Simona Zampetti

Wrist Circumference Is a Clinical Marker of Insulin Resistance in Overweight and Obese Children and Adolescents

Background— Excess fat is one of the main determinants of insulin resistance, representing the metabolic basis for developing future cardiovascular disease. The aim of the current study was to find an easy-to-detect clinical marker of insulin resistance which can be used to identify young subjects at increased risk of cardiovascular disease. Methods and Results— Four-hundred and seventy-seven overweight/obese children and adolescents (mean age 10.31±2.80 years) were consecutively enrolled. Standard deviation score body mass index, fasting biochemical parameters, and homeostasis model assessment of insulin resistance were evaluated. Statistical differences were investigated using multiple linear regression analysis. Manual measure of wrist circumference was evaluated in all children and adolescents. Fifty-one subjects, randomly selected, underwent nuclear magnetic resonance imaging of the wrist to evaluate transversal wrist area at the Lister tubercle level. A statistically significant association was found between manual measure of wrist circumference and insulin levels or homeostasis model assessment of insulin resistance (&bgr;=0.34 and 0.35, respectively; P<10−5 for both comparisons). These associations were more significant than those between SD score body mass index and insulin levels or homeostasis model assessment of insulin resistance (&bgr;=0.12 and 0.10, respectively; P⩽0.02 for both comparisons). Nuclear magnetic resonance imaging acquisition clarified that the association between wrist circumference and insulin levels or homeostasis model assessment of insulin resistance reflected the association with bone tissue-related areas (P⩽0.01 for both) but not with the adipose tissue ones (P>0.05), explaining 20% and 17% of the variances of the 2 parameters. Conclusions— Our findings suggest a close relationship among wrist circumference, its bone component, and insulin resistance in overweight/obese children and adolescents, opening new perspectives in the prediction of cardiovascular disease.

A new variation in the promoter region, the −604 C>T, and the Leu72Met polymorphism of the ghrelin gene are associated with protection to insulin resistance

Objective:Previous studies suggested that polymorphisms in the coding region of the preproghrelin were involved in the etiology of obesity and might modulate glucose-induced insulin secretion. We evaluated the association of a new variation, −604C>T, in the promoter region of the ghrelin gene, of Leu72Met (247C>A) and of Gln90Leu (265A>T), all haplotype-tagging single nucleotide polymorphisms (SNPs), with measures of insulin sensitivity in 1420 adult individuals.Research methods:The three SNPs were genotyped using ABI PRISM 7900 HT Sequence Detection System. We used multiple linear regression analysis for quantitative traits and THESIAS software for haplotype analysis.Results:We observed a protective effect exerted by Met72 variant of Leu72Met SNP on insulin resistance parameters; a significant decreasing trend from Leu/Leu to Leu/Met and to Met/Met homozygous subjects in triglycerides, fasting insulin levels and HOMA-IR index (P=0.02, 0.01 and 0.003, respectively), and, consistently, an increase in ghrelin levels (P=0.003) was found. A significant decrease from CC to TC and to TT genotypes in insulin levels and HOMA-IR index was also detected (P=0.00l for both), but only in subjects homozygous for Leu72, where the protective effect of Met72 was not present. The haplotype analysis results supported the data obtained by the evaluation of each single SNP, showing the highest value of insulin levels and HOMA-IR index in the −604c247c haplotype intermediate value in −604T247C and lowest value in −604C247A.Conclusion:Our observations suggest a protective role of the Met72 variant and of −604 T allele in modulating insulin resistance. These SNPs or an unknown functional variant in linkage disequilibrium could increase ghrelin levels and probably insulin sensitivity.

GADA Titer-Related Risk for Organ-Specific Autoimmunity in LADA Subjects Subdivided according to Gender (NIRAD Study 6)

