We have investigated the developmental regulation of the rat insulin-like growth factor I (IGF-I) receptor gene in various tissues using a sensitive and specific solution hybridization/RNase protection assay. For this purpose we characterized rat IGF-I receptor cDNAs that were cloned from a simian virus 40-transformed rat granulosa cell cDNA library. The specific cDNA clone used in these studies encoded the putative signal peptide and the first 53 amino acids of the a subunit and was -94% homologous to its human counterpart.

Rodent models of pituitary tumorigenesis have implicated the retinoblastoma (Rb) pathway in the development of pituitary tumors. Previously, we reported that loss of p16 expression rather than loss of Rb occurs in most human pituitary adenomas. This alteration in these tumors is not associated with p16 mutation or frequent homozygous p16 gene loss. Our laboratory has now demonstrated that in most human pituitary tumors, the 5' CpG island of the p16 gene is extensively methylated. The high frequency of p16 gene methylation in human pituitary tumors suggests that this alteration is an early and perhaps required event in pituitary cell transformation.

IntroductionThe efficacy and safety of taspoglutide, a long-acting human glucagon-like peptide-1 analog, were compared with sitagliptin or placebo, as adjunct to metformin, in patients with inadequately controlled type 2 diabetes.MethodsIn this randomized, double-blind, double-dummy, parallel-group trial, patients were randomized to taspoglutide 10 mg once weekly (QW), 20 mg QW, 100 mg sitagliptin once daily (QD), or placebo for 24 weeks, followed by 28-week short-term and 104-week long-term extension periods. The primary endpoint was change in glycosylated hemoglobin (HbA1c) after 24 weeks.ResultsIn this study, 666 patients (baseline HbA1c, 7.96% [SD, 0.87]; fasting plasma glucose, 9.61 mmol/L [2.56]; body weight, 92.4 kg [19.3]) were randomized to taspoglutide 10 mg QW (n = 190), 20 mg QW (n = 198), 100 mg sitagliptin QD (n = 185), or placebo (n = 93) for 24 weeks. After 24 weeks, least squares mean (SE) HbA1c reductions were greater with taspoglutide 10 mg (−1.23% [0.06]) and 20 mg (−1.30% [0.06]) versus sitagliptin (−0.89% [0.06]) or placebo (−0.10% [0.08]). Mean treatment differences with taspoglutide 10 mg and 20 mg were −0.34 (95% confidence intervals [CI]: −0.49, −0.19) and −0.41 (−0.56, −0.26) versus sitagliptin; and −1.13 (−1.31, −0.95) and −1.20 (−1.38, −1.02) versus placebo. Weight loss was greater with taspoglutide 10 mg (−1.8 kg [0.3]) and 20 mg (−2.6 kg [0.3]) than sitagliptin (−0.9 kg [0.3]) or placebo (−0.5 kg [0.4]). Effects on HbA1c and weight loss continued through 52 weeks of treatment. No cases of severe hypoglycemia occurred with any active treatment. Gastrointestinal adverse events, and allergic and injection-site reactions were higher in the taspoglutide groups, causing higher discontinuation rates. Anti-taspoglutide antibodies were confirmed in 46% of patients.ConclusionTaspoglutide demonstrated better efficacy on glycemic control and weight loss than sitagliptin, but a high incidence of adverse events led to high discontinuation rates. The safety profile of taspoglutide in this trial was similar to other trials in the clinical program, and led to the discontinuation of dosing.

Background: The efficacy/safety of device-supported versus routine titration with Gla-300 in type 2 diabetes (T2DM) was evaluated. Method: AUTOMATIX was a 16-week, randomized, open-label, parallel-group, multicenter, noninferiority trial in insulin-treated or insulin-naïve people with T2DM. The fasting self-monitored plasma glucose (FSMPG) target was 90-130 mg/dL (5.0-7.2 mmol/L). Primary endpoint: proportion of participants achieving target FSMPG at week 16 without severe hypoglycemia. Secondary endpoints included: proportion reaching FSMPG target without confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia; time to first achieve FSMPG target; mean FSMPG and HbA1c change (baseline to week 16). Safety endpoints included hypoglycemia and adverse events. Patient-reported outcomes (PROs) were also assessed. Results: Participants were randomized to device-supported (n = 75) or routine titration (n = 76); 17 participants in the device-supported group discontinued device use. Noninferiority was achieved for the primary endpoint (device-supported: 45.9%, routine: 36.8%; weighted difference: 9.04 [95% CI: −6.75, 24.83]), but not superiority ( P = .262). The proportion reaching FSMPG target range without confirmed (≤70 mg/dL [≤3.9 mmol/L]) or severe hypoglycemia was 34.3% vs 14.5%, respectively. The time at which 50% of the participants achieved the FSMPG target was less in the device-supported than routine titration arm (10 vs 13 weeks). Least squares mean HbA1c reduction, safety profiles, and PROs were similar in both arms. Mean “ease of use” score for the device, assessed by healthcare professionals and participants on a scale of 1-7, was ≥6. Conclusions: Device-supported self-titration had a good safety/efficacy profile, and was noninferior to routine titration and well accepted by diabetes specialists and patients.

Objective: This study assessed the efficacy and safety of once-weekly taspoglutide in patients with type 2 diabetes mellitus inadequately controlled with metformin plus pioglitazone compared with placebo. Design:In this randomized, double-blind, parallel-group, placebo-controlled trial (T-emerge 3), 326 patients were randomized to once-weekly sc injections of taspoglutide 10 mg, taspoglutide 20 mg (10 mg for first 4 wk), or placebo. The primary endpoint was change from baseline in glycosylated hemoglobin (HbA1c) at 24 wk.Results: A significant reduction in HbA1c was observed with taspoglutide 10 mg and 20 mg vs. placebo (least square mean Ϫ1.35 and Ϫ1.40% vs. Ϫ0.45%, respectively; P Ͻ 0.0001). A greater proportion of taspoglutide-treated patients reached HbA1c target 7% or less (69.8 and 76.1% vs. 35.1%). With taspoglutide 10 mg and 20 mg vs. placebo, significantly greater reductions in fasting plasma glucose [Ϫ1.87 mmol/liter (Ϫ34 mg/dl) and Ϫ2.12 mmol/liter (Ϫ38 mg/dl) vs. Ϫ0.57 mmol/ liter (Ϫ10 mg/dl); P Ͻ 0.0001], improvements in homeostasis model assessment of ␤-cell function score (20.65 and 33.52 vs. Ϫ2.03; P Ͻ 0.0001), and significant weight loss (Ϫ0.64 kg and Ϫ1.04 kg vs. 0.59 kg; P Ͻ 0.01) were observed. Adverse events were generally mild to moderate; the most frequent adverse events with taspoglutide 10 mg, taspoglutide 20 mg, and placebo were nausea (35, 44, and 10%), vomiting (21, 24, and 2%), and injection site reactions (24, 24, and 5%). Conclusions:Taspoglutide provided glycemic control with weight loss as add-on therapy to metformin plus pioglitazone for inadequately controlled type 2 diabetes mellitus. (J Clin Endocrinol Metab 97: 2370 -2379, 2012)