Mariano J. Taverna

Lipid accumulation product: a powerful marker of metabolic syndrome in healthy population

OBJECTIVE The metabolic syndrome (MS) is a cluster of cardiometabolic factors, which predisposes to diabetes and cardiovascular disease (CVD). Early detection of high-risk individuals for MS using accurate measures of insulin resistance (IR) could improve detection and prevention of CVD and diabetes. The aim of this study was to explore the ability of lipid accumulation product (LAP), compared with traditional measures of IR, to identify MS. DESIGN In total, 768 Spanish adults were recruited. MS was assessed using the revised criteria of National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) and International Diabetes Federation (IDF). Measures of IR such as homeostasis model assessment of IR and LAP, an index of lipid accumulation based on a combination of waist circumference and serum triglycerides, were calculated. Receiver operating characteristic analysis was performed in order to detect the parameter with the best predictive capability for MS. RESULTS The prevalence of MS-NCEP/ATP III and MS-IDF was 15.1 and 20.5% for men respectively, and 15.4 and 17.5% for women. LAP showed the highest diagnostic accuracy for MS-NCEP/ATP III (area under the curve 0.91 and 0.90 among males and females) and MS-IDF (0.88 for both males and females). This was confirmed by internal validation using 20 000 bootstrap samples. Among males and females, different LAP cut-off values exhibited high sensitivity (78-85%) and specificity (78-85%) for MS-NCEP/ATP III and MS-IDF identification with elevated efficiency (proportion of positives and negatives classified correctly by the test=78-85%). When the sample was stratified according to decades of life, LAP exhibited a slightly lower performance among women than men, especially for MS-IDF detection. CONCLUSIONS In non-diabetic adults LAP has a strong and reliable diagnostic accuracy for MS-IDF and, especially, MS-NCEP/ATP III among females and, in particular, among males from Spain.

A functional nonsynonymous toll-like receptor 4 gene polymorphism is associated with metabolic syndrome, surrogates of insulin resistance, and syndromes of lipid accumulation.

Toll-like receptor 4 (TLR4) plays a key role in the activation of innate immune responses. Loss-of-function mutations in TLR4 prevent diet-induced obesity and insulin resistance (IR). We conducted a population cross-sectional study to evaluate whether Asp299Gly (rs4986790) TLR4 gene polymorphism is associated with metabolic syndrome (MS), surrogates of IR, and syndromes of lipid accumulation (SLAs) in Argentinean healthy male subjects. rs4986790 was genotyped in 621 healthy unrelated male blood donors. National Cholesterol Education Program/Adult Treatment Panel III-MS (NCEP/ATP III-MS); SLAs such as enlarged waist elevated triglyceride syndrome (EWET), hypertriglyceridemic waist (HW), and overweight-lipid syndrome (OLS); and surrogates of IR were assessed. The prevalence of MS, OLS, and EWET was significantly higher among Asp299Asp carriers (P < .05). These findings were confirmed using 32 000 bootstrap samples. Surrogate markers of IR were also significantly higher in Asp299Asp carriers (P < .05). Most findings were especially strengthened among individuals with C-reactive protein below the 95th percentile and/or total cholesterol to high-density lipoprotein cholesterol ratio >or=5. This is the first report to find, in Argentinean healthy male blood donors, associations between the Asp299Asp genotype of rs4986790 TLR4 gene polymorphism and high risk for NCEP/ATP III-MS, SLAs, and surrogates of IR. These findings are consistent with previous functional and observational studies showing that Asp299 allele, in comparison with Gly299, is associated with increased TLR4 activation, higher levels of inflammatory cytokines, acute-phase reactants and soluble adhesion molecules, and higher risk of atherosclerosis.

Ability of Lipid Accumulation Product to Identify Metabolic Syndrome in Healthy Men From Buenos Aires

The metabolic syndrome is a constellation of cardiovascular and metabolic risk factors associated with insulin resistance, which predisposes individuals to diabetes, and appears to be a multifactorial risk factor for cardiovascular disease, although its clinical significance remains controversial (1). Since it may become useful to be able to predict who will develop metabolic syndrome, we explored the value of lipid accumulation product (LAP), a novel index of central lipid accumulation, which has been associated with cardiovascular disease (2) and diabetes (3). LAP is based on a combination of waist circumference and triglyceride: \[LAP = (WC − 65) × TG for men and (WC − 58) × TG for women\] (2), where TG is triglyceride and WC is waist circumference. We conducted a cross-sectional population-based survey on metabolic syndrome in Argentinian healthy individuals in order to identify single …

