Impact of a Collective Intelligence Tailored Messaging System on Smoking Cessation: The Perspect Randomized Experiment
BACKGROUND: Outside health care, content tailoring is driven algorithmically using machine learning compared to the rule-based approach used in current implementations of computer-tailored health communication (CTHC) systems. A special class of machine learning systems ("recommender systems") are used to select messages by combining the collective intelligence of their users (ie, the observed and inferred preferences of users as they interact with the system) and their user profiles. However, this approach has not been adequately tested for CTHC.
OBJECTIVE: Our aim was to compare, in a randomized experiment, a standard, evidence-based, rule-based CTHC (standard CTHC) to a novel machine learning CTHC: Patient Experience Recommender System for Persuasive Communication Tailoring (PERSPeCT). We hypothesized that PERSPeCT will select messages of higher influence than our standard CTHC system. This standard CTHC was proven effective in motivating smoking cessation in a prior randomized trial of 900 smokers (OR 1.70, 95% CI 1.03-2.81).
METHODS: PERSPeCT is an innovative hybrid machine learning recommender system that selects and sends motivational messages using algorithms that learn from message ratings from 846 previous participants (explicit feedback), and the prior explicit ratings of each individual participant. Current smokers (N=120) aged 18 years or older, English speaking, with Internet access were eligible to participate. These smokers were randomized to receive either PERSPeCT (intervention, n=74) or standard CTHC tailored messages (n=46). The study was conducted between October 2014 and January 2015. By randomization, we compared daily message ratings (mean of smoker ratings each day). At 30 days, we assessed the intervention's perceived influence, 30-day cessation, and changes in readiness to quit from baseline.
RESULTS: The proportion of days when smokers agreed/strongly agreed (daily rating > /=4) that the messages influenced them to quit was significantly higher for PERSPeCT (73%, 23/30) than standard CTHC (44%, 14/30, P=.02). Among less educated smokers (n=49), this difference was even more pronounced for days strongly agree (intervention: 77%, 23/30; comparison: 23%, 7/30, P < .001). There was no significant difference in the frequency which PERSPeCT randomized smokers agreed or strongly agreed that the intervention influenced them to quit smoking (P=.07) and use nicotine replacement therapy (P=.09). Among those who completed follow-up, 36% (20/55) of PERSPeCT smokers and 32% (11/34) of the standard CTHC group stopped smoking for one day or longer (P=.70).
CONCLUSIONS: Compared to standard CTHC with proven effectiveness, PERSPeCT outperformed in terms of influence ratings and resulted in similar cessation rates.
CLINICALTRIAL: Clinicaltrials.gov NCT02200432; https://clinicaltrials.gov/ct2/show/NCT02200432 (Archived by WebCite at http://www.webcitation.org/6lEJY1KEd).
Association of Left Atrial Function Index With Late Atrial Fibrillation Recurrence after Catheter Ablation
INTRODUCTION: Although catheter ablation (CA) for atrial fibrillation (AF) is commonly used to improve symptoms, AF recurrence is common and new tools are needed to better inform patient selection for CA. Left atrial function index (LAFI), an echocardiographic measure of atrial mechanical function, has shown promise as a noninvasive predictor of AF. We hypothesized that LAFI would relate to AF recurrence after CA.
METHODS AND RESULTS: All AF patients undergoing index CA were enrolled in a prospective institutional AF Treatment Registry between 2011 and 2014. LAFI was measured post hoc from pre-ablation clinical echocardiographic images in 168 participants. Participants were mostly male (33% female), middle-aged (60 +/- 10 years), obese and had paroxysmal AF (64%). Mean LAFI was 25.9 +/- 17.6. Over 12 months of follow-up, 78 participants (46%) experienced a late AF recurrence. In logistic regression analyses adjusting for factors known to be associated with AF, lower LAFI remained associated with AF recurrence after CA [OR 0.04 (0.01-0.67), P = 0.02]. LAFI discriminated AF recurrence after CA slightly better than CHADS2 (C-statistic 0.60 LAFI, 0.57 CHADS2). For participants with persistent AF, LAFI performed significantly better than CHADS2 score (C statistic = 0.79 LAFI, 0.56 CHADS2, P = 0.02).
