Primary outcomes from Partner2Lose: A randomized controlled trial to evaluate partner involvement on long-term weight loss.

Background: Partner support is associated with better weight loss outcomes in observational studies, but randomized trials show mixed results for including partners. Unclear is whether teaching communication skills to couples will improve weight loss in index participants. Purpose: To compare the efficacy of a partner-assisted intervention versus participant-only weight management program on long-term weight loss. Methods: This community-based study took place in Madison, WI. Index participants were eligible if they met obesity guideline criteria to receive weight loss counseling, were aged 74 years or younger, lived with a partner, and had no medical contraindications to weight loss; partners were aged 74 years or younger and not underweight. Couples were randomized 1:1 to a partner-assisted or participant-only intervention. Index participants in both arms received an evidence-based weight management program. In the partner-assisted arm, partners attended half of the intervention sessions, and couples were trained in communication skills. The primary outcome was index participant weight at 24 months, assessed by masked personnel; secondary outcomes were 24-month self-reported caloric intake and average daily steps assessed by an activity tracker. General linear mixed models were used to compare group differences in these outcomes following intent-to-treat principles. Results: Among couples assigned to partner-assisted (n=115) or participant-only intervention (n=116), most index participants identified as female (67%) and non-Hispanic White (87%). Average baseline age was 47.27 years (SD 11.51 years) and weight was 106.55 kg (SD 19.41 kg). The estimated mean 24-month weight loss was similar in the partner-assisted (2.66 kg) and participant-only arms (2.89 kg) (estimated mean difference, 0.23 kg [95% CI, -1.58, 2.04 kg]). There were no differences in 24-month average daily caloric intake (50 cal [95% CI: -233, 132 cal]) or steps (806 steps [95% CI: -1675, 64 steps]). The percentage of participants reporting an adverse event with at least possible attribution to the intervention did not differ by arm (partner-assisted: 9%, participant-only, 3%, p=0.11). Conclusions: Partner-assisted and individual weight management interventions led to similar outcomes in index participants. Trial registration: Clinicaltrials.gov NCT03801174.

Sodium-glucose cotransporter-2 inhibitor use in kidney transplant recipients.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are novel oral hypoglycemic agents garnering much attention for their substantial benefits. These recent data have positioned SGLT2i at the forefront of diabetic chronic kidney disease (CKD) and heart failure management. SGLT2i use post-kidney transplant is an emerging area of research. Highlights from this mini review include the following: Empagliflozin is the most prescribed SGLT2i in kidney transplant recipients (KTRs), median time from transplant to initiation was 3 years (range: 0.88-9.6 years). Median baseline estimated glomerular filtration rate (eGFR) was 66.7 mL/min/1.73 m2 (range: 50.4-75.8). Median glycohemoglobin (HgbA1c) at initiation was 7.7% (range: 6.9-9.3). SGLT2i were demonstrated to be effective short-term impacting HgbA1c, eGFR, hemoglobin/hematocrit, serum uric acid, and serum magnesium levels. They are shown to be safe in KTRs with low rates of infections, hypoglycemia, euglycemic diabetic ketoacidosis, and stable tacrolimus levels. More data is needed to demonstrate long-term outcomes. SGLT2i appear to be safe, effective medications for select KTRs. Our present literature, though limited, is founded on precedent robust research in CKD patients with diabetes. Concurrent research/utilization of SGLT2i is vital to not only identify long-term patient, graft and cardiovascular outcomes of these agents, but also to augment management in KTRs.

Metformin Monotherapy Alters the Human Plasma Lipidome Independent of Clinical Markers of Glycemic Control and Cardiovascular Disease Risk in a Type 2 Diabetes Clinical Cohort.

