Effectiveness of a culturally tailored diabetes education curriculum with real-time continuous glucose monitoring in a Latinx population with type 2 diabetes: the CUT-DM with CGM for Latinx randomised controlled trial study protocol.

INTRODUCTION: The prevalence of type 2 diabetes (T2D) is increasing in the Latinx community. Despite telehealth and technology becoming more available, these resources are not reaching the Latinx population. Diabetes education is a cornerstone of treatment; however, access to culturally tailored content is a barrier to the Latinx population. Real-time continuous glucose monitoring (RT-CGM) is a patient-empowering tool that can improve glycaemic control, but it is not readily available for Latinx patients with T2D. We aim to evaluate a culturally tailored diabetes self-management education and support (DSMES) curriculum, using a team-based approach to improve glycaemic control, promote healthy behaviours and enhance patient access with the use of telehealth in Latinx individuals. The primary aim of the study is to evaluate the additive effectiveness of RT-CGM on glycaemia and behavioural changes among Latinx patients undergoing a culturally tailored DSMES. A sub aim of the study is to evaluate family members' change in behaviours. METHODS: We propose a randomised controlled trial of blinded versus RT-CGM with 100 Latinx participants with T2D who will receive DSMES via telemedicine over 12 weeks (n=50 per group). The study will be conducted at a single large federally qualified health centre system. The control group will receive culturally tailored DSMES and blinded CGM. The intervention group will receive DSMES and RT-CGM. The DSMES is conducted by community health educators weekly over 12 weeks in Spanish or English, based on participant's language preference. Patients in the RT-CGM group will have cyclical use with a goal of 50 days wear time. The primary outcomes are changes in haemoglobin A1c and CGM-derived metrics at 3 and 6 months. The secondary outcomes include participants' self-management knowledge and behaviour and household members' change in lifestyle. ETHICS AND DISSEMINATION: The study proposal was approved by the University of Washington ethics/institutional review board (IRB) Committee as minimal risk (IRB ID: STUDY00014396) and the Sea Mar IRB committee. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT05394844.

Telementoring With Project ECHO: A New Era in Diabetes-Related Continuing Education for Primary Care to Address Health Disparities.

Project ECHO® is a telementoring workforce development model that targets under-resourced communities lacking access to specialty care. The model builds virtual communities of practice, including specialists and community primary care professionals (PCPs) to combat clinical inertia and health disparities. While the ECHO model has gained global recognition, implementation of the model related to diabetes is lagging compared to other specialty conditions. This review highlights diabetes-endocrine (ENDO)-focused ECHOs using data reported in the ECHO Institute's centralized data repository (iECHO) and the learning collaborative for diabetes ECHOs. It also describes the implementation of diabetes ECHOs and their evaluation. Learner and patient-centered outcomes related to diabetes ECHOs are reviewed. Program implementation and evaluations have demonstrated utility of the ECHO model for diabetes programs to (1) address unmet needs of diabetes care in the primary care setting, (2) improve knowledge and confidence in managing complex diabetes and change provider prescribing habits, (3) improve patient outcomes, and (4) address diabetes quality improvement practices in primary care. More studies with broader collaboration among sites are needed to evaluate the model related to diabetes, especially applied to addressing therapeutic inertia, adoption of diabetes technology, and reducing health disparities.

Improving Specialty Care Access via Telemedicine.

Introduction: Telehealth is a potential solution to persistent disparities in health and health care access by eliminating structural barriers to care. However, its adoption in urban underserved settings has been limited and remains poorly characterized. Methods: This is a prospective cohort study of patients receiving telemedicine (TM) consultation for specialty care of diabetes, hypertension, and/or kidney disease with a Federally Qualified Health Center (FQHC) as the originating site and an academic medical center (AMC) multispecialty group practice as the distant site in an urban setting. Primary data were collected onsite at a local FQHC and an urban AMC between March 2017 and March 2020, before the COVID-19 pandemic. Clinical outcomes of study participants were compared with matched controls (CON) from a sister FQHC site who were referred for traditional in-person specialty visits at the AMC. No-show rates for study participants were calculated and compared to their no-show rates for standard (STD) in-person specialty visits at the AMC during the study period. A patient satisfaction questionnaire was administered at the end of each TM visit. Results: Visit attendance data were analyzed for 104 patients (834 visits). The no-show rate was 15%. The adjusted odds ratio for no-show for TM versus STD visits was 1.03 [0.66-1.63], p = 0.87. There were no significant differences between TM and CON groups in the change from pre- to intervention periods for mean arterial pressure (p = 0.26), serum creatinine (p = 0.90), or estimated glomerular filtration rate (p = 0.56). The reduction in hemoglobin A1c was significant at a trend level (p = 0.053). Patients indicated high overall satisfaction with TM. Discussion: The study demonstrated improved glycemic control and equivalent outcomes in TM management of hypertension and kidney disease with excellent patient satisfaction. This supports ongoing efforts to increase the availability of TM to improve access to care for urban underserved populations.

