Preventing Adverse Outcomes for Bereaved Youth: Indirect Effects From a Randomized Trial of the Family Bereavement Program on Fear of Abandonment, Grief, and Mental Health.

OBJECTIVES: We investigated whether the self-system belief of fear of abandonment mediated the effects of intervention-induced change in 2 protective factors-positive parenting and adaptive coping-and one risk factor-stressful events-on youth mental health problems and maladaptive grief. This study extends prior research on fear of abandonment in youth who experience parental death by examining pathways through which a program reduced fear of abandonment and, in turn, affected subsequent pathways to child mental health problems in the context of a randomized experiment. METHODS: This is a secondary data analysis study. We used data from the 4-wave longitudinal 2-arm parallel randomized controlled trial of the Family Bereavement Program conducted between 1996 and 1999 in a large city in the Southwestern United States. The sample consisted of 244 offspring between 8 and 16 at the pretest. They were assessed again at posttest, 11-month follow-up, and 6-year follow-up. Offspring, caregivers, and teachers provided data. RESULTS: Mediation analyses indicated that intervention-induced reductions in stressful events were prospectively associated with a lower fear of abandonment. For girls, fear of abandonment was related to self-reported maladaptive grief and teacher-reported internalizing problems 6 years later. CONCLUSIONS: This study extends prior research on the relation between intervention-induced changes in risk and protective factors and improvements in outcomes of bereaved youth. The findings support the reduction of stressful events as a key proximal target of prevention programs for bereaved children.

Effects of a preventive parenting intervention for bereaved families on the intergenerational transmission of parenting attitudes: Mediating processes.

This study evaluated whether the Family Bereavement Program (FBP), a prevention program for parentally bereaved families, improved parenting attitudes toward parental warmth and physical punishment in young adult offspring 15 years after participation and identified mediational cascade pathways. One hundred fifty-six parents and their 244 offspring participated. Data were collected at pretest (ages 8-16), posttest, and six- and 15-year follow-ups. Ethnicity of offspring was: 67% non-Hispanic Caucasian, 16% Hispanic, 7% African American, 3% Native American, 1% Asian or Pacific Islander, and 6% other; 54% were males. There was a direct effect of the FBP on attitudes toward physical punishment; offspring in the FBP had less favorable attitudes toward physical punishment. There were also indirect effects of the FBP on parenting attitudes. The results supported a cascade effects model in which intervention-induced improvements in parental warmth led to fewer externalizing problems in adolescence/emerging adulthood, which in turn led to less favorable attitudes toward physical punishment. In addition, intervention-induced improvements in parental warmth led to improvements in anxious romantic attachment in mid-to-late adolescence/emerging adulthood, which led to more favorable attitudes toward parental warmth in emerging/young adulthood. These findings suggest that the effects of relatively brief prevention programs may persist into subsequent generations.

Longitudinal Effects of PostDivorce Interparental Conflict on Children's Mental Health Problems Through Fear of Abandonment: Does Parenting Quality Play a Buffering Role?

In a sample of 559 children (ages 9-18), researchers investigated whether: (a) fear of abandonment mediated the association between postdivorce interparental conflict (IPC) and mental health problems, and (b) parent-child relationship quality moderated the association between IPC and fear of abandonment. Mediation analyses indicated that pretest IPC predicted fear of abandonment 3 months later, which then predicted child- and teacher-reported mental health problems 10 months later. The hypothesized protective effect of a high-quality parent-child relationship was not observed. IPC predicted fear of abandonment for all children, except for those with low- and moderate-quality father-child relationships, for whom IPC was not significantly related to fear of abandonment. Findings highlight the need to optimize child coping programs and improve parenting-after-divorce programs to reduce IPC.

Developmental cascade effects of a parenting-focused program for divorced families on competence in emerging adulthood.

This 15-year longitudinal follow-up of a randomized controlled trial of a parenting-focused preventive intervention for divorced families examined cascade models of program effects on offsprings' competence. It was hypothesized that intervention-induced improvements in parenting would lead to better academic, work, peer, and romantic competence in emerging adulthood through effects on behavior problems and competencies during adolescence. Families (N = 240) participated in the 11-session program or literature control condition when children were ages 9-12. Data were drawn from assessments at pretest, posttest, and follow-ups at 3 and 6 months and 6 and 15 years. Results showed that initial intervention effects of parenting on externalizing problems in adolescence cascaded to work outcomes in adulthood. Parenting effects also directly impacted work success. For work outcomes and peer competence, intervention effects were moderated by initial risk level; the program had greater effects on youths with higher risk at program entry. In addition, intervention effects on parenting led to fewer externalizing problems that in turn cascaded to better academic outcomes, which showed continuity into emerging adulthood. Results highlight the potential for intervention effects of the New Beginnings Program to cascade over time to affect adult competence in multiple domains, particularly for high-risk youths.

