M. Loredana Marcovecchio

Insulin resistance in children: Consensus, perspective, and future directions

OBJECTIVE Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points. PARTICIPANTS The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants. EVIDENCE An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children. CONSENSUS PROCESS The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement. CONCLUSIONS Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.

Prevalence of Abnormal Lipid Profiles and the Relationship With the Development of Microalbuminuria in Adolescents With Type 1 Diabetes

OBJECTIVE To explore the prevalence of lipid abnormalities and their relationship with albumin excretion and microalbuminuria in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS The study population comprised 895 young subjects with type 1 diabetes (490 males); median age at the baseline assessment was 14.5 years (range 10–21.1), and median diabetes duration was 4.8 years (0.2–17). A total of 2,194 nonfasting blood samples were collected longitudinally for determination of total cholesterol, LDL cholesterol, HDL cholesterol, TG, and non-HDL cholesterol. Additional annually collected data on anthropometric parameters, A1C, and albumin-to-creatinine ratio (ACR) were available. RESULTS Total cholesterol, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol were higher in females than in males (all P < 0.001). A significant proportion of subjects presented sustained lipid abnormalities during follow-up: total cholesterol >5.2 mmol/l (18.6%), non-HDL cholesterol >3.4 mmol/l (25.9%), TG >1.7 mmol/l (20.1%), and LDL cholesterol >3.4 mmol/l (9.6%). Age and duration were significantly related to all lipid parameters (P < 0.001); A1C was independently related to all parameters (P < 0.001) except HDL cholesterol, whereas BMI SD scores were related to all parameters (P < 0.05) except total cholesterol. Total cholesterol and non-HDL cholesterol were independently related to longitudinal changes in ACR (B coefficient ± SE): 0.03 ± 0.01/1 mmol/l, P = 0.009, and 0.32 ± 0.014/1 mmol/l, P = 0.02, respectively. Overall mean total cholesterol and non-HDL cholesterol were higher in microalbuminuria positive (n = 115) than in normoalbuminuric subjects (n = 780): total cholesterol 4.7 ± 1.2 vs. 4.5 ± 0.8 mmol/l (P = 0.04) and non-HDL cholesterol 3.2 ± 1.2 vs. 2.9 ± 0.8 mmol/l (P = 0.03). CONCLUSIONS In this longitudinal study of adolescents with type 1 diabetes, sustained lipid abnormalities were related to age, duration, BMI, and A1C. Furthermore, ACR was related to both total cholesterol and non-HDL cholesterol, indicating a potential role in the pathogenesis of diabetic nephropathy.

Microvascular and macrovascular complications in children and adolescents

Kim C Donaghuea,b, R Paul Wadwac, Linda A Dimegliod, Tien Y Wonge, Francesco Chiarellif, M Loredana Marcovecchiof, Mona Salemg, Jamal Razah, Paul L Hofmani and Maria E Craiga,b,j aInstitute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, Australia; bDiscipline of Paediatrics and Child Health, University of Sydney, Sydney, Australia; cBarbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Denver, CO, USA; dPediatric Endocrinology and Diabetology, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA; eSingapore National Eye Centre, Singapore Eye Research Institute, Singapore, Singapore; fDepartment of Paediatrics, University of Chieti, Chieti, Italy; gDepartment of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt; hNational Institute of Child Health, Karachi, Pakistan; iLiggins Institute, University of Auckland, Auckland, New Zealand and jSchool of Women’s and Children’s Health, University of New South Wales, Sydney, Australia

Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT): Urinary screening and baseline biochemical and cardiovascular assessments