CONCLUSION: LAFI, an echocardiographic measure of atrial function, is associated with AF recurrence after CA and has improved ability to discriminate AF recurrence as compared to the CHADS-2 score, especially among persistent AF patients. Since LAFI can be calculated using standard 2D echocardiographic images, it may be a helpful tool for predicting AF recurrence.
The Role of Managed Care Pharmacy in Improving Access to Naloxone: Findings from the AMCP Addiction Treatment Advisory Group
Kimberly Lenz, PharmD, a clinical pharmacy manager in the Office of Clinical Affairs, provided insight and expertise for this report as a member of the Academy of Managed Care Pharmacy's Addiction Treatment Advisory Group. The group's report identifies barriers to care and details how managed care organizations can better address the opioid addiction crisis, including improving access to naloxone and Medication Assisted Therapies (MAT) as well as ensuring benefit design will support alternative pain management methods.
Over 100 million Americans have criminal records, and the U.S. incarcerates seven times more citizens than most developed countries. The burden of incarceration disproportionately affects people of color and ethnic minorities, and those living in poverty. While 95% of incarcerated people return to society, recidivism rates are high with nearly 75% arrested again within five years of release. Criminal records impede access to employment and other social services such as shelter and health care. Justice-involved people have higher rates of substance, mental health, and some chronic medical disorders than the general population; furthermore, the incarcerated population is rapidly aging. Only a minority of academic health science centers are engaged in health services research, workforce training, or correctional health care. This commentary provides rationale and a blueprint for engagement of academic health science institutions to harness their capabilities to tackle one of the country's most vexing public health crises.
Recruitment and Retention of Community Health Center Primary Care Physicians post MA Health Care Reform: 2008 vs. 2013 Physician Surveys
OBJECTIVES: In 2008 and 2013, the University of Massachusetts Medical School and the Massachusetts League of Community Health Centers surveyed community health center (CHC) primary care physicians (PCPs) to identify factors related to preparedness, recruitment and retention. The survey was repeated to determine the impact of Massachusetts health care reform.
METHODS: An online survey was sent to 677 PCPs at 46 CHCs. New questions addressed patient-centered redesign, language competencies, and interprofessional care.
ESULTS: With 48% responding, PCPs were significantly more prepared in 2013 to practice in a CHC. Intent to continue practicing in a CHC was related to age, length of time in practice, language skills, teaching, research, compensation, model of care, professional development, and practice goals.
CONCLUSIONS: Outcomes illustrate opportunities to prepare medical students and residents for CHC careers and recruit and retain this vital workforce. Retention efforts must include teaching, administration, research, and professional development opportunities.
OBJECTIVE: To assess the impact of a Massachusetts Medicaid policy change (the Children's Behavioral Health Initiative; CBHI, which required and reimbursed behavioral health [BH] screening with standardized tools at well child visits and developed intensive home- and community-based BH services) on primary care practice examining the relationship of BH screening to subsequent BH service utilization.
STUDY DESIGN: Using a repeated cross-sectional design, our 2010 and 2012 Medicaid study populations each included 2000 children/adolescents under the age of 21 years. For each year, the population was randomly selected and stratified into 4 age groups, with 500 members selected per group. Two data sources were used: medical records and Medicaid claims.
RESULTS: The CBHI had a large impact on formal BH screening and treatment utilization among children/adolescents enrolled in Medicaid. Screening increased substantially (73%: 2010; 74%: 2012) since the baseline/premandate period (2007) when only 4% of well child visits included a formal screen. BH utilization increased among those formally screened but decreased among those with informal assessments.
CONCLUSIONS: CBHI implementation transformed the relationship between primary care and BH services. Changes in regulation and payment resulted in widespread BH screening in Massachusetts primary care practices caring for children/adolescents on Medicaid.
PROBLEM: From November 2010 to August 2013, 161 adults with acquired brain injury in Massachusetts transitioned from long-term care settings to the community through a Medicaid-funded waiver. Most participants transitioned with minimal risk; for some, the transition resulted in an increase in risk incidents above the rest. Specifically, despite risk mitigation efforts, 11% of the participants accounted for more than 75% of the reported first year incidents.
