcao-Pires, I.; Musters, R.J.; Kupreishvili, K.; Ijsselmuiden, A.J.; Schalkwijk, C.G.; Bronzwaer, J.G.; Diamant, M.; et al. Diastolic stiffness of the failing diabetic heart: Importance of fibrosis, advanced glycation end products, and myocyte resting tension. Circulation 2008, 117, 43–51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Fiorina, P.; La Rocca, E.; Astorri, E.; Lucignani, G.; Rossetti, C.; Fazio, F.; Giudici, D.; di Carlo, V.; Cristallo, M.; Pozza, G.; et al. Reversal of left ventricular diastolic dysfunction after kidney-pancreas transplantation in type 1 diabetic uremic patients. Diabetes Care 2000, 23, 1804–1810. [Google Scholar] [CrossRef] [Green Version]
  78. Ciftel, M.; Ertug, H.; Parlak, M.; Akcurin, G.; Kardelen, F. Investigation of endothelial dysfunction and arterial stiffness in children with type 1 diabetes mellitus and the association with diastolic dysfunction. Diabetes Vasc. Dis. Res. 2014, 11, 19–25. [Google Scholar] [CrossRef] [Green Version]
  79. Astorri, E.; Fiorina, P.; Contini, G.A.; Albertini, D.; Magnati, G.; Astorri, A.; Lanfredini, M. Isolated and preclinical impairment of left ventricular filling in insulin-dependent and non-insulin-dependent diabetic patients. Clin. Cardiol. 1997, 20, 536–540. [Google Scholar] [CrossRef] [PubMed]
  80. Ozdemir, O.; Koksoy, A.Y.; Bulus, A.D.; Andiran, N.; Yagli, E. The effects of type 1 diabetes mellitus on cardiac functions in children: Evaluation by conventional and tissue Doppler echocardiography. J. Pediatr. Endocrinol. Metab. 2016, 29, 1389–1395. [Google Scholar] [CrossRef] [PubMed]
  81. Yoldas, T.; Orun, U.A.; Sagsak, E.; Aycan, Z.; Kaya, O.; Ozgur, S.; Karademir, S. Subclinical left ventricular systolic and diastolic dysfunction in type 1 diabetic children and adolescents with good metabolic control. Echocardiography 2018, 35, 227–233. [Google Scholar] [CrossRef] [PubMed]
  82. Shah, A.S.; Khoury, P.R.; Dolan, L.M.; Ippisch, H.M.; Urbina, E.M.; Daniels, S.R.; Kimball, T.R. The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults. Diabetologia 2011, 54, 722–730. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Adal, E.; Koyuncu, G.; Aydin, A.; Celebi, A.; Kavunoglu, G.; Cam, H. Asymptomatic cardiomyopathy in children and adolescents with type 1 diabetes mellitus: Association of echocardiographic indicators with duration of diabetes mellitus and metabolic parameters. J. Pediatr. Endocrinol. Metab. 2006, 19, 713–726. [Google Scholar] [CrossRef] [PubMed]
  84. Levitt, K.L.; Gidding, S.S.; Bacha, F.; Hirst, K.; McKay, S.; Pyle, L.; Lima, J.A.; Group, T.S. Alterations in left ventricular, left atrial, and right ventricular structure and function to cardiovascular risk factors in adolescents with type 2 diabetes participating in the TODAY clinical trial. Pediatr. Diabetes 2015, 16, 39–47. [Google Scholar]
  85. Brunvand, L.; Heier, M.; Brunborg, C.; Hanssen, K.F.; Fugelseth, D.; Stensaeth, K.H.; Dahl-Jorgensen, K.; Margeirsdottir, H.D. Advanced glycation end products in children with type 1 diabetes and early reduced diastolic heart function. BMC Cardiovasc. Disord. 2017, 17, 133. [Google Scholar] [CrossRef] [Green Version]
  86. Kir, M.; Cetin, B.; Demir, K.; Yilmaz, N.; Kizilca, O.; Demircan, T.; Unal, N.; Bober, E.; Saylam, G.S. Can ambulatory blood pressure monitoring detect early diastolic dysfunction in children with type 1 diabetes mellitus: Correlations with B-type natriuretic peptide and tissue Doppler findings. Pediatr. Diabetes 2016, 17, 21–27. [Google Scholar] [CrossRef]
