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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 PPARγ2 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 PPARγ2 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 PPARγ2 P12P genotype. Among PPARγ2 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 PPARγ2 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. [ABSTRACT FROM AUTHOR]

Glycoprotein PC-1 inhibits insulin signaling and, when overexpressed, plays a role in human insulin resistance. Mechanisms of PC-1 overexpression are unknown. We have identified a haplotype in the 3'-untranslated region of the PC-1 gene that may modulate PC-1 expression and confer an increased risk for insulin resistance. Individuals from Sicily, Italy, carrying the "P" haplotype (i.e., a cluster of three single nucleotide polymorphisms: G2897A, G2906C, and C2948T) were at higher risk (P < 0.01) for insulin resistance and had higher (P < 0.05) levels of plasma glucose and insulin during an oral glucose tolerance test and higher levels of cholesterol, HDL cholesterol, and systolic blood pressure. They also had higher (P < 0.05-0.01) PC-1 protein content in both skeletal muscle and cultured skin fibroblasts. In CHO cells transfected with either P or wild-type cDNA, specific PC-1 mRNA half-life was increased for those transfected with P (t/2 = 3.73 +/- 1.0 vs. 1.57 +/- 0.2 h; P < 0.01). In a population of different ethnicity (Gargano, East Coast Italy), patients with type 2 diabetes (the most likely clinical outcome of insulin resistance) had a higher P haplotype frequency than healthy control subjects (7.8 vs. 1.5%, P < 0.01), thus replicating the association between the P allele and the insulin resistance-related abnormalities observed among Sicilians. In conclusion, we have identified a possible molecular mechanism for PC-1 overexpression that confers an increased risk for insulin resistance-related abnormalities. [ABSTRACT FROM AUTHOR]

Aging is a risk factor for the development of multiple chronic diseases, including cardiovascular disease, cancer and dementia. Life expectancy has increased in certain countries but this phenomenon is associated with a reduction of years of healthy life. Aging is associated with a number of physical and functional changes, especially sarcopenia. Sarcopenia is a clinical condition associated with a decrease in skeletal muscle and muscle strength, however, sarcopenia is a reversible condition. On the basis of the current scientific literature, sarcopenia could more appropriately capture an individual's vulnerability to negative health-related outcomes since it represents an early form of the chronic diseases. Recognition of this clinical condition can improve the management of older individuals in many different clinical settings. Despite the limitations of the indirect methods used to study body composition, the Italian College of the Academic Nutritionists ME/49 recommends that health authorities and health professionals around the world should make a greater effort to diagnose sarcopenia earlier and to manage it more effectively. In line with the development of cancer screening, the use of two diagnostic tools for sarcopenia (BIA and DXA) should be implemented.

