Increasing Physical Activity in Empty Nest and Retired Populations Online: A Randomized Feasibility Study.

The onset of retirement and children leaving the family home may offer a "window of opportunity" for individuals to influence regular moderate- to vigorous-intensity physical activity; therefore, this study examines the feasibility of a moderate- to vigorous-intensity physical activity intervention among recently retired participants (RET) and parents (P) with children who recently left the family home. A total of 46 inactive RET and nine inactive P were randomized to a 10-week web intervention (n = RET = 25/P = 4) or waitlist control (n = RET = 21/P = 5). Intervention techniques followed the multiprocess action control framework. Enrollment (37.5% for P; 40% for RET), retention (89% for P; 83% for RET), and satisfaction were high. One hundred percent of intervention-sectioned participation increased moderate- to vigorous-intensity physical activity compared with 52% of controls; large effect size differences were observed for key multiprocess action control constructs. Participants were highly satisfied with the intervention; however, recruitment challenges of P support moving to a randomized controlled trial for only the RET group.

Development of poly(lactide-co-glycolide) microparticles for sustained delivery of meloxicam.

Poly(lactide-co-glycolide) (PLGA) polymers have been widely used for drug delivery due to their biodegradability and biocompatibility. One of the objectives of encapsulating a drug in PLGA microparticles (MPs) is to achieve an extended supply of the drug through sustained release, which can range from weeks to months. Focusing on the applications needing a relatively short-term delivery, we investigated formulation strategies to achieve a drug release from PLGA MPs for two weeks, using meloxicam as a model compound. PLGA MPs produced by the traditional oil/water (O/W) single emulsion method showed only an initial burst release with minimal increase in later-phase drug release. Alternatively, encapsulating meloxicam as solid helped reduce the initial burst release. The inclusion of magnesium hydroxide [Mg(OH)2] enhanced later-phase drug release by neutralizing the developing acidity that limited the drug dissolution. The variation of solid meloxicam and Mg(OH)2 quantities allowed for flexible control of meloxicam release, yielding MPs with distinct in vitro release kinetics. When subcutaneously injected into rats, the MPs with relatively slow in vitro drug release kinetics showed in vivo drug absorption profiles consistent with in vitro trend. However, the MPs that rapidly released meloxicam showed an attenuated in vivo absorption, suggesting premature precipitation of fast-released meloxicam. In summary, this study demonstrated the feasibility of controlling drug release from the PLGA MPs over weeks based on the physical state of the encapsulated drug and the inclusion of Mg(OH)2 to neutralize the microenvironmental pH of the MPs.

Photoacoustic imaging reveals mechanisms of rapid-acting insulin formulations dynamics at the injection site.

OBJECTIVE: Ultra-rapid insulin formulations control postprandial hyperglycemia; however, inadequate understanding of injection site absorption mechanisms is limiting further advancement. We used photoacoustic imaging to investigate the injection site dynamics of dye-labeled insulin lispro in the Humalog® and Lyumjev® formulations using the murine ear cutaneous model and correlated it with results from unlabeled insulin lispro in pig subcutaneous injection model. METHODS: We employed dual-wavelength optical-resolution photoacoustic microscopy to study the absorption and diffusion of the near-infrared dye-labeled insulin lispro in the Humalog and Lyumjev formulations in mouse ears. We mathematically modeled the experimental data to calculate the absorption rate constants and diffusion coefficients. We studied the pharmacokinetics of the unlabeled insulin lispro in both the Humalog and Lyumjev formulations as well as a formulation lacking both the zinc and phenolic preservative in pigs. The association state of insulin lispro in each of the formulations was characterized using SV-AUC and NMR spectroscopy. RESULTS: Through experiments using murine and swine models, we show that the hexamer dissociation rate of insulin lispro is not the absorption rate-limiting step. We demonstrated that the excipients in the Lyumjev formulation produce local tissue expansion and speed both insulin diffusion and microvascular absorption. We also show that the diffusion of insulin lispro at the injection site drives its initial absorption; however, the rate at which the insulin lispro crosses the blood vessels is its overall absorption rate-limiting step. CONCLUSIONS: This study provides insights into injection site dynamics of insulin lispro and the impact of formulation excipients. It also demonstrates photoacoustic microscopy as a promising tool for studying protein therapeutics. The results from this study address critical questions around the subcutaneous behavior of insulin lispro and the formulation excipients, which could be useful to make faster and better controlled insulin formulations in the future.