  87. Brunvand, L.; Fugelseth, D.; Stensaeth, K.H.; Dahl-Jorgensen, K.; Margeirsdottir, H.D. Early reduced myocardial diastolic function in children and adolescents with type 1 diabetes mellitus a population-based study. BMC Cardiovasc. Disord. 2016, 16, 103. [Google Scholar] [CrossRef] [Green Version]
  88. Gusso, S.; Pinto, T.E.; Baldi, J.C.; Robinson, E.; Cutfield, W.S.; Hofman, P.L. Diastolic function is reduced in adolescents with type 1 diabetes in response to exercise. Diabetes Care 2012, 35, 2089–2094. [Google Scholar] [CrossRef] [Green Version]
  89. Pinto, T.E.; Gusso, S.; Hofman, P.L.; Derraik, J.G.; Hornung, T.S.; Cutfield, W.S.; Baldi, J.C. Systolic and diastolic abnormalities reduce the cardiac response to exercise in adolescents with type 2 diabetes. Diabetes Care 2014, 37, 1439–1446. [Google Scholar] [CrossRef] [Green Version]
  90. Gusso, S.; Pinto, T.; Baldi, J.C.; Derraik, J.G.B.; Cutfield, W.S.; Hornung, T.; Hofman, P.L. Exercise Training Improves but Does Not Normalize Left Ventricular Systolic and Diastolic Function in Adolescents with Type 1 Diabetes. Diabetes Care 2017, 40, 1264–1272. [Google Scholar] [CrossRef] [Green Version]
  91. Wiltshire, E.J.; Gent, R.; Hirte, C.; Pena, A.; Thomas, D.W.; Couper, J.J. Endothelial dysfunction relates to folate status in children and adolescents with type 1 diabetes. Diabetes 2002, 51, 2282–2286. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. Singh, T.P.; Groehn, H.; Kazmers, A. Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus. J. Am. Coll. Cardiol. 2003, 41, 661–665. [Google Scholar] [CrossRef] [Green Version]
  93. Bradley, T.J.; Slorach, C.; Mahmud, F.H.; Dunger, D.B.; Deanfield, J.; Deda, L.; Elia, Y.; Har, R.L.; Hui, W.; Moineddin, R.; et al. Early changes in cardiovascular structure and function in adolescents with type 1 diabetes. Cardiovasc. Diabetol. 2016, 15, 31. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Nascimento, A.; Sequeira, I.J.; Vasconcelos, D.F.; Gandolfi, L.; Pratesi, R.; Nobrega, Y.K.M. Endothelial dysfunction in children with type 1 diabetes mellitus. Arch. Endocrinol. Metab. 2017, 61, 476–483. [Google Scholar] [CrossRef] [Green Version]
  95. Pillay, S.; Anderson, J.; Couper, J.; Maftei, O.; Gent, R.; Pena, A.S. Children With Type 1 Diabetes Have Delayed Flow-Mediated Dilation. Can. J. Diabetes 2018, 42, 276–280. [Google Scholar] [CrossRef]
  96. Bruzzi, P.; Predieri, B.; Patianna, V.D.; Salvini, A.; Rossi, R.; Modena, M.G.; Iughetti, L. Longitudinal evaluation of endothelial function in children and adolescents with type 1 diabetes mellitus: A long-term follow-up study. Pediatr. Int. 2014, 56, 188–195. [Google Scholar] [CrossRef]
  97. Urbina, E.M.; Isom, S.; Bell, R.A.; Bowlby, D.A.; D’Agostino, R., Jr.; Daniels, S.R.; Dolan, L.M.; Imperatore, G.; Marcovina, S.M.; Merchant, A.T.; et al. Burden of Cardiovascular Risk Factors Over Time and Arterial Stiffness in Youth with Type 1 Diabetes Mellitus: The SEARCH for Diabetes in Youth Study. J. Am. Heart Assoc. 2019, 8, e010150. [Google Scholar] [CrossRef]
  98. Nathan, D.M.; Lachin, J.; Cleary, P.; Orchard, T.; Brillon, D.J.; Backlund, J.Y.; O’Leary, D.H.; Genuth, S.; Diabetes, C.; Complications, T.; et al. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N. Engl. J. Med. 2003, 348, 2294–2303. [Google Scholar]