SOLUTION: A registered nurse Care Manager was engaged in a pilot program to address the needs of participants at the highest risk. Based on incidents or potential for incidents, 30 participants were enrolled in care management (CM).
METHODS: Secondary data analysis, interviews, and surveys assessed whether CM was associated with a decrease in incidents and to what extent participants and providers were satisfied with CM.
RESULTS: Care management was significantly associated with a decrease in incidents including hospitalizations and emergency room visits. Participants, Case Managers, and service providers were highly satisfied with the Care Manager.
CONCLUSIONS: Focusing on a specific population with increased risk, clearly explaining the purpose of CM, and remaining flexible when addressing the complex and individual nature of risk management are important strategies to ensure an effective CM program.
Pregnancy Characteristics and Outcomes among Women at Risk for Disability from Health Conditions Identified in Medical Claims
BACKGROUND: Women with disabilities are at risk for poor birth outcomes. Little is known about specific potentially disabling health conditions and their effects on pregnancies. Using hospital claims, we identified women at risk for disability and evaluated the relationship between disability risk and demographic characteristics, pregnancy risks, and infant and maternal outcomes.
METHODS: The 2006 through 2009 Massachusetts Pregnancy to Early Life Longitudinal data system linked birth certificate and hospital claims one year pre-pregnancy through delivery. Access Risk Classification System categorized International Classification of Diseases, Ninth Revision, Clinical Modification/Current Procedural Terminology codes into disability risk groups (no/limited vs. medium/high). Generalized estimating equations evaluated the association between disability risk and infant and maternal outcomes.
RESULTS: Of 221,867 women, 14,701 (6.6%) were at medium or high risk of disability. Health conditions were classified as circulatory (23%), musculoskeletal (10%), nervous system/sensory (13%), other physical (19%), two or more physical (5%), mental illness (24%), and comorbid mental/physical (6%). Women at risk of disability were more likely than others to have socioeconomic and pregnancy risks, and adverse infant and maternal outcomes. Socioeconomic and risk profile varied by health condition category. Adjusted risk ratios for preterm birth ranged from 1.2 (95% confidence interval [CI], 1.1-1.4) for women with nervous system/sensory diagnoses to 1.6 (95% CI, 1.4-1.9) for women with two or more physical diagnoses; risk ratios for maternal delivery hospitalization for more than 5 days ranged from 1.5 (95% CI, 1.2-1.9) for women with musculoskeletal diagnoses to 3.0 (95% CI, 2.5-3.6) for women with comorbid mental/physical diagnoses.
CONCLUSIONS: Disability risk identified through claims is associated with poor infant and maternal outcomes. Risk profiles vary by underlying health condition.
BACKGROUND: Breakthrough direct-acting antivirals set a new standard in the management of hepatitis C virus (HCV) with regard to cure rates and improved tolerability; however, the health care system is challenged by the cost of these medications.
OBJECTIVE: To describe the effect of a comprehensive HCV medication management program on optimized regimen use, prior authorization (PA) modifications, and medication cost avoidance in a state Medicaid program.
METHODS: This program consists of a 2-tiered prescriber outreach: (1) regimen outreach to promote optimized regimen selection and (2) refill outreach to support medication adherence. PA criteria were developed to identify optimized regimens, taking into account member- and virus-specific factors as well as cost. Prescriber outreach was conducted to recommend the use of an optimized regimen as applicable. Successful regimen outreach was defined as the number of members for whom a recommendation was accepted. A refill report identified members without a subsequent paid HCV medication claim within 25 days of the previous claim and outreach to the prescriber's office was performed. The outcome measure for refill outreach was the number and type of PA modifications made secondary to outreach (closure or extension). Cost avoidance was calculated for members who completed treatment with an optimized regimen. Return on investment (ROI) was calculated for the program.