Initial Validation and Measurement Invariance of the Active Inhibition Scale Among Traumatized and Grieving Youth.

The Active Inhibition Scale (AIS; Ayers, Sandler, & Twohey, 1998) is an 11-item, self-report measure of emotional suppression among children and adolescents. Previous research with the AIS has linked emotional suppression to several clinically significant outcomes, such as posttraumatic stress symptoms (PTSS) and suicide, among trauma-exposed and bereaved youth; however, there are no published evaluations of its psychometric properties. We examined the factor structure and criterion validity of the AIS in two samples. Sample 1 included youth (M = 12.22 years, SD = 2.96, range: 6-18 years; 55.4% female) referred to an outpatient psychology clinic specializing in childhood trauma and grief. Sample 2 included youth (M = 13.18 years, SD = 2.58, range: 8-18 years; 61.8% female) referred to a community grief counseling center. Confirmatory factor analytic results supported a one-factor solution, Cronbach's α = .94. Additionally, AIS scores correlated positively with PTSS, depression, and maladaptive grief, rs = .43-.64. Evidence of factorial invariance was found across gender, race/ethnicity, and age group. Emotional suppression scores were higher among girls compared to boys, Black and Hispanic youth compared to White youth, and older compared to younger age groups. The magnitude of correlations between AIS and symptom measure scores was comparable across groups. These results support the reliability and criterion validity of the AIS with diverse youth populations and underscore the role that emotional suppression may play in explaining group differences in mental health symptoms.

Saturated Raman scattering for sub-diffraction-limited imaging.

We present a scheme for a sub-diffraction-limited Raman microscope. The scheme combines the concept from stimulated depletion microscopy with femtosecond stimulated Raman scattering. The suppression of the Raman signal in a three-beam setup with only two involved wavelength-components was accomplished by the saturation of the Raman scattering. A reduction of the Raman signal of up to 79% could be measured with only a single Raman resonance involved. Based on this signal suppression, a resolution enhancement by a factor of 2 could be verified in a first proof-of-concept measurement, opening up a pathway toward label-free sub-diffraction-limited imaging.

Coping in context: The effects of long-term relations between interparental conflict and coping on the development of child psychopathology following parental divorce.

Exposure to high levels of postdivorce interparental conflict is a well-documented risk factor for the development of psychopathology, and there is strong evidence of a subpopulation of families for which conflict persists for many years after divorce. However, existing studies have not elucidated differential trajectories of conflict within families over time, nor have they assessed the risk posed by conflict trajectories for development of psychopathology or evaluated potential protective effects of children's coping to mitigate such risk. We used growth mixture modeling to identify longitudinal trajectories of child-reported conflict over a period of six to eight years following divorce in a sample of 240 children. We related the trajectories to children's mental health problems, substance use, and risky sexual behaviors and assessed how children's coping prospectively predicted psychopathology in the different conflict trajectories. We identified three distinct trajectories of conflict; youth in two high-conflict trajectories showed deleterious effects on measures of psychopathology at baseline and the six-year follow-up. We found both main effects of coping and coping by conflict trajectory interaction effects in predicting problem outcomes at the six-year follow-up. The study supports the notion that improving youth's general capacity to cope adaptively is a potentially modifiable protective factor for all children facing parental divorce and that children in families with high levels of postdivorce conflict are a particularly appropriate group to target for coping-focused preventive interventions.

Redesigning Implementation Measurement for Monitoring and Quality Improvement in Community Delivery Settings.