Development of hot-melt extruded drug/polymer matrices for sustained delivery of meloxicam.

For effective resolution of regional subacute inflammation and prevention of biofouling formation, we have developed a polymeric implant that can release meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, in a sustained manner. Meloxicam-loaded polymer matrices were produced by hot-melt extrusion, with commercially available biocompatible polymers, poly(ε-caprolactone) (PCL), poly(lactide-co-glycolide) (PLGA), and poly(ethylene vinyl acetate) (EVA). PLGA and EVA had a limited control over the drug release rate partly due to the acidic microenvironment and hydrophobicity, respectively. PCL allowed for sustained release of meloxicam over two weeks and was used as a carrier of meloxicam. Solid-state and image analyses indicated that the PCL matrices encapsulated meloxicam in crystalline clusters, which dissolved in aqueous medium and generated pores for subsequent drug release. The subcutaneously implanted meloxicam-loaded PCL matrices in rats showed pharmacokinetic profiles consistent with their in vitro release kinetics, where higher drug loading led to faster drug release. This study finds that the choice of polymer platform is crucial to continuous release of meloxicam and the drug release rate can be controlled by the amount of drug loaded in the polymer matrices.

The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: A post hoc analysis.

In a phase 2 trial of once-weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide dose-dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL-40 (also known as chitinase-3 like-protein-1), intercellular adhesion molecule 1 (ICAM-1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL-40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM-1 levels versus placebo and dulaglutide, and high-sensitivity C-reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N-terminal-pro hormone B-type natriuretic peptide levels were not significantly changed in any group. YKL-40, hsCRP, and ICAM-1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis-generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk.

What Predicts the Physical Activity Intention-Behavior Gap? A Systematic Review.

BACKGROUND: Intention is theorized as the proximal determinant of behavior in many leading theories and yet intention-behavior discordance is prevalent. PURPOSE: To theme and appraise the variables that have been evaluated as potential moderators of the intention-physical activity (I-PA) relationship using the capability-opportunity-motivation- behavior model as an organizational frame. METHODS: Literature searches were concluded in August 2020 using seven common databases. Eligible studies were selected from English language peer-reviewed journals and had to report an empirical test of moderation of I-PA with a third variable. Findings were grouped by the moderator variable for the main analysis, and population sample, study design, type of PA, and study quality were explored in subanalyses. RESULTS: The search yielded 1,197 hits, which was reduced to 129 independent studies (138 independent samples) of primarily moderate quality after screening for eligibility criteria. Moderators of the I-PA relationship were present among select variables within sociodemographic (employment status) and personality (conscientiousness) categories. Physical capability, and social and environmental opportunity did not show evidence of interacting with I-PA relations, while psychological capability had inconclusive findings. By contrast, key factors underlying reflective (intention stability, intention commitment, low goal conflict, affective attitude, anticipated regret, perceived behavioral control/self-efficacy) and automatic (identity) motivation were moderators of I-PA relations. Findings were generally invariant to study characteristics. CONCLUSIONS: Traditional intention theories may need to better account for key I-PA moderators. Action control theories that include these moderators may identify individuals at risk for not realizing their PA intentions. Prospero # CRD42020142629.

Velcro compression wraps as an alternative form of compression therapy for venous leg ulcers: a review.

The first-line treatment for venous leg ulcers (VLUs) is compression therapy, most commonly, with compression bandages. A similar treatment measure is used for lymphoedema in the form of Velcro compression wraps (VCWs). However, the use of VCWs for VLUs is less evident, and a direct comparison to compression bandaging is not evident. This review explores the evidence to support the use of VCWs for the treatment of VLUs in order to raise awareness of alternative forms of compression therapy. Nine primary research studies were analysed, from which four key themes emerged: quality of life, cost of treatment, ulcer healing time and pressure maintenance. The findings suggest that VCWs decrease material costs by at least 50%, and further savings may be realised by reducing the costs associated with nursing time. The benefits of promoting self-care, maintaining compression, and eliciting greater healing rates are clearly evident, and the impact on quality of life is substantiated.