CONTEXT Latent autoimmune diabetes in adults (LADA) includes a heterogeneous population wherein, based on glutamic acid decarboxylase antibody (GADA) titer, different subgroups of subjects can be identified. OBJECTIVE The aim of the present study was to evaluate GADA titer-related risk for β-cell and other organ-specific autoimmunity in LADA subjects. METHODS Adult-onset autoimmune diabetes subjects (n=236) and type 2 diabetes (T2DM) subjects (n=450) were characterized for protein tyrosine phosphatase (IA-2IC and IA-2(256-760)), zinc transporter 8 (ZnT8), thyroid peroxidase, (TPO), steroid 21-hydroxylase (21-OH), tissue transglutaminase (tTG), and antiparietal cell (APC) antibodies. RESULTS High GADA titer compared to low GADA titer showed a significantly higher prevalence of IA-2IC, IA-2(256-760), ZnT8, TPO, and APC antibodies (P≤0.04 for all comparison). 21-OH antibodies were detected in 3.4% of high GADA titer. A significant decreasing trend was observed from high GADA to low GADA and to T2DM subjects for IA-2(256-760), ZnT8, TPO, tTG, and APC antibodies (P for trend≤0.001). TPO was the only antibody showing a different prevalence between gender; low GADA titer and T2DM female patients had a higher frequency of TPO antibody compared to males (P=0.0004 and P=0.0006, respectively), where the presence of high GADA titer conferred an odds ratio of 8.6 for TPO compared to low GADA titer. After subdividing high and low GADA titer subjects according to the number of antibodies, we observed that 73.3% of high GADA titer subjects were positive for at least one or more antibodies, compared to 38.3% of low GADA titer (P<0.0001). CONCLUSIONS In LADA subjects, high GADA titer was associated with a profile of more severe autoimmunity and, in male gender, specifically predisposed to thyroid autoimmunity. A regular screening for other antibodies is recommended in LADA patients according to GADA titer and gender.

The PTPN22 1858T Gene Variant in Type 1 Diabetes Is Associated With Reduced Residual β-Cell Function and Worse Metabolic Control

OBJECTIVE Evidence has been reported for a new susceptible locus for type 1 diabetes, the protein tyrosine phosphatase nonreceptor type 2 (PTPN22), which encodes a lymphoid-specific phosphatase. The aim of the study was to evaluate the influence of the C1858T variant of the PTPN22 gene on beta-cell function as measured by C-peptide levels from time of disease diagnosis through 12 months follow-up in a prospective series of 120 consecutive type 1 diabetic subjects. RESEARCH DESIGN AND METHODS The C1858T polymorphism was genotyped using TaqMan. Fasting C-peptide, A1C, and insulin requirements were determined at diagnosis and every 3 months for 12 months; their change during follow-up was analyzed using the general linear model repeated-measures procedure. RESULTS Fasting C-peptide levels were significantly lower and A1C levels were significantly higher in subjects carrying the PTPN22 1858T variant than in subjects homozygous for C1858 from time of disease diagnosis through 12 months of intensive insulin therapy follow-up (P = 0.008 and P = 0.01, respectively). These findings were independent of age at onset, sex, and HLA risk groups. The trend in C-peptide and A1C levels in the 12-month period did not differ significantly between subjects with or without the 1858T variant. Insulin dose was similar in the 1858T carriers and noncarriers. CONCLUSIONS Type 1 diabetic subjects carrying the 1858T variant show significantly lower beta-cell function and worse metabolic control at diagnosis and throughout the study period than subjects homozygous for C1858; these differences remain unchanged over the course of the first year after diagnosis.

Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD Study 5).

Diabet. Med. 27, 701–704 (2010)

Association of β2 adrenergic receptor polymorphisms and related haplotypes with triglyceride and LDL-cholesterol levels

Adrenergic receptors regulate lipid mobilization, energy expenditure and glycogen breakdown. The β2 adrenergic receptor (β2-AR) gene may constitute a potential candidate gene to explain part of the genetic predisposition to human obesity and correlated traits. With regard to the association between β2-AR gene polymorphisms and obesity-related metabolic disorders, published reports give conflicting results. We investigated the role of three polymorphisms, and related haplotypes of the β2-AR in the obesity and related traits in a cohort of overweight/obese subjects. We characterized one single nucleotide polymorphism (SNP) in the promoter region (5′LC-Cys19Arg) and two in the coding region (Gly16Arg and Gln27Glu) of the β2-AR in 642 consecutively recruited overweight/obese subjects in whom extensive clinical and biochemical analysis was performed. The effect of the polymorphisms on quantitative variables was investigated using multiple linear regression analysis. 5′LC-Cys19 homozygous showed higher triglyceride and LDL-cholesterol levels compared to 5′LC-Arg19 homozygous (P=0.03 and P=0.01, respectively). Similar increase in triglyceride and LDL-cholesterol levels was observed for Arg/Arg genotype compared to Gly/Gly genotype of Gly16Arg polymorphism (P=0.02 and P=0.01, respectively) and for Gln/Gln genotype compared to Glu/Glu genotype of the Gln27Glu polymorphism (P=0.01 and P=0.03, respectively). The 5′LC-Cys19Arg16Gln27 haplotype determined a significant increase in triglyceride and LDL-cholesterol levels compared to 5′LC-Arg19Gly16Glu27 haplotype (P=0.05 and P=0.02, respectively). Our findings provide additional weight to previous observations on the influence of these three genetic variants on lipid phenotypes; particularly on the increase of triglycerides and LDL-cholesterol levels in overweight/obese subjects carrying the 5′LC-Cys19Arg16Gln27 haplotype.