OBJECTIVE We assessed the association between early increases in albumin excretion and cardiovascular (CV) and renal markers in a large cohort of young people with type 1 diabetes. RESEARCH DESIGN AND METHODS As part of preliminary screening for a multicenter, randomized controlled trial of statins/ACE inhibitors, we measured albumin–creatinine ratio (ACR) in six early morning urine samples from 3,353 adolescents (10–16 years of age) and calculated tertiles based on an established algorithm. From those subjects deemed to be at higher risk (upper ACR tertile), we recruited 400 into the intervention study (trial cohort). From those subjects deemed to be at lower risk (middle–lower ACR tertiles), we recruited 329 to the observation cohort. At baseline, vascular measurements (carotid intima-media thickness, pulse wave velocity [PWV], flow-mediated dilatation, digital pulse amplitude tonometry), renal markers (symmetric dimethylarginine, cystatin C, creatinine), and CV disease markers (lipids and apolipoproteins [Apo] A-1 and B, C-reactive protein, asymmetric dimethylarginine) were assessed. RESULTS Age- and sex-adjusted PWV was higher in the trial than in the observational cohort (5.00 ± 0.84 vs. 4.86 ± 0.70 m/s; P = 0.021). Similarly, non-HDL cholesterol (2.95 ± 0.83 vs. 2.81 ± 0.78 mmol/L; P = 0.02) and ApoB–ApoA-1 ratio (0.50 ± 0.14 vs. 0.47 ± 0.11; P = 0.04) were higher in the trial cohort. Cystatin C and creatinine were decreased (0.88 ± 0.13 vs. 0.90 ± 0.13 mg/L, P = 0.04; 51.81 ± 10.45 vs. 55.35 ± 11.05 μmol/L, P < 0.001; respectively) and estimated glomerular filtration rate (137.05 ± 23.89 vs. 129.31 ± 22.41 mL/min/1.73 m2; P < 0.001) increased in the trial compared with the observational cohort. CONCLUSIONS Our data demonstrate that in adolescents with type 1 diabetes, the group with the highest tertile of albumin excretion showed more evidence of early renal and CV disease than those in the lower tertiles.

Role of Chronic and Acute Hyperglycemia in the Development of Diabetes Complications

Chronic hyperglycemia, as assessed by hemoglobin A1c (HbA1c) levels, has been associated with the development of microvascular and macrovascular complications of diabetes. Several studies have shown that acute hyperglycemia can add to the effect of chronic hyperglycemia in inducing tissue damage. Acute hyperglycemia can activate the same metabolic and hemodynamic pathways as chronic hyperglycemia. In particular, it is associated with increased mitochondrial production of reactive oxidant species, which have been suggested as the link between hyperglycemia and the activation of downstream pathways, mediating tissue damage. Studies performed in subjects with diabetes have shown that there is a positive association between HbA1c and both fasting and postprandial glucose levels. However, it appears that the contribution of these two parameters to the total HbA1c concentrations varies according to the degree of metabolic control. Postprandial glucose excursions are predominant in patients with a good or mild glycemic control, whereas the contribution of fasting hyperglycemia is stronger as glycemic control worsens. Glucose variability, like the intra-day glucose fluctuations from peaks to nadirs, is another important parameter, which, mainly in subjects with type 2 diabetes, has emerged as an HbA1c-independent risk factor for the development of vascular complications. Based on the current knowledge on the association not only of HbA1c, but also of fasting and postprandial glucose, with diabetes complications, it is paramount that antidiabetes strategies are directed at improving all these components in order to reduce the burden associated with diabetes.

A1C Variability as an Independent Risk Factor for Microalbuminuria in Young People With Type 1 Diabetes

OBJECTIVE To assess the potential association between A1C variability (A1C-SD) and microalbuminuria in young people with type 1 diabetes. RESEARCH DESIGN AND METHODS Serially collected samples for A1C measurement were available for 1,232 subjects with childhood-onset type 1 diabetes recruited to the Oxford Regional Prospective Study and the Nephropathy Family Study. RESULTS The median (range) number of A1C assessments was 4 (2–16). Mean intrapersonal A1C was 9.5% and A1C-SD was 0.91. Mean A1C and A1C-SD values were higher in subjects with microalbuminuria (n = 227) than in those with normoalbuminuria (10.3 vs. 9.4%; 1.12 vs. 0.86, P < 0.001). In a Cox regression model, A1C-SD was independently associated with microalbuminuria (hazard ratio 1.31 [95% CI 1.01–1.35]). CONCLUSIONS In the current study, A1C variability was an independent variable that added to the effect of A1C on the risk for microalbuminuria in youth with type 1 diabetes, a population highly vulnerable to vascular complications.

Liver Steatosis in Obese Prepubertal Children: A Possible Role of Insulin Resistance

Objective: To determine whether in obese prepubertal children insulin resistance (IR) is associated with the development of liver steatosis.

