Safety planning intervention and follow-up: A telehealth service model for suicidal individuals in emergency department settings: Study design and protocol.

BACKGROUND: The Safety Planning Intervention with follow-up services (SPI+) is a promising suicide prevention intervention, yet many Emergency Departments (EDs) lack the resources for adequate implementation. Comprehensive strategies addressing structural and organizational barriers are needed to optimize SPI+ implementation and scale-up. This protocol describes a test of one strategy in which ED staff connect at-risk patients to expert clinicians from a Suicide Prevention Consultation Center (SPCC) via telehealth. METHOD: This stepped wedge, cluster-randomized trial compares the effectiveness, implementation, cost, and cost offsets of SPI+ delivered by SPCC clinicians versus ED-based clinicians (enhanced usual care; EUC). Eight EDs will start with EUC and cross over to the SPCC phase. Blocks of two EDs will be randomly assigned to start dates 3 months apart. Approximately 13,320 adults discharged following a suicide-related ED visit will be included; EUC and SPCC samples will comprise patients from before and after SPCC crossover, respectively. Effectiveness data sources are electronic health records, administrative claims, and the National Death Index. Primary effectiveness outcomes are presence of suicidal behavior and number/type of mental healthcare visits and secondary outcomes include number/type of suicide-related acute services 6-months post-discharge. We will use the same data sources to assess cost offsets to gauge SPCC scalability and sustainability. We will examine preliminary implementation outcomes (reach, adoption, fidelity, acceptability, and feasibility) through patient, clinician, and health-system leader interviews and surveys. CONCLUSION: If the SPCC demonstrates clinical effectiveness and health system cost reduction, it may be a scalable model for evidence-based suicide prevention in the ED.

Phase II Trial of Concurrent Nivolumab and Radiation Therapy for Muscle-Invasive Bladder Cancer of Older or Chemotherapy-Ineligible Patients.

PURPOSE: Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. METHODS AND MATERIALS: Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. RESULTS: Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). CONCLUSIONS: Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival.

Mobile Crisis Services: A Clinician Survey of Current Suicide Prevention Practices and Barriers to Care Delivery.

Mobile crisis teams (MCTs) deploy clinicians to assist individuals in acute crisis in the community. Little is known about the extent to which these teams provide evidence-based practices (EBPs) for suicide prevention nor the barriers they face. We surveyed 120 MCT clinicians across the United States about their: (1) use of suicide risk screening and assessment tools; (2) strategies used to address suicide risk (both EBPs and non-EBPs); and (3) perceived barriers to high-quality MCT services. Nearly all clinicians reported use of validated suicide screening tools and generic "safety planning." However, a sizeable minority also reported use of non-EBPs. Open-ended responses suggested many client/family-, clinician-, and systems-level barriers to MCT use of EBPs for suicide prevention. We identified several targets for future implementation efforts, including the need for de-implementation strategies to reduce use of ineffective and potentially harmful practices, and unique aspects of MCTs that require tailored implementation supports.

Advancing Suicide Intervention Strategies for Teens (ASSIST): study protocol for a multisite randomised controlled trial.

INTRODUCTION: Brief interventions that reduce suicide risk following youth's experience with acute care due to suicidality are needed. METHODS AND ANALYSIS: The study will use a three-arm randomised controlled trial designed to test the effectiveness of the Safety Planning Intervention with structured follow-up (SPI+) and the Collaborative Assessment and Management of Suicidality (CAMS) compared with enhanced usual care. The primary outcomes measure will be suicidal events, defined as death by suicide, attempted suicide, preparatory acts toward imminent suicidal behaviour or suicidal ideation resulting in a change in emergency evaluation or inpatient admission. Secondary measures will be the number of suicide attempts and severity of suicidal ideation. The experimental interventions, SPI+ and CAMS, consist of up to eight sessions over approximately 8 weeks that are designed to manage (SPI+) or treat (CAMS) patient-identified 'drivers' of suicidal thoughts and behaviours. Mechanisms and moderators of change will be evaluated to understand treatment impacts. ETHICS AND DISSEMINATION: This study has been approved by the Seattle Children's Institutional Review Board and is monitored by external agencies including the University of Washington Institute for Translational Health Sciences, and a National Institute of Mental Health (NIMH)-appointed Data Safety and Monitoring Board. Trial results will help establish evidence towards safe and effective treatment strategies for youth transitioning from acute to outpatient care due to a suicidal crisis. The data will be shared with the NIMH Data Archives and disseminated through publications and conferences. TRIAL REGISTRATION NUMBER: NCT05078970.