RESULTS: Between December 18, 2013, and January 31, 2015, 911 members had PA requests approved for simeprevir, sofosbuvir, or ledipasvir/ sofosbuvir. Of these members, 223 (24.5%) met the criteria for regimen outreach. Pharmacist interventions to treat with an optimized regimen were accepted for 135 members (60.5%). Following implementation of prescriber outreach to promote refills, between March 10, 2014, and January 31, 2015, offices were informed of an upcoming refill for 515 members. As a result of outreach, 19.6% of members had a subsequent PA modification. Sixty-nine approved PAs (for 68 members) were closed after correspondence with the prescriber, and 33 approved PAs (for 33 members) were extended. The total projected cost avoidance was $3,770,097. The comprehensive HCV medication management program demonstrated an ROI of $10.28 for every $1 spent.
CONCLUSIONS: A comprehensive HCV medication management program can help contain costs while ensuring that members have access to most clinically appropriate regimens.
Quality health care relies upon communication in a patient's preferred language. Language access in health care occurs when individuals are: (1) Welcomed by providers regardless of language ability; and (2) Offered quality language services as part of their care. Federal law generally requires access to health care and quality language services for deaf and Limited English Proficient (LEP) patients in health care settings, but these patients still find it hard to access health care and quality language services.Meanwhile, several states are implementing Medicaid Accountable Care Organization (ACO) initiatives to reduce health care costs and improve health care quality. Alternative payment methods used in these initiatives can give Accountable Care Organizations more flexibility to design linguistically accessible care, but they can also put ACOs at increased financial risk for the cost of care. If these new payment methods do not account for differences in patient language needs, ACO initiatives could have the unintended consequence of rewarding ACOs who do not reach out to deaf and LEP communities or offer quality language services.We reviewed public documents related to Medicaid ACO initiatives in six states. Some of these documents address language access. More could be done, however, to pay for language access efforts. This article describes Medicaid ACO initiatives and explores how different payment tools could be leveraged to reward ACOs for increased access to care and quality language services. We find that a combination of payment tools might be helpful to encourage both access and quality.
New developments that provide opportunities to enhance cost-effective diabetes care include advances in the pharmacologic treatment of diabetes, new drug delivery devices, innovations in patient management strategies, contracting strategies that incentivize effective interventions, and mobile health technologies. Payers must carefully consider the utility of these advances when making coverage decisions and designing benefits. To engage national stakeholders in a discussion about how to utilize innovations in diabetes care to optimize patient outcomes, the Academy of Managed Care Pharmacy organized the Partnership Forum on Navigating Innovations in Diabetes Care in Arlington, Virginia, on July 19-20, 2016. The forum explored current trends and advances in diabetes treatments and engaged in discussions about how organizations can leverage these emerging options to develop strategies that improve coordination of care and patient outcomes, while managing limited health resources. Additionally, stakeholders were tasked with identifying gaps in evidence that hinder decision making around novel therapies and other advances that are of direct relevance to managed care organizations.
Histopathological Characterization of the Dystrophic Phenotype and Development of Therapeutic Candidates for a Gene Therapy Pre-Clinical Study in Dysferlin Deficient Mice
Dysferlin deficient muscular dystrophy is a devastating disease that leads to loss of mobility and quality of life in patients. Dysferlin is a 230 kD protein primarily expressed in skeletal muscle that functions in membrane resealing. Dysferlin loss of function leads to a decrease in the membrane resealing response after injury in skeletal muscle, which is thought to cause degeneration of the musculature over time. Dysferlin cDNA is 7.4 kb and exceeds AAV packaging capacity of ~ 5kb. This thesis focuses on the generation of mini dysferlin mutants that can be packaged in AAV for downstream testing of therapeutic efficacy. In addition, this thesis creates the groundwork for preclinical studies in mice that can potentially be translated to human patients. A mouse model for dysferlin deficiency was characterized and key disease phenotypes were identified. In addition, cell lines carrying a genetically encoded calcium indicator protein, gCaMP, were established to measure mini dysferlin resealing capacity and for downstream testing in vivo.
Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2)
Carcinoembryonic antigen-related cell adhesion molecule 2 (CEACAM2) regulates food intake as demonstrated by hyperphagia in mice with the Ceacam2 null mutation (Cc2(-/-)). This study investigated whether CEACAM2 also regulates insulin secretion. Ceacam2 deletion caused an increase in beta-cell secretory function, as assessed by hyperglycemic clamp analysis, without affecting insulin response. Although CEACAM2 is expressed in pancreatic islets predominantly in non-beta-cells, basal plasma levels of insulin, glucagon and somatostatin, islet areas, and glucose-induced insulin secretion in pooled Cc2(-/-) islets were all normal. Consistent with immunofluorescence analysis showing CEACAM2 expression in distal intestinal villi, Cc2(-/-) mice exhibited a higher release of oral glucose-mediated GLP-1, an incretin that potentiates insulin secretion in response to glucose. Compared with wild type, Cc2(-/-) mice also showed a higher insulin excursion during the oral glucose tolerance test. Pretreating with exendin(9-39), a GLP-1 receptor antagonist, suppressed the effect of Ceacam2 deletion on glucose-induced insulin secretion. Moreover, GLP-1 release into the medium of GLUTag enteroendocrine cells was increased with siRNA-mediated Ceacam2 down-regulation in parallel to an increase in Ca(2+) entry through L-type voltage-dependent Ca(2+) channels. Thus, CEACAM2 regulates insulin secretion, at least in part, by a GLP-1-mediated mechanism, independent of confounding metabolic factors.
Emerging evidence for beneficial macrophage functions in atherosclerosis and obesity-induced insulin resistance
The discovery that obesity promotes macrophage accumulation in visceral fat led to the emergence of a new field of inquiry termed "immunometabolism". This broad field of study was founded on the premise that inflammation and the corresponding increase in macrophage number and activity was a pathologic feature of metabolic diseases. There is abundant data in both animal and human studies that supports this assertation. Established adverse effects of inflammation in visceral fat include decreased glucose and fatty acid uptake, inhibition of insulin signaling, and ectopic triglyceride accumulation. Likewise, in the atherosclerotic plaque, macrophage accumulation and activation results in plaque expansion and destabilization. Despite these facts, there is an accumulating body of evidence that macrophages also have beneficial functions in both atherosclerosis and visceral obesity. Potentially beneficial functions that are common to these different contexts include the regulation of efferocytosis, lipid buffering, and anti-inflammatory effects. Autophagy, the process by which cytoplasmic contents are delivered to the lysosome for degradation, is integral to many of these protective biologic functions. The macrophage utilizes autophagy as a molecular tool to maintain tissue integrity and homeostasis at baseline (e.g., bone growth) and in the face of ongoing metabolic insults (e.g., fasting, hypercholesterolemia, obesity). Herein, we highlight recent evidence demonstrating that abrogation of certain macrophage functions, in particular autophagy, exacerbates both atherosclerosis and obesity-induced insulin resistance. Insulin signaling through mammalian target of rapamycin (mTOR) is a crucial regulatory node that links nutrient availability to macrophage autophagic flux. A more precise understanding of the metabolic substrates and triggers for macrophage autophagy may allow therapeutic manipulation of this pathway. These observations underscore the complexity of the field "immunometabolism", validate its importance, and raise many fascinating and important questions for future study.
Genetic ablation of lymphocytes and cytokine signaling in nonobese diabetic mice prevents diet-induced obesity and insulin resistance
Obesity is characterized by a dysregulated immune system, which may causally associate with insulin resistance and type 2 diabetes. Despite widespread use of nonobese diabetic (NOD) mice, NOD with severe combined immunodeficiency (scid) mutation (SCID) mice, and SCID bearing a null mutation in the IL-2 common gamma chain receptor (NSG) mice as animal models of human diseases including type 1 diabetes, the underlying metabolic effects of a genetically altered immune system are poorly understood. For this, we performed a comprehensive metabolic characterization of these mice fed chow or after 6 wk of a high-fat diet. We found that NOD mice had approximately 50% less fat mass and were 2-fold more insulin sensitive, as measured by hyperinsulinemic-euglycemic clamp, than C57BL/6 wild-type mice. SCID mice were also more insulin sensitive with increased muscle glucose metabolism and resistant to diet-induced obesity due to increased energy expenditure ( approximately 10%) and physical activity ( approximately 40%) as measured by metabolic cages. NSG mice were completely protected from diet-induced obesity and insulin resistance with significant increases in glucose metabolism in peripheral organs. Our findings demonstrate an important role of genetic background, lymphocytes, and cytokine signaling in diet-induced obesity and insulin resistance.