Insulin, Not the Preservative m-cresol, Instigates Loss of Infusion Site Patency Over Extended Durations of CSII in Diabetic Swine.

Insulin infusion sets worn for more than 4-5 days have been associated with a greater risk of unexplained hyperglycemia, a phenomenon that has been hypothesized to be caused by an inflammatory response to preservatives such as m-cresol and phenol. In this cross-over study in diabetic swine, we examined the role of the preservative m-cresol in inflammation and changes in infusion site patency. Insulin pharmacokinetics (PK) and glucose pharmacodynamics (PD) were measured on delivery of a bolus of regular human insulin U-100 (U-100R), formulated with or without 2.5 mg/mL m-cresol, to fasted swine following 0, 3, 5, 7, and 10 days of continuous subcutaneous insulin infusion (CSII). In a subsequent study with the same animals, biopsies were evaluated from swine wearing infusion sets infusing nothing, saline, or U-100R either with or without 2.5 mg/mL m-cresol, following 3, 7, and 10 days of CSII. Exposure to m-cresol did not impact any PK or PD endpoints. PK and PD responses dropped markedly from Days 7-10, regardless of the presence of m-cresol. Histopathology results suggest an additive inflammatory response to both the infusion set and the insulin protein itself, peaking at Day 7 and remaining stable beyond.

Increasing Physical Activity in Empty Nest and Retired Populations Online: A Randomized Feasibility Trial Protocol.

Despite the extensive evidence on the benefits of physical activity (PA) in older adults, including reduced risk of disease, mortality, falls, and cognitive and functional decline, most do not attain sufficient PA levels. Theoretical work suggests that behavioral change interventions are most effective during life transitions, and as such, a theory-based, online intervention tailored for recently retired and empty nest individuals could lend support for increasing levels of PA. The aim of this study is to examine the feasibility of the intervention and study procedures for a future controlled trial. This study has a randomized controlled trial design with an embedded qualitative and quantitative process evaluation. Participants are randomized at 1:1 between the intervention and waitlist controls. Potential participants are within six months of their final child leaving the familial home or within six months of retiring (self-defined), currently not meeting the Canadian PA guidelines, have no serious contraindications to exercise, and are residing in Victoria, British Columbia, Canada. Participants are recruited by online and print flyers as well as in-person at community events. The study aims to recruit 40 empty nest and 40 retired participants; half of each group received the intervention during the study period. The internet-delivered intervention is delivered over a 10-week period, comprising 10 modules addressing behavior change techniques associated with PA. Primary outcomes relate to recruitment, attrition, data collection, intervention delivery, and acceptability. Secondary behavioral outcomes are measured at baseline and post-treatment (10 weeks). Intervention-selected participants are invited to an optional qualitative exit interview. The results of this feasibility study will inform the planning of a randomized effectiveness trial, that will examine the behavior change, health-related fitness, and well-being outcomes by exploring how reflexive processes of habit and identity may bridge adoption and maintenance in behavioral adherence.

ß-Cell Glucagon-Like Peptide-1 Receptor Contributes to Improved Glucose Tolerance After Vertical Sleeve Gastrectomy.

Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible for this remain incompletely defined. Glucagon-like peptide-1 (GLP-1) is a gut hormone that contributes to the maintenance of glucose homeostasis and is elevated after VSG. VSG-induced increases in postprandial GLP-1 secretion have been proposed to contribute to the glucoregulatory benefits of VSG; however, previous work has been equivocal. In order to test the contribution of enhanced ß-cell GLP-1 receptor (GLP-1R) signaling we used a ß-cell-specific tamoxifen-inducible GLP-1R knockout mouse model. Male ß-cell-specific Glp-1r(ß-cell+/+) wild type (WT) and Glp-1r(ß-cell-/-) knockout (KO) littermates were placed on a high-fat diet for 6 weeks and then switched to high-fat diet supplemented with tamoxifen for the rest of the study. Mice underwent sham or VSG surgery after 2 weeks of tamoxifen diet and were fed ad libitum postoperatively. Mice underwent oral glucose tolerance testing at 3 weeks and were euthanized at 6 weeks after surgery. VSG reduced body weight and food intake independent of genotype. However, glucose tolerance was only improved in VSG WT compared with sham WT, whereas VSG KO had impaired glucose tolerance relative to VSG WT. Augmentation of glucose-stimulated insulin secretion during the oral glucose tolerance test was blunted in VSG KO compared with VSG WT. Therefore, our data suggest that enhanced ß-cell GLP-1R signaling contributes to improved glucose regulation after VSG by promoting increased glucose-stimulated insulin secretion.