Effects of Patient Suicide on Professional Practice Among Mental Health Providers.

INTRODUCTION: The loss of a patient to suicide has an enormous impact on clinicians, but few studies have examined its effects. METHOD: In this retrospective study, we compared clinicians who have and have not experienced a patient suicide using a survey of 2157 outpatient clinicians from 169 New York clinics to determine differences in their suicide prevention knowledge, practices, training, and self-efficacy. RESULTS: Approximately 25% of the clinician respondents lost patients to suicide; psychiatrists, nurses/nurse practitioners, and those with more years of experience were disproportionately affected. After controlling for these demographic/professional differences, clinicians who had experienced patient suicide reported feeling that they had insufficient training, despite actually having more suicide prevention training, greater knowledge of suicide prevention practices, and feeling more comfortable working with suicidal patients than clinicians who had not lost a patient to suicide. There were no differences in self-efficacy or utilization of evidence-based clinical practices. CONCLUSIONS: Controlling for demographic/professional differences, clinicians who experienced a patient suicide had more training, knowledge, and felt more comfortable working with suicidal patients. It is critical that sufficient training be available to clinicians, not only to reduce patient deaths, but also to help clinicians increase their comfort, knowledge, skill, and ability to support those bereaved by suicide loss.

Suicide and Telehealth Treatments: A PRISMA Scoping Review.

BACKGROUND: This PRISMA scoping review explored worldwide research on the delivery of suicide-specific interventions through an exclusive telehealth modality. Research over telehealth modalities with suicidal individuals highlights the importance of facilitating participants' access to treatments despite location and circumstances (e.g., rural, expenses related to appointments, etc.). AIM: The review sought evidence of outcomes of trials or projects in which both the patient and therapist attended sessions conjointly and openly discussed suicide over a telehealth modality (e.g., phone, zoom). METHOD: To explore this topic the authors searched for research trials and quality improvement projects using Ovid Medline, Ovid Embase, Ovid PsycINFO, EBSCO Social Services Abstracts, and Web of Science on 3/3/2021. RESULTS: Nine different articles were included that each spanned distinct treatments, with eight being research studies and one being a quality improvement project. LIMITATIONS: Publications featuring ongoing or upcoming research in which complete study results were not available did not meet inclusion criteria for this review. CONCLUSION: Several important research gaps were identified. While this approach has been largely understudied, exclusive telehealth delivery of suicide-specific interventions has great potential for the prevention of suicidality, especially in the era of COVID-19 and beyond.

Predictors of Intentional Self -Harm Among Medicaid Mental Health Clinic Clients In New York.

