Altered metabolic parameters in association with antipsychotic medication use in diabetes: A population based case-control study.

AIMS: This study assess differences in clinical variables in diabetes patients prescribed antipsychotic medication and determines relative schizophrenia prevalence in the diabetes population. METHODS: This population-based case-control study utilizing Scotland's national diabetes registry (SCI-diabetes) and linked psychiatric hospital discharge data (SMR04) established diabetes phenotypes in a patient cohort prescribed long term antipsychotic medication (n=2362) (cases). Cases were matched 1:10 to diabetes patients not prescribed antipsychotic medication (controls) for BMI, gender; diabetes type; birth year; diagnosis date; smoking status. Sub-groups with defined schizophrenia (n=196) or bipolar disorder (n=190) were further examined. Schizophrenia prevalence in the diabetes versus general population was compared. RESULTS: During follow up, antipsychotic prescription was associated with lower HbA1c (55.1 (95% CI 54.5-55.8) or 7.2 (95% CI 7.1-7.3)% vs 58.2 (58.0-58.4) mmol or 7.5 (95% CI 7.5-7.5)% p<0.001) lower serum total cholesterol, 4.2 (4.1-4.2) vs 4.3 (4.2-4.3) mmol/l, p<0.001, lower blood pressure (systolic 130 (130.17-131.29) vs 134 (134.3-134.7) mmHg, p<0.001), higher prescription of oral hypoglycaemic medication (42% (40-45) vs 38% (37-39) p<0.001), similar statin prescriptions (85% (81-89) vs 85% (84-86), p=0.55), and lower retinopathy rates (28% (25.6-30.5) vs 32% (31.5-33.1), p<0.001). HbA1c at diagnosis was similar (p=0.27). Schizophrenia prevalence was higher in the diabetes versus general population with differences across age groups (Scottish population versus diabetic population rate of 522.2 (522.1-522.3) versus 717.4 (703.4-731.9) per 100,000). CONCLUSIONS: We confirm higher diabetes rates in schizophrenia up to age 70, similar attendance rates and clinical measurements that are not worse in a large well-matched population-based Scottish sample prescribed antipsychotic medication versus matched general diabetes patients.

PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer.

Tumour cells can use strategies that make them resistant to nutrient deprivation to outcompete their neighbours. A key integrator of the cell's responses to starvation and other stresses is amino-acid-dependent mechanistic target of rapamycin complex 1 (mTORC1). Activation of mTORC1 on late endosomes and lysosomes is facilitated by amino-acid transporters within the solute-linked carrier 36 (SLC36) and SLC38 families. Here, we analyse the functions of SLC36 family member, SLC36A4, otherwise known as proton-assisted amino-acid transporter 4 (PAT4), in colorectal cancer. We show that independent of other major pathological factors, high PAT4 expression is associated with reduced relapse-free survival after colorectal cancer surgery. Consistent with this, PAT4 promotes HCT116 human colorectal cancer cell proliferation in culture and tumour growth in xenograft models. Inducible knockdown in HCT116 cells reveals that PAT4 regulates a form of mTORC1 with two distinct properties: first, it preferentially targets eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and second, it is resistant to rapamycin treatment. Furthermore, in HCT116 cells two non-essential amino acids, glutamine and serine, which are often rapidly metabolised by tumour cells, regulate rapamycin-resistant mTORC1 in a PAT4-dependent manner. Overexpressed PAT4 is also able to promote rapamycin resistance in human embryonic kidney-293 cells. PAT4 is predominantly associated with the Golgi apparatus in a range of cell types, and in situ proximity ligation analysis shows that PAT4 interacts with both mTORC1 and its regulator Rab1A on the Golgi. These findings, together with other studies, suggest that differentially localised intracellular amino-acid transporters contribute to the activation of alternate forms of mTORC1. Furthermore, our data predict that colorectal cancer cells with high PAT4 expression will be more resistant to depletion of serine and glutamine, allowing them to survive and outgrow neighbouring normal and tumorigenic cells, and potentially providing a new route for pharmacological intervention.

Analysis of the T-cell micro-environment in Epstein-Barr virus-related post-transplantation B lymphoproliferative disease.

Epstein-Barr virus (EBV) post-transplantation B lymphoproliferative disease (BLPD) may undergo regression after immunosuppression withdrawal and restoration of EBV-specific cytotoxic T-cell (CTL) activity in the immunocompromised allografted host. The presence of morphologically normal T cells in the BLPD micro-environment may influence tumour behaviour in vivo. In this immunopathological study, the phenotype and the number of T cells and other immunoregulatory cells have been investigated in seven primary and four recurrent BLPD biopsies from nine solid organ transplant recipients. BLPD with either viral lymphadenopathic or polymorphic lymphoma appearances was found to contain sizeable T-cell populations, mainly of memory/helper (TCR alpha/beta +, CD3+, CD4+, CD45RO+) type. Cytotoxic (TCR alpha/beta +, CD3, CD8+, Tia-1+) T cells were strikingly low in all samples. Low CD28 and CD25 expression suggested that secondary signals for functional and sustained T-cell activation may be deficient in these tumours. No close correlation was found between the degree of T-cell infiltration and clinical outcome, although appreciably higher number of CD8+ T cells were detected in three BLPD tumours showing prolonged clinical remission after treatment. While some level of EBV-specific T-cell function may be present in untreated BLPD, the overall findings of this study suggest that the nature of T-cell infiltrates may reflect a response to immunosuppressive therapy rather than to EBV infection per se. The possibility that a local EBV-specific T-cell response is generated in BLPD undergoing regression after treatment needs to be investigated.