A Tale of Two Sites: Lessons on Leadership from the Implementation of a Long-term Care Delivery Model (CDM) in Western Canada.

Residential, long-term care serves vulnerable older adults in a facility-based environment. A new care delivery model (CDM) designed to promote more equitable care for residents was implemented in a health region in Western Canada. Leaders and managers faced challenges in implementing this model alongside other concurrent changes. This paper explores the question: How did leadership style influence team functioning with the implementation of the CDM? Qualitative data from interviews with leadership personnel (directors and managers, residential care coordinators and clinical nurse educators), and direct care staff (registered nurses, licensed practical nurses, health care aides, and allied health therapists), working in two different facilities comprise the main sources of data for this study. The findings reveal that leaders with a servant leadership style were better able to create and sustain the conditions to support successful model implementation and higher team functioning, compared to a facility in which the leadership style was less inclusive and proactive, and more resistant to the change. Consequently, staff at the second facility experienced a greater sense of overload with the implementation of the CDM. This study concludes that strong leadership is key to facilitating team work and job satisfaction in a context of change.

Characterization and quantification of oxyntomodulin in human and rat plasma using high-resolution accurate mass LC-MS.

BACKGROUND: A thorough understanding of the biological role of oxyntomodulin (OXM) has been limited by the availability of sensitive and specific analytical tools for reliable in vivo characterization. Here, we utilized immunoaffinity capture coupled with high-resolution accurate mass LC-MS detection to quantify OXM and its primary catabolites. RESULTS: Quantification of intact OXM 1-37 in human and rat plasma occurred in pre- and post-prandial samples. Profiles for the major catabolites were observed allowing kinetic differences to be assessed between species. CONCLUSION: A validated assay in human and rat plasma was obtained for OXM 1-37 and its catabolites, 3-37 and 4-37. The value of full scan high-resolution accurate mass detection without selected reaction monitoring for low-abundance peptide quantification was also demonstrated.

Discovery of 6-(4-{[5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy}piperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia.

The farnesoid X receptor (FXR) is a member of the "metabolic" subfamily of nuclear receptors. Several FXR agonists have been reported in the literature to have profound effects on plasma lipids in animal models. To discover novel and effective therapies for dyslipidemia and atherosclerosis, we have developed a series of potent FXR agonists that robustly lower plasma LDL and vLDL in LDLr-/- mice. To this end the novel piperidinylisoxazole system LY2562175 was discovered. This molecule is a potent and selective FXR agonist in vitro and has robust lipid modulating properties, lowering LDL and triglycerides while raising HDL in preclinical species. The preclinical ADME properties of LY2562175 were consistent with enabling once daily dosing in humans, and it was ultimately advanced to the clinic for evaluation in humans. The synthesis and biological profile of this molecule is discussed.

Fully Implantable Arterial Blood Glucose Device for Metabolic Research Applications in Rats for Two Months.

BACKGROUND: Chronic continuous glucose monitoring options for animal research have been very limited due to various technical and biological challenges. We provide an evaluation of a novel telemetry device for continuous monitoring of temperature, activity, and plasma glucose levels in the arterial blood of rats for up to 2 months. METHODS: In vivo testing in rats including oral glucose tolerance tests (OGTTs) and intraperitoneal glucose tolerance tests (IPGTTs) and ex vivo waterbath testing were performed to evaluate acute and chronic sensor performance. Animal studies were in accordance with the guidelines for the care and use of laboratory animals and approved by the corresponding animal care and use committees (Data Sciences International, Eli Lilly). RESULTS: Results demonstrated the ability to record continuous measurements for 75 days or longer. Bench testing demonstrated a high degree of linearity over a range of 20-850 mg/dL with R(2) = .998 for linear fit and .999 for second order fit (n = 8 sensors). Evaluation of 6 rats over 28 days with 52 daily and OGTT test strip measurements each resulted in mean error of 3.8% and mean absolute relative difference of 16.6%. CONCLUSIONS: This device provides significant advantages in the quality and quantity of data that can be obtained relative to existing alternatives such as intermittent blood sampling. These devices provide the opportunity to expand the understanding of both glucose metabolism and homeostasis and to work toward improved therapies and cures for diabetes.

