Adiponectin is a protein secreted by adipocytes that modulates insulin action. To assess whether variants of this gene contribute to the prevalence of insulin resistance in Caucasians, we genotyped 413 nondiabetic individuals for two single nucleotide polymorphisms (SNPs) at this locus. The two SNPs (45T→G and 276G→T) were chosen because of their association with type 2 diabetes in Japanese. Whereas each polymorphism was significantly associated with some correlate of insulin resistance, the haplotype defined by the two together was strongly associated with many components of the insulin resistance syndrome. Homozygotes for the risk haplotype had higher body weight (P = 0.03), waist circumference (P = 0.004), systolic (P = 0.01) and diastolic (P = 0.003) blood pressure, fasting glucose (P = 0.02) and insulin (P = 0.005) levels, homeostasis model assessment (HOMA) for insulin resistance (P = 0.003), and total to HDL cholesterol ratio (P = 0.01). Homozygotes also had significantly lower plasma levels of adiponectin (P = 0.03), independent of sex, age, and body weight. In an independent study group of 614 Caucasians, including 310 with type 2 diabetes, the risk haplotype was confirmed to be associated with increased body weight (P = 0.03) but not with type 2 diabetes per se. We conclude that variability at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome, but given the nature of the two SNPs, the risk haplotype is most probably a marker in linkage disequilibrium with an as yet unidentified polymorphism that affects plasma adiponectin levels and insulin sensitivity.

Recent evidence points to molecules secreted by the adipose tissue, or adipokines, as possible links between increased adipose mass and metabolic abnormalities. Among these molecules, adiponectin has drawn much attention because of its insulin-sensitizing and antiatherogenic actions, suggesting that genetic deficits in its production or action may contribute to insulin resistance and coronary artery disease (CAD). A meta-analysis of the data published to date supports this hypothesis. Two independent effects, corresponding to the two linkage disequilibrium blocks that can be identified at the adiponectin locus, appear to be present. In the 5′ block, the g.−11391G→A variant has a modest but significant effect on adiponectinemia, with a mean difference between genotypes of 1.64 ng/ml (95% CI 0.88–2.41). In the 3′ block, the g.+276G→T variant is a strong determinant of insulin resistance and CAD, with minor allele homozygotes having a lower homeostasis model assessment of insulin resistance (HOMA_IR) index (−0.36 units, 95% CI 0.24–0.47) and a lower cardiovascular risk (odds ratio 0.55, 95% CI 0.38–0.80) than carriers of other genotypes. No consistent effect on BMI or risk of type 2 diabetes is evident. Polymorphisms in the genes coding for the adiponectin receptors may also influence the risk of insulin resistance and CAD, but data on these genes are still too sparse to draw firm conclusions. In summary, the studies published to date indicate that polymorphisms at the adiponectin locus are indeed predictors of circulating adiponectin levels, insulin sensitivity, and atherosclerosis, highlighting the pivotal role of this adipokine in the modulation of metabolism and atherogenesis.

Several lines of evidence suggest a pathogenic role of insulin resistance on kidney dysfunction. Potential mechanisms are mostly due to the effect of single abnormalities related to insulin resistance and clustering into the metabolic syndrome. Hyperinsulinemia, which is inevitably associated to insulin resistance in non diabetic states, also appears to play a role on kidney function by inducing glomerular hyperfiltration and increased vascular permeability. More recently, adipocytokine which are linked to insulin resistance, low grade inflammation, endothelial dysfunction and vascular damage have been proposed as additional molecules able to modulate kidney function. In addition, recent evidences point also to a role of insulin resistance at the level of the podocyte, an important player in early phases of diabetic kidney damage, thus suggesting a new mechanism through which a reduction of insulin action can affect kidney function. In fact, mouse models not expressing the podocyte insulin receptor develop podocytes apoptosis, effacement of its foot processes along with thickening of the glomerular basement membrane, increased glomerulosclerosis and albuminuria. A great number of epidemiological studies have repeatedly reported the association between insulin resistance and kidney dysfunction in both non diabetic and diabetic subjects. Among these, studies addressing the impact of insulin resistance genes on kidney dysfunction have played the important role to help establish a cause-effect relationship between these two traits. Finally, numerous independent intervention studies have shown that a favourable modulation of insulin resistance has a positive effect also on urinary albumin and total protein excretion. In conclusion, several data of different nature consistently support the role of insulin resistance and related abnormalities on kidney dysfunction. Intervention trials designed to investigate whether treating insulin resistance ameliorates also hard renal end-points are both timely and needed.