Aim: A large body of evidence supports a role of polyphenols in the prevention of chronic diseases, i.e. type 2 diabetes (DMT2), cardiovascular diseases and some types of cancer. In the present manuscript, the effect of polyphenol/phenolic compounds on the main cardio-metabolic risk factors (body weight, blood pressure, blood glucose concentrations, plasma lipids, inflammation and oxidative stress) in humans will be discussed., Data Synthesis: Epidemiological evidence supports the beneficial effects of polyphenol-rich diets in the prevention of T2D risk. However, the available evidence from randomized controlled clinical trials did not allow the identification of specific phenolic compounds or polyphenol-rich foods that effectively improve cardio-metabolic risk factors. The most promising results in terms of the management of cardio-metabolic risk factors derive from RCTs based on a long-term intake of polyphenol-rich foods and beverages. Therefore, future studies should focus on a diet containing different classes of polyphenols rather than a specific food or phenolic compound. The hypothesis is that a polyphenol-rich diet may have a pleiotropic effect on cardiometabolic risk factors thanks to the specific action of different polyphenol subclasses., Conclusion: The lack of conclusive evidence on the effectiveness of polyphenols in the management of cardio-metabolic risk factors does not allow recommendation of their use as supplements to reduce T2D and CVD risk. However, the daily consumption of naturally polyphenol-rich foods and beverages might be advised according to the current nutritional dietary recommendation., (Copyright © 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Intragastric balloon (BioEnterics Intragastric Balloon, BIB®) or pharmacotherapy are possible options for the treatment of obese patients when traditional approaches have failed. The aim of our study was to compare in obese patients the effect on weight loss and metabolic changes of lifestyle modifications associated with either BIB or pharmacotherapy or the two treatments in sequence as a maintenance strategy for weight loss., Methods: Fifty obese patients were recruited and randomly assigned to lifestyle modifications combined with either BIB for 6 months (n = 30) or sibutramine (pharmacotherapy group) for 1 year (n = 20). After BIB removal, patients were randomly assigned to either correct lifestyle (BIB/lifestyle) or lifestyle plus pharmacotherapy (BIB/pharmacotherapy)., Results: At 6 months, patients treated with BIB lost significantly (P < 0.05) more weight (percent of initial weight lost, %IWL = 14.5 ± 1.2; percent of excess BMI lost, %EBL = 37.7 ± 3.2) than patients who received pharmacological treatment (%IWL = 9.1 ± 1.5, %EBL = 25.3 ± 4.1). At 1 year, the weight lost was significantly (P < 0.05) greater in patients treated with either BIB/pharmacotherapy (%IWL = 15.8 ± 2.3%, %EBL = 41.3 ± 6.7%) or BIB/lifestyle (%IWL = 14.3 ± 2.7, %EBL = 34.9 ± 6.5%) in respect to pharmacotherapy group (%IWL = 8.0 ± 1.4%, %EBL = 22.1 ± 3.9%). Moreover, patients treated sequentially with BIB/lifestyle or BIB/pharmacotherapy showed a significant (P < 0.05) improvement in insulin sensitivity and triglycerides levels., Conclusions: BIB represents an efficacious long-term obesity treatment when supplemental strategies, as lifestyle modifications or pharmacotherapy, are established for weight maintenance after its removal.

Objective: Obesity and cardiovascular disease recognize a common metabolic soil and may therefore share part of their genetic background. Genome-wide association studies have identified variability at the SH2B1 locus as a predictor of obesity. We investigated whether SNP rs4788102, which captures the entire SH2B1 variability, is associated with coronary artery disease (CAD) and/or myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM)., Design and Setting: SNP rs4788102 was typed in 2015 White subjects with T2DM from three CAD case-control studies [n=740 from the Gargano Hearth Study (GHS, Italy); n=818 from the Joslin Hearth Study (JHS, Boston); n=457 from the University of Catanzaro (CZ, Italy)]., Results: SNP rs4788102 (G/A) was not associated with CAD (overall allelic OR=1.06, 95% CI=0.93-1.21; p=0.37). On the contrary, it was associated with MI in GHS (1.42, 1.12-1.81; p=0.004) and in the three samples analyzed together (1.21, 1.04-1.41; p=0.016). Insulin stimulated nitric oxide synthase (NOS) activity in human vein endothelial cells from G/G (n=4, p=0.03) but not the G/A (n=5, p=0.83) genotype. Of the SNPs in perfect LD with rs4788102, one (rs7498665) affects amino acid polarity (Ala484Thr) and falls into a highly conserved protein segment of SH2B1 containing a class II SH3 domain binding site., Conclusions: Variability at the SH2B1 obesity locus is associated with MI in diabetic patients and with reduced insulin-stimulated NOS activity in human endothelial cells. Further studies are needed to replicate this association and dissect the biology underlying this finding., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: To study the role of the ENPP1 Q121 variant on glucose homeostasis in whites from Italy., Research Design and Methods: We conducted case-control studies in 764 adults (from two independent samples of 289 nonobese and 485 obese individuals) and 240 overweight/obese children undergoing oral glucose tolerance testing (OGTT). Early-phase insulin secretion and insulin sensitivity (the insulinogenic index and the insulin sensitivity index) and their interplay (the disposition index) were calculated., Results: In adult subjects, glucose profiles during OGTT were significantly (P = 2 x 10(-2)) different across K121Q genotype groups and higher in QQ than KK individuals (P = 5 x 10(-2)). The insulinogenic index was significantly reduced in QQ (18.5 +/- 3.4) compared with both KK (31.6 +/- 1.0; P = 2.2 x 10(-7)) and KQ (30.5 +/- 1.5; P = 3.2 x 10(-6)) individuals. KQ individuals also showed a reduced insulin sensitivity index compared with KK subjects (P = 3.6 x 10(-2)). The disposition index was lower in QQ carriers than in KQ and KK individuals (P = 8 x 10(-3) and 4 x 10(-4), respectively) and lower in KQ than in KK individuals (P = 3 x 10(-2)). Data obtained in overweight/obese children were very similar to those observed in adults, with QQ individuals showing (compared with KQ and KK subjects) a reduced insulinogenic index (P = 7 x 10(-3) and 2 x 10(-2), respectively) and disposition index (P = 2 x 10(-2) and 7 x 10(-3), respectively)., Conclusions: Homozygous carriers of the ENPP1 Q121 variant are characterized by an altered glucose homeostasis. Reduced early-phase insulin secretion and inefficient interplay between insulin secretion and sensitivity, which occur at early ages, are major determinants of this defect.