  99. Polak, J.F.; Backlund, J.Y.; Cleary, P.A.; Harrington, A.P.; O’Leary, D.H.; Lachin, J.M.; Nathan, D.M.; Group, D.E.R. Progression of carotid artery intima-media thickness during 12 years in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study. Diabetes 2011, 60, 607–613. [Google Scholar] [CrossRef] [Green Version]
  100. Krantz, J.S.; Mack, W.J.; Hodis, H.N.; Liu, C.R.; Liu, C.H.; Kaufman, F.R. Early onset of subclinical atherosclerosis in young persons with type 1 diabetes. J. Pediatr. 2004, 145, 452–457. [Google Scholar] [CrossRef]
  101. American Diabetes Association. 13. Children and Adolescents: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020, 43 (Suppl. S1), S163–S182. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Donaghue, K.C.; Marcovecchio, M.L.; Wadwa, R.P.; Chew, E.Y.; Wong, T.Y.; Calliari, L.E.; Zabeen, B.; Salem, M.A.; Craig, M.E. ISPAD Clinical Practice Consensus Guidelines 2018: Microvascular and macrovascular complications in children and adolescents. Pediatr. Diabetes 2018, 19 (Suppl. S27), 262–274. [Google Scholar] [CrossRef] [PubMed]
  103. Pivovarov, J.A.; Taplin, C.E.; Riddell, M.C. Current perspectives on physical activity and exercise for youth with diabetes. Pediatr. Diabetes 2015, 16, 242–255. [Google Scholar] [CrossRef] [PubMed]
  104. Biester, T.; Kordonouri, O.; Danne, T. Pharmacotherapy of type1 diabetes in children and adolescents: More than insulin? Ther. Adv. Endocrinol. Metab. 2018, 9, 157–166. [Google Scholar] [CrossRef] [PubMed]
  105. Anderson, J.J.A.; Couper, J.J.; Giles, L.C.; Leggett, C.E.; Gent, R.; Coppin, B.; Pena, A.S. Effect of Metformin on Vascular Function in Children With Type 1 Diabetes: A 12-Month Randomized Controlled Trial. J. Clin. Endocrinol. Metab. 2017, 102, 4448–4456. [Google Scholar] [CrossRef] [PubMed]
  106. Group, T.S.; Zeitler, P.; Hirst, K.; Pyle, L.; Linder, B.; Copeland, K.; Arslanian, S.; Cuttler, L.; Nathan, D.M.; Tollefsen, S.; et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N. Engl. J. Med. 2012, 366, 2247–2256. [Google Scholar] [CrossRef] [PubMed]
  107. Narasimhan, S.; Weinstock, R.S. Youth-onset type 2 diabetes mellitus: Lessons learned from the TODAY study. Mayo Clin. Proc. 2014, 89, 806–816. [Google Scholar] [CrossRef] [Green Version]
  108. Kelsey, M.M.; Geffner, M.E.; Guandalini, C.; Pyle, L.; Tamborlane, W.V.; Zeitler, P.S.; White, N.H.; Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study Group. Presentation and effectiveness of early treatment of type 2 diabetes in youth: Lessons from the TODAY study. Pediatr. Diabetes 2016, 17, 212–221. [Google Scholar] [CrossRef] [Green Version]
  109. Bacha, F.; Cheng, P.; Gal, R.L.; Kollman, C.; Tamborlane, W.V.; Klingensmith, G.J.; Manseau, K.; Wood, J.; Beck, R.W.; Pediatric Diabetes Consortium. Initial Presentation of Type 2 Diabetes in Adolescents Predicts Durability of Successful Treatment with Metformin Monotherapy: Insights from the Pediatric Diabetes Consortium T2D Registry. Horm. Res. Paediatr. 2018, 89, 47–55. [Google Scholar] [CrossRef]
  110. Bjornstad, P.; Schafer, M.; Truong, U.; Cree-Green, M.; Pyle, L.; Baumgartner, A.; Garcia Reyes, Y.; Maniatis, A.; Nayak, S.; Wadwa, R.P.; et al. Metformin Improves Insulin Sensitivity and Vascular Health in Youth with Type 1 Diabetes Mellitus. Circulation 2018, 138, 2895–2907. [Google Scholar] [CrossRef]
