We investigated the association of the Ϫ11,391GϾA, Ϫ11,377GϾC, ϩ45TϾG, and ϩ276GϾT adiponectin single-nucleotide polymorphisms (SNPs) and expected haplotypes with the insulin resistance (IR) state in overweight/ obese children; by using the haplotype background analysis, we also assessed the effect of each SNP independently. GG genotype at the Ϫ11,391 locus was associated with higher fasting insulin levels and homeostasis model assessment-IR index and lower adiponectin levels compared with GA ϩ AA genotypes (p ϭ 0.01, 0.002, and 0.03, respectively). Those heterozygous and homozygous for G allele at the Ϫ11,377 locus showed higher fasting glucose (p ϭ 0.001 for both), fasting insulin (p ϭ 0.001 for both), homeostasis model assessment-IR index (p Ͻ 0.001 for both), and triglyceride levels (p ϭ 0.02 and 0.03, respectively) and lower adiponectin levels (p ϭ 0.002 and 0.02, respectively) compared with C homozygotes. The ϩ45G carriers showed higher fasting and 2-hour glucose levels (p ϭ 0.01 for both) and lower adiponectin levels (p ϭ 0.02) compared with non-carriers. Haplotype analysis suggested that, considering the same haplotypic background, each of the three polymorphisms exerted an independent effect on investigated parameters. The Ϫ11,391GϾA, Ϫ11,377CϾG, and ϩ45TϾG SNPs are associated with IR syndrome in overweight/obese children; they independently influence the investigated variables. The effect of ϩ45TϾG SNP seems to be marginal compared with the promoter SNPs. The GGT haplotype is associated with the highest degree of IR.

Several genetic variants of peroxisome proliferator-activated receptor-c2 (PPAR-c2) have been identified, among which Pro12Ala, a missense mutation in exon 2, is highly prevalent in Caucasian populations. Up to now, conflicting results with regard to the association between this mutation and complex traits, such as obesity, insulin sensitivity and Type 2 diabetes, have been reported. We investigated the influence of the Pro12Ala polymorphism of PPAR-c2 on insulin sensitivity in a large Italian population sample, n ¼ 1215, in whom extensive clinical and biochemical analyses were performed. To estimate the insulin sensitivity status, the homeostasis model assessment of insulin resistance (HOMA-IR) was calculated; in the obese/ overweight subjects an oral glucose tolerance test (OGTT) was also performed and the Matsuda insulin sensitivity index (ISI) calculated. The insulin secretion index (homeostasis model assessment of percent b-cell function, HOMA-b%) was utilized to evaluate b-cell function. The effect of the Pro12Ala polymorphism on quantitative variables was tested using multiple linear regression analysis. X12Ala (either Pro12Ala or Ala12Ala) genotype was associated with significantly lower fasting insulin levels compared to Pro/Pro (P ¼ 0.01 after correction for multiple comparisons) in all subjects. Consistent with this finding, significantly lower HOMA-IR was observed in X12Ala carriers (P ¼ 0.013 after correction for multiple comparisons) in all cohort. Moreover, no significant interaction effect was observed between body mass index and X12Ala polymorphism and between gender and X12Ala polymorphism in modulating insulin sensitivity. Our observations substantially extend previous findings and demonstrated that X12Ala variant is significantly associated with greater insulin sensitivity.

FOR THE IMMUNOTHERAPY DIABETES (IMDIAB) GROUP 3OBJECTIVE -Evidence has been reported for a new susceptible locus for type 1 diabetes, the protein tyrosine phosphatase nonreceptor type 2 (PTPN22), which encodes a lymphoidspecific phosphatase. The aim of the study was to evaluate the influence of the C1858T variant of the PTPN22 gene on ␤-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 ϭ 0.008 and P ϭ 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 ␤-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.

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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, À604C4T, in the promoter region of the ghrelin gene, of Leu72Met (247C4A) and of Gln90Leu (265A4T), all haplotypetagging 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 ¼ 0.02, 0.01 and 0.003, respectively), and, consistently, an increase in ghrelin levels (P ¼ 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 ¼ 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 À604 T 247 C and lowest value in À604 C 247 A . Conclusion: Our observations suggest a protective role of the Met72 variant and of À604 T allele in modulating insulin resistance. These SNPs or an unknown functional variant in linkage disequilibrium could increase ghrelin levels and probably insulin sensitivity.

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Adrenergic receptors regulate lipid mobilization, energy expenditure and glycogen breakdown. The b 2 adrenergic receptor (b 2 -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 b 2 -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 b 2 -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 0 LC-Cys19Arg) and two in the coding region (Gly16Arg and Gln27Glu) of the b 2 -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 0 LC-Cys19 homozygous showed higher triglyceride and LDL-cholesterol levels compared to 5 0 LC-Arg19 homozygous (P ¼ 0.03 and P ¼ 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 ¼ 0.02 and P ¼ 0.01, respectively) and for Gln/Gln genotype compared to Glu/Glu genotype of the Gln27Glu polymorphism (P ¼ 0.01 and P ¼ 0.03, respectively).

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 À11391G4A and À11377C4G 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 ¼ 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 À11391 had lower M (mg/kg min)/fat-free mass (FFM) index and adiponectin levels compared to subjects with GA þ AA genotypes (P ¼ 0.002 and P ¼ 0.03, respectively) and subjects carrying the À11377G variant had lower M (mg/kg min)/FFM index and adiponectin levels compared to noncarriers (P ¼ 0.003 and P ¼ 0.03, respectively). Our results imply that the two promoter SNPs, À11391G4A and À11377C4G, of the adiponectin gene are associated with a reduced insulin sensitivity evaluated by hyperinsulinemic-euglycemic clamp in obese subjects.