Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. There are several possible explanations for these observations, but one is the existence of epigenetic differences. To address this issue, we examined the global and locus-specific differences in DNA methylation and histone acetylation of a large cohort of monozygotic twins. We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype.

The expression of interleukin-1–receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1β in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis.

The aim of the study was to compare the efficacy and safety of liraglutide in type 2 diabetes mellitus vs placebo and insulin glargine (A21Gly,B31Arg,B32Arg human insulin), all in combination with metformin and glimepiride. This randomised (using a telephone or web-based randomisation system), parallel-group, controlled 26 week trial of 581 patients with type 2 diabetes mellitus on prior monotherapy (HbA_1c 7.5–10%) and combination therapy (7.0–10%) was conducted in 107 centres in 17 countries. The primary endpoint was HbA_1c. Patients were randomised (2:1:2) to liraglutide 1.8 mg once daily (n = 232), liraglutide placebo (n = 115) and open-label insulin glargine (n = 234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily). Investigators, participants and study monitors were blinded to the treatment status of the liraglutide and placebo groups at all times. The number of patients analysed as intention to treat were: liraglutide n = 230, placebo n = 114, insulin glargine n = 232. Liraglutide reduced HbA_1c significantly vs glargine (1.33% vs 1.09%; −0.24% difference, 95% CI 0.08, 0.39; p = 0.0015) and placebo (−1.09% difference, 95% CI 0.90, 1.28; p < 0.0001). There was greater weight loss with liraglutide vs placebo (treatment difference –1.39 kg, 95% CI 2.10, 0.69; p = 0.0001), and vs glargine (treatment difference −3.43 kg, 95% CI 4.00, 2.86; p < 0.0001). Liraglutide reduced systolic BP (−4.0 mmHg) vs glargine (+0.5 mmHg; −4.5 mmHg difference, 95% CI 6.8, −2.2; p = 0.0001) but not vs placebo (p = 0.0791). Rates of hypoglycaemic episodes (major, minor and symptoms only, respectively) were 0.06, 1.2 and 1.0 events/patient/year, respectively, in the liraglutide group (vs 0, 1.3, 1.8 and 0, 1.0, 0.5 with glargine and placebo, respectively). A slightly higher number of adverse events (including nausea at 14%) were reported with liraglutide, but only 9.8% of participants in the group receiving liraglutide developed anti-liraglutide antibodies. Liraglutide added to metformin and sulfonylurea produced significant improvement in glycaemic control and bodyweight compared with placebo and insulin glargine. The difference vs insulin glargine in HbA_1c was within the predefined non-inferiority margin.