  111. Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 2117–2128. [Google Scholar] [CrossRef] [PubMed]
  112. Marso, S.P.; Daniels, G.H.; Brown-Frandsen, K.; Kristensen, P.; Mann, J.F.; Nauck, M.A.; Nissen, S.E.; Pocock, S.; Poulter, N.R.; Ravn, L.S.; et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 311–322. [Google Scholar] [CrossRef] [Green Version]
  113. Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.L.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G.; Bull, S.; et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 2019, 380, 2295–2306. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Gerstein, H.C.; Colhoun, H.M.; Dagenais, G.R.; Diaz, R.; Lakshmanan, M.; Pais, P.; Probstfield, J.; Riesmeyer, J.S.; Riddle, M.C.; Ryden, L.; et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): A double-blind, randomised placebo-controlled trial. Lancet 2019, 394, 121–130. [Google Scholar] [CrossRef]
  115. Mathieu, C.; Rudofsky, G.; Phillip, M.; Araki, E.; Lind, M.; Arya, N.; Thoren, F.; Scheerer, M.F.; Iqbal, N.; Dandona, P. Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 52-week results from a randomized controlled trial. Diabetes Obes. Metab. 2020, in press. [Google Scholar] [CrossRef] [PubMed]
  116. Van Meijel, L.A.; Rooijackers, H.M.; Tack, C.J.; de Galan, B.E. Effect of the GLP-1 receptor agonist exenatide on impaired awareness of hypoglycemia in type 1 diabetes; a randomized controlled trial. J. Clin. Endocrinol. Metab. 2019, in press. [Google Scholar] [CrossRef] [PubMed]
  117. Dellepiane, S.; Ben Nasr, M.; Assi, E.; Usuelli, V.; Letizia, T.; D’Addio, F.; Zuccotti, G.V.; Fiorina, P. Sodium glucose cotransporters inhibitors in type 1 diabetes. Pharmacol. Res. 2018, 133, 1–8. [Google Scholar] [CrossRef]
  118. Tamborlane, W.V.; Barrientos-Perez, M.; Fainberg, U.; Frimer-Larsen, H.; Hafez, M.; Hale, P.M.; Jalaludin, M.Y.; Kovarenko, M.; Libman, I.; Lynch, J.L.; et al. Liraglutide in Children and Adolescents with Type 2 Diabetes. N. Engl. J. Med. 2019, 381, 637–646. [Google Scholar] [CrossRef]
  119. American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020, 43 (Suppl. S1), S14–S31. [Google Scholar] [CrossRef] [Green Version]
  120. Bassi, R.; Trevisani, A.; Tezza, S.; Ben Nasr, M.; Gatti, F.; Vergani, A.; Farina, A.; Fiorina, P. Regenerative therapies for diabetic microangiopathy. Exp. Diabetes Res. 2012, 2012, 916560. [Google Scholar] [CrossRef]
  121. El Samahy, M.H.; Matter, R.M.; Youssef, O.I.; Shams El Din El Telbany, M.A.; Kamal, N.A. Relation between carotid intima media thickness and oxidative stress markers in type 1 diabetic children and adolescents. J. Diabetes Metab. Disord. 2013, 12, 50. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. El-Asrar, M.A.; Elbarbary, N.S.; Ismail, E.A.; Bakr, A.A. Circulating angiopoietin-2 levels in children and adolescents with type 1 diabetes mellitus: Relation to carotid and aortic intima-media thickness. Angiogenesis 2016, 19, 421–431. [Google Scholar] [CrossRef] [PubMed]
  123. Sochett, E.; Noone, D.; Grattan, M.; Slorach, C.; Moineddin, R.; Elia, Y.; Mahmud, F.H.; Dunger, D.B.; Dalton, N.; Cherney, D.; et al. Relationship between serum inflammatory markers and vascular function in a cohort of adolescents with type 1 diabetes. Cytokine 2017, 99, 233–239. [Google Scholar] [CrossRef] [PubMed]