BACKGROUND: Behavioral health outpatients are at risk for self-harm. Identifying individuals or combination of risk factors could discriminate those at elevated risk for self-harm. METHODS: The study population (N = 248,491) included New York State Medicaid-enrolled individuals aged 10 to 64 with mental health clinic services between November 1, 2015 to November 1, 2016. Self-harm episodes were defined using ICD-10 codes from emergency department and inpatient visits. Multi-predictor logistic regression models were fit on a subsample of the data and compared to a testing sample based on discrimination performance (Area Under the Curve or AUC). RESULTS: Of N = 248,491 patients, 4,224 (1.70%) had an episode of intentional self-harm. Factors associated with increased self-harm risk were age 17-25, being female and having recent diagnoses of depression (AOR=4.3, 95%CI: 3.6-5.0), personality disorder (AOR=4.2, 95%CI: 2.9-6.1), or substance use disorder (AOR=3.4, 95%CI: 2.7-4.3) within the last month. A multi-predictor logistic regression model including demographics and new psychiatric diagnoses within 90 days prior to index date had good discrimination and outperformed competitor models on a testing sample (AUC=0.86, 95%CI:0.85-0.87). LIMITATIONS: New York State Medicaid data may not be generalizable to the entire U.S population. ICD-10 codes do not allow distinction between self-harm with and without intent to die. CONCLUSIONS: Our results highlight the usefulness of recency of new psychiatric diagnoses, in predicting the magnitude and timing of intentional self-harm risk. An algorithm based on this finding could enhance clinical assessments support screening, intervention and outreach programs that are at the heart of a Zero Suicide prevention model.

Youths' and Young Adults' Experiences of Police Involvement During Initiation of Involuntary Psychiatric Holds and Transport.

Over the past decade, police involvement in behavioral health crisis response has generated concern and controversy. Despite the salience and timeliness of this topic, the literature on service user experiences of interactions with officers is small and studies of youths and young adults are nonexistent. The authors aimed to investigate youths' and young adults' experiences of police involvement in involuntary psychiatric hold initiation and transport. In-depth interviews were conducted with 40 participants (ages 16-27) who had experienced an involuntary hold; the 28 participants who reported police involvement are the focus of this analysis. Data were inductively coded, and codes were grouped into larger themes. A majority of participants reported negative experiences; major themes characterizing negative encounters were the framing of distress as criminal or of intervention as disciplinary rather than therapeutic, perceived aggression and callousness from police officers, and poor communication. The authors also characterized the positive experiences of officer involvement reported by a minority of participants and youths' perspectives on the degree of control officers could exert over initiation and transport decisions. Findings help center the voices of youths and young adults with mental health challenges and raise important questions about contemporary policies regarding police involvement in crisis response and, more broadly, about coercive responses to distress or emotional crisis.

A Case Study of Long-Range Rotary Wing Critical Care Transport in the Battlefield Environment.

Military medical evacuation continues to grow both in distance and transport times. With the need for long-range transport of greater than 2 hours, crews are having to manage critical care patients for longer trips. This case study evaluates one specific event in which long-range transport of a sick noncombat patient required an enroute critical care team. Medical electronics and other equipment require special attention. Oxygen bottles and batteries for medical devices become the limiting factor in transport from point to point. Having to juggle multiple data streams requires prioritization and reassessment of interventions. Using the mnemonic "bottles, bags, batteries, battlefield environment" keeps the transport paramedic and enroute care nurse on track to effectively deliver the patient to the next level of care. Consideration should be given to such mnemonics for long critical care transports.

Is the outpatient mental health workforce ready to save lives? Suicide prevention training, knowledge, self-efficacy, and clinical practices prior to the implementation of a statewide suicide prevention initiative.

OBJECTIVE: Many public health approaches to suicide prevention emphasize connecting at-risk individuals to professional treatment. However, it is unclear to what degree the outpatient mental health workforce has the requisite knowledge and skills to provide the evidence-based care needed to help those at risk. In this project, prior to the implementation of a statewide suicide prevention initiative, we assessed the baseline suicide prevention training and clinical practices of the New York State outpatient mental health workforce, a group likely representative of the broader U.S. clinical workforce. METHOD: A workforce survey of suicide prevention training and clinical practices was administered to 2,257 outpatient clinicians, representing 169 clinics serving approximately 90,000 clients. Clinicians were asked to complete the survey online, and all responses were confidential. RESULTS: Clinicians reported substantial gaps in their suicide prevention knowledge and training. The vast majority reported moderate self-efficacy working with suicidal clients and endorsed using evidence-based assessment procedures, but varied in utilization of recommended intervention practices. CONCLUSIONS: This study highlights gaps in clinicians' training and clinical practices that need to be overcome to provide evidence-based suicide care. Promisingly, positive associations were found between training and clinician knowledge, self-efficacy, and use of evidence-based practices.