The field of prevention has established the potential to promote child adjustment across a wide array of outcomes. However, when evidence-based prevention programs have been delivered at scale in community settings, declines in implementation and outcomes have resulted. Maintaining high quality implementation is a critical challenge for the field. We describe steps towards the development of a practical system to monitor and support the high-quality implementation of evidence-based prevention programs in community settings. Research on the implementation of an evidence-based parenting program for divorcing families called the "New Beginnings Program" serves as an illustration of the promise of such a system. As a first step, we describe a multidimensional theoretical model of implementation that links aspects of program delivery with improvements in participant outcomes. We then describe research on the measurement of each of these implementation dimensions and test their relations to intended program outcomes. As a third step, we develop approaches to the assessment of these implementation constructs that are feasible to use in community settings and to establish their reliability and validity. We focus on the application of machine learning algorithms and web-based data collection systems to assess implementation and provide support for high quality delivery and positive outcomes. Examples are presented to demonstrate that valid and reliable measures can be collected using these methods. Finally, we envision how these measures can be used to develop an unobtrusive system to monitor implementation and provide feedback and support in real time to maintain high quality implementation and program outcomes.

Long-term Effects of a Parenting Preventive Intervention on Young Adults' Attitudes Toward Divorce and Marriage.

This study examined whether the New Beginnings Program (NBP), a parenting-focused preventive intervention designed to reduce children's post-divorce mental health problems, affected attitudes toward divorce and marriage in young adults whose mothers had participated 15 years earlier. Participants (M = 25.6 years; 50% female; 88% Caucasian) were from 240 families that had participated in a randomized experimental trial (NBP vs. literature control). Analyses of covariance showed that program effects on both types of attitudes were moderated by gender. Males in the NBP reported more positive attitudes toward marriage and less favorable attitudes toward divorce than males in the literature control.

Attendance Trajectory Classes Among Divorced and Separated Mothers and Fathers in the New Beginnings Program.

We examined attendance trajectories among mothers and fathers in the effectiveness trial of the New Beginnings Program, a parenting-focused prevention program for divorced and separated parents. We also investigated attendance trajectory class differences on two sets of pretest covariates: one set previously linked to participation in programs not specifically targeting divorced parents (i.e., sociodemographics, perceived parenting skills, child problem behaviors, parent psychological distress) and another that might be particularly salient to participation in the context of divorce (i.e., interparental conflict, level of parent-child contact, previous marital status to the ex-spouse). For mothers and fathers, results supported four attendance trajectory classes: (1) non-attenders (NA), (2) early dropouts (ED), (3) declining attenders (DA), and (4) sustained attenders (SA). In the final model testing multiple covariates simultaneously, mothers who were EDs and DAs were more likely to be Latina than SAs, and EDs reported more interparental conflict than SAs. Mother trajectory groups did not differ on parenting skills, child problem behavior, or mother-child contact in the final or preliminary models. In the final model for fathers, EDs rated their children higher on externalizing than DAs, had less contact with their children than DAs and NAs, and reported less distress than SAs. Father trajectory groups did not differ on fathers' age, ethnicity, income, perceived parenting skills, or interparental conflict in the final or preliminary models. Results highlight qualitatively distinct latent classes of mothers and fathers who disengage from a parenting intervention at various points. We discuss implications for intervention engagement strategies and translational science.

The Cascading Effects of Multiple Dimensions of Implementation on Program Outcomes: a Test of a Theoretical Model.

This study tests a theoretical cascade model in which multiple dimensions of facilitator delivery predict indicators of participant responsiveness, which in turn lead to improvements in targeted program outcomes. An effectiveness trial of the 10-session New Beginnings Program for divorcing families was implemented in partnership with four county-level family courts. This study included 366 families assigned to the intervention condition who attended at least one session. Independent observers provided ratings of program delivery (i.e., fidelity to the curriculum and process quality). Facilitators reported on parent attendance and parents' competence in home practice of program skills. At pretest and posttest, children reported on parenting and parents reported child mental health. We hypothesized effects of quality on attendance, fidelity and attendance on home practice, and home practice on improvements in parenting and child mental health. Structural Equation Modeling with mediation and moderation analyses were used to test these associations. Results indicated quality was significantly associated with attendance, and attendance moderated the effect of fidelity on home practice. Home practice was a significant mediator of the links between fidelity and improvements in parent-child relationship quality and child externalizing and internalizing problems. Findings provide support for fidelity to the curriculum, process quality, attendance, and home practice as valid predictors of program outcomes for mothers and fathers. Future directions for assessing implementation in community settings are discussed.

Addressing Methodologic Challenges and Minimizing Threats to Validity in Synthesizing Findings from Individual-Level Data Across Longitudinal Randomized Trials.