The genes responsible for insulin resistance are poorly defined. Plasma cell differentiation antigen (PC-1) glycoprotein inhibits insulin receptor signaling and is associated with insulin resistance. We describe here a novel polymorphism in exon 4 of the PC-1 gene (K121Q) and demonstrate that it is strongly associated with insulin resistance in 121 healthy nonobese (BMI <30 kg/m2) nondiabetic (by oral glucose tolerance test [OGTT]) Caucasians from Sicily. Compared with 80 KK subjects, Q allele carriers (n = 41, 39 KQ and 2 QQ) showed higher glucose and insulin levels during OGTT (P < 0.001 by two-way analysis of variance) and insulin resistance by euglycemic clamp (M value = 5.25 +/- 1.38 [n = 24] vs. 6.30 +/- 1.39 mg x kg(-1) x min(-1) [n = 49], P = 0.005). Q carriers had higher risk of being hyperinsulinemic and insulin resistant (odds ratio [CI]: 2.99 [1.28-7.0], P < 0.001). Insulin receptor autophosphorylation was reduced (P < 0.01) in cultured skin fibroblasts from KQ versus KK subjects. Skeletal muscle PC-1 content was not different in 11 KQ versus 32 KK subjects (33 +/- 16.1 vs. 17.5 +/- 15 ng/mg protein, P = 0.3). These results suggest a cause-effect relationship between the Q carrying genotype and the insulin resistance phenotype, and raise the possibility that PC-1 genotyping could identify individuals who are at risk of developing insulin resistance, a condition that predisposes to type 2 diabetes and coronary artery disease.

Context: In patients with adrenal incidentalomas, subclinical hypercortisolism (SH) is associated with an increased prevalence of the metabolic syndrome. The effect of surgical/conservative approach is debated. Objective: The objective of the study was to determine the effect of the surgical and conservative approaches on the metabolic syndrome in patients with adrenal incidentalomas. Design: This was a retrospective longitudinal study (18–48 months follow-up). Setting: The study was conducted on an in- and outpatient basis. Patients: One hundred eight patients with adrenal incidentalomas were studied for the presence of SH, which was diagnosed in the presence of more than two of the following: urinary free cortisol greater than 70 μg per 24 h (193 nmol per 24 h), cortisol after 1 mg dexamethasone suppression test greater than 3.0 μg/dl (83 nmol/liter), ACTH less than 10 pg/ml (2.2 pmol/liter). Interventions: Surgery was performed in 25 patients with SH (group TrSH+) and 30 without SH (group TrSH−), whereas the conservative approach was chosen by 16 patients with SH (group UntrSH+) and 37 without SH (group UntrSH−). Main Outcome Measures: During the follow-up, the improvement/worsening of body weight, blood pressure, or glucose and cholesterol levels was defined in the presence of a greater than 5% weight decrease/increase and following the European Society of Cardiology or the Adult Treatment Panel III criteria, respectively. Results: In group TrSH+, weight, blood pressure, and glucose levels improved (32, 56, and 48%, respectively) more frequently than in group UntrSH+ (12.5%, P = 0.05; 0.0%, P < 0.0001; 0.0%, P = 0.001; and 0.0%, P = 0.0014, respectively). In group UntrSH+, blood pressure, glucose, and low-density lipoprotein levels worsened more frequently (50.0, 37.5, and 50.0%, respectively) than in group TrSH+ (0.0%, P < 0.0001; 0.0%, P = 0.001; and 20.0%, P = 0.05, respectively). Conclusions: Regarding the various components of the metabolic syndrome, in patients with adrenal incidentalomas and SH, surgery is beneficial.

CD36 is a class B scavenger receptor recognizing a variety of ligands including long-chain fatty acids and modified LDL. We investigated whether genetic variability at this locus is a determinant of free fatty acid (FFA) plasma levels and risk of coronary artery disease (CAD) in Caucasians. Typing of 21 polymorphic markers, evenly spanning the CD36 gene, revealed two linkage disequilibrium (LD) blocks that could be tagged by five polymorphisms (−33137A>G, −31118G>A, 25444G>A, 27645del>ins and 30294G>C). In 585 non-diabetic individuals of Caucasian origin, the 30294G>C polymorphism was significantly associated with FFA levels (P=0.02)—an effect that was especially visible among men (P=0.009). A similar association was observed in this gender at −33137 (P=0.008) and −31118 (P=0.028). When the five tag polymorphisms were considered together, men carrying the AGGIG haplotype had 31% higher FFA (P=0.0002) and 20% higher triglycerides (P=0.025) than non-carriers. The same haplotype was associated with increased risk of CAD in 197 type 2 diabetic individuals from the US (OR=2.3, 95% CI 1.2–4.2). A similar tendency was observed in a group of 321 type 2 diabetic individuals from Italy (OR=1.4, 0.9–2.3), resulting in an overall relative risk of 1.6 (1.1–2.3, P=0.015) in the two populations considered together. By targeted resequencing, we identified a common variant in the CD36 promoter that is in strong LD with the AGGIG haplotype and could be partly responsible for these findings. In conclusion, this comprehensive study of CD36 variability indicates that the common polymorphisms at this locus modulate lipid metabolism and cardiovascular risk in Caucasians.