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Insulin resistance (IR) is pathogenic for type 2 diabetes and coronary artery disease (CAD). The K121Q polymorphism of the ENPP1/PC-1 gene is associated with IR. Our aim was to investigate the role of the 121Q variant on the risk of type 2 diabetes and CAD. Nondiabetic control subjects (n ‫؍‬ 638), type 2 diabetic patients without CAD (n ‫؍‬ 535), and type 2 diabetic patients with CAD (n ‫؍‬ 434) from Italy and the U.S. were studied. The proportion of 121Q carriers progressively increased in the three groups (27.4, 28.8, and 33.2%, respectively; adjusted P value ‫؍‬ 0.027). Among diabetic patients (n ‫؍‬ 969), 121Q carriers had an increased risk of developing type 2 diabetes before the age of 65 years (adjusted odds ratio [OR] 2.26, 95% CI 1.26 -4.03; P ‫؍‬ 0.006) and having a myocardial infarction (MI) (n ‫؍‬ 156) by 50 years of age (3.17, 1.46 -6.88, P ‫؍‬ 0.007). The 121Q variant was also associated with an increased risk for CAD (1.47, 1.01-2.18; P ‫؍‬ 0.049) in diabetic patients who did not smoke (n ‫؍‬ 546). In conclusion, the ENPP1/PC-1 121Q variant is associated with a progressive deterioration of the IR-atherogenic phenotype; among diabetic individuals, it is also associated with earlier onset of type 2 diabetes and MI. Diabetes 54:3021-3025, 2005

BackgroundHigh serum resistin has been associated with increased risk of cardiovascular disease in the general population, Only sparse and conflicting results, limited to Asian individuals, have been reported, so far, in type 2 diabetes. We studied the role of serum resistin on coronary artery disease, major cardiovascular events and all-cause mortality in type 2 diabetes.MethodsWe tested the association of circulating resistin concentrations with coronary artery disease, major cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and all-cause mortality in 2,313 diabetic patients of European ancestry from two cross-sectional and two prospective studies. In addition, the expression of resistin gene (RETN) was measured in blood cells of 68 diabetic patients and correlated with their serum resistin levels.ResultsIn a model comprising age, sex, smoking habits, BMI, HbA1c, and insulin, antihypertensive and antidyslipidemic therapies, serum resistin was associated with coronary artery disease in both cross-sectional studies: OR (95%CI) per SD increment = 1.35 (1.10–1.64) and 1.99 (1.55–2.55). Additionally, serum resistin predicted incident major cardiovascular events (HR per SD increment = 1.31; 1.10–1.56) and all-cause mortality (HR per SD increment = 1.16; 1.06–1.26). Adjusting also for fibrinogen levels affected the association with coronary artery disease and incident cardiovascular events, but not that with all cause-mortality. Finally, serum resistin was positively correlated with RETN mRNA expression (rho = 0.343).ConclusionsThis is the first study showing that high serum resistin (a likely consequence, at least partly, of increased RETN expression) is a risk factor for cardiovascular disease and all-cause mortality in diabetic patients of European ancestry.

Adiponectin is a circulating enhancer of insulin action that is secreted by the adipose tissue. In epidemiological studies, serum levels of this protein predict the risk of type 2 diabetes and cardiovascular events. Serum adiponectin levels have been associated with variants at the adiponectin (APM1) and PPARgamma2 loci and have also been linked to markers on 5p15 and 14q13. We investigated the role of these four loci in regulating serum adiponectin in a Caucasian population from Italy. Four haplotype-tagging single-nucleotide polymorphisms (ht-SNPs) (-11377 C>G, -4041 A>C, +45 T>G, and +276 G>T) at the APM1 locus and the PPARgamma2 Pro12Ala polymorphism were examined for association with serum adiponectin in 413 unrelated, nondiabetic individuals. Of the five SNPs tested, +276G>T was the only one to be associated with serum adiponectin (P = 0.032), with "TT" individuals having higher adiponectin levels than other subjects. In a variance-components analysis of 737 nondiabetic members of 264 nuclear families, adiponectin heritability was 30%, with a small but significant proportion explained by the +276 genotype ( P = 0.0034). Suggestive evidence of linkage with adiponectin levels was observed on chromosome 14q13, with a LOD of 2.92 (P = 0.000057) after including the APM1 +276 genotype in the model. No linkage was observed at 5p15. Our data indicate a strong genetic control of serum adiponectin. A small proportion of this can be attributed in our population to variability at the APM1 locus, but an as yet unidentified gene on 14q13 appears to play a much bigger role.

