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While elevated serum adiponectin and resistin levels have been singly associated with all-cause mortality in patients with type 2 diabetes (T2D), their combined effect has never been studied. We investigated such joint effect in patients with T2D and its possible modulation by several demographic and clinical conditions, known to affect per se mortality rate.Patients with T2D from the Gargano Mortality Study (GMS; N = 895, follow-up = 10.5 ± 3.7 years; 290 events) and the Foggia Mortality Study (FMS; N = 519, follow-up = 7.1 ± 2.5 years; 140 events) were examined.As singly considered, adiponectin and resistin were independently associated with mortality rate in GMS and FMS (p 0.0001 for both). The two studies were then pooled, for investigating the nature of the joint effect of the two adipokines. In such sample, both adipokines were associated with death, independent of each other and of several additional covariates (p = 0.01-4.58 × 10(-12)). Of note, no adiponectin-by-resistin interaction was observed (p = 0.40), thus pointing to an additive effect of the two adipokines. As compared to individuals with low levels of both adiponectin and resistin (i.e. below median values), those with high levels of both adipokines had an HR (95%CI) for death of 3.02 (2.26-4.03). Such increased risk was more pronounced in individuals with relatively low abdominal adiposity (p for HR heterogeneity below or above the median value of waist circumference = 0.03).Adiponectin and resistin show an additive independent effect on all-cause mortality in patients with T2D. Such effect is modified by abdominal adiposity.

Objective : We have previously reported the combined effect of SNPs perturbing insulin signaling ( ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on insulin resistance (IR), type 2 diabetes (T2D) and cardiovascular events. We here investigated whether such a combined effect affects also all-cause mortality in a sample of 1851 Whites of European ancestry. Methods : We investigated a first sample of 721 patients, 232 deaths, 3389 person-years (py). Replication was assessed in two samples of patients with T2D: the Gargano Mortality Study (GMS) of 714 patients, 127 deaths, 5426 py and the Joslin Kidney Study (JKS) comprising 416 patients, 214 deaths, 5325 py. Results : In the first sample, individuals carrying 1 or ≥2 risk alleles had 33% ( p = 0.06) and 51% ( p = 0.02) increased risk of mortality, as compared with individuals with no risk alleles. A similar, though not significant, trend was obtained in the two replication samples only for subject carrying ≥ 2 risk alleles. In a pooled analysis, individuals carrying ≥2 risk alleles had higher mortality rate as compared to those carrying 0 risk alleles (HR = 1.34, 95%CI = 1.08–1.67; p = 0.008), and as compared to those carrying only one risk allele (HR = 1.41, 95%CI = 1.13–1.75; p = 0.002). This association was independent from several possible confounders including sex, age, BMI, hypertension and diabetes status. Conclusion : Our data suggest that variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a role of abnormal insulin signaling on mortality risk.