Socio-economic differences in cardiovascular disease risk factor prevalence in people with type 2 diabetes in Scotland: a cross-sectional study.

AIM: To describe the association between socio-economic status and prevalence of key cardiovascular risk factors in people with type 2 diabetes in Scotland. METHODS: A cross-sectional study of 264 011 people with type 2 diabetes in Scotland in 2016 identified from the population-based diabetes register. Socio-economic status was defined using quintiles of the area-based Scottish Index of Multiple Deprivation (SIMD) with quintile (Q)1 and Q5 used to identify the most- and least-deprived fifths of the population, respectively. Logistic regression models adjusted for age, sex, health board, history of cardiovascular disease and duration of diabetes were used to estimate odds ratios (ORs) for Q1 compared with Q5 for each risk factor. RESULTS: The mean (sd) age of the study population was 66.7 (12.8) years, 56% were men, 24% were in Q1 and 15% were in Q5. Crude prevalence in Q1/Q5 was 24%/8.8% for smoking, 62%/49% for BMI ≥ 30 kg/m2 , 44%/40% for HbA1c ≥ 58 mmol/mol (7.5%), 31%/31% for systolic blood pressure (SBP) ≥ 140 mmHg, and 24%/25% for total cholesterol ≥ 5 mmol/l, respectively. ORs [95% confidence intervals (CI)] were 3.08 (2.95-3.21) for current smoking, 1.48 (1.44-1.52) for BMI ≥ 30 kg/m2 , 1.11 (1.08-1.15) for HbA1c ≥ 58 mmol/mol (7.5%), 1.03 (1.00-1.06) for SBP ≥ 140 mmHg and 0.87 (0.84-0.90) for total cholesterol ≥ 5 mmol/l. CONCLUSIONS: Socio-economic deprivation is associated with higher prevalence of smoking, BMI ≥ 30 kg/m2 and HbA1c ≥ 58 mmol/mol (7.5%), and lower prevalence of total cholesterol ≥ 5 mmol/l among people with type 2 diabetes in Scotland. Effective approaches to reducing inequalities are required as well as reducing risk factor prevalence across the whole population.

Incident ischaemic stroke and Type 2 diabetes: trends in incidence and case fatality in Scotland 2004-2013.

AIM: To describe trends in first ischaemic stroke incidence and case fatality in adults with and without a diagnosis of Type 2 diabetes prior to their ischaemic stroke event in Scotland between 2004 and 2013. METHODS: Using population-wide hospital admission, death and diabetes datasets, we conducted a retrospective cohort study. Negative binomial and logistic regression models were used to calculate year-specific incidence and case-fatality rates for people with Type 2 diabetes and for people without diabetes. RESULTS: During 41.0 million person-years of follow-up there were 69 757 ischaemic stroke events. Type 2 diabetes prevalence among patients who experienced ischaemic stroke increased from 13.5% to 20.3% between 2004 and 2013. Stroke incidence rates declined by 2.7% (95% CI 2.4, 3.0) annually for people with and without diabetes [diabetes/year interaction: rate ratio 0.99 (95% CI 0.98, 1.01)]. Type 2 diabetes was associated with an increased risk of ischaemic stroke in men [rate ratio 1.23 (95% CI 1.17, 1.30)] and women [rate ratio 1.41 (95% CI 1.35, 1.48)]. Case-fatality rates were 14.2% and 12.7% in people with Type 2 diabetes and without diabetes, respectively. Case fatality declined by 3.5% (95% CI 2.7, 4.5) annually [diabetes/year interaction: odds ratio 1.01 (95% CI 0.98, 1.02)]. CONCLUSIONS: Ischaemic stroke incidence declined no faster in people with a diagnosis of Type 2 diabetes than in people without diabetes. Increasing prevalence of Type 2 diabetes among stroke patients may mean that declines in case fatality over time will be less marked in the future.

Caspase-2 is required for cell death induced by cytoskeletal disruption.

Caspase-2 is one of the most conserved caspases, yet its biological function remains a matter of controversy. In the present article we analysed mouse embryonic fibroblasts (MEFs) from caspase-2 knockout mice for their sensitivity to various apoptosis inducing agents. We found that cell death induced by drugs that disrupt cytoskeleton is significantly inhibited in Casp2(-/-) MEFs. These drugs included zoledronic acid, vincristine, cytochalasin D and paclitaxel. We demonstrate that MEFs lacking Casp2 show clonogenic survival following drug treatment, whereas all Casp2(+/+) MEFs die, indicating that caspase-2 is required for apoptosis induced by cytoskeletal disruption. We further found that caspase-2 mediates apoptosis via Piddosome, Bid and Bax activation, and cytochrome c release. In the absence of caspase-2, Bid and Bax activation, and cytochrome c release are significantly delayed following drug treatment. Our data provide strong support for a context-dependent function of caspase-2 in apoptosis.

The biochemical mechanism of caspase-2 activation.