The prosthetic rehabilitation is a surgical alternative in functional-aesthetic facial reconstruction when the conventional reconstructive surgery cannot be applied either because of the psychophysical conditions of the patient or because of an excessive substance loss. From May 2002, 35 facial prosthesis (111 implants) have been positioned. Defects were congenital (N = 12), consequent to trauma (N = 8) and to demolitive surgery for malignant tumors (N= 8), and infection (N = 7). In 4 patients, implants were placed in previously irradiated areas. A total of 111 titanium implants were placed to support 21 auricular prostheses (bilateral in 2 cases), 4 orbital prostheses, 8 nasal prostheses, and 2 complex midfacial prostheses. Implant failure was observed for 2 of the 3 implants placed to support a nasal epithesis in a patient with hepatitis C virus, with an important parodontal disease, who experienced a postinfective necrosis of the nose after a liver transplantation; it was necessary to place an adhesive prosthesis. An implant failure was also observed in a diabetic patient with an extensive midfacial defects due to a mycotic infection, but it did not compromise the retention of the prosthesis. According to our experience, the indication to epithesis is when the conventional reconstructive interventions is inapplicable.

Abstract. Menzaghi C, Salvemini L, Paroni G, De Bonis C, Mangiacotti D, Fini G, Doria A, Di Paola R, Trischitta V (IRCCS ''Casa Sollievo della Sofferenza'', San Giovanni Rotondo (FG), Italy, Joslin Diabetes Center and Harvard Medical School, Boston, MA, USA, ''Sapienza'' University; IRCCS Casa Sollievo della Sofferenza-Mendel Institute, Rome, Italy). Circulating HMW adiponectin isoform is heritable and shares a common genetic background with insulin resistance in nondiabetic White Caucasians from Italy: evidence from a family-based study. J Intern Med 2010; 267: 287-294.Objective. Reduced circulating adiponectin levels contribute to the aetiology of insulin resistance. Adiponectin circulates in three different isoforms: high molecular weight (HMW), medium molecular weight (MMW) and low molecular weight (LMW) isoforms. The genetics of adiponectin isoforms is mostly unknown. Our aim was to investigate whether and to which extent circulating adiponectin isoforms are heritable and whether they share common genetic backgrounds with insulin resistance-related traits.Methods. In a family-based sample of 640 nondiabetic White Caucasians from Italy, serum adiponectin isoforms concentrations were measured by ELISA. Three single nucleotide polymorphisms (SNPs) in the ADI-POQ gene previously reported to affect total adiponectin levels (rs17300539, rs1501299 and rs677395) were genotyped. The heritability of adiponectin isoform levels was assessed by variance component analysis. A linear mixed effects model was used to test the association between SNPs and adiponectin isoforms. Bivariate analyses were conducted to study genetic correlations between adiponectin isoforms levels and other insulin resistance-related traits.Results. All isoforms were highly heritable (h 2 = 0.60-0.80, P = 1.0 · 10 )13 -1.0 · 10 )23 ). SNPs rs17300539, rs1501299 and rs6773957 explained a significant proportion of HMW variance (2-9%, P = 1.0 · 10 )3 -1.0 · 10 )5 ). In a multiple-SNP model, only rs17300539 and rs1501299 remained associated with HMW adiponectin (P = 3.0 · 10 )4 and 2.0 · 10). Significant genetic correlations (P = 1.0 · 10 )2 -1.0 · 10 )5 ) were observed between HMW adiponectin and fasting insulin, homeostasis model assessment of insulin resistance, HDL cholesterol and the metabolic syndrome score. Only rs1501299 partly accounted for these genetic correlations.Conclusion. Circulating levels of adiponectin isoforms are highly heritable. The genetic control of HMW adiponectin is shared in part with insulin resistancerelated traits and involves, but is not limited to, the ADIPOQ locus.