Type 2 diabetes (T2D) is a rising pandemic worldwide. Diet and lifestyle changes are typically the first intervention for T2D. When this intervention fails, the biguanide metformin is the most common pharmaceutical therapy. Yet its full mechanisms of action remain unknown. In this work, we applied an ultrahigh resolution, mass spectrometry-based platform for untargeted plasma metabolomics to human plasma samples from a case-control observational study of nondiabetic and well-controlled T2D subjects, the latter treated conservatively with metformin or diet and lifestyle changes only. No statistically significant differences existed in baseline demographic parameters, glucose control, or clinical markers of cardiovascular disease risk between the two T2D groups, which we hypothesized would allow the identification of circulating metabolites independently associated with treatment modality. Over 3000 blank-reduced metabolic features were detected, with the majority of annotated features being lipids or lipid-like molecules. Altered abundance of multiple fatty acids and phospholipids were found in T2D subjects treated with diet and lifestyle changes as compared with nondiabetic subjects, changes that were often reversed by metformin. Our findings provide direct evidence that metformin monotherapy alters the human plasma lipidome independent of T2D disease control and support a potential cardioprotective effect of metformin worthy of future study. SIGNIFICANCE STATEMENT: This work provides important new information on the systemic effects of metformin in type 2 diabetic subjects. We observed significant changes in the plasma lipidome with metformin therapy, with metabolite classes previously associated with cardiovascular disease risk significantly reduced as compared to diet and lifestyle changes. While cardiovascular disease risk was not a primary outcome of our study, our results provide a jumping-off point for future work into the cardioprotective effects of metformin, even in well-controlled type 2 diabetes.

Plasma Prostaglandin E2 Metabolite Levels Predict Type 2 Diabetes Status and One-Year Therapeutic Response Independent of Clinical Markers of Inflammation.

Over half of patients with type 2 diabetes (T2D) are unable to achieve blood glucose targets despite therapeutic compliance, significantly increasing their risk of long-term complications. Discovering ways to identify and properly treat these individuals is a critical problem in the field. The arachidonic acid metabolite, prostaglandin E2 (PGE2), has shown great promise as a biomarker of ß-cell dysfunction in T2D. PGE2 synthesis, secretion, and downstream signaling are all upregulated in pancreatic islets isolated from T2D mice and human organ donors. In these islets, preventing ß-cell PGE2 signaling via a prostaglandin EP3 receptor antagonist significantly improves their glucose-stimulated and hormone-potentiated insulin secretion response. In this clinical cohort study, 167 participants, 35 non-diabetic, and 132 with T2D, were recruited from the University of Wisconsin Hospital and Clinics. At enrollment, a standard set of demographic, biometric, and clinical measurements were performed to quantify obesity status and glucose control. C reactive protein was measured to exclude acute inflammation/illness, and white cell count (WBC), erythrocyte sedimentation rate (ESR), and fasting triglycerides were used as markers of systemic inflammation. Finally, a plasma sample for research was used to determine circulating PGE2 metabolite (PGEM) levels. At baseline, PGEM levels were not correlated with WBC and triglycerides, only weakly correlated with ESR, and were the strongest predictor of T2D disease status. One year after enrollment, blood glucose management was assessed by chart review, with a clinically-relevant change in hemoglobin A1c (HbA1c) defined as ≥0.5%. PGEM levels were strongly predictive of therapeutic response, independent of age, obesity, glucose control, and systemic inflammation at enrollment. Our results provide strong support for future research in this area.

Validating a Self-Reported Medication Nonadherence Measure in the Context of Multiple Chronic Diseases and Routes of Medication Administration Among Patients with Type 2 Diabetes.

