AimsTo evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in elderly patients (aged ≥65 years) with type 2 diabetes (T2D) in six phase III clinical trials.MethodsPatients were grouped into two age groups: ≥65 and <65 years. Pooled analysis for glycated haemoglobin (HbA1c) change from baseline, percentage of patients achieving HbA1c targets, and gastrointestinal tolerability were evaluated at 26 weeks for each dulaglutide dose. Change in weight from baseline and rates of hypoglycaemia were evaluated for each individual study.ResultsA total of 958 of 5171 (18.5%) patients were aged ≥65 years. The reductions in HbA1c were similar between age groups for dulaglutide 1.5 mg‐treated patients {least squares [LS] mean for patients aged ≥65 years: −1.24 [95% confidence interval (CI) −1.36, −1.12] and for patients aged <65 years: −1.29 [95% CI −1.38, −1.20]} and for dulaglutide 0.75 mg‐treated patients [LS mean for patients aged ≥65 years: −1.16 (95% CI −1.29, −1.03) and for patients aged <65 years: −1.10 (95% CI −1.19, −1.01)] at 26 weeks. The percentages of patients who achieved HbA1c targets of <7, <8 or <9% were also similar in the two groups with both dulaglutide doses. Patients aged ≥65 years had similar weight change to patients aged <65 years. Severe hypoglycaemic events were infrequent. A similar incidence of gastrointestinal adverse events was observed in each age group with both dulaglutide doses.ConclusionBoth dulaglutide doses were well tolerated, with similar efficacy in patients with T2D aged ≥65 years to those aged <65 years. Dulaglutide can be considered a safe and effective treatment option for use in older adults.

A conformational change, termed the T --> R transition, which can be detected by visible, circular dichoric, and fluorescence spectroscopy, occurs in native insulin and tryptophan substituted insulin analogs ([TrpB25]-, [TrpB26]-, [GlyB24,TrpB25]-, and [GlyB24,TrpB26]insulin) upon binding specific alcohol ligands, including phenol and cyclohexanol. In these studies we have demonstrated that changes in the visible absorbance spectrum of an insulin6(Co2+)2 solution are not a definitive means of determining the occurrence of T --> R transitions in the presence of alcohol ligands. We also have presented evidence that fast protein liquid chromatography (FPLC) can be used to determine the aggregation state of insulin and that des-octapeptide(B23-30)insulin (DOI) forms Zn(2+)-coordinated hexamers that appear to be stabilized by the T --> R transformation. Using fluorescence spectroscopy, we have shown that in the presence of specific alcohol ligands the B-chain COOH-terminal residues, particularly position B25, of hexameric, as well as monomeric insulin undergo a conformational change which appears to be related to the T --> R transformation. Circular dichroic studies indicate that a conformation similar to the R-state of metal-coordinated hexameric insulin can be induced by binding cyclohexanol; however, this new conformational state (RI-state) exists independent of divalent metal ion coordination, and therefore of hexamer formation. We further show that monomeric insulin can be induced to assume the RI-state upon alcohol binding, therefore illustrating the first defined conformational change described for monomeric insulin. We suggest that this new conformation may be an intermediate state in the T --> R transformation in metal-coordinated hexameric insulin, such that T --> RI --> R. The model presented here of the structural adjustments undergone by insulin upon binding cyclohexanol provides further insight into the conformational flexibility of insulin in solution.

Inducing tissue-specific genetic alterations under temporal control allows for the analysis of gene function in particular cell types at specified points in time. We have generated a system for tetracycline-controlled expression of Cre recombinase in mice using the unique CreTeR vector. The gonadotroph-specific bovine a-subunit (Ba) promoter fragment was subcloned into the CreTeR vector, creating a technique for highly regulated expression of Cre recombinase exclusively in pituitary gonadotrophs. Control of Cre recombinase in the CreTeR vector was demonstrated in LbT2 pituitary cell lines, where Cre protein was detected in cells treated with doxycycline, but not in untreated cells. In transgenic mice, Cre was expressed in pituitary gonadotrophs of mice treated with doxycycline, but not in non-pituitary tissues or in transgenic mice not treated with doxycycline. We demonstrated Cre expression in the gonadotroph by immunostaining showing co-localization of Cre recombinase with the b-subunit of LH (LH-b). Furthermore, by crossing Ba/CreTeR with R26R mice, we were able to demonstrate functional recombination within pituitary gonadotrophs, detected by lacZ expression. The Ba/CreTeR mice described here can be used to study the function of virtually any gene in the gonadotroph; in particular, this will be useful in studying genes, which may have distinct roles in development and in the adult.

[GlyB24]insulin is a novel insulin analog which maintains nearly full biological activity [Mirmira, R. G., & Tager, H. S. (1989) J. Biol. Chem. 264, 6349-6354] even though its structure, as determined by 2D NMR, shows complete loss of the characteristic B-chain beta-turn [Hua, Q. X., Shoelson, S. E., Kochoyan, M., & Weiss, M. A. (1991) Nature 354, 238-241], which in native insulin allows the extended B-chain C-terminal region to fold against the central B-chain helix. In these studies, steady-state anisotropy measurements and fluorescence quenching analysis of the tryptophan-substituted analogs [TrpB25]insulin and [GlyB24,TrpB25]insulin have been used to study the structure of the C-terminal region of the B-chain and have demonstrated that [GlyB24]insulin mutants maintain the normal B-chain conformation to a degree comparable to that of native (PheB24) insulin at neutral pH. The tryptophan-substituted, B-chain C-terminally truncated analogs [TrpB25-alpha-carboxamide]despentapeptide(B26-B30)-insulin (DPI) and [GlyB24,TrpB25-alpha-carboxamide]DPI also significantly retain the characteristic insulin B-chain fold in solution with [GlyB24,TrpB25-alpha-carboxamide]DPI being more tightly folded than its corresponding PheB24-analog ([TrpB25-alpha-carboxamide]DPI), as assessed by these methods. The results of anisotropy measurements are consistent with the existence of a correlation between the high-affinity receptor binding of [GlyB24]insulin and the partial maintenance of the B-chain beta-turn under physiologic conditions. Thus we conclude that only analogs which possess, or can readily assume, this oriented structure can form high-affinity binding complexes with insulin receptor.