Translation of siRNA technology into the clinic is limited by the need for improved delivery systems that target specific cell types. Macrophages are particularly attractive targets for RNAi therapy because they promote pathogenic inflammatory responses in a number of important human diseases. We previously demonstrated that a multicomponent formulation of beta-1,3-d-glucan-encapsulated siRNA particles (GeRPs) can specifically and potently silence genes in mouse macrophages. A major advance would be to simplify the GeRP system by reducing the number of delivery components, thus enabling more facile manufacturing and future commercialization. Here we report the synthesis and evaluation of a simplified glucan-based particle (GP) capable of delivering siRNA in vivo to selectively silence macrophage genes. Covalent attachment of small-molecule amines and short peptides containing weak bases to GPs facilitated electrostatic interaction of the particles with siRNA and aided in the endosomal release of siRNA by the proton-sponge effect. Modified GPs were nontoxic and were efficiently internalized by macrophages in vitro. When injected intraperitoneally (i.p.), several of the new peptide-modified GPs were found to efficiently deliver siRNA to peritoneal macrophages in lean, healthy mice. In an animal model of obesity-induced inflammation, i.p. administration of one of the peptide-modified GPs (GP-EP14) bound to siRNA selectively reduced the expression of target inflammatory cytokines in the visceral adipose tissue macrophages. Decreasing adipose tissue inflammation resulted in an improvement of glucose metabolism in these metabolically challenged animals. Thus, modified GPs represent a promising new simplified system for the efficient delivery of therapeutic siRNAs specifically to phagocytic cells in vivo for modulation of inflammation responses.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85alpha regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome - a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome-associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism.
Standard Definitions and Common Data Elements for Clinical Trials in Patients With Alcoholic Hepatitis: Recommendation From the NIAAA Alcoholic Hepatitis Consortia
Heavy drinkers are at risk for a spectrum of histologic alcohol-related liver injury: steatosis, alcoholic steatohepatitis (ASH), alcohol-related fibrosis, and cirrhosis. Alcoholic hepatitis (AH), the clinical entity associated with severe ASH, has high short-term mortality. The standard-of-care therapy, prednisolone, has limited efficacy and many side effects; no other treatment has consistently shown survival benefit. The National Institute on Alcohol Abuse and Alcoholism (NIAAA)-funded Alcoholic Hepatitis Consortia carry out translational research on pathophysiologic mechanisms, genetic and environmental risk factors, phase II clinical trials, and development of biomarkers. The consortia members were convened by the National Institutes of Health to address diagnostic criteria and practical issues related to clinical AH research, and to develop a set of common data elements to harmonize ongoing and future trials. This was accomplished through 3 face-to-face meetings of the investigators and representatives of the National Institutes of Health, and subsequent electronic communications over the course of 6 months. Evidence for the recommendations was based on published trials and observational data from several of the consortia members. A draft manuscript was iteratively reviewed by members of the consortia. The goal was to reach agreements on recommendations and definitions that could facilitate trial design, and simultaneously be tested by research groups pooling their data. The recommendations made here are specifically directed to achieve better uniformity in clinical trials, rather than serving as clinical practice guidelines.
Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice
Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.
The global incidence of obesity and its comorbidities continues to rise along with a demand for novel therapeutic interventions. Brown adipose tissue (BAT) is attracting attention as a therapeutic target because of its presence in adult humans and high capacity to dissipate energy as heat, and thus burn excess calories, when stimulated. Another potential avenue for therapeutic intervention is to induce, within white adipose tissue (WAT), the formation of brown-like adipocytes called brite (brown-like-in-white) or beige adipocytes. However, understanding how to harness the potential of these thermogenic cells requires a deep understanding of their developmental origins and regulation. Recent cell-labeling and lineage-tracing experiments are beginning to shed light on this emerging area of adipocyte biology. We review here adipocyte development, giving particular attention to thermogenic adipocytes.