Carbohydrate response element-binding protein (ChREBP) plays a pivotal role in beta cell glucotoxicity.

AIMS/HYPOTHESIS: This study was aimed at the elucidation of the pathogenesis of glucotoxicity, i.e. the mechanism whereby hyperglycaemia damages pancreatic beta cells. The identification of pathways in the process may help identify targets for beta cell-protective therapy. Carbohydrate response element-binding protein (ChREBP), a transcription factor that regulates the expression of multiple hyperglycaemia-induced genes, is produced in abundance in pancreatic beta cells. We hypothesise that ChREBP plays a pivotal role in mediating beta cell glucotoxicity. METHODS: We assessed the role of ChREBP in glucotoxicity in 832/13 beta cells, isolated mouse islets and human pancreas tissue sections using multiple complementary approaches under control and high-glucose-challenge conditions as well as in adeno-associated virus-induced beta cell-specific overexpression of Chrebp (also known as Mlxipl) in mice. RESULTS: Under both in vitro and in vivo conditions, ChREBP activates downstream target genes, including fatty acid synthase and thioredoxin-interacting protein, leading to lipid accumulation, increased oxidative stress, reduced insulin gene transcription/secretion and enhanced caspase activity and apoptosis, processes that collectively define glucotoxicity. Immunoreactive ChREBP is enriched in the nucleuses of beta cells in pancreatic tissue sections from diabetic individuals compared with non-diabetic individuals. Finally, we demonstrate that induced beta cell-specific Chrebp overexpression is sufficient to phenocopy the glucotoxicity manifestations of hyperglycaemia in mice in vivo. CONCLUSIONS/INTERPRETATION: These data indicate that ChREBP is a key transcription factor that mediates many of the hyperglycaemia-induced activations in a gene expression programme that underlies beta cell glucotoxicity at the molecular, cellular and whole animal levels.

Tuberculous meningitis among adults with and without HIV infection. Experience in an urban public hospital.

BACKGROUND: Tuberculous meningitis remains a frequently diagnosed entity in urban US hospitals, with the incidence increasing as a consequence of infection with the human immunodeficiency virus (HIV). OBJECTIVE: To describe the occurrence, characteristics, and therapeutic responses of tuberculous meningitis among adult patients of an urban public hospital, with special attention to the effects of HIV infection. DESIGN: Retrospective clinical review of all cases identified among adults over a 12-year interval, collecting demographic and clinical variables. SETTING: A 550-bed urban teaching hospital. MAIN OUTCOME MEASURE: Nine-month outcome stratified by survival. RESULTS: Among 31 adult patients identified as having definite or probable tuberculous meningitis, a majority (n = 20 [65%]) were infected with HIV. Cumulative rates of occurrence per 100 000 persons over the 12 years of the study were estimated at 1.72 for those without HIV infection and 400 for those with HIV infection. The most common symptoms at presentation were fever (83% [24/ 29]) and abnormal mental status (71% [20/28]). One or more abnormalities were present in the cerebrospinal fluid of 97% (30/31) of subjects, and 74% (23/31) had cerebrospinal fluid cultures positive for Mycobacterium tuberculosis. Neuroimaging of 28 patients revealed 1 or more abnormalities in 82% (n = 23). Among 30 patients with available outcome data at 9 months, 43% (n = 13) had died, 40% (n = 12) had survived without sequelae, and 17% (n = 5) had survived with morbidity. HIV infection had no discernible effect on findings. CONCLUSIONS: Tuberculous meningitis remains relatively common among indigent urban nonwhite populations. While HIV infection has contributed to the increased incidence of tuberculous meningitis, it has not significantly altered the presenting clinical, laboratory, or radiographic findings or the response to therapy of this disease. Parameters associated in a multivariate regression analysis with mortality at 9 months were black race and the absence of corticosteroid use.