This study investigated the role of the ENPP1/PC-1 gene K121Q polymorphism in predicting BMI (kg/m2) in non-diabetic individuals. Three independent samples (n = 631, n = 304, and n = 505) of adult whites were analyzed. Selection criteria were fasting plasma glucose level <126 mg/dL, absence of severe obesity (BMI > or =40 kg/m2), and lack of treatment known to modulate BMI. In Sample 1, BMI values were different in individuals carrying the K121/K121 (KK), K121/Q121 (KQ), and Q121/Q121 (QQ) genotypes (25.5 +/- 4.3, 25.3 +/- 4.1, and 22.8 +/- 2.5 kg/m2, respectively (adjusted p = 0.022); BMI values in Samples 2 and 3 also tended to be different, although the differences, after adjustment for age and sex, did not reach statistical significance. When data were pooled, BMI values were 25.8 +/- 4.4, 25.6 +/- 4.4, and 23.6 +/- 3.3 kg/m2 in KK, KQ, and QQ individuals (adjusted p = 0.029). According to a recessive model, QQ individuals had lower BMI values than KK and KQ individuals combined (23.6 +/- 3.3 kg/m2 vs. 25.7 +/- 4.4 kg/m2; adjusted p = 0.008). These data suggest that the QQ genotype of the ENPP1/PC-1 gene is associated with lower BMI. If similar results are confirmed in prospective studies, the K121Q polymorphism may help identify people at risk for obesity.

Resistin is overexpressed in human adipose tissue of obese individuals and is likely to modulate insulin sensitivity. Resistin is, therefore, a candidate gene for insulin resistance. We searched for polymorphisms in the resistin gene by single strand conformation polymorphism and direct sequencing. An ATG triplet repeat in the 3'-untranslated region was identified and considered for association with insulin resistance. Three alleles were identified (allele 1: 8 repeats, allele frequency, 0.3%; allele 2: 7 repeats; allele frequency, 94.5%; allele 3: 6 repeats; allele frequency, 5.2%). Two hundred and three unrelated white Caucasian nondiabetic subjects from Sicily and 456 from the Gargano area (center east coast of Italy) were analyzed. Among Sicilians, subjects carrying allele 3 had a lower fasting insulin and insulin resistance index (homeostasis model assessment of insulin resistance; P < 0.001 for both) and glucose (P = 0.025) and insulin (P = 0.002) levels during the oral glucose tolerance test. In subjects from Gargano, those carrying allele 3 had lower fasting plasma glucose levels and serum triglycerides (P = 0.01 for both). When the 2 populations were analyzed together, subjects carrying allele 3 had lower fasting insulin levels (P < 0.005), homeostasis model assessment of insulin resistance (P < 0.005), and serum triglycerides (P = 0.01). In conclusion, our data suggest that subjects carrying allele 3 of the resistin gene are characterized by relatively high insulin sensitivity.