  124. Rostampour, N.; Fekri, K.; Hashemi-Dehkordi, E.; Obodiat, M. Association between Vascular Endothelial Markers and Carotid Intima-Media Thickness in Children and Adolescents with Type 1 Diabetes Mellitus. J. Clin. Diagn. Res. 2017, 11, SC01–SC05. [Google Scholar] [CrossRef]
  125. Karavanaki, K.; Tsouvalas, E.; Vakaki, M.; Soldatou, A.; Tsentidis, C.; Kaparos, G.; Augoulea, A.; Alexandrou, A.; Lambrinoudaki, I. Carotid intima media thickness and associations with serum osteoprotegerin and s-RANKL in children and adolescents with type 1 diabetes mellitus with increased risk for endothelial dysfunction. J. Pediatr. Endocrinol. Metab. 2018, 31, 1169–1177. [Google Scholar] [CrossRef]
  126. Urbina, E.M.; Dabelea, D.; D’Agostino, R.B., Jr.; Shah, A.S.; Dolan, L.M.; Hamman, R.F.; Daniels, S.R.; Marcovina, S.; Wadwa, R.P. Effect of type 1 diabetes on carotid structure and function in adolescents and young adults: The SEARCH CVD study. Diabetes Care 2013, 36, 2597–2599. [Google Scholar] [CrossRef] [Green Version]
  127. Pezeshki Rad, M.; Farrokh, D.; Vakili, R.; Omidbakhsh, M.; Mohammadi, M. The Association between Carotid Intima-Media Thickness and the Duration of Type 1 Diabetes in Children. Iran. J. Pediatr. 2014, 24, 249–254. [Google Scholar]
  128. Atabek, M.E.; Akyurek, N.; Eklioglu, B.S.; Alp, H. Impaired systolic blood dipping and nocturnal hypertension: An independent predictor of carotid intima-media thickness in type 1 diabetic patients. J. Diabetes Complicat. 2014, 28, 51–55. [Google Scholar] [CrossRef]
  129. Terlemez, S.; Bulut, Y.; Unuvar, T.; Tokgoz, Y.; Eryilmaz, U.; Celik, B. Evaluation of arterial stiffness in children with type 1 diabetes using the oscillometric method. J. Diabetes Complicat. 2016, 30, 864–867. [Google Scholar] [CrossRef]
  130. Lilje, C.; Cronan, J.C.; Schwartzenburg, E.J.; Owers, E.M.; Clesi, P.; Gomez, R.; Stender, S.; Hempe, J.; Chalew, S.A.; Cardinale, J.P. Intima-media thickness at different arterial segments in pediatric type 1 diabetes patients and its relationship with advanced glycation end products. Pediatr. Diabetes 2018, 19, 450–456. [Google Scholar] [CrossRef]
  131. Podgorski, M.; Szatko, K.; Stanczyk, M.; Pawlak-Bratkowska, M.; Fila, M.; Bieniek, E.; Tkaczyk, M.; Grzelak, P.; Lukaszewski, M. Two-Dimensional Speckle Tracking Versus Applanation Tonometry in Evaluation of Subclinical Atherosclerosis in Children with Type 1 Diabetes Mellitus. Med. Sci. Monit. 2019, 25, 7289–7294. [Google Scholar] [CrossRef] [PubMed]
  132. Glackin, S.; Islam, N.; Henderson, A.M.; Dionne, J.M.; Harris, K.C.; Panagiotopoulos, C.; Devlin, A.M. Ambulatory blood pressure and carotid intima media thickness in children with type 1 diabetes. Pediatr. Diabetes 2020, 21, 358–365. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Modifiable and Unmodifiable Cardiovascular Risk Factors in Children and Adolescents with Diabetes.
Table 1. Modifiable and Unmodifiable Cardiovascular Risk Factors in Children and Adolescents with Diabetes.
Modifiable Risk FactorsUnmodifiable Risk Factors
ObesityYounger age at diabetes onset
Waist circumferenceDiabetes duration
Insulin resistanceFamily history
Hyperglycemia
Hypoglycemia
Glucose variability
Hypertension
Microalbuminuria
Dyslipidemia
Smoking
Alchol
Table
Table 2. Studies Evaluating Cardiovascular Biomarkers in Children and Adolescents with Diabetes.
Table 2. Studies Evaluating Cardiovascular Biomarkers in Children and Adolescents with Diabetes.