The glucose clamp reveals an association between adiponectin gene polymorphisms and insulin sensitivity in obese subjects.

Results concerning the association of adiponectin gene polymorphisms (single-nucleotide polymorphisms, SNPs) with obesity, type 2 diabetes (T2DM), metabolic disorders and insulin resistance have not lead to definite conclusions. The aim of our study was to investigate a possible association between the −11391G>A and −11377C>G SNPs of adiponectin gene and measure of insulin sensitivity evaluated by the hyperinsulinemic-euglycemic clamp in a group of ‘uncomplicated’ obese subjects (with no associated comorbidities) (n=99, mean age 35 years) with a history of obesity lasting at least 10 years. The study of uncomplicated obese subjects, free of possible confounding factors that could interfere with insulin sensitivity, such as pharmacological treatment, provides a good model to assess insulin sensitivity per se. We observed that subjects homozygous for the G allele at locus −11391 had lower M (mg/kg min)/fat-free mass (FFM) index and adiponectin levels compared to subjects with GA+AA genotypes (P=0.002 and P=0.03, respectively) and subjects carrying the −11377G variant had lower M (mg/kg min)/FFM index and adiponectin levels compared to noncarriers (P=0.003 and P=0.03, respectively). Our results imply that the two promoter SNPs, −11391G>A and −11377C>G, of the adiponectin gene are associated with a reduced insulin sensitivity evaluated by hyperinsulinemic-euglycemic clamp in obese subjects.

Adult-onset autoimmune diabetes: current knowledge and implications for management

Adult-onset autoimmune diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive autoimmune process and a mild metabolic decompensation at onset compared with young-onset type 1 diabetes mellitus (T1DM). The majority of patients with adult-onset autoimmune diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent autoimmune diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult-onset autoimmune diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset autoimmune diabetes and highlight the similarities and differences with classic T1DM and type 2 diabetes mellitus.

High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7)

OBJECTIVE The aim of this study was to determine whether glutamic acid decarboxylase antibody (GADA) titer and other clinical parameters could define the risk of progression to insulin therapy in latent autoimmune diabetes in adults (LADA) patients during a 7-year follow-up. METHODS This study involved 220 LADA and 430 type 2 diabetes subjects followed up for 7 years from the time of GADA screening to evaluate their progression toward insulin therapy. Kaplan-Meier curves and multivariate logistic regression analysis were performed to identify the markers capable of influencing this progression. RESULTS During the follow-up, the drop out was 4% in both groups. A total of 119 (56.1%) out of 212 LADA patients required insulin during the 7 years of follow-up. The Kaplan-Meier plots showed that 74/104 (71.1%) of high GADA titer required insulin compared with 45/108 (41.6%) of low GADA titer and with 86/412 (20.9%) of type 2 diabetes (P<0.0001 for both). A BMI of ≤25 kg/m2 and IA-2IC and zinc transporter 8 (ZnT8) positivity were also shown as the markers of faster progression (P<0.0001 for both). The proportion of LADA patients requiring insulin was significantly higher in the group of subjects treated also with sulfonylurea in the first year from diagnosis compared with those treated with diet and/or insulin sensitizers (P<0.001). The multivariate analysis confirmed that the presence of high GADA titer was a significant predictor of insulin requirement (P<0.0001, OR=6.95). CONCLUSIONS High GADA titer, BMI ≤ 25, ZnT8 and IA-2IC positivity and sulfonylurea treatment, in the first year from diagnosis, significantly increase the progression toward insulin requirement in LADA patients.

Low-risk HLA genotype in Type 1 diabetes is associated with less destruction of pancreatic B-cells 12 months after diagnosis.

Aims  The role of human leukocyte antigen (HLA) genes in the susceptibility to Type 1 diabetes (T1DM) is well known. However, we do not know whether the degree of pancreatic B‐cell destruction depends on different HLA genetic risk. The aim of this study was to analyse the influence of DRB1* and DQB1* genes on the rate of pancreatic B‐cell loss in a prospective series of 120 consecutive newly diagnosed T1DM subjects in the first 12 months after diagnosis.