Study comparing the effect of pioglitazone in combination with either metformin or sulphonylureas on lipid profile and glycaemic control in patients with type 2 diabetes (ECLA).

OBJECTIVE: To explore whether the improvement of lipid profile and glycaemic control observed in randomized control trials with pioglitazone (PIO) is replicated under conditions of general clinical practice. RESEARCH DESIGN AND METHODS: We studied 2388 patients with type 2 diabetes (T2DM) not adequately controlled by monotherapy on either metformin (MET) or sulphonylurea (SU). Addition of a second drug, according to the treating physician's choice, resulted in three groups, PIO + MET, PIO + SU and MET + SU, followed for twelve months, while efficacy and safety parameters were measured at baseline, at six and at twelve months. RESULTS: A total of 2116 (88.6%) patients completed the study. Diabetic control and lipid profile improved in all three groups, but the improvement was always greater in the two PIO groups. At 12 months PIO + SU and PIO + MET groups compared to SU + MET showed greater increase in HDL cholesterol (8.3% and 9.2 versus 4.3% p < 0.001) and greater decrease in HbA1c (1.53% and 1.46% versus 0.97%, p < 0.001 for both), in triglycerides (20.7% and 21.5% versus 15.2%, p < 0.001) and in LDL cholesterol (15.2% and 14.6% versus 11.3%, p < 0.001 and p < 0.01, respectively). All changes were greater in patients already taking hypolipidaemic drugs. As ECLA was an observational study, the major limitation is the introduction of confounding bias which, however, was accounted for in the statistical analysis. CONCLUSIONS: Since improvement of both glycaemic control and lipid profile are considered main targets in the management of the diabetic patient, the results of the present study, conducted under conditions of everyday clinical practice, show that pioglitazone may be considered a potential choice for the treatment of type 2 diabetes, when lifestyle and metformin fail.

BmCbZ, an insect-specific factor featuring a composite DNA-binding domain, interacts with BmC/EBPgamma.

A novel factor featuring a composite AT hook/basic region-leucine zipper DNA-binding domain was isolated from Bombyx mori follicular cells. Screening of EST databases derived from a variety of metazoans revealed the exclusive presence of BmCbZ homologues in insect species. BmCbZ characteristic features and gene organization are discussed, in comparison to other known bZIP factors. We concordantly propose that this factor establishes a new insect-specific bZIP family. We further present the isolation of the silkmoth homologue of mammalian C/EBPgamma, BmC/EBPgamma, and in vitro evidence for its interaction with BmCbZ. The formation of a BmCbZ-BmC/EBPgamma heterodimer is a prerequisite for binding to specific C/EBP recognition sites on chorion gene promoters, most probably via both major and minor groove interactions.

A novel role for the Bombyx Slbo homologue, BmC/EBP, in insect choriogenesis.

One previously unidentified cDNA clone coding for a C/EBP factor, BmC/EBP, was isolated from Bombyx mori follicular cells. This is the first time that a C/EBP factor has been isolated and characterized in Lepidoptera. We provide information concerning structural features and developmental specificity, as well as in vitro interaction properties with chorion gene promoter modules. BmC/EBP was capable of effectively recognizing homologous binding sites from chorion gene promoters derived from flies and other moths, despite significant diversity of chorion structure, gene organization, and gene expression profiles. We propose that the relative concentration of BmC/EBP, in relation to its differential binding affinity for promoter cis-elements, results in activation or repression of silkmoth chorion gene expression.

In vitro analysis of Bombyx mori early chorion gene regulation: stage specific expression involves interactions with C/EBP-like and GATA factors.

This is the first attempt to identify regulatory elements that are involved in early choriogenesis of the silkworm Bombyx mori. A new cis element in the promoter region of five early chorion genes was identified. The consensus sequence of this element matches the consensus of the C/EBP DNA binding site. Moreover, this sequence interacts with a 70 kD protein (pX2) present in follicular nuclear extracts and complex formation exhibits early developmental specificity. There is strong evidence that this factor belongs to the C/EBP family. Surprisingly, the same protein binds with the same developmental specificity to a similar sequence of a late chorion gene promoter, which has been previously defined as the binding site for a putative late specific factor, BCFII. The possibility that pX2 and BCFII are isoforms or modifications of the same protein factor, which is presumably able to bind to the highly similar sequence elements of both early and late genes, is discussed. A hypothesis involving protein-protein interactions between C/EBP (pX2/BCFII) and GATA during choriogenesis is presented to explain the temporal specificity of chorion genes.

The biolistic method as a tool for testing the differential activity of putative silkmoth chorion gene promoters.

Bombyx mori unpaired early chorion gene copies 6F6.1,.2 and.3 are exceptions to the typical organization and distribution pattern of known early ErA/ErB, middle A/B and late HcA/HcB divergently transcribed gene pairs. Contrary to such pairs, the boundaries of the 6F6 regulatory sequences are not easily defined; moreover, they share common sequence elements with the regulatory sequences of middle and late genes. In order to perform a functional study of the tissue and temporal specificity of the 6F6 putative promoter region, we decided to apply biolistics. In the present work, use of a region from the 6F6.2 5' untranslated sequence, spanning nucleotides -138 to the cap site, gave an expected expression pattern of a lacZ reporter gene. Temporal specificity was further verified by control experiments using the cloned intergenic sequence of the late gene pair HcA/B.12, which resulted in lacZ expression in late choriogenic follicles. At present, despite the recent successful germinal transgenesis of Bombyx mori, the biolistic transient expression system seems to be the most rapid technique to pursue the functional study of the promoter region of early chorion genes, including the three unconventional early 6F6 genes.