Molecular pathology of oxidative stress in diabetic angiopathy: Role of mitochondrial and cellular pathways

Diabetes mellitus is characterized by chronic hyperglycaemia and a significant risk of developing micro- and macrovascular complications. Growing evidence suggests that increased oxidative stress, induced by several hyperglycaemia-activated pathways, is a key factor in the pathogenesis of endothelial dysfunction and vascular disease. Reactive oxidant molecules, which are produced at a high rate in the diabetic milieu, can cause oxidative damage of many cellular components and activate several pathways linked with inflammation and apoptosis. Among the mechanisms involved in oxidative stress generation, mitochondria and uncoupling proteins are of particular interest and there is growing evidence suggesting their pivotal role in the pathogenesis of diabetic complications. Other important cellular sources of oxidants include nicotinamide adenine dinucleotide phosphate oxidases and uncoupling endothelial nitric oxide synthase. In addition, diabetes is associated with reduced antioxidant defences, which generally contrast the deleterious effect of oxidant species. This concept underlines a potential beneficial role of antioxidant therapy for the prevention and treatment of diabetic vascular disease. However, large scale trials with classical antioxidants have failed to show a significant effect on major cardiovascular events, thus underlying the need of further investigations in order to develop therapies to prevent and/or delay the development of micro- and macrovascular complications.

Microvascular disease in children and adolescents with type 1 diabetes and obesity.

The incidence of type 1 diabetes (T1D) is increasing worldwide and is associated with a significant burden, mainly related to the development of vascular complications. Over the last decades, concomitant with the epidemic of childhood obesity, there has been an increasing number of cases of type 2 diabetes (T2D) among children and adolescents. Microvascular complications of diabetes, which include nephropathy, retinopathy and neuropathy, are characterized by damage to the microvasculature of the kidney, retina and neurons. Although clinically evident microvascular complications are rarely seen among children and adolescents with diabetes, there is clear evidence that their pathogenesis and early signs develop during childhood and accelerate during puberty. Diabetic vascular complications are often asymptomatic during their early stages, and once symptoms develop, there is little to be done to cure them. Therefore, screening needs to be started early during adolescence and, in the case of T2D, already at diagnosis. Identification of risk factors and subclinical signs of complications is essential for the early implementation of preventive and therapeutic strategies, which could change the course of vascular complications and improve the prognosis of children, adolescents and young adults with diabetes.

Triglycerides-to-HDL ratio as a new marker of endothelial dysfunction in obese prepubertal children

OBJECTIVE To investigate whether there is an association of the triglyceride-to-HDL cholesterol (TG:HDL-C) ratio with cardiovascular risk factors and early signs of vascular damage in obese prepubertal children. DESIGN AND METHODS In 50 obese (27 boys, 7.8±1.4 years) and 37 normal-weight (20 boys; 7.3±1.5 years) prepubertal children, anthropometric measurements, oxidative stress markers (urinary isoprostanes (PGF2α (prostaglandin F2α)), soluble receptor for advanced glycation end-products (sRAGE)) and insulin sensitivity (homeostasis model assessment of insulin resistance (HOMA-IR) and whole-body insulin sensitivity index (WBISI)) were evaluated. Lipids profile was assessed and the TG:HDL-C ratio was calculated. In addition, high-resolution ultrasound was performed to assess carotid intima-media thickness (cIMT). RESULTS Obese children showed significantly higher values of the TG:HDL-C ratio (1.9±1.1 vs 1.2±0.6, P=0.002) compared with controls. After dividing the population in tertiles of the TG:HDL-C ratio (<1.04, 1.04-1.67, >1.67), cIMT (P=0.0003), and HOMA-IR (P=0.0001) progressively increased from the lower to the upper tertile, whereas WBISI (P=0.0003) and sRAGE (P=0.05) progressively decreased. In a regression model, the TG:HDL ratio was significantly and positively associated with cIMT (r=0.493; P=0.0005). A cutoff point for TG:HDL-C ratio of 1.12 had 81% sensitivity and 49% specificity in the identification of children with cIMT values in the upper quartile (Area under the curve values from receiver operating characteristic curves=0.633±0.065, P=0.045). CONCLUSION This study confirms the reliability of the TG:HDL-C ratio as a useful marker of cardiovascular risk. Interestingly, our results underline that the TG:HDL-C ratio is directly related with early signs of vascular damage already present in prepubertal children.