Stepping Forward With Real-Time Continuous Glucose Monitoring in the Primary Care Practice.

The goal of this activity is that learners will be better able to use real-time CGM (rtCGM) in appropriate patients with type 2 diabetes.

Use of Premixed Insulin, Metformin, and a Glucagon-Like Peptide 1 Receptor Agonist as a Therapeutic Approach for Uncontrolled Type 2 Diabetes.

OBJECTIVE | To explore the use of premixed insulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, and metformin as combination therapy for type 2 diabetes. DESIGN AND METHODS | All adult patients with type 2 diabetes who had been prescribed premixed insulin and a GLP-1 receptor agonist simultaneously at our outpatient clinic were selected for retrospective review. We reviewed A1C, weight, cumulative daily insulin dose, and adverse events over 12 months. RESULTS | A total of 72 patients received premixed insulin and a GLP-1 receptor agonist, of which 32 met inclusion criteria. The average duration of type 2 diabetes for these patients was 14.2 ± 7.1 years. Mean A1C at baseline was 10.5 ± 2.1%. At 12 months, mean A1C was 8.3 ± 1.9%. The change in mean A1C after 12 months was -2.2% (95% CI -3.433 to -1.014, P <0.0001). At 12 months, the mean cumulative insulin dose was 33.3 units less than before the therapy change (95% CI -57.13 to -9.46, P = 0.0030). Average weight change at 12 months was -2.2 kg (95% CI -27.6 to 37.6, P = NS). After 12 months, 61% of included patients (19 of 31) had an A1C ≤8%. Six additional patients were not included in analysis because they stopped the regimen after <3 months because of adverse events. CONCLUSION | Despite a decreased cumulative daily dose of insulin, patients with historically uncontrolled type 2 diabetes using metformin, premixed insulin, and a GLP-1 receptor agonist in combination experienced improved glycemic control over 12 months. Prospective randomized trials are needed to better assess the potential benefit of this combination therapy.

Continuous Glucose Monitoring As a Behavior Modification Tool.

Real-time continuous glucose monitoring (CGM) use may lead to behavioral modifications in food selection and physical activity, but there are limited data on the utility of CGM in facilitating lifestyle changes. This article describes an 18-item survey developed to explore whether patients currently using CGM believe the technology has caused them to change their behavior.

Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Mice and Humans.

OBJECTIVE: Aging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-associated insulin resistance is due to increased adiposity or other age-related factors. To address this question, the impact of aging on insulin sensitivity was investigated independently of changes in body composition. METHODS: Cohorts of mice aged 4 to 8 months ("young") and 18 to 27 months ("aged") exhibiting similar body composition were characterized for glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analyses. The relationship between aging and insulin resistance in humans was investigated in 1,250 nondiabetic Mexican Americans who underwent hyperinsulinemic-euglycemic clamps. RESULTS: In mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. While aging did not diminish glucose tolerance, hyperinsulinemic-euglycemic clamps demonstrated impaired insulin sensitivity and reduced insulin clearance in aged mice on chow and high-fat diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican American males. CONCLUSIONS: This study demonstrates that in addition to altered body composition, adiposity-independent mechanisms also contribute to aging-associated insulin resistance in mice and humans.

Behavior Modification in Prediabetes and Diabetes: Potential Use of Real-Time Continuous Glucose Monitoring.

Real-time continuous glucose monitoring (RT-CGM) provides real time glucose readings to participants wearing the device. The ability to see changes in glucose has the potential to provide immediate feedback to users on food choices and physical activity. The National Diabetes Prevention Program is currently the only reimbursable intervention for diabetes prevention and weight loss. The purpose of this article is to review the CGM literature on measurements other than Hemoglobin A1c (HbA1c) changes and hypoglycemia and discuss RT-CGM potential use as a behavior modification tool for lifestyle changes and weight reduction in people with prediabetes and type 2 diabetes (T2D).

Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis.

