SummaryPlasticity is a hallmark of macrophages, and in response to environmental signals these cells undergo different forms of polarized activation, the extremes of which are called classic (M1) and alternative (M2). Rapamycin (RAPA) is crucial for survival and functions of myeloid phagocytes, but its effects on macrophage polarization are not yet studied. To address this issue, human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon-c or interleukin-4 (IL-4), respectively. The presence of RAPA (10 ng/ml) induced macrophage apoptosis in M2 but not in M1. Beyond the impact on survival in M2, RAPA reduced CXCR4, CD206 and CD209 expression and stem cell growth factor-b, CCL18 and CCL13 release. In contrast, in M1 RAPA increased CD86 and CCR7 expression and IL-6, tumour necrosis factor-a and IL-1b release but reduced CD206 and CD209 expression and IL-10, vascular endothelial growth factor and CCL18 release. In view of the in vitro data, we examined the in vivo effect of RAPA monotherapy (0Á1 mg/kg/day) in 12 patients who were treated for at least 1 month before islet transplant. Cytokine release by Toll-like receptor 4-stimulated peripheral blood mononuclear cells showed a clear shift to an M1-like profile. Moreover, macrophage polarization 21 days after treatment showed a significant quantitative shift to M1. These results suggest a role of mammalian target of rapamycin (mTOR) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2-related diseases through mTOR inhibitor treatment.

Purpose: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action.Experimental Design:We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population.Results: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n ¼ 31) or without metformin (n ¼ 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P ¼ 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin.Conclusions: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy.

Although long considered a promising treatment option for type 1 diabetes, pancreatic islet cell transformation has been hindered by immune system rejection of engrafted tissue. The identification of pathways that regulate post-transplant detrimental inflammatory events would improve management and outcome of transplanted patients. Here, we found that CXCR1/2 chemokine receptors and their ligands are crucial negative determinants for islet survival after transplantation. Pancreatic islets released abundant CXCR1/2 ligands (CXCL1 and CXCL8). Accordingly, intrahepatic CXCL1 and circulating CXCL1 and CXCL8 were strongly induced shortly after islet infusion. Genetic and pharmacological blockade of the CXCL1-CXCR1/2 axis in mice improved intrahepatic islet engraftment and reduced intrahepatic recruitment of polymorphonuclear leukocytes and NKT cells after islet infusion. In humans, the CXCR1/2 allosteric inhibitor reparixin improved outcome in a phase 2 randomized, open-label pilot study with a single infusion of allogeneic islets. These findings indicate that the CXCR1/2-mediated pathway is a regulator of islet damage and should be a target for intervention to improve the efficacy of transplantation. IntroductionAchieving long-lasting insulin independence after portal vein islet transplantation has improved, but remains challenging. Nonspecific immune activation (1-6), along with preexisting and transplant-induced auto-and allospecific immune responses (7-9), are components affecting outcome; these are not fully suppressed by ongoing protocols of generalized immunosuppression. Increasing general immunosuppression potency is not ideal because of side effects. Consequently, the development of novel protocols that specifically target proinflammatory immune cell compartments that impede islet function and survival is compelling.

Type 2 diabetes is associated with risk of cancer. Hyperinsulinemia and insulin resistance may be the link with cancer, but whether this is independent of the diabetes status, obesity/visceral obesity and metabolic syndrome is uncertain and the present study wanted to address this issue. Fifteen-year all-cause, CVD and cancer mortality data were obtained through the Regional Health Registry in 2,011 out of 2,074 Caucasian middle-aged individuals of the Cremona Study, a population study on the prevalence of diabetes mellitus in Italy in which anthropometric and metabolic characteristics were collected. During the 15-year observation period, 495 deaths were registered: 221 CVD related and 180 cancer related. Age and sex were independently associated with all-cause, cancer and CVD mortality rates. Age- and sex-adjusted analysis showed that HOMA-IR, cigarette smoking and diabetes were independently associated with all-cause mortality; HOMA-IR, systolic blood pressure and fibrinogen were independently associated with CVD mortality; HOMA-IR and smoking habit were independently associated with cancer mortality. Individuals in the highest quintile of serum insulin had a 62% higher risk of cancer mortality (HR = 1.62 95% CI: 1.19-2.20; P < 0.0022) and 161% higher risk of gastrointestinal cancer mortality (HR = 2.61 95% CI: 1.73-3.94; P < 0.0001). Age- and sex-adjusted analysis showed that hyperinsulinemia/insulin resistance is associated with cancer mortality independently of diabetes, obesity/visceral obesity and the metabolic syndrome.

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