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BACKGROUND: Obesity is common in type 2 diabetes (T2DM) and is associated with increased risk of morbidity and all-cause mortality. This analysis describes weight changes associated with insulin detemir initiation in real-life clinical practice. METHODS: Study of Once-Daily Levemir (SOLVE) was a 24-week international observational study of once-daily insulin detemir as add-on therapy in patients with T2DM receiving oral hypoglycaemic agents (OHAs). RESULTS: 17,374 participants were included in the analysis: mean age 62 ± 12 years; weight 80.8 ± 17.6 kg; body mass index (BMI) 29.2 ± 5.3 kg/m2; diabetes duration 10 ± 7 years; HbA1c 8.9 ± 1.6%. HbA1c decreased by 1.3 ± 1.5% during the study, with insulin doses of 0.27 ± 0.17 IU/kg. Patients with higher BMI had higher pre-insulin HbA1c, and similar reductions in HbA1c with insulin therapy. Weight decreased from 80.8 ± 17.6 kg to 80.3 ± 17.0 kg (change of -0.6 [95% CI -0.65; -0.47] kg), with 35% of patients losing >1 kg. Patients with the highest pre-insulin BMI lost the greatest amount of weight: BMI < 25: +0.8 [95% CI: 0.6; 0.9] kg, 25 ≤ BMI < 30: -0.2 [95% CI: -0.3; -0.8] kg, 30 ≤ BMI < 35: -1.0 [95% CI: -1.1; -0.8] kg; BMI ≥ 35: -1.9 [95% CI: -2.2; -1.6] kg. Minor hypoglycaemia decreased with increasing BMI: 2.3 and 1.3 events per patient year for BMI <25 and ≥ 35, respectively. CONCLUSIONS: Overall, patients with poorly controlled T2DM achieved significant reductions in HbA1c after initiation of once-daily insulin detemir therapy, without weight gain. The favourable impact of insulin detemir on weight may not apply to other insulin preparations. TRIAL REGISTRATIONS: ClinicalTrials.gov, NCT00825643 and NCT00740519.

The appearance of the notochord represented a milestone in Deuterostome evolution. The notochord is necessary for the development of the chordate body plan and for the formation of the vertebral column and numerous organs. It is known that the transcription factor Brachyury is required for notochord formation in all chordates, and that it controls transcription of a large number of target genes. However, studies of the structure of the cis-regulatory modules (CRMs) through which this control is exerted are complicated in vertebrates by the genomic complexity and the pan-mesodermal expression territory of Brachyury. We used the ascidian Ciona, in which the single-copy Brachyury is notochord-specific and CRMs are easily identifiable, to carry out a systematic characterization of Brachyury-downstream notochord CRMs. We found that Ciona Brachyury (Ci-Bra) controls most of its targets directly, through non-palindromic binding sites that function either synergistically or individually to activate early- and middle-onset genes, respectively, while late-onset target CRMs are controlled indirectly, via transcriptional intermediaries. These results illustrate how a transcriptional regulator can efficiently shape a shallow gene regulatory network into a multi-tiered transcriptional output, and provide insights into the mechanisms that establish temporal read-outs of gene expression in a fast-developing chordate embryo., PLoS Biology, 11(10), e1001697; 2013

Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at the Massachusetts Institute of Technology and the Woods Hole Oceanographic Institution September 2003, DNA sequencing and phylogenetic analyses were conducted to investigate evolutionary relationships between taxa within the metazoan clade Lophotrochozoa. Chapter 1 presents an introduction to phylogenetics of the Metazoa and the clade Lophotrochozoa. Chapter 2 analyzes higher level relationships between the major groups within the phylum Mollusca using sequences of the nuclear ribosomal large-subunit RNA gene (LSD rDNA). Results presented provide the first molecular evidence for a close relationship between the Scaphopoda and Cephalopoda. Phylogenetic trees with this topology were found to have likelihood scores significantly better than those for phylogenies constrained to fit the Diasoma hypothesis grouping Scaphopoda and Bivalvia as sister taxa. Chapter 3 utilizes LSU rDNA sequences to analyze relationships between diverse phyla within the clade Lophotrochozoa. LSU rDNA sequences were found to provide greater resolution than has been provided by previous analyses of the nuclear small-subunit ribosomal RNA gene (SSU rDNA). Analysis ofLSU rDNA sequences recovered the monophyly of several phyla, such as Mollusca and Anelida, whose members are found to be paraphyletic using SSU rDNA sequences alone. Results also suggest that the clade Platyzoa, including rotifers and platyhelminthes, may have arisen within the Lophotrochozoa, rather than as a sister group to lophotrochozoans. Chapter 4 investigates the Hox gene complement of the bryozoan Bugula turrita. Six Hox genes were recovered, including an ortholog of the posterior class gene Post2, which is a synapomorphy for the Lophotrochozoa. The identification of a Post2 ortholog provides evidence of a close relationship between the Bryozoa and other lophotrochozoan phyla., This work was supported by a grant from the National Science Foundation, DEB-0075618 "Genomic approaches to metazoan evolution; lophotrochozoans and Hox genes" to Kenneth Halanych. Bryozoan Hox research was supported by a Doctoral dissertation Improvement Grant from the National Science Foundation, DEB-OI04984 "Phylogenetic inference from bryozoan Hox genes" to Kenneth Halanych and Yale Passamaneck. Additional support was provided by the Woods Hole Oceanographic Institution Education Office.

DNA sequencing and phylogenetic analyses were conducted to investigate evolutionary relationships between taxa within the metazoan clade Lophotrochozoa. Chapter 1 presents an introduction to phylogenetics of the Metazoa and the clade Lophotrochozoa. Chapter 2 analyzes relationships between the major groups within the phylum Mollusca using sequences of the nuclear ribosomal large-subunit RNA gene (LSU rDNA). Results presented provide the first molecular evidence for a close relationship between the Scaphopoda and Cephalopoda. Chapter 3 utilizes LSU rDNA sequences to analyze relationships between phyla within the clade Lophotrochozoa. LSU rDNA sequences provided greater resolution than have previous analyses of the nuclear small-subunit ribosomal RNA gene (SSU rDNA). Analysis of LSU rDNA sequences recovered the monophyly of several phyla, such as Mollusca and Annelida, whose members are found to be paraphyletic using SSU rDNA sequences alone. Results also suggest that the clade Platyzoa may have arisen within the Lophotrochozoa. Chapter 4 investigates the Hox gene complement of the bryozoan Bugula turrita. Six Hox genes were recovered, including an ortholog of the posterior class gene Post2, which is a synapomorphy for the Lophotrochozoa. The identification of a Post2 ortholog provides evidence of a close relationship between the Bryozoa and other lophotrochozoan phyla., Prepared in cooperation with Massachusetts Institute of Technology, Cambridge, MA.