The human transmembrane 6 superfamily member 2 (TM6SF2) gene has been implicated in plasma lipoprotein metabolism, alcoholic and non-alcoholic fatty liver disease and myocardial infarction in multiple genome-wide association studies. To investigate the role of Tm6sf2 in metabolic homeostasis, we generated mice with elevated expression using adeno-associated virus (AAV)-mediated gene delivery. Hepatic overexpression of mouse Tm6sf2 resulted in phenotypes previously observed in Tm6sf2-deficient mice including reduced plasma lipid levels, diminished hepatic triglycerides secretion and increased hepatosteatosis. Furthermore, increased hepatic Tm6sf2 expression protected against the development of atherosclerosis in LDL-receptor/ApoB48-deficient mice. In cultured human hepatocytes, Tm6sf2 overexpression reduced apolipoprotein B secretion and resulted in its accumulation within the endoplasmic reticulum (ER) suggesting impaired ER-to-Golgi trafficking of pre-very low-density lipoprotein (VLDL) particles. Analysis of two metabolic trait-associated coding polymorphisms in the human TM6SF2 gene (rs58542926 and rs187429064) revealed that both variants impact TM6SF2 expression by affecting the rate of protein turnover. These data demonstrate that rs58542926 (E167K) and rs187429064 (L156P) are functional variants and suggest that they influence metabolic traits through altered TM6SF2 protein stability. Taken together, our results indicate that cellular Tm6sf2 level is an important determinant of VLDL metabolism and further implicate TM6SF2 as a causative gene underlying metabolic disease and trait associations at the 19p13.11 locus.

Embryonic viability, lipase deficiency, hypertriglyceridemia and neonatal lethality in a novel LMF1-deficient mouse model.

BACKGROUND: Lipase Maturation Factor 1 (LMF1) is an ER-chaperone involved in the post-translational maturation and catalytic activation of vascular lipases including lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL). Mutations in LMF1 are associated with lipase deficiency and severe hypertriglyceridemia indicating the critical role of LMF1 in plasma lipid homeostasis. The currently available mouse model of LMF1 deficiency is based on a naturally occurring truncating mutation, combined lipase deficiency (cld), which may represent a hypomorphic allele. Thus, development of LMF1-null mice is needed to explore the phenotypic consequences of complete LMF1 deficiency. FINDINGS: In situ hybridization and qPCR analysis in the normal mouse embryo revealed ubiquitous and high-level LMF1 expression. To investigate if LMF1 was required for embryonic viability, a novel mouse model based on a null-allele of LMF1 was generated and characterized. LMF1-/- progeny were born at Mendelian ratios and exhibited combined lipase deficiency, hypertriglyceridemia and neonatal lethality. CONCLUSION: Our results raise the possibility of a previously unrecognized role for LMF1 in embryonic development, but indicate that LMF1 is dispensable for the viability of mouse embryo. The novel mouse model developed in this study will be useful to investigate the full phenotypic spectrum of LMF1 deficiency.

The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism.

Sel1L is an essential adaptor protein for the E3 ligase Hrd1 in the endoplasmic reticulum (ER)-associated degradation (ERAD), a universal quality-control system in the cell; but its physiological role remains unclear. Here we show that mice with adipocyte-specific Sel1L deficiency are resistant to diet-induced obesity and exhibit postprandial hypertriglyceridemia. Further analyses reveal that Sel1L is indispensable for the secretion of lipoprotein lipase (LPL), independent of its role in Hrd1-mediated ERAD and ER homeostasis. Sel1L physically interacts with and stabilizes the LPL maturation complex consisting of LPL and lipase maturation factor 1 (LMF1). In the absence of Sel1L, LPL is retained in the ER and forms protein aggregates, which are degraded primarily by autophagy. The Sel1L-mediated control of LPL secretion is also seen in other LPL-expressing cell types including cardiac myocytes and macrophages. Thus, our study reports a role of Sel1L in LPL secretion and systemic lipid metabolism.

Lipase maturation factor 1 (lmf1) is induced by endoplasmic reticulum stress through activating transcription factor 6α (Atf6α) signaling.

Lipase maturation factor 1 (Lmf1) is a critical determinant of plasma lipid metabolism, as demonstrated by severe hypertriglyceridemia associated with its mutations in mice and human subjects. Lmf1 is a chaperone localized to the endoplasmic reticulum (ER) and required for the post-translational maturation and activation of several vascular lipases. Despite its importance in plasma lipid homeostasis, the regulation of Lmf1 remains unexplored. We report here that Lmf1 expression is induced by ER stress in various cell lines and in tunicamycin (TM)-injected mice. Using genetic deficiencies in mouse embryonic fibroblasts and mouse liver, we identified the Atf6α arm of the unfolded protein response as being responsible for the up-regulation of Lmf1 in ER stress. Experiments with luciferase reporter constructs indicated that ER stress activates the Lmf1 promoter through a GC-rich DNA sequence 264 bp upstream of the transcriptional start site. We demonstrated that Atf6α is sufficient to induce the Lmf1 promoter in the absence of ER stress, and this effect is mediated by the TM-responsive cis-regulatory element. Conversely, Atf6α deficiency induced by genetic ablation or a dominant-negative form of Atf6α abolished TM stimulation of the Lmf1 promoter. In conclusion, our results indicate that Lmf1 is an unfolded protein response target gene, and Atf6α signaling is sufficient and necessary for activation of the Lmf1 promoter. Importantly, the induction of Lmf1 by ER stress appears to be a general phenomenon not restricted to lipase-expressing cells, which suggests a lipase-independent cellular role for this protein in ER homeostasis.

Primary squamous cell carcinoma of the thyroid gland: a case report and review.

BACKGROUND: Primary squamous cell carcinoma (SCC) of the thyroid gland is a rare malignancy that presents with advanced disease and poor prognosis. METHODS: A 75-year-old woman with a history of Hashimoto thyroiditis presented with 6 months of dysphagia and stridor. Imaging revealed a thyroid mass invading the larynx. Primary SCC of the thyroid was diagnosed by histopathologic and immunohistochemical evaluation. Total thyroidectomy, total laryngectomy, bilateral modified neck dissection, and adjuvant radiotherapy (RT) were performed. Radiologic follow-up at 21 months demonstrated no disease and total length of survival was 31 months. RESULTS: Despite an aggressive T4aN0M0 tumor, survival in this case was more than double the median survival rate previously reported. Concomitant Hashimoto thyroiditis is rare and histopathologic and immunohistochemical evaluation is imperative for an accurate diagnosis. CONCLUSION: The case and literature reported here support that a thorough diagnostic workup of primary SCC of the thyroid with aggressive locoregional surgery and adjuvant RT may improve the length of survival.

Heterogeneity of responses to real-time continuous glucose monitoring (RT-CGM) in patients with type 2 diabetes and its implications for application.

OBJECTIVE: To characterize glucose response patterns of people who wore a real-time continuous glucose monitor (RT-CGM) as an intervention to improve glycemic control. Participants had type 2 diabetes, were not taking prandial insulin, and interpreted the RT-CGM data independently. RESEARCH DESIGN AND METHODS: Data were from the first 12 weeks of a 52-week, prospective, randomized trial comparing RT-CGM (n = 50) with self-monitoring of blood glucose (n = 50). RT-CGM was used in 8 of the first 12 weeks. A1C was collected at baseline and quarterly. This analysis included 45 participants who wore the RT-CGM ≥4 weeks. Analyses examined the RT-CGM data for common response patterns-a novel approach in this area of research. It then used multilevel models for longitudinal data, regression, and nonparametric methods to compare the patterns of A1C, mean glucose, glycemic variability, and views per day of the RT-CGM device. RESULTS: There were five patterns. For four patterns, mean glucose was lower than expected as of the first RT-CGM cycle of use given participants' baseline A1C. We named them favorable response but with high and variable glucose (n = 7); tight control (n = 14); worsening glycemia (n = 6); and incremental improvement (n = 11). The fifth was no response (n = 7). A1C, mean glucose, glycemic variability, and views per day differed across patterns at baseline and longitudinally. CONCLUSIONS: The patterns identified suggest that targeting people with higher starting A1Cs, using it short-term (e.g., 2 weeks), and monitoring for worsening glycemia that might be the result of burnout may be the best approach to using RT-CGM in people with type 2 diabetes not taking prandial insulin.

Long-term proteasomal inhibition in transgenic mice by UBB(+1) expression results in dysfunction of central respiration control reminiscent of brainstem neuropathology in Alzheimer patients.

Aging and neurodegeneration are often accompanied by a functionally impaired ubiquitin-proteasome system (UPS). In tauopathies and polyglutamine diseases, a mutant form of ubiquitin B (UBB(+1)) accumulates in disease-specific aggregates. UBB(+1) mRNA is generated at low levels in vivo during transcription from the ubiquitin B locus by molecular misreading. The resulting mutant protein has been shown to inhibit proteasome function. To elucidate causative effects and neuropathological consequences of UBB(+1) accumulation, we used a UBB(+1) expressing transgenic mouse line that models UPS inhibition in neurons and exhibits behavioral phenotypes reminiscent of Alzheimer's disease (AD). In order to reveal affected organs and functions, young and aged UBB(+1) transgenic mice were comprehensively phenotyped for more than 240 parameters. This revealed unexpected changes in spontaneous breathing patterns and an altered response to hypoxic conditions. Our findings point to a central dysfunction of respiratory regulation in transgenic mice in comparison to wild-type littermate mice. Accordingly, UBB(+1) was strongly expressed in brainstem regions of transgenic mice controlling respiration. These regions included, e.g., the medial part of the nucleus of the tractus solitarius and the lateral subdivisions of the parabrachial nucleus. In addition, UBB(+1) was also strongly expressed in these anatomical structures of AD patients (Braak stage #6) and was not expressed in non-demented controls. We conclude that long-term UPS inhibition due to UBB(+1) expression causes central breathing dysfunction in a transgenic mouse model of AD. The UBB(+1) expression pattern in humans is consistent with the contribution of bronchopneumonia as a cause of death in AD patients.