An Integrated Model of Nature and Nurture Factors that Contribute to Addiction and Recovery.

BACKGROUND: In the context of the opioid epidemic and growing awareness of addiction as a public health concern, there are efforts to inform the public, patients, families, and policy makers about the factors that contribute to addiction and facilitate recovery. Several theoretical models provide useful frameworks for this discussion, but each of them has limitations. OBJECTIVES: This paper presents an accessible yet comprehensive theoretical model that integrates empirical evidence about addiction etiology and recovery using the nature-nurture paradigm. RESULTS: The model presents substance use along a continuum, and identifies risk and protective factors in multiple domains that have been identified by research. The domains on the nature side of the model include genetic and biological factors, comorbid psychiatric and medical disorders, physiological reinforcement of substance use, and changes to neural mechanisms. The domains on the nurture side of the model include sociocultural factors, environmental factors, personality, emotions, cognitions, psychological reinforcement of substance use, and cognitive and behavioral changes. The progression from increased or decreased substance use to addiction or recovery is mediated by changes in neural mechanisms and cognitive and behavioral changes, which have feedback loops with the physiological and psychological reinforcement.Conclusions/Importance: This model is a useful heuristic, consistent with a public health framework, for discussing addiction and recovery with patients, their families, and the public. This integrated model of nature and nurture factors has the potential to inform clinical practice, consultation, research, prevention programs, educational programs, and public policy.

Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors.

AIM: To investigate the mechanisms underlying improvements in blood pressure (BP) and congestive heart failure outcomes following treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor. RESEARCH DESIGN AND METHODS: A total of 52 patients with type 2 diabetes (T2D) with an HbA1c of less than 8% participated in this prospective, double-blind and placebo-controlled study. Patients were randomized (1:1) to either dapagliflozin 10 mg daily or placebo for 12 weeks. Half the patients were also monitored for 6 h following their first dose for acute effects on BP. Blood and urine samples were collected and levels of angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide, cyclic adenosine monophosphate, cyclic guanosine monophosphate (cGMP) and neprilysin were measured. The expression of angiotensin-converting enzyme, guanylate cyclase and phosphodiesterase 5 (PDE5) was measured in circulating mononuclear cells (MNC). RESULTS: A total of 24 and 23 patients receiving dapagliflozin and placebo, respectively, completed the 12-week study. Systolic BP decreased significantly, compared with placebo, both after single-dose (by 7 ± 3 mmHg) and 12-week (by 7 ± 2 mmHg) treatment with dapagliflozin. Dapagliflozin suppressed angiotensin II and angiotensinogen (by 10.5 ± 2.1 and 1.45 ± 0.42 µg/mL, respectively) and increased ANP and cGMP (by 34 ± 11 and 29 ± 11 pmol/mL, respectively) compared with the placebo group. cGMP levels also increased acutely following a single dose of dapagliflozin. Dapagliflozin also suppressed PDE5 expression by 26% ± 11% in MNC. There were no changes observed in the other vasoactive mediators investigated. CONCLUSIONS: Dapagliflozin administration in T2D resulted in both acute and chronic reduction in systolic BP, a reduction in vasoconstrictors and an increase in vasodilators. These changes may potentially contribute to its antihypertensive effects and its benefits in congestive cardiac failure.

A randomized, controlled trial of the safety planning intervention: Research design and methods.