Human pancreatic ß-cell G1/S molecule cell cycle atlas.

Expansion of pancreatic ß-cells is a key goal of diabetes research, yet induction of adult human ß-cell replication has proven frustratingly difficult. In part, this reflects a lack of understanding of cell cycle control in the human ß-cell. Here, we provide a comprehensive immunocytochemical "atlas" of G1/S control molecules in the human ß-cell. This atlas reveals that the majority of these molecules, previously known to be present in islets, are actually present in the ß-cell. More importantly, and in contrast to anticipated results, the human ß-cell G1/S atlas reveals that almost all of the critical G1/S cell cycle control molecules are located in the cytoplasm of the quiescent human ß-cell. Indeed, the only nuclear G1/S molecules are the cell cycle inhibitors, pRb, p57, and variably, p21: none of the cyclins or cdks necessary to drive human ß-cell proliferation are present in the nuclear compartment. This observation may provide an explanation for the refractoriness of human ß-cells to proliferation. Thus, in addition to known obstacles to human ß-cell proliferation, restriction of G1/S molecules to the cytoplasm of the human ß-cell represents an unanticipated obstacle to therapeutic human ß-cell expansion.

Cytoplasmic-nuclear trafficking of G1/S cell cycle molecules and adult human ß-cell replication: a revised model of human ß-cell G1/S control.

Harnessing control of human ß-cell proliferation has proven frustratingly difficult. Most G1/S control molecules, generally presumed to be nuclear proteins in the human ß-cell, are in fact constrained to the cytoplasm. Here, we asked whether G1/S molecules might traffic into and out of the cytoplasmic compartment in association with activation of cell cycle progression. Cdk6 and cyclin D3 were used to drive human ß-cell proliferation and promptly translocated into the nucleus in association with proliferation. In contrast, the cell cycle inhibitors p15, p18, and p19 did not alter their location, remaining cytoplasmic. Conversely, p16, p21, and p27 increased their nuclear frequency. In contrast once again, p57 decreased its nuclear frequency. Whereas proliferating ß-cells contained nuclear cyclin D3 and cdk6, proliferation generally did not occur in ß-cells that contained nuclear cell cycle inhibitors, except p21. Dynamic cytoplasmic-nuclear trafficking of cdk6 was confirmed using green fluorescent protein-tagged cdk6 and live cell imaging. Thus, we provide novel working models describing the control of cell cycle progression in the human ß-cell. In addition to known obstacles to ß-cell proliferation, cytoplasmic-to-nuclear trafficking of G1/S molecules may represent an obstacle as well as a therapeutic opportunity for human ß-cell expansion.

Comparative pharmacokinetics studies of immediate- and modified-release formulations of glipizide in pigs and dogs.

The utility of pigs as preclinical animals for pharmaceutical development was assessed by evaluating the pharmacokinetics and pharmacodynamics of glipizide (Glucotrol®) following oral administration of immediate-release (IR) and modified-release (MR) formulations. Doses of 10 and 30 mg were administered to six male pigs in a crossover design. Blood samples were collected at selected time-points up to 48 h after dose. Relative to the IR formulation, the time to reach the maximum concentration (t(max) ) was delayed with the MR formulation from 1.3 to 8.7 h with the 10 mg dose and to 6.2 h with the 30 mg dose. The relative bioavailability (BA) was approximately 92% at 10 mg and 79% at 30 mg dose. The area under the curve of the plasma concentration versus time curve (AUC) increased nearly proportionally with the dose. Interanimal coefficient of variation (CV) in AUC ranged from approximately 40% to 60%. Blood glucose results suggest that pigs demonstrate formulation-dependent response to glipizide. Compared with the pigs, the 10 mg MR formulation in dogs showed a higher AUC CV of approximately 80%, a t(max) of 5.5 h, and a lower relative BA of 18%. These data indicate that the MR formulation performed less consistently in dogs as compared with humans, whereas the porcine absorption kinetics and BA were consistent with published clinical data.