Introduction: Patients with diabetes may take oral and injectable medications and often have comorbid chronic diseases. It is unclear whether to assess nonadherence for oral and injectable medications separately or combined and for comorbid conditions separately or combined. Research Design and Methods: We conducted two cognitive interview studies among patients with type 2 diabetes who were prescribed medications for oral or injectable diabetes medications (Study 1) or at least one diabetes, blood pressure, and cholesterol medication (Study 2). Participants completed the two-domain DOSE-Nonadherence measure, which assesses extent of nonadherence and reasons for nonadherence. We asked about interpretation of instructions and items, recall period, ability to respond accurately with separate versus combined versions, and comprehensiveness of reasons for nonadherence to injectable medications. Results: Based on Study 1 (n=14), nonadherence to injectable and oral medications should be assessed separately. Participants believe they can respond accurately to 7-day recall period for daily medications and a one-month recall period for weekly injectable medications. New reasons for nonadherence to injectable medications were perceived as relevant. Based on Study 2 (n-12), nonadherence to medications for diabetes, blood pressure, and cholesterol should be assessed separately. Conclusion: Although separate versions increase response time, it may improve accuracy. Responses to the measure can facilitate conversations about nonadherence between providers and patients to inform clinical decision-making.

A Method to Deliver Automated and Tailored Intervention Content: 24-month Clinical Trial.

BACKGROUND: The use of digital technologies and software allows for new opportunities to communicate and engage with research participants over time. When software is coupled with automation, we can engage with research participants in a reliable and affordable manner. Research Electronic Data Capture (REDCap), a browser-based software, has the capability to send automated text messages. This feature can be used to automate delivery of tailored intervention content to research participants in interventions, offering the potential to reduce costs and improve accessibility and scalability. OBJECTIVE: This study aimed to describe the development and use of 2 REDCap databases to deliver automated intervention content and communication to index participants and their partners (dyads) in a 2-arm, 24-month weight management trial, Partner2Lose. METHODS: Partner2Lose randomized individuals with overweight or obesity and cohabitating with a partner to a weight management intervention alone or with their partner. Two databases were developed to correspond to 2 study phases: one for weight loss initiation and one for weight loss maintenance and reminders. The weight loss initiation database was programmed to send participants (in both arms) and their partners (partner-assisted arm) tailored text messages during months 1-6 of the intervention to reinforce class content and support goal achievement. The weight maintenance and reminder database was programmed to send maintenance-related text messages to each participant (both arms) and their partners (partner-assisted arm) during months 7-18. It was also programmed to send text messages to all participants and partners over the course of the 24-month trial to remind them of group classes, dietary recall and physical activity tracking for assessments, and measurement visits. All text messages were delivered via Twilio and were unidirectional. RESULTS: Five cohorts, comprising 231 couples, were consented and randomized in the Partner2Lose trial. The databases will send 53,518 automated, tailored text messages during the trial, significantly reducing the need for staff to send and manage intervention content over 24 months. The cost of text messaging will be approximately US $450. Thus far, there is a 0.004% known error rate in text message delivery. CONCLUSIONS: Our trial automated the delivery of tailored intervention content and communication using REDCap. The approach described provides a framework that can be used in future behavioral health interventions to create an accessible, reliable, and affordable method for intervention delivery and engagement that requires minimal trial-specific resources and personnel time. TRIAL REGISTRATION: ClinicalTrials.gov NCT03801174; https://clinicaltrials.gov/ct2/show/NCT03801174?term=NCT03801174.

Human Islet Expression Levels of Prostaglandin E2 Synthetic Enzymes, But Not Prostaglandin EP3 Receptor, Are Positively Correlated with Markers of ß-Cell Function and Mass in Nondiabetic Obesity.

Elevated islet production of prostaglandin E2 (PGE2), an arachidonic acid metabolite, and expression of prostaglandin E2 receptor subtype EP3 (EP3) are well-known contributors to the ß-cell dysfunction of type 2 diabetes (T2D). Yet, many of the same pathophysiological conditions exist in obesity, and little is known about how the PGE2 production and signaling pathway influences nondiabetic ß-cell function. In this work, plasma arachidonic acid and PGE2 metabolite levels were quantified in a cohort of nondiabetic and T2D human subjects to identify their relationship with glycemic control, obesity, and systemic inflammation. In order to link these findings to processes happening at the islet level, cadaveric human islets were subject to gene expression and functional assays. Interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) mRNA levels, but not those of EP3, positively correlated with donor body mass index (BMI). IL-6 expression also strongly correlated with the expression of COX-2 and other PGE2 synthetic pathway genes. Insulin secretion assays using an EP3-specific antagonist confirmed functionally relevant upregulation of PGE2 production. Yet, islets from obese donors were not dysfunctional, secreting just as much insulin in basal and stimulatory conditions as those from nonobese donors as a percent of content. Islet insulin content, on the other hand, was increased with both donor BMI and islet COX-2 expression, while EP3 expression was unaffected. We conclude that upregulated islet PGE2 production may be part of the ß-cell adaption response to obesity and insulin resistance that only becomes dysfunctional when both ligand and receptor are highly expressed in T2D.

