Eli Lilly and Company

About: Eli Lilly and Company is a company organization based out in Indianapolis, Indiana, United States. It is known for research contribution in the topics: Population & Agonist. The organization has 17826 authors who have published 22835 publications receiving 946714 citations. The organization is also known as: Eli Lily.

Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy.

Abstract: Myotonic dystrophy type I (DM1), which is caused by a non-coding CTG-repeat expansion in the dystrophia myotonica-protein kinase (DMPK) gene, is an RNA-mediated disease. Expanded CUG repeats in transcripts of mutant DMPK form nuclear foci that recruit muscleblind-like (MBNL) proteins, a family of alternative splicing factors. Although transcripts of mutant DMPK and MBNL proteins accumulate in nuclear RNA foci, it is not clear whether foci formation is required for splicing mis-regulation. Here, we use a co-transfection strategy to show that both CUG and CAG repeats form RNA foci that colocalize with green fluorescent protein (GFP)-MBNL1 and endogenous MBNL1. However, only CUG repeats alter splicing of the two tested pre-mRNAs, cardiac troponin T (cTNT) and insulin receptor (IR). Using FRAP, we demonstrate that GFP-MBNL1 in CUG and CAG foci have similar half-times of recovery and fractions of immobile molecules, suggesting that GFP-MBNL1 is bound by both CUG and CAG repeats. We also find an immobile fraction of GFP-MBNL1 in DM1 fibroblasts and a similar rapid exchange in endogenous CUG RNA foci. Therefore, formation of RNA foci and disruption of MBNL1-regulated splicing are separable events.

Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery.

Abstract: n engl j med 353;20 www.nejm.org november 17, 2005 2192 to the editor: The causal links between bariatric surgery and pancreatic nesidioblastosis are unclear. Service et al. (July 21 issue)1 suggest a link between nesidioblastosis and glucagon-like peptide 1 (GLP-1), since GLP-1 causes beta-cell expansion in animal models of diabetes. GLP-1 and the incretin mimetic exenatide enhance insulin secretion in a glucose-dependent manner.2,3 Similarly, incretin-induced beta-cell expansion appears to be glucose-dependent. It is relevant that studies of two years’ duration in normal mice and rats of exenatide at doses of more than 100 times those given to humans showed no pathological changes in the islets (data on file, Amylin Pharmaceuticals); a study of nine months’ duration in healthy cynomolgus monkeys at doses of more than 400 times those used in humans showed minimal-to-mild islet hypercellularity with no increase in islet size (data on file, Amylin Pharmaceuticals). There have been no reports of recurrent, severe hypoglycemia or of nesidioblastosis in patients with type 2 diabetes mellitus during more than 2670 patient-years of exposure to exenatide. Given that neither experimental nor clinical evidence suggests that GLP-1 or exenatide induces nesidioblastosis, and given the multiple hormonal and metabolic changes that occur after bariatric surgery,4-6 we would suggest that the link between bariatric surgery and nesidioblastosis is multifactorial. Further study may lead to insights concerning the regulation of beta-cell function and growth. Thomas Carpenter, Ph.D.

Pretreatment deoxycytidine kinase levels predict in vivo gemcitabine sensitivity.

Abstract: Deoxycytidine kinase (dCK) is essential for the phosphorylation of gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analogue active against various solid tumors. Cytidine deaminase (CDA) catalyzes the degradation of gemcitabine. We determined whether dCK and/or CDA levels would predict response to gemcitabine. Activities of dCK and CDA were measured in a panel of eight gemcitabine-sensitive and -resistant tumors of a different origin (pancreas, lung, colon, ovary, and head and neck) grown as s.c. tumors in mice. Sensitivity to gemcitabine was expressed as treated versus control (tumor volume treated mice/control mice). Gemcitabine was given on days 0, 3, 6, and 9 (q3dx4) at its maximum tolerated dose. In addition, we measured the mRNA expression and protein levels of dCK in seven human tumor xenografts. dCK activity (mean +/- SE) ranged from 3.3+/-0.3 to 18.4+/-1.2 nmol/h/mg protein. Sensitivity to gemcitabine, expressed as treated versus control, ranged from 0.98 to 0.02, and the activity of CDA varied from 2+/-2 to 411+/-4 nmol/h/mg protein. In contrast to CDA, dCK activity was clearly related to gemcitabine sensitivity (p = -0.93; P < 0.001). This indicates that dCK might be an important prognostic marker for gemcitabine sensitivity. Protein levels were significantly related to both dCK activity (r = 0.96; P < 0.001) and gemcitabine sensitivity (rho = -0.96; P < 0.001). dCK expression as determined by competitive template reverse transcriptase PCR was significantly related with the dCK activity (r = 0.88; P = 0.025) and protein levels (p = 0.80; P = 0.052) but not with gemcitabine sensitivity, suggesting a post-translational regulation of dCK. In conclusion, the clear correlation between dCK levels and gemcitabine sensitivity in various murine tumors and human tumor xenografts may be a prognostic parameter when considering gemcitabine therapy.

Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes

Abstract: OBJECTIVE To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS Obese subjects ( n = 152; age 46 ± 12 years, female 82%, weight 108.6 ± 23.0 kg, BMI 39.6 ± 7.0 kg/m 2 , IGT or IFG 25%) were randomized to receive exenatide ( n = 73) or placebo ( n = 79), along with lifestyle intervention, for 24 weeks. RESULTS Exenatide-treated subjects lost 5.1 ± 0.5 kg from baseline versus 1.6 ± 0.5 kg with placebo (exenatide − placebo, P P CONCLUSIONS Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.