Integrative Data Analysis (IDA) encompasses a collection of methods for data synthesis that pools participant-level data across multiple studies. Compared with single-study analyses, IDA provides larger sample sizes, better representation of participant characteristics, and often increased statistical power. Many of the methods currently available for IDA have focused on examining developmental changes using longitudinal observational studies employing different measures across time and study. However, IDA can also be useful in synthesizing across multiple randomized clinical trials to improve our understanding of the comprehensive effectiveness of interventions, as well as mediators and moderators of those effects. The pooling of data from randomized clinical trials presents a number of methodological challenges, and we discuss ways to examine potential threats to internal and external validity. Using as an illustration a synthesis of 19 randomized clinical trials on the prevention of adolescent depression, we articulate IDA methods that can be used to minimize threats to internal validity, including (1) heterogeneity in the outcome measures across trials, (2) heterogeneity in the follow-up assessments across trials, (3) heterogeneity in the sample characteristics across trials, (4) heterogeneity in the comparison conditions across trials, and (5) heterogeneity in the impact trajectories. We also demonstrate a technique for minimizing threats to external validity in synthesis analysis that may result from non-availability of some trial datasets. The proposed methods rely heavily on latent variable modeling extensions of the latent growth curve model, as well as missing data procedures. The goal is to provide strategies for researchers considering IDA.

"Home Practice Is the Program": Parents' Practice of Program Skills as Predictors of Outcomes in the New Beginnings Program Effectiveness Trial.

An examination of the content and processes of evidence-based programs is critical for empirically evaluating theories about how programs work, the "action theory" of the program (West et al. in American Journal of Community Psychology, 21, 571-605, 1993). The New Beginnings Program (NBP; Wolchik et al., 2007), a parenting-after-divorce preventive intervention, theorizes that program-induced improvements in parenting across three domains: positive relationship quality, effective discipline, and protecting children from interparental conflict, will reduce the negative outcomes that are common among children from divorced families. The process theory is that home practice of program skills related to these parenting domains is the primary mechanism leading to positive change in parenting. This theory was tested using multi-rater data from 477 parents in the intervention condition of an effectiveness trial of the NBP (Sandler et al. 2016a, 2016b). Four research questions were addressed: Does home practice of skills predict change in the associated parenting outcomes targeted by the program? Is the effect above and beyond the influence of attendance at program sessions? What indicators of home practice (i.e., attempts, fidelity, efficacy, and competence) are most predictive of improvements in parenting? Do these indicators predict parenting improvements in underserved subpopulations (i.e., fathers and Latinos)? Structural Equation Modeling analyses indicated that parent-reported efficacy and provider-rated parent competence of home practice predicted improvements in the targeted parenting domains according to both parent and child reports. Moreover, indicators of home practice predicted improvements in parenting for fathers and Latinos, although patterns of effects varied by parenting outcome.

Constructed wetlands for water quality improvements: Benefit transfer analysis from Ohio.

Water resources provide many benefits that generate value for residents and recreation users alike but run-off from agricultural and impervious surfaces can impair water quality, reducing any generated value. A possible solution to this problem is the construction of treatment wetlands to remove excessive nutrients from water bodies. This study uses environmental and economic data to approximate the costs of constructing and operating free surface water wetlands to remove phosphorus and estimates the amenity and recreational benefits of the resulting improvements in water quality for 24 lakes in Ohio. A ten percent improvement in water quality from a decrease in phosphorus loadings generates positive net benefits for all lakes in the sample with a lifetime cost benefit ratio of 2.92. The study also examines the potential use of constructed wetlands as the sole strategy to achieve a reduction goal for phosphorus loadings and find that the costs of doing so are prohibitive. Constructed wetlands can be a cost-effective component of a comprehensive strategy for small-scale nutrient reduction and water quality improvements for surface water bodies, but other treatment methods would be required to achieve any proposed targeted improvements.

Does Shared Parenting Help or Hurt Children in High Conflict Divorced Families?

