Comparative cardiovascular morbidity and mortality in patients taking different insulin regimens for type 2 diabetes: a systematic review.

OBJECTIVES: To summarise the literature evaluating the association between different insulin regimens and the incidence of cardiovascular morbidity and mortality in adults with type 2 diabetes. DESIGN: Systematic review. METHODS: Multiple biomedical databases (The Cochrane Library, PubMed, EMBASE, and International Pharmaceutical Abstracts) were searched from their inception to February 2014. References of included studies were hand searched. Randomised controlled trials (RCTs), cohort studies or case-control studies examining adults (≥18 years) with type 2 diabetes taking any type, dose and/or regimen of insulin were eligible for inclusion in this review. OUTCOME MEASURES: Primary outcomes were cardiovascular morbidity and mortality including fatal and/or non-fatal myocardial infarction, fatal and/or non-fatal stroke, major adverse cardiac events and cardiovascular death. All-cause mortality was assessed as a secondary outcome. RESULTS: Of the 3122 studies identified, 2 RCTs and 6 cohort studies were selected. No case-control studies met the inclusion criteria. The studies examined a total of 109,910 patients. Quantitative synthesis of the results from included studies was not possible due to a large amount of clinical heterogeneity. Each study evaluated cardiovascular outcomes across different insulin-exposure contrasts. RCTs did not identify any difference in cardiovascular risks among a fixed versus variable insulin regimen, or a prandial versus basal regimen, albeit clinically important risks and benefits cannot be ruled out due to wide CIs. Findings from cohort studies were variable with an increased and decreased risk of cardiovascular events and all-cause mortality being reported. CONCLUSIONS: This systematic review of randomised and non-randomised studies identifies a substantive gap in the literature surrounding the cardiovascular morbidity and mortality of patients using different regimens of insulin. There is a need for more consistent high-quality evidence investigating the impact of insulin use on cardiovascular outcomes in patients with type 2 diabetes. PROSPERO: CRD42014007631.

LKB1 catalytically deficient mutants enhance cyclin D1 expression.

Mutations in the serine-threonine tumor-suppressor kinase LKB1 are responsible for Peutz-Jeghers syndrome, characterized by hamartomatous proliferation and an increased risk of developing cancer. Mutations in lkb1 have also been identified in sporadic cancers, suggesting a wider role for LKB1 in cancer that is not limited to hamartomatous polyposis syndromes. Here, we show that LKB1 catalytically deficient mutants, when introduced into DLD1p21-/-p53-/- colorectal cancer cells, allowed for progression of cells through to S phase of cell cycle and elicited the expression of Rb, cyclin E, and cyclin A2 whereas the introduction of LKB1 lead to G1 cell cycle arrest independent of p21(WAF/CIP1) and/or p53 expression. Furthermore, we show that LKB1 catalytically deficient mutants activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. In addition to compromising the tumor-suppressor function of LKB1, our findings highlight an emerging role for LKB1 catalytically deficient mutants, a gain of oncogenic properties.