Protocol for Partner2Lose: A randomized controlled trial to evaluate partner involvement on long-term weight loss.

BACKGROUND: Behavioral interventions produce clinically significant weight reduction, with many participants regaining weight subsequently. Most interventions focus on an individual, but dietary and physical activity behaviors occur with, or are influenced by, domestic partners. According to interdependence theory, couples who approach behavior change as a problem to be tackled together versus independently are more likely to utilize communal coping processes to promote behavior change. We utilized interdependence theory to develop a partner-assisted intervention to increase long-term weight loss. METHODS: Community-dwelling individuals (index participants) cohabitating with a partner with 1) overweight and at least one obesity-related comorbidity or 2) obesity are randomized to participate in a standard weight management program alone or with their partner. The weight management program involves biweekly, in-person, group sessions focusing on weight loss for six months, followed by three group sessions and nine telephone calls focusing on weight loss maintenance for twelve months. In the partner-assisted arm, partners participate in half of the group sessions and telephone calls. Couples receive training in principles of cognitive behavioral therapy for couples, including sharing thoughts and feelings and joint problem solving, to increase communal coping. The primary outcome is participant weight loss at 24 months, with caloric intake and moderate-intensity physical activity as secondary outcomes. Partner weight and caloric intake will also be analyzed. Mediation analyses will examine the role of interdependence variables and social support. DISCUSSION: This trial will provide knowledge about effective ways to promote long-term weight loss and the role of interdependence constructs in weight loss. Clinical trials identifier: NCT03801174.

Trends in Hip Fracture Mortality in Wisconsin and the United States, 1999-2017.

INTRODUCTION: Hip fracture affects >300,000 Americans each year, and the mortality rate following these fractures is high. METHODS: Authors searched the Centers for Disease Control and Prevention Wide-Ranging Online Database for Epidemiologic Research (WONDER) for incidences of hip fracture as a contributing cause of death and stratified by sex, age, race, ethnicity, state, month of death, and underlying cause of death across the United States and Wisconsin. RESULTS: Wisconsin has the third-highest age-adjusted death rate for hip fracture in the United States. Those who die from hip fracture are most likely to do so in a nursing home. Hip fracture deaths occur more frequently between October and March and often are associated with respiratory illness. CONCLUSION: Hip fracture is a major contributing cause of death. Wisconsin residents are particularly affected by this risk.

Daily Sodium Monitoring and Fluid Intake Protocol: Preventing Recurrent Hospitalization in Adipsic Diabetes Insipidus.

Management of diabetes insipidus (DI) is usually facilitated by an intact thirst mechanism prompting water ingestion in times of rising osmolality. Maintenance of eunatremia can be quite difficult in patients with DI and adipsia because of the absence of this homeostatic mechanism. Few published protocols for management of these complex cases exist. We report a case of a 16-year-old girl who had a diagnosis of craniopharyngioma with preoperative hypopituitarism and central DI. She underwent transsphenoidal resection in 2013 and additionally developed postoperative cognitive impairment and hypothalamic dysfunction, including adipsia. She subsequently experienced widely dysregulated sodium levels, necessitating inpatient care ∼30% of days in 2014 and 2015. We created a protocol for this patient that uses a fixed daily dose of subcutaneous DDAVP combined with daily modulation of fluid intake based on daily serum sodium measurement. The protocol provides guidance for the day's fluid intake based on both the current sodium result and the rate of change from the previous day. Since the adoption of the protocol in June 2016, the patient has had a dramatic reduction in hospitalizations. Use of a protocol for providing recommendations for fluid intake based on the sodium level and rate of change may help to maintain normal sodium levels in such patients, decreasing hospitalization and improving quality of life.

