Insertion of mobile DNA sequences typically has deleterious effects on host fitness, and thus diverse mechanisms have evolved to control mobile element proliferation across the tree of life. Mobility of the Ty1 retrotransposon in Saccharomyces yeasts is regulated by a novel form of copy number control (CNC) mediated by a self-encoded restriction factor derived from the Ty1 gag capsid gene that inhibits virus-like particle function. Here, we survey a panel of wild and human-associated strains of S. cerevisiae and S. paradoxus to investigate how genomic Ty1 content influences variation in Ty1 mobility. We observe high levels of mobility for a canonical Ty1 tester element in permissive strains that either lack full-length Ty1 elements or only contain full-length copies of the Ty1’ subfamily that have a divergent gag sequence. In contrast, low levels of canonical Ty1 mobility are observed in restrictive strains carrying full-length Ty1 elements containing canonical gag. Phylogenomic analysis of full-length Ty1 elements revealed that Ty1’ is the ancestral subfamily present in wild strains of S. cerevisiae, and that canonical Ty1 in S. cerevisiae is a derived subfamily that acquired gag from S. paradoxus by horizontal transfer and recombination. Our results provide evidence that variation in the ability of S. cerevisiae and S. paradoxus strains to repress canonical Ty1 transposition via CNC is encoded by the genomic content of different Ty1 subfamilies, and that self-encoded forms of transposon control can spread across species boundaries by horizontal transfer.

Insulin degludec (IDeg) is a basal insulin with an ultra-long and stable glucose-lowering effect with low within-patient variability. IDeg was previously shown to be associated with significantly lower rates of discrete episodes of confirmed hypoglycemia and nocturnal-confirmed hypoglycemia vs. insulin glargine (IGlar) in patients with type 2 diabetes (T2D). This post-hoc meta-analysis of patients with T2D compared IDeg and IGlar with respect to rates of recurrent-confirmed hypoglycemia. Five phase 3a, randomized, treat-to-target trials (26 or 52 weeks) compared once-daily IDeg (n=2262) and IGlar (n=1110) in patients with T2D. One trial used basal-bolus (BB) therapy with mealtime insulin aspart; all other trials used basal-oral therapy (BOT). Recurrent-confirmed hypoglycemia (PG<3.1 mmol/L or severe) was defined as pairs of episodes within 24 hours of one another. In the BB trial, 38% (IDeg) and 43% (IGlar) of patients experienced recurrent hypoglycemia, compared with 6.1% (IDeg) vs. 6.6% (IGlar) in the BOT trials. No significant difference in rates of recurrent-confirmed hypoglycemia was found between treatments for the overall meta-analysis (estimated rate ratio (ERR) IDeg/IGlar: 0.82 [0.65; 1.03], p=0.09) or BOT (ERR: 0.92 [0.62; 1.38], p=0.70) populations. For the BB trial, recurrent-confirmed hypoglycemia was 27% lower with IDeg vs. IGlar (ERR: 0.73 [0.54; 0.99], p=0.04). IDeg is not associated with increased risk of new-confirmed hypoglycemic episodes within 24 hours of a previous episode in BOT-treated T2D patients, and showed a reduced risk in patients treated with BB therapy.

This article reports on the short-term findings of a randomized, double-blind, placebo-controlled crossover trial that demonstrated the prowess of the glucagon-like peptide-1 analogue liraglutide, used as an adjunct to insulin, in promoting glycemic control in type 1 diabetes [Heller SR et al. EASD 2013 (abstr 3); NCT01536665].

AbstractHypoglycaemia unawareness can be a devastating complication in both types of diabetes. It is probably becoming more common as patients are urged to tighten their glycaemic control. The effects of improving glycaemic control on the background of increasing duration of diabetes are the main known risk factors for the condition. Antecedent hypoglycaemia diminishes physiological responses, and impairs the ability to identify further episodes, leading to a vicious downwards spiral and a high risk of further severe hypoglycaemic episodes. Fully established hypoglycaemia unawareness is thankfully rare, but difficulty in recognising the onset of hypoglycaemia is common. Therefore effective treatments to reverse or prevent hypoglycaemia unawareness are urgently needed.This review article examines the evidence around the pathophysiology of hypoglycaemia unawareness, and current therapeutic strategies. Copyright © 2011 John Wiley & Sons.