BACKGROUND: Brief interventions for suicide risk among patients treated in acute care settings like the emergency department are needed. The Safety Planning Intervention is a promising approach but has yet to undergo a high quality, individual level randomized controlled trial. PURPOSE: This paper describes the methods associated with an individual level randomized controlled trial of the Safety Planning Intervention compared to a control condition comprised of reviewing risk factors and warning signs. METHODS: The sample comprised patients 18 years and older presenting to one of three different emergency departments with suicide related emergencies (target n = 484). Eligible patients were approached, consented, and randomized to the intervention (Safety Planning Intervention) or control (risk factors and warning signs). They were assessed at 1, 3 and 6 months after their index visit. The primary outcome is suicidal behavior. The study also assessed mechanisms of action. Data analyses are pending. CONCLUSIONS: We identified and addressed key challenges to studying suicidal patients in the emergency department, including difficulty enrolling during the emergency department visit, ascertaining outcomes in patients that are historically very difficult to follow, and addressing the ambiguity of suicidal behavior. ClinicalTrials.gov Identifier: NCT03227991.

Most Individuals Are Seen in Outpatient Medical Settings Prior to Intentional Self-Harm and Suicide Attempts Treated in a Hospital Setting.

The objective of this quantitative retrospective study is to understand healthcare patterns prior to self-harm, which may inform prevention efforts and identify intervention sites. Medicaid claims within 30, 60, 90, and 365 days prior to hospital-treated self-harm between 11/1/2015 and 11/1/2016 in New York State (N = 7492) were examined. Numbers and proportions were calculated for all service types. Participants were predominately 15-34, female, and White. Most (97%) had prior-year services, 94% outpatient care (73% behavioral health, 90% medical), 69% emergency department (37% behavioral health, 59% medical), and 42% inpatient services (34% behavioral health, 20% medical). About 86% received services within 90 days and 80% within 60 days. Utilization was high within 30 days prior, with 69% having one or more services. Medical services were more common than behavioral health (94% versus 79% in prior year); outpatient (94%) was more common than emergency (69%) and inpatient (42%) care. Given that most patients received health services within 30 days and almost all saw providers within the year prior, the findings indicate that improved prevention efforts within the healthcare system can reduce the incidence of self-harm.

Zero suicide implementation-effectiveness trial study protocol in outpatient behavioral health using the A-I-M suicide prevention model.

BACKGROUND: The treatment of suicidal patients often suffers owing to a lack of integrated care and standardized approaches for identifying and reducing risk. The National Strategy for Suicide Prevention endorsed the Zero Suicide (ZS) model, a multi-component, system-wide approach to identify, engage, and treat suicidal patients. The ZS model is a framework for suicide prevention in healthcare systems with the aspirational goal of eliminating suicide in healthcare. While the approach is widely endorsed, it has yet to be evaluated in a systematic manner. This trial evaluates two ZS implementation strategies statewide in specialty mental health clinics. METHODS/STUDY DESIGN: This trial is the first large-scale implementation of the ZS model in mental health clinics using the Assess, Intervene, and Monitor for Suicide Prevention (A-I-M) clinical model. Using a hybrid effectiveness-implementation type 1 design, we are testing the effectiveness of ZS implementation in 186 mental health clinics in 95 agencies in New York State. Agencies are randomly assigned to either: "Basic Implementation" (BI; a large group didactic learning collaboratives) or "Enhanced Implementation" (EI; participatory small group learning collaboratives; enhanced consultation for site champions). Primary outcomes include suicidal behaviors, hospitalizations and Emergency Department visits; implementation outcomes include protocol adoption, protocol fidelity and barriers/facilitators to implementation. DISCUSSION: This project has the potential to have a significant public health impact by determining the effectiveness of the ZS model in mental health clinics, a setting where suicide attempts and suicides occur at a higher rate than any other healthcare setting. It will also provide guidance on the implementation level required to achieve uptake and sustainability of ZS. TRIAL REGISTRATION: N/A.

Liraglutide treatment in overweight and obese patients with type 1 diabetes: A 26-week randomized controlled trial; mechanisms of weight loss.