Nuclear localization of pyruvate dehydrogenase complex-E2 (PDC-E2), a mitochondrial enzyme, and its role in signal transducer and activator of transcription 5 (STAT5)-dependent gene transcription.

STAT (signal transducer and activator of transcription) proteins play a critical role in cellular response to a wide variety of cytokines and growth factors by regulating specific nuclear genes. STAT-dependent gene transcription can be finely tuned through the association with co-factors in the nucleus. We showed previously that STAT5 (including 5a and 5b) specifically interacts with a mitochondrial enzyme PDC-E2 (E2 subunit of pyruvate dehydrogenase complex) in both leukemic T cells and cytokine-stimulated cells. However, the functional significance of this novel association remains largely unknown. Here we report that PDC-E2 may function as a co-activator in STAT5-dependent nuclear gene expression. Subcellular fractionation analysis revealed that a substantial amount of PDC-E2 was constitutively present in the nucleus of BaF3, an interleukin-3 (IL-3)-dependent cell line. IL-3-induced tyrosine-phosphorylated STAT5 associated with nuclear PDC-E2 in co-immunoprecipitation analysis. These findings were confirmed by confocal immunofluorescence microscopy showing constant nuclear localization of PDC-E2 and its co-localization with STAT5 after IL-3 stimulation. Similar to mitochondrial PDC-E2, nuclear PDC-E2 was lipoylated and associated with PDC-E1. Overexpression of PDC-E2 in BaF3 cells augmented IL-3-induced STAT5 activity as measured by reporter assay with consensus STAT5-binding sites. Consistent with the reporter data, PDC-E2 overexpression in BaF3 cells led to elevated mRNA levels of endogenous SOCS3 (suppressor of cytokine signaling 3) gene, a known STAT5 target. We further identified two functional STAT5-binding sites in the SOCS3 gene promoter important for its IL-3-inducibility. The observation that both cis-acting elements were essential to detect the stimulatory effect by PDC-E2 strongly supports the role of PDC-E2 in up-regulating the transactivating ability of STAT5. All together, our results reveal a novel function of PDC-E2 in the nucleus. It also raises the possibility of nuclear-mitochondrial crosstalk through the interaction between STAT5 and PDC-E2.

Suppressor of cytokine signaling 1 interacts with oncogenic lymphocyte-specific protein tyrosine kinase.

Lymphocyte-specific protein tyrosine kinase (Lck) plays a key role in T cell signal transduction and is tightly regulated by phosphorylation and dephosphorylation. Lck can function as an oncoprotein when overexpressed or constantly activated by mutations. Our previous studies showed that Lck-induced cellular transformation could be suppressed by enforced expression of suppressor of cytokine signaling 1 (SOCS1), a SOCS family member involved in the negative feedback control of cytokine signaling. We observed attenuated Lck kinase activity in SOCS1-expressing cells, suggesting an important role of SOCS in regulating Lck functions. It remains largely unknown whether and how SOCS proteins interact with the oncogenic Lck kinase. Here, we report that among four SOCS family proteins, SOCS1, SOCS2, SOCS3 and CIS (cytokine-inducible SH2 domain containing protein), SOCS1 has the highest affinity in binding to the oncogenic Lck kinase. We identified the positive regulatory phosphotyrosine 394 residue in the kinase domain as the key interacting determinant in Lck. Additionally, the Lck kinase domain alone is sufficient to bind SOCS1. While the SH2 domain in SOCS1 is important in its association with the oncogenic Lck kinase, other functional domains may also contribute to overall binding affinity. These findings provide important mechanistic insights into the role of SOCS proteins as tumor suppressors in cells transformed by oncogenic protein tyrosine kinases.