The rs1801278 G > A polymorphism of IRS-1 is associated with metabolic syndrome in healthy nondiabetic men. Modulation by cigarette smoking status

AIMS To explore associations between IRS-1 rs1801278 G>A polymorphism and metabolic syndrome (MS). METHODS rs1801278 G>A was genotyped in 610 healthy Argentinian men. RESULTS GA carriers had lower risk of MS (OR=0.52, P=0.045), particularly among smokers (OR=0.10, P=0.006). CONCLUSIONS rs1801278 GA carriers had lower risk of MS, especially among smokers.

Epidemiology of Diabetes

Diabetes mellitus is a chronic, metabolic disease defined by increased concentrations of blood glucose which leads, over time, to progressive damage in most tissues and organs including heart, blood vessels, eyes, kidneys, skin, and nerves. The most common is type 2 diabetes, commonly in adults, which occurs as result of the combination of insulin resistance with pancreatic beta cell insufficiency, with 50% of patients requiring insulin treatment within 10 years [1]. Type 1 diabetes, more frequent in children and adolescents, is a chronic autoimmune disease in which autoreactive T lymphocytes and inflammation cause severe loss of beta cells [2]. The incidence of diabetes exhibits an alarming pandemic scenario, in large part due to the global obesity epidemic [3]. Diabetes causes premature death, severe disability and great economic burden. Therefore, there is a globally agreed target to stop the growing incidence of diabetes and obesity by 2025 [4].

Clinical and genetic features of Argentinian children with diabetes-onset before 12 months of age: Successful transfer from insulin to oral sulfonylurea

AIMS Neonatal diabetes mellitus (NDM) is a rare monogenic disorder, reported to affect less than 2 cases per 100,000 infants. There are two types, permanent (PNDM) and transient (TNDM). We describe our clinical experience in determining and comparing the genetic basis of diabetes in children with onset before 6months versus those diagnosed between 6 and 12months of age. METHODS We reviewed medical records of children with diabetes diagnosed before 12months of age. Genetic testing was performed in all cases. RESULTS 12 patients were diagnosed with diabetes before 6months of age (PNDM=6; TNDM=6), and 11 patients between 6 and 12months (all with permanent diabetes). Among children with PNDM, we identified three different KCNJ11 mutations in 5 patients, and one novel ABCC8 mutation in a single patient. Among children with TNDM, we detected a KCNJ11 and ABCC8 mutation each in a single patient and methylation abnormalities at chromosome 6q24 in 4 patients. Among children with diabetes diagnosed between 6 and 12months, 1 patient had an INS mutation and one patient was homozygous for an SLC19A2 mutation which confirmed a diagnosis of thiamine-responsive megaloblastic anaemia syndrome. Five of the patients with an ABCC8 or KCNJ11 mutation have successfully transferred from insulin to glibenclamide whist 1 child demonstrated a partial response to sulfonylurea treatment. CONCLUSIONS Investigating the underlying genetic basis of diabetes in children with onset before 1year is useful for choosing the most efficient treatment, the basis of Personalized Medicine.

Genetic epidemiology of diabetic retinopathy

Diabetic retinopathy (DR) is the leading cause of vision loss and blindness among adults in developed countries. Despite intensive antidiabetic treatment, the global prevalence of DR is growing due to an increasing incidence and prolonged survival of diabetic individuals. As a complex disease, DR is a consequence of multiple interactions between environmental and genetic factors. Racial differences in incidence, familial aggregation and candidate gene association studies suggest that genetic factors play a role in the etiology of DR. Despite approximately 30 years of research, the molecular genetics of DR is still in its infancy owing to the low quality of most research studies. To date, only a few genetic markers from one gene, AKR1B1 (aldose reductase) – the first enzyme involved in the polyol pathway of glucose metabolism that converts glucose into sorbitol – have been identified. Successful genetic epidemiology requires a high sample size, longitudinal designs, analysis of large haplotype blocks integrated by tag single nucleotide polymorphisms identified by means of human haplotype map (HapMap) data, genome-wide association studies using high density microarray-based single nucleotide polymorphism genotyping and pharmacogenomic approaches. An urgent move from old genetics to modern genomics is necessary to boost the ability to identify genes contributing to the development and progression of DR.