Despite a recent shift in the allocation of parenting time arrangements following divorce, there is no clear consensus regarding the effects of shared parenting on children's adjustment in high conflict families. We propose key questions and methodological options to increase the ability of results from well-designed empirical studies to inform practice and policy. We review eleven studies of the relations between parenting time and quality of parenting with children's adjustment in high conflict divorced families. Despite heterogeneity of the methods used across the studies some tentative conclusions can be made based on findings across multiple studies. Higher levels of shared parenting were related to poorer child adjustment in samples with high conflict many years following the divorce, but typically not in samples that assessed conflict during the divorcing process or in the two or three years following the divorce. There is also evidence that the effects of shared parenting on child adjustment in the presence of high conflict differs by gender, and that high quality of parenting by at least one parent is associated with better child adjustment in high conflict divorces. Implications for policy and practice are discussed as well as directions for research to strengthen the knowledge base to inform policy.

A Longitudinal Study of the Effects of Child-Reported Maternal Warmth on Cortisol Stress Response 15 Years After Parental Divorce.

OBJECTIVES: The experience of parental divorce during childhood is associated with an increased risk of behavioral and physical health problems. Alterations in adrenocortical activity may be a mechanism in this relation. Parent-child relationships have been linked to cortisol regulation in children exposed to adversity, but prospective research is lacking. We examined maternal warmth in adolescence as a predictor of young adults' cortisol stress response 15 years after parental divorce. METHODS: Participants included 240 youth from recently divorced families. Mother and child reports of maternal warmth were assessed at 6 time points across childhood, adolescence, and young adulthood. Offspring salivary cortisol was measured in young adulthood before and after a social stress task. Structural equation modeling was used to predict cortisol response from maternal warmth across early and late adolescence. RESULTS: Higher child-reported maternal warmth in early adolescence predicted higher child-reported maternal warmth in late adolescence (standardized regression = 0.45, standard error = 0.065, p < .01), which predicted lower cortisol response to a challenging interpersonal task in young adulthood (standardized regression = -0.20, standard error = 0.094, p = .031). Neither mother-reported warmth in early adolescence nor late adolescence was significantly related to offspring cortisol response in young adulthood. CONCLUSIONS: Results suggest that for children from divorced families, a warm mother-child relationship after divorce and across development, as perceived by the child, may promote efficient biological regulation later in life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01407120.

Developmental cascade models of a parenting-focused program for divorced families on mental health problems and substance use in emerging adulthood.

A developmental cascade model from functioning in adolescence to emerging adulthood was tested using data from a 15-year longitudinal follow-up of 240 emerging adults whose families participated in a randomized, experimental trial of a preventive program for divorced families. Families participated in the program or literature control condition when the offspring were ages 9-12. Short-term follow-ups were conducted 3 months and 6 months following completion of the program when the offspring were in late childhood/early adolescence. Long-term follow-ups were conducted 6 years and 15 years after program completion when the offspring were in middle to late adolescence and emerging adulthood, respectively. It was hypothesized that the impact of the program on mental health and substance use outcomes in emerging adulthood would be explained by developmental cascade effects of program effects in adolescence. The results provided support for a cascade effects model. Specifically, academic competence in adolescence had cross-domain effects on internalizing problems and externalizing problems in emerging adulthood. In addition, adaptive coping in adolescence was significantly, negatively related to binge drinking. It was unexpected that internalizing symptoms in adolescence were significantly negatively related to marijuana use and alcohol use. Gender differences occurred in the links between mental health problems and substance use in adolescence and mental health problems and substance use in emerging adulthood.

Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength.

UNLABELLED: A role for gut hormone in bone physiology has been suspected. We evidenced alterations of microstructural morphology (trabecular and cortical) and bone strength (both at the whole-bone--and tissue-level) in double incretin receptor knock-out (DIRKO) mice as compared to wild-type littermates. These results support a role for gut hormones in bone physiology. INTRODUCTION: The two incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), have been shown to control bone remodeling and strength. However, lessons from single incretin receptor knock-out mice highlighted a compensatory mechanism induced by elevated sensitivity to the other gut hormone. As such, it is unclear whether the bone alterations observed in GIP or GLP-1 receptor deficient animals resulted from the lack of a functional gut hormone receptor, or by higher sensitivity for the other gut hormone. The aims of the present study were to investigate the bone microstructural morphology, as well as bone tissue properties, in double incretin receptor knock-out (DIRKO) mice. METHODS: Twenty-six-week-old DIRKO mice were age- and sex-matched with wild-type (WT) littermates. Bone microstructural morphology was assessed at the femur by microCT and quantitative X-ray imaging, while tissue properties were investigated by quantitative backscattered electron imaging and Fourier-transformed infrared microscopy. Bone mechanical response was assessed at the whole-bone- and tissue-level by 3-point bending and nanoindentation, respectively. RESULTS: As compared to WT animals, DIRKO mice presented significant augmentations in trabecular bone mass and trabecular number whereas bone outer diameter, cortical thickness, and cortical area were reduced. At the whole-bone-level, yield stress, ultimate stress, and post-yield work to fracture were significantly reduced in DIRKO animals. At the tissue-level, only collagen maturity was reduced by 9 % in DIRKO mice leading to reductions in maximum load, hardness, and dissipated energy. CONCLUSIONS: This study demonstrated the critical role of gut hormones in controlling bone microstructural morphology and tissue properties.

