Differences in HbA1C at the time of diabetes diagnosis in the adult population of Ontario, Canada.

AIMS: To determine the proportion of adults with HbA1c≥8.0% (64mmol/mol) at diabetes diagnosis, as an indicator of delayed diagnosis or less intensive screening. METHODS: We conducted a cross-sectional population-level study using clinical, administrative and immigration data from Ontario, Canada. We identified all individuals diagnosed with diabetes between June 2012 and June 2015, and determined the HbA1c between 60days prior to and 30days after diagnosis. Individuals were stratified based on many sociodemographic, clinical and primary care characteristics, and the proportion with HbA1c≥8.0% (64mmol/mol) was determined. RESULTS: Mean HbA1c at diabetes diagnosis in the population was 7.3±1.9% (56±21mmol/mol), and 21.1% had HbA1c≥8.0% (64mmol/mol) at diagnosis. Factors for which there were important differences in the proportion with HbA1c≥8.0% (64mmol/mol) included age, sex, ethnicity, comorbidities, frequency of primary care and primary care rostering. CONCLUSIONS: In a real-world population-level setting, more than one-fifth of individuals diagnosed with diabetes have HbA1c levels ≥8.0% (64mmol/mol), suggesting a delay in diagnosis due to inadequate screening. Differences were found based on age, sex and clinical factors, but not based on socioeconomic or immigration factors.

High Mobility Group A2 protects cancer cells against telomere dysfunction.

The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) plays important roles in the repair and protection of genomic DNA in embryonic stem cells and cancer cells. Here we show that HMGA2 localizes to mammalian telomeres and enhances telomere stability in cancer cells. We present a novel interaction of HMGA2 with the key shelterin protein TRF2. We found that the linker (L1) region of HMGA2 contributes to this interaction but the ATI-L1-ATII molecular region of HMGA2 is required for strong interaction with TRF2. This interaction was independent of HMGA2 DNA-binding and did not require the TRF2 interacting partner RAP1 but involved the homodimerization and hinge regions of TRF2. HMGA2 retained TRF2 at telomeres and reduced telomere-dysfunction despite induced telomere stress. Silencing of HMGA2 resulted in (i) reduced binding of TRF2 to telomere DNA as observed by ChIP, (ii) increased telomere instability and (iii) the formation of telomere dysfunction-induced foci (TIF). This resulted in increased telomere aggregation, anaphase bridges and micronuclei. HMGA2 prevented ATM-dependent pTRF2T188 phosphorylation and attenuated signaling via the telomere specific ATM-CHK2-CDC25C DNA damage signaling axis. In summary, our data demonstrate a unique and novel role of HMGA2 in telomere protection and promoting telomere stability in cancer cells. This identifies HMGA2 as a new therapeutic target for the destabilization of telomeres in HMGA2+ cancer cells.