Impaired insulin action plays a major role in the pathogenesis of type 2 diabetes, a chronic metabolic disorder which imposes a tremendous burden to morbidity and mortality worldwide. Unraveling the molecular mechanisms underlying insulin resistance would improve setting up preventive and treatment strategies of type 2 diabetes. Down-regulation of GALNT2, an UDPN-acetyl-alpha-D-galactosamine polypeptideN-acetylgalactosaminyltransferase-2 (ppGalNAc-T2), causes impaired insulin signaling and action in cultured human liver cells. In addition, GALNT2 mRNA levels are down-regulated in liver of spontaneously insulin resistant, diabetic Goto-Kakizaki rats. To investigate the role of GALNT2 in human hyperglycemia, we measured GALNT2 mRNA expression levels in peripheral whole blood cells of 84 non-obese and 46 obese non-diabetic individuals as well as of 98 obese patients with type 2 diabetes. We also measured GALNT2 mRNA expression in human U937 cells cultured under different glucose concentrations. In vivo studies indicated that GALNT2 mRNA levels were significantly reduced from non obese control to obese non diabetic and to obese diabetic individuals (p<0.001). In vitro studies showed that GALNT2 mRNA levels was reduced in U937 cells exposed to high glucose concentrations (i.e. 25 mmol/l glucose) as compared to cells exposed to low glucose concentration (i.e. 5.5 mmol/l glucose +19.5 mmol/l mannitol). In conclusion, our data indicate that GALNT2 is down-regulated in patients with type 2 diabetes and suggest that this association is, at least partly, secondary to hyperglycemia. Further studies are needed to understand whether GALNT2 down-regulation plays a pathogenic role in maintaining and/or aggravating the metabolic abnormalities of diabetic milieu.

Insulin resistance is believed to be under the control of several genes often interacting each other. However, whether genetic epistasis does in fact modulate human insulin sensitivity is unknown. In 338 healthy unrelated subjects from Sicily, all nondiabetic and not morbidly obese, we investigated whether two gene polymorphisms previously associated with insulin resistance (namely PC-1 K121Q and PPARgamma2 P12A) affect insulin sensitivity by interacting. PC-1 X121Q subjects showed higher level of fasting glucose, lower insulin sensitivity (by both the Matsuda insulin sensitivity index and M values at clamp, the latter performed in a subgroup of 113 subjects representative of the overall cohort) and higher insulin levels during the oral glucose tolerance test (OGTT) than PC-1 K121K subjects. In contrast, no difference in any of the measured variables was observed between PPARgamma2 P12P and X12A individuals. The deleterious effect of the PC-1 X121Q genotype on each of these three variables was significant and entirely dependent upon the coexistence of the PPARgamma2 P12P genotype. Among PPARgamma2 P12P carriers also fasting insulin and glucose levels during OGTT were higher in PC-1 X121Q than in K121K individuals. In contrast, no deleterious effect of the PC-1 X121Q genotype was observed among PPARgamma2 X12A carriers; rather, in these subjects a lower body mass index and consequently lower fasting insulin level was observed in PC-1 X121Q than in K121K carriers. Overall, a significant interaction between the two genes was observed on body mass index, insulin levels (both fasting and after OGTT) and both insulin sensitivity (i.e., insulin sensitivity index and M value) and insulin secretion (i.e., HOMA-B%) indexes.