Equity in public health standards: a qualitative document analysis of policies from two Canadian provinces.

INTRODUCTION: Promoting health equity is a key goal of many public health systems. However, little is known about how equity is conceptualized in such systems, particularly as standards of public health practice are established. As part of a larger study examining the renewal of public health in two Canadian provinces, Ontario and British Columbia (BC), we undertook an analysis of relevant public health documents related to equity. The aim of this paper is to discuss how equity is considered within documents that outline standards for public health. METHODS: A research team consisting of policymakers and academics identified key documents related to the public health renewal process in each province. The documents were analyzed using constant comparative analysis to identify key themes related to the conceptualization and integration of health equity as part of public health renewal in Ontario and BC. Documents were coded inductively with higher levels of abstraction achieved through multiple readings. Sets of questions were developed to guide the analysis throughout the process. RESULTS: In both sets of provincial documents health inequities were defined in a similar fashion, as the consequence of unfair or unjust structural conditions. Reducing health inequities was an explicit goal of the public health renewal process. In Ontario, addressing "priority populations" was used as a proxy term for health equity and the focus was on existing programs. In BC, the incorporation of an equity lens enhanced the identification of health inequities, with a particular emphasis on the social determinants of health. In both, priority was given to reducing barriers to public health services and to forming partnerships with other sectors to reduce health inequities. Limits to the accountability of public health to reduce health inequities were identified in both provinces. CONCLUSION: This study contributes to understanding how health equity is conceptualized and incorporated into standards for local public health. As reflected in their policies, both provinces have embraced the importance of reducing health inequities. Both concepualized this process as rooted in structural injustices and the social determinants of health. Differences in the conceptualization of health equity likely reflect contextual influences on the public health renewal processes in each jurisdiction.

Parental perceptions of sibling relationships in families rearing a child with a chronic condition.

This study examined sibling relationships in families raising children with autism, Down syndrome, orthopedic conditions, and diabetes. Parents from 108 families independently completed the 28-item Schaefer Sibling Inventory of Behavior. Parents rated siblings as very empathetic, fairly often kind and involved, and rarely avoidant. Mothers rated sibling empathy higher than fathers did and older siblings more avoidant than younger siblings. Fathers rated male siblings kinder than female siblings; they also rated siblings of children with Down syndrome or autism more kind and involved than siblings of children with orthopedic conditions or diabetes. Sibling intervention efforts should consider these findings and be individualized according to the need of each child and family.

cMyc is a principal upstream driver of beta-cell proliferation in rat insulinoma cell lines and is an effective mediator of human beta-cell replication.

Adult human ß-cells replicate slowly. Also, despite the abundance of rodent ß-cell lines, there are no human ß-cell lines for diabetes research or therapy. Prior studies in four commonly studied rodent ß-cell lines revealed that all four lines displayed an unusual, but strongly reproducible, cell cycle signature: an increase in seven G(1)/S molecules, i.e. cyclins A, D3, and E, and cdk1, -2, -4, and -6. Here, we explore the upstream mechanism(s) that drive these cell cycle changes. Using biochemical, pharmacological and molecular approaches, we surveyed potential upstream mitogenic signaling pathways in Ins 1 and RIN cells. We used both underexpression and overexpression to assess effects on rat and human ß-cell proliferation, survival and cell cycle control. Our results indicate that cMyc is: 1) uniquely up-regulated among other candidates; 2) principally responsible for the increase in the seven G(1)/S molecules; and, 3) largely responsible for proliferation in rat ß-cell lines. Importantly, cMyc expression in ß-cell lines, although some 5- to 7-fold higher than normal rat ß-cells, is far below the levels (75- to 150-fold) previously associated with ß-cell death and dedifferentiation. Notably, modest overexpression of cMyc is able to drive proliferation without cell death in normal rat and human ß-cells. We conclude that cMyc is an important driver of replication in the two most commonly employed rat ß-cell lines. These studies reverse the current paradigm in which cMyc overexpression is inevitably associated with ß-cell death and dedifferentiation. The cMyc pathway provides potential approaches, targets, and tools for driving and sustaining human ß-cell replication.