Sustained treatment with a stable long-acting oxyntomodulin analogue improves metabolic control and islet morphology in an experimental model of type 1 diabetes.

AIM: To assess the therapeutic benefits of regulatory peptides other than insulin, which have to date received limited consideration in the context of type 1 diabetes. METHODS: We assessed the effects of subchronic administration of the stable, oxyntomodulin (Oxm) analogue, (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL], for 28 days in streptozotocin (STZ)-induced insulin-deficient diabetic mice. RESULTS: Twice-daily injection with (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL] significantly countered the excessive food and fluid intake in STZ-induced diabetic mice, and maintained normal body weight. Lean body mass was normalized, whilst fat mass was significantly increased compared with control STZ-induced diabetic mice. In addition, circulating glucose was significantly reduced by the Oxm analogue, whilst plasma and pancreatic insulin concentrations were increased and glucagon decreased by day 28. Plasma lipid profile was normalized by (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL] administration and circulating amylase was not significantly altered by induction of diabetes or Oxm analogue therapy. This was associated with significantly improved glucose tolerance and insulin secretion. Peripheral insulin sensitivity was also significantly improved by Oxm analogue treatment. Histological examination of pancreata showed beneficial elevations of total islet and ß-cell area, associated with an increase in the number of smaller-sized islets. Further analysis revealed enhanced islet cell proliferation relative to apoptosis in Oxm analogue-treated mice. CONCLUSION: These studies emphasize the potential of stable Oxm-based peptides, such as (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL], as therapeutic agents for insulin-deficient type 1 diabetes.

Pharmacological characterization and antidiabetic activity of a long-acting glucagon-like peptide-1 analogue conjugated to an antithrombin III-binding pentasaccharide.

AIMS: To examine the biological characteristics of a novel glucagon-like peptide-1 (GLP-1) conjugate, in which an antithrombin III (ATIII)-binding pentasaccharide is conjugated to d-Ala(8) GLP-1 using a tetraethylene glycol linker. METHODS: We assessed GLP-1 receptor binding, cAMP generation and insulin secretory activity of the GLP-1 conjugate in vitro. Circulating half-life, glucose homeostatic and subchronic therapeutic effectiveness were then examined in vivo. RESULTS: The half-life of the GLP-1 conjugate in mice was ∼11 h. In vitro insulin secretion from clonal ß cells and islets was increased (p < 0.001) by the conjugate. The conjugate had half maximum effective concentration values of 1.3 × 10(-7) and 9.9 × 10(-8) M for displacement of (125) I-GLP-1 in competitive GLP-1 receptor binding and cAMP generation, respectively. Glucose tolerance in normal mice, immediately and 4 h after conjugate injection, resulted in significant (p < 0.001) improvements in blood glucose. These effects persisted for >48 h after administration. Daily treatment (21 days) of high-fat-fed and ob/ob mice with 25 nmol/kg conjugate resulted in significant improvement in glucose tolerance (p < 0.001) and reductions in glycated haemoglobin (HbA1c; p < 0.01) equivalent to or better than with exenatide or liraglutide. Treatment of C57BL/KsJ db/db mice for 15 days with 100 nmol/kg conjugate significantly (p < 0.001) reduced glucose and raised plasma insulin. Oral glucose tolerance was significantly (p < 0.001) improved and both 24-h glucose profile (p < 0.001) and HbA1c levels (p < 0.001) were reduced. Islet size (p < 0.001) and pancreatic insulin content were increased without change of islet cell proliferation or apoptosis. CONCLUSION: These data show that d-Ala(8) GLP-1(Lys(37) ) pentasaccharide exerts significant antidiabetic actions and has a projected pharmacokinetic/pharmacodynamic profile that merits further evaluation in humans for a possible once-weekly dosing regimen.