AIM: To investigate the effects of liraglutide treatment on glycaemic control and adipose tissue metabolism in overweight and obese people with type 1 diabetes (T1DM). RESEARCH DESIGN AND METHODS: A total of 84 adult overweight and obese patients with T1DM, with no detectable C-peptide, were randomized (1:1) to either placebo or 1.8 mg/d liraglutide for 6 months. Blood samples were collected at 0, 12 and 26 weeks. Subcutaneous adipose tissue biopsies, a high-calorie high-fat meal challenge test, continuous glucose monitoring, dual-energy X-ray absorptiometry and MRI were performed before and at the end of treatment. RESULTS: In all, 37 and 27 patients who received liraglutide and placebo, respectively, completed the study. Glycated haemoglobin fell by 0.41 ± 0.18% (4.5±1.4 mmol/mol) from baseline after liraglutide treatment (P = 0.001), and by 0.29 ± 0.19% (3.1±2.0 mmol/mol) compared to placebo (P = 0.1). There was no increase in hypoglycaemia, while the time spent in normal glycaemia increased (P = 0.015) and time spent in hyperglycaemia decreased (P = 0.019). Body weight fell significantly in the liraglutide group, mostly in the form of fat mass loss (including visceral fat), with no change in lean mass. Systolic blood pressure (SBP) also fell after liraglutide treatment. Liraglutide also caused a significant increase in the expression of adipose tissue triglyceride lipase, carnitine palmitoyl transferase-1, peroxisome proliferator-activated receptor (PPAR)α, PPARδ, uncoupling protein-2 and type 2 iodothyronine deiodinase in the adipose tissue. CONCLUSIONS: Liraglutide improves glycaemia, reduces adiposity and SBP. Liraglutide also stimulates mechanisms involved with an increase in lipid oxidation and thermogenesis, while conserving lean body mass.

Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis.

CONTEXT: Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit, possibly due to its diuretic effects and hemoconcentration. OBJECTIVE: Since type 2 diabetes is a proinflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in proinflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis. DESIGN: Prospective, randomized, and placebo-controlled study. SETTING: Single endocrinology center. PATIENTS: Fifty-two obese type 2 diabetes patients. INTERVENTION: Patients were randomized (1:1) to either dapagliflozin (10 mg daily) or placebo for 12 weeks. Blood samples were collected before and after treatments and serum, plasma, and mononuclear cells (MNC) were prepared. MAIN OUTCOME MEASURE: Hepcidin and other hematopoietic factors. RESULTS: Following dapagliflozin treatment, there was a significant fall in HbA1c and a significant increase in hemoglobin concentration and hematocrit. Dapagliflozin treatment significantly reduced circulating hepcidin and ferritin concentrations while causing a significant increase in levels of the hepcidin inhibitor, erythroferrone, and a transient increase in erythropoietin. Additionally, dapagliflozin increased plasma transferrin levels and expression of transferrin receptors 1 and 2 in MNC, while there was no change in the expression of the iron cellular transporter, ferroportin. Dapagliflozin treatment also caused a decrease in hypoxia-induced factor-1α expression in MNC while it increased the expression of its inhibitor, prolyl hydroxylase-2. There were no significant changes in any of these indices in the placebo group. CONCLUSIONS: We conclude that dapagliflozin increases erythropoiesis and hematocrit through mechanisms that involve the suppression of hepcidin and the modulation of other iron regulatory proteins.

Testosterone Increases the Expression and Phosphorylation of AMP Kinase α in Men With Hypogonadism and Type 2 Diabetes.

