- Please check and comment entries here.
Cardiovascular risk onset in children and adolescents with diabetes mellitus
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.
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 . 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 . 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 . 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 . In addition, prediabetes affects nearly 5% of children aged between 6 and 10 years . 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 . 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% . 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 . Younger patients with T2D showed an impaired insulin secretion and detectable circulating autoantibodies . 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 .
2. 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 . 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 . 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 . 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 . Continuous systemic chronic inflammation from childhood accelerates plaque formation and contributes to its growth . 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 . Indeed, the inflammatory state was only partially reverted by pharmacological therapy  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 . 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 . Interestingly, pro-inflammatory marker levels seem to also be elevated in lean adolescents with diabetes and good glycemic control . 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 . More recently, a putative role for microbiome in the activation of gut and systemic inflammation was suggested in children and adolescents with diabetes . 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 . 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.
3. 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 . In the management of children and adolescents with diabetes, a pivotal role is played by health education . The identification of a nutritional educational plan, with the aim of managing the intake of nutrients is essential . Regular physical activity improves glycemic control, insulin sensitivity, lipid profile, body composition, wellbeing and cardiovascular health . Therapeutic strategies used in the treatment of young patients with T1D and T2D partially differ from those used in adults . 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 . 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 . 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 . 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 . 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 . A growing number of studies showed that metformin enhances insulin sensitivity and reduces insulin dose in youth with T1D, but also improves vascular markers .
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 . Moreover, their effectiveness and safety are also being tested in the treatment of patients with T1D . 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 .
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. 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 . 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 .
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.
This entry is adapted from 10.3390/ijms21144928
- 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.
- 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.
- 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.
- Jensen, E.T.; Dabelea, D. Type 2 Diabetes in Youth: New Lessons from the SEARCH Study. Curr. Diab. Rep. 2018, 18, 36.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Zhang, Y.; Zhang, H.; Li, P. Cardiovascular risk factors in children with type 1 diabetes mellitus. J. Pediatr. Endocrinol. Metab. 2019, 32, 699–705.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- American Diabetes Association. 13. Children and Adolescents: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020, 43 (Suppl. S1), S163–S182.
- 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.
- 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.
- 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.
- 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.
- 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.
- Narasimhan, S.; Weinstock, R.S. Youth-onset type 2 diabetes mellitus: Lessons learned from the TODAY study. Mayo Clin. Proc. 2014, 89, 806–816.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. 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.
- 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.
- 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.
- American Diabetes Association. 2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020, 43 (Suppl. S1), S14–S31.
- 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.
- 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.