AuthorPublication YearSampleAgeHbA1cDM DurationPeripheral Biomarkers
DMHCDMHCDMHC
Glowinska [69]2005512715.5 ± 3.815.2 ± 2.1NANANA↑ sICAM-1, sVCAM, sE-selectin
Schwab [52]2007944012.3 (8.5–16.8)12.3 (7.5–15.2)7.7 (6.8–10.0)4.8 (1.2–5-5)3.8 (1.8–9.8)↑ hs-CRP, L-selectin, sICAM, vWF, PAP, PAI
Zorena [56]2013533212.5 ± 2.9 13.8 ± 3.37.6 ± 1.13.2 ± 0.84.3 ± 2.5 ↑ AGEs, TNF-α, VEGF, IL-12
El Samahy [121]201350509.7 ± 3.49.8 ± 3.1NANA4.5 ± 3.5↑NO
Machnica [55]2014522014.0 ± 3.013.0 ± 3.07.1 ± 0.9NA5.0 ± 1.9↑ sVCAM, TNF-α, IL-6
Eltayeb [53]2014303011.1 ± 3.89.8 ± 3.59.7 ± 2.24.9 ± 0.43.9 ± 0.6↑ hsCRP, CECs ↓ vitamin C
Aburawi 1 [70]2016794718.6 ± 4.8 17.5 ± 4.69.4 ± 2.1 NA6.8 ± 4.1↑ sICAM-1, sVCAM
Aburawi 2 [70]2016554723.3 ± 5.8 17.5 ± 4.67.8 ± 2.5NA4.3 ± 3.1↑ sICAM-1, sVCAM
El-Asrar 1 [122]2016213011.5 ± 3.110.7 ± 3.27.4 ± 0.9NA8.0 ± 1.6↑Angiopoietin-2
El-Asrar 2 [122]2016393011.4 ± 3.710.7 ± 3.29.1 ± 1.3NA8.3 ± 1.8↑Angiopoietin-2
Sochett [123]2017515914.8 (10.9–16.8)13.9 (10.0–17.0)9.0 ± 1.05.0 ± 0.06.7 (2.0–16.8)↑ EGF, PDGF-BB, sCD40L, PDGF-AA, GRO
Rostampour [124]2017292911.7 ± 1.910.7 ± 2.0NANANA↑ sICAM-1
Fathollahi [71]2018483924.2 ± 8.228.5 ± 7.2NANANA↑ sICAM-1 = sVCAM ↓ sE-selectin
Karavanaki [125]2018562812.0 ± 2.712.1 ± 3.38.0 ± 1.54.1 ± 0.95.4 ± 2.8= OPG, RANKL
Zhang [54]201917515012.1 ± 2.512.2 ± 1.977.8 ± 1.34.9 ± 1.64.7 ± 2.4↑ TNF-α, IL-4, hs-CRP, leptin
Data are presented as mean ± SD or median (range). Abbreviations: DM, diabetes mellitus; HC, health control; NA, not available; sICAM-1, serum intercellular adhesion molecule-1; sVCAM-1, serum vascular cell adhesion molecule-1; sE-selectin, serum E-selectin; hs-CRP, high sensitivity-C reactive protein; vWF, von Willebrand factor antigen; PAP, plasmin/ α 2-antiplasmin complex; PAI, plasminogen activator inhibitor; AGEs, advanced glycation end-products; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor; IL-12, interleukin-12; NO, nitric oxide; CECs, circulating endothelial cells; EGF, endothelial growth factor; PDGF-BB, platelet-derived growth factor-BB; sCD40L, soluble cluster of differentiation 40 ligand; PDGF-AA, platelet-derived growth factor-AA; GRO, growth regulated oncogene; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor kappa ligand.
Table
Table 3. Studies Evaluating Non-invasive Vascular Test in Children and Adolescents with Diabetes.
Table 3. Studies Evaluating Non-invasive Vascular Test in Children and Adolescents with Diabetes.