A unified model for initiator caspase activation has previously been proposed based on the biochemical analysis of caspase-8 and -9. Caspase-2 is structurally related to caspase-9, but its mechanism of activation is not known. Using an uncleavable mutant of caspase-2, we show that dimerization (and not processing) is the key event that drives initial procaspase-2 activation. Following dimerization, caspase-2 undergoes autocatalytic cleavage that promotes its stable dimerization and further enhances the catalytic activity of caspase-2. Although the caspase-2 zymogen does not require cleavage for the initial acquisition of activity, intersubunit cleavage is required to generate levels of activity required to induce cell death by overexpression. We also provide evidence that the reported disulfide bond linkage between two caspase-2 monomers is dispensable for caspase-2 dimerization. As caspase-2 does not require cleavage for its initial activation, our findings confirm caspase-2 to be a bona fide initiator caspase.

Apoptosis in liver damage produced by tunicamycin.

OBJECTIVE: To determine whether apoptosis contributes to hepatocyte loss in tunicamycin poisoning. DESIGN: Groups of four guinea pigs were given 400 microg/kg of tunicamycin subcutaneously and killed at 24 h intervals up to 72 h post-injection. Livers were examined by routine histological methods and ancillary techniques (TUNEL staining, endonuclease activation, caspase activity, and electron microscopy) to ascertain whether any hepatocyte injury was apoptotic. RESULTS: Many hepatocytes exposed to tunicamycin showed evidence of apoptosis in the form of nuclear karyorrhexis with chromatin margination and crescent formation, TUNEL-positivity, DNA laddering, elevated caspase activity and apoptotic body formation. CONCLUSION: Tunicamycin caused the death of many hepatocytes in the livers of guinea pigs by apoptosis.

Characterization of the Drosophila caspase, DAMM.

Caspases are main effectors of apoptosis in metazoans. Genome analysis indicates that there are seven caspases in Drosophila, six of which have been previously characterized. Here we describe the cloning and characterization of the last Drosophila caspase, DAMM. Similar to mammalian effector caspases, DAMM lacks a long prodomain. We show that the DAMM precursor, along with the caspases DRONC and DECAY, is partially processed in cells undergoing apoptosis. Recombinant DAMM produced in Escherichia coli shows significant catalytic activity on a pentapeptide caspase substrate. Low levels of damm mRNA are ubiquitously expressed in Drosophila embryos during early stages of development. Relatively high levels of damm mRNA are detected in larval salivary glands and midgut, and in adult egg chambers. Ectopic expression of DAMM in cultured cells induces apoptosis, and similarly, transgenic overexpression of DAMM, but not of a catalytically inactive DAMM mutant, in Drosophila results in a rough eye phenotype. We demonstrate that expression of the catalytically inactive DAMM mutant protein significantly suppresses the rough eye phenotype due to the overexpression of HID, suggesting that DAMM may be required in a hid-mediated cell death pathway.

Debcl, a proapoptotic Bcl-2 homologue, is a component of the Drosophila melanogaster cell death machinery.

Bcl-2 family of proteins are key regulators of apoptosis. Both proapoptotic and antiapoptotic members of this family are found in mammalian cells, but no such proteins have been described in insects. Here, we report the identification and characterization of Debcl, the first Bcl-2 homologue in Drosophila melanogaster. Structurally, Debcl is similar to Bax-like proapoptotic Bcl-2 family members. Ectopic expression of Debcl in cultured cells and in transgenic flies causes apoptosis, which is inhibited by coexpression of the baculovirus caspase inhibitor P35, indicating that Debcl is a proapoptotic protein that functions in a caspase-dependent manner. debcl expression correlates with developmental cell death in specific Drosophila tissues. We also show that debcl genetically interacts with diap1 and dark, and that debcl-mediated apoptosis is not affected by gene dosage of rpr, hid, and grim. Biochemically, Debcl can interact with several mammalian and viral prosurvival Bcl-2 family members, but not with the proapoptotic members, suggesting that it may regulate apoptosis by antagonizing prosurvival Bcl-2 proteins. RNA interference studies indicate that Debcl is required for developmental apoptosis in Drosophila embryos. These results suggest that the main components of the mammalian apoptosis machinery are conserved in insects.

DECAY, a novel Drosophila caspase related to mammalian caspase-3 and caspase-7.

Caspases are key effectors of programmed cell death in metazoans. In Drosophila, four caspases have been described so far. Here we describe the identification and characterization of the fifth Drosophila caspase, DECAY. DECAY shares a high degree of homology with the members of the mammalian caspase-3 subfamily, particularly caspase-3 and caspase-7. DECAY lacks a long prodomain and thus appears to be a class II effector caspase. Ectopic expression of DECAY in cultured cells induces apoptosis. Recombinant DECAY exhibited substrate specificity similar to the mammalian caspase-3 subfamily. Low levels of decay mRNA are ubiquitously expressed in Drosophila embryos during early stages of development but its expression becomes somewhat spatially restricted in some tissues. During oogenesis decay mRNA was detected in egg chambers of all stages consistent with a role for DECAY in apoptosis of nurse cells. Relatively high levels of decay mRNA are expressed in larval salivary glands and midgut, two tissues which undergo histolysis during larval/pupal metamorphosis, suggesting that DECAY may play a role in developmentally programmed cell death in Drosophila.