CONTEXT: Adenosine 5'-monophosphate-activated protein kinase-α (AMPKα) is a mediator of exercise-induced glucose uptake in skeletal muscle. OBJECTIVE: We evaluated whether AMPKα expression and phosphorylation are reduced in skeletal muscle and adipose tissue of patients with hypogonadotropic hypogonadism (HH), and whether testosterone replacement therapy results in restoration of the expression and phosphorylation of AMPKα. DESIGN: This is a secondary analysis of a previously completed trial that showed an insulin-sensitizing effect of testosterone therapy in men with type 2 diabetes and HH. SETTING: Clinical research center at university. PATIENTS: Thirty-two men with HH and 32 eugonadal men were compared at baseline. INTERVENTIONS: Men with HH were treated with intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Quadriceps muscle biopsies and subcutaneous abdominal fat biopsies were obtained before and after 4-hour euglycemic hyperinsulinemic clamp, prior to and after testosterone or placebo therapy. OUTCOME MEASURES AND RESULTS: mRNA expression of AMPKα in hypogonadal men was lower by 37% in adipose tissue and 29% in skeletal muscle, respectively, compared with levels in eugonadal men, while phosphorylated AMPKα was lower by 22% and 28%, respectively. Following testosterone replacement, the expression of AMPKα did not alter in the fasting state but increased markedly by 41% and 46% in adipose tissue and muscle, respectively, after the clamp. In contrast, phosphorylated AMPKα increased by 69% in muscle after testosterone therapy but did not change following the clamp. CONCLUSIONS: Testosterone modulates the expression of AMPKα and phosphorylated AMPKα. These effects may contribute to the improved insulin sensitivity following testosterone therapy.

Acute effects of insulin on skeletal muscle growth and differentiation genes in men with type 2 diabetes.

AIMS: Insulin has anabolic effects on skeletal muscle. However, there is limited understanding of the molecular mechanisms underlying this effect in humans. We evaluated whether the skeletal muscle expression of satellite cell activator fibroblast growth factor 2 (FGF2) and muscle growth and differentiation factors are modulated acutely by insulin during euglycemic-hyperinsulinemic clamp (EHC). DESIGN AND METHODS: This is a secondary investigation and analysis of samples obtained from a previously completed trial investigating the effect of testosterone replacement in males with hypogonadotropic hypogonadism and type 2 diabetes. Twenty men with type 2 diabetes underwent quadriceps muscle biopsies before and after 4 h of EHC. RESULTS: The infusion of insulin during EHC raised the expression of myogenic growth factors, myogenin (by 72 ± 20%) and myogenin differentiation protein (MyoD; by 81 ± 22%). Insulin reduced the expression of muscle hypertrophy suppressor, myogenic regulatory factor 4 (MRF4) by 34 ± 14%. In addition, there was an increase in expression of FGF receptor 2, but not FGF2, following EHC. The expression of myostatin did not change. CONCLUSIONS: Insulin has an acute potent effect on expression of genes that can stimulate muscle differentiation and growth.

Increase in Osteocalcin Following Testosterone Therapy in Men With Type 2 Diabetes and Subnormal Free Testosterone.

CONTEXT: One-third of men with type 2 diabetes have subnormal free testosterone concentrations. We evaluated the following: (i) whether bone mineral density (BMD) and bone strength are affected by gonadal status in type 2 diabetes and (ii) the effect of testosterone replacement on markers of osteoblast and osteoclast activity. DESIGN: This is a secondary analysis of a previously completed, randomized, placebo-controlled trial. Ninety-four men with type 2 diabetes were recruited; 44 had subnormal free testosterone concentrations. Men with subnormal free testosterone concentrations were randomized to receive intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Dual energy X-ray absorptiometry scans were performed at baseline and at 23 weeks. RESULTS: Men with subnormal free testosterone had similar BMD compared with men with normal free testosterone. However, bone strength indices were lower in men with subnormal free testosterone. BMD was related to free estradiol concentrations (r = 0.37, P = 0.004 at hip), whereas bone strength was related to free testosterone concentrations (r = 0.41, P < 0.001). Testosterone replacement increased osteocalcin concentrations [mean change (95% CI), 3.52 (0.45, 6.59), P = 0.008]. C-Terminal telopeptide (CTx) concentrations also increased at 15 weeks but reverted to baseline following that. There were no changes in other bone turnover markers or BMD. CONCLUSION: We conclude that testosterone replacement resulted in an increase in osteocalcin and a transient increase in CTx, indicating an increase in osteoblastic activity and transient increase in bone breakdown. Therefore, a major action of testosterone is to increase bone turnover in men with type 2 diabetes.