AuthorPublication YearSampleAgeHbA1cDM DurationNon-Invasive Vascular Test
DMHCDMHCDMHC
Urbina [126]201340220618.8 ± 3.319.2 ± 3.38.9 ± 1.85.0 ± 0.39.8 ± 3.8↑ bulb cIMT = cIMT, PWV
El Samahy [121]201350509.7 ± 3.49.8 ± 3.1NANA4.5 ± 3.5↑ cIMT
Eltayeb [53]2014303011.1 ± 3.89.8 ± 3.59.7 ± 2.24.9 ± 0.43.9 ± 0.6↑ cIMT ↓ FMD
Ciftel [78]2014424013.2 ± 2.613.0 ± 2.89.0 ± 1.4NA6.9 ± 1.7↑ cIMT ↓ FMD
Pezeshki Rad [127]2014404010.6 ± 4.110.5 ± 3.29.4 ± 2.7NA4.2 ± 3.0↑ cIMT
Atabek [128]201415910012.3 ± 4.212.2 ± 4.59.7 ± 2.55.3 ± 1.83.8 ± 2.5↑ cIMT
Shah [40]201540220618.8 ± 3.319.2 ± 3.38.9 ± 1.85.0 ± 0.39.8 ± 3.8↑ PWV
Bradley [93]201619917814.4 ± 1.614.4 ± 2.18.5 ± 1.25.4 ± 0.27.2 ± 3.1↑ = PWV
El-Asrar 1 [122]2016213011.5 ± 3.110.7 ± 3.27.4 ± 0.9NA8.0 ± 1.6↑ cIMT, aIMT
El-Asrar 2 [122]2016393011.4 ± 3.710.7 ± 3.29.1 ± 1.3NA8.3 ± 1.8↑ cIMT, aIMT
Terlemez [129]2016727712.8 ± 3.712.3 ± 1.68.6 ± 1.9NA3.9 ± 2.6↑ PWV
Nascimento [94]201722588.6 ± 1.78.3 ± 1.88.8 ± 1.55.3 ± 0.2> 5 = FMD, cIMT
Nascimento [94]201795810.1 ± 1.28.3 ± 1.89.5 ± 1.75.3 ± 0.2< 5↓FMD = cIMT
Rostampour [124]2017292911.7 ± 1.910.7 ± 2.0NANANA↑ cIMT
Pillay [95]2018382813.0 ± 2.913.9 ± 2.78.8(6.6–14)5.2(4.7–5.7)5.4 ± 4.6↓ FMD
Lilje [130]2018383813.4 ± 3.45.8 ± 4.39.7 ± 1.6NA5.8 ± 4.3↑aIMT, fIMT = cIMT
Karavanaki [125]2018562812.0 ± 2.712.1 ± 3.38.0 ± 1.54.1 ± 0.95.4 ± 2.8= cIMT
Zhang [54]201917515012.1 ± 2.512.2 ± 1.97.8 ± 1.34.9 ± 1.64.7 ± 2.4↑ cIMT, aIMT ↓ FMD
Podgorski [131]2019505013.4 ± 3.813.1 ± 4.17.6 ± 1.2NA6.5 ± 3.8↑ PWV = cIMT
Glackin [132]2020572913.9 ± 2.315.1 ± 2.27.8 ± 1.85.3 ± 0.35.4 ± 4.1= cIMT
Data are presented as mean ± SD or median (range). Abbreviations: DM, diabetes mellitus; HC, health control; NA, not available; cIMT, carotid intima media thickness; PWV, pulse wave velocity; FMD, flow mediated dilatation; aIMT, aortic intima media thickness; fIMT, femoral intima media thickness.
Table
Table 4. Effects of Hypoglycemic Therapies on Different Outcomes in Children and Adolescents with Diabetes.
Table 4. Effects of Hypoglycemic Therapies on Different Outcomes in Children and Adolescents with Diabetes.
Hypoglycemic TherapyDiabetes ControlInsulin SensitivityBlood PressureAtherogenic ProfileCV HealthBody Weight
Education↑NANANA↑NA
Diet↑⟷NA↓⟷↓
Physical activity↑↑⟷↓↑↓
Insulin↑⟷↑↑⟷↑
Metformin↑↑⟷⟷↑⟷/↓
GLP1RA↑NA⟷⟷NA↓
Abbreviations: CV, cardiovascular; NA, not available.

Share and Cite

MDPI and ACS Style

Pastore, I.; Bolla, A.M.; Montefusco, L.; Lunati, M.E.; Rossi, A.; Assi, E.; Zuccotti, G.V.; Fiorina, P. The Impact of Diabetes Mellitus on Cardiovascular Risk Onset in Children and Adolescents. Int. J. Mol. Sci. 2020, 21, 4928. https://doi.org/10.3390/ijms21144928

AMA Style

Pastore I, Bolla AM, Montefusco L, Lunati ME, Rossi A, Assi E, Zuccotti GV, Fiorina P. The Impact of Diabetes Mellitus on Cardiovascular Risk Onset in Children and Adolescents. International Journal of Molecular Sciences. 2020; 21(14):4928. https://doi.org/10.3390/ijms21144928

Chicago/Turabian Style

Pastore, Ida, Andrea Mario Bolla, Laura Montefusco, Maria Elena Lunati, Antonio Rossi, Emma Assi, Gian Vincenzo Zuccotti, and Paolo Fiorina. 2020. "The Impact of Diabetes Mellitus on Cardiovascular Risk Onset in Children and Adolescents" International Journal of Molecular Sciences 21, no. 14: 4928. https://doi.org/10.3390/ijms21144928

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop