Characterizing Diabetes Empowerment and Motivation for Changing Health Behaviors Among People with Type 2 Diabetes: A Cross-Sectional Survey.

INTRODUCTION: Effectively engaging people with type 2 diabetes (T2D) earlier in their health journeys is critical to prevent downstream complications. Digitally based diabetes programs are a growing component of care delivery that have the potential to engage individuals outside of traditional clinic-based settings and use personalized data to pair people to tailored diabetes self-management interventions. Knowing an individuals' diabetes empowerment and health-related motivation can help drive appropriate recommendations for personalized interventions. We aimed to characterize diabetes empowerment and motivation towards changing health behaviors among participants in Level2, a T2D specialty care organization in the USA that combines wearable technology with personalized clinical support. METHODS: A cross-sectional online survey was conducted among people enrolled in Level2 (February-March 2021). Distributions of respondent-reported diabetes empowerment and health motivation were analyzed using Motivation and Attitudes Toward Changing Health (MATCH) and Diabetes Empowerment Scale Short Form (DES-SF) scales, respectively. Associations between MATCH and DES-SF scores with Level2 engagement measures and glycemic control were analyzed. RESULTS: The final analysis included 1258 respondents with T2D (mean age 55.7 ± 8.4 years). Respondents had high average MATCH (4.19/5) and DES-SF (4.02/5) scores. The average MATCH subscores for willingness (4.43/5) and worthwhileness (4.39/5) were higher than the average ability subscore (3.73/5). Both MATCH and DES-SF scores showed very weak correlations with Level2 engagement measures and glycemic control (ρ = - 0.18-0.19). CONCLUSIONS: Level2 survey respondents had high average motivation and diabetes empowerment scores. Further research is needed to validate sensitivity of these scales to detect changes in motivation and empowerment over time and to determine whether differences in scores can be used to pair people to personalized interventions.

Real-world retrospective analysis of outcomes in patients undergoing bariatric surgery with class 1 obesity.

BACKGROUND: NIH-established indications for bariatric surgery were set close to 3 decades ago. OBJECTIVES: The purpose of this study was to evaluate outcomes in patients undergoing bariatric surgery with class I obesity, a class that does not fall into current indications. SETTING: University Hospital. METHODS: De-identified records from a clinic system's Electronic Health Record database were accessed to identify adult patients undergoing Roux-en-Y gastric bypass (RYGB) (n = 566) and sleeve gastrectomy (SG) (n = 730). Patients were compared in terms of resolution of co-morbidities and weight loss outcomes at 3 years following surgery. A mixed effects model was used, adjusting for the type of surgery, the number of quarters after the surgery when the averaged measurements were taken, and the interaction between these two variables. RESULTS: Patients lost up to 20% of their initial body mass index (BMI). Being of younger age, female, and having an obesity-related co-morbidity were associated with greater weight loss. At around 2 years after the surgery, the likelihood of being in remission from type 2 diabetes reached 45%. Remission probabilities for hypertension are 60% for RYGB and 50% for SG, 3 years after the surgery. On the other hand, the probabilities of remission from hyperlipidemia are close to 50% and 25% for RYGB and SG at 2 years. There was no difference between the BMI trajectories and remission from type 2 diabetes (T2D) when comparing the 2 groups. CONCLUSIONS: Bariatric surgery is effective in weight loss and resolution of comorbidities in patients with class I obesity. This data further supports the need to revisit the current indication criteria.

Retrospective comparative study of the effectiveness of bariatric surgery on 3-year outcomes in the real-world clinical setting.

BACKGROUND: Bariatric surgery has shown an improvement in obesity and obesity-related disease in many clinical trials and single center studies. However, real-world data, including data from non-centers of excellence, is sparse. OBJECTIVES: To provide clinical outcomes of patients who underwent bariatric surgery in real-world clinical setting. SETTING: Academic Institution. METHODS: Adults with obesity undergoing Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and a control group (CG) between 2007 and 2019 were identified. The CG represented patients with a previous visit to a bariatric surgeon without a subsequent surgery. Cohorts were matched on age, gender, ethnicity, baseline body mass index (BMI), and presence of diabetes and hypertension. Groups were compared in terms of co-morbidities, weight loss, and chronic conditions for three years. RESULTS: A total of 61 313 patients were identified. From these, 14 916 RYGB and 20 867 SG patients were matched to the CG (n = 16 562). The median BMI loss three years after surgery was 28.7% (interquartile range [IQR] 20.8%-36.2%) and 20.5% (IQR 13.5%-28.6%) for RYGB and SG groups, respectively. The CG had a median BMI loss of 6.7% with IQR of 20.4% decrease to 1.78% gain. At three years postoperatively, HbA1C decreased by 13% for RYGB and 5.9% for the SG group. The probabilities of remission from diabetes, hypertension, and low high-density lipoprotein cholesterol were significantly higher among patients who had surgery compared to the CG. For both RYGB and SG, the estimated probabilities of remission were similar. CONCLUSION: This study shows that bariatric surgery performed in the real-world clinical setting is an effective therapy for various expressions of the metabolic syndrome with results that are comparable to randomized control trials.

Risk Factors Associated with COVID-19 Hospitalization and Mortality: A Large Claims-Based Analysis Among People with Type 2 Diabetes Mellitus in the United States.

INTRODUCTION: Diabetes has been identified as a high-risk comorbidity for COVID-19 hospitalization. We evaluated additional risk factors for COVID-19 hospitalization and in-hospital mortality in a nationwide US database. METHODS: This retrospective study utilized the UnitedHealth Group Clinical Discovery Database (January 1, 2019-July 15, 2020) containing de-identified nationwide administrative claims, SARS-CoV-2 laboratory test results, and COVID-19 inpatient admissions data. Logistic regression was used to understand risk factors for hospitalization and in-hospital mortality among people with type 2 diabetes (T2D) and in the overall population. Robustness of associations was further confirmed by subgroup and sensitivity analyses in the T2D population. RESULTS: A total of 36,364 people were identified who were either SARS-CoV-2+ or hospitalized for COVID-19. T2D was associated with increased COVID-19-related hospitalization and mortality. Factors associated with increased hospitalization risk were largely consistent in the overall population and the T2D subgroup, including age, male sex, and these top five comorbidities: dementia, metastatic tumor, congestive heart failure, paraplegia, and metabolic disease. Biguanides (mainly metformin) were consistently associated with lower odds of hospitalization, whereas sulfonylureas and insulins were associated with greater odds of hospitalization among people with T2D. CONCLUSION: In this nationwide US analysis, T2D was identified as an independent risk factor for COVID-19 complications. Many factors conferred similar risk of hospitalization across both populations; however, particular diabetes medications may be markers for differential risk. The insights on comorbidities and medications may inform population health initiatives, including prevention efforts for high-risk patient populations such as those with T2D.

Empowering Patients and Providers With More and Better Data: Innovative Concepts in Type 2 Diabetes Management.

IN BRIEF In this article, the authors discuss several innovative concepts UnitedHealth Group Research & Development is exploring to help patients manage their type 2 diabetes. The article focuses on efforts to use remote support programs and wearable technology to empower patients to take more active roles in managing their health and to foster more interactive patient-provider conversations. Additionally, the authors reflect on how such efforts could particularly benefit medically underserved communities. They offer observations from claims data about current health outcomes and costs in underserved areas.

Developing a Biased Unmatched Bivalent Ligand (BUmBL) Design Strategy to Target the GPCR Homodimer Allosteric Signaling (cAMP over ß-Arrestin 2 Recruitment) Within the Melanocortin Receptors.

Understanding the functional relevance of G protein-coupled receptor (GPCR) homodimerization has been limited by the insufficient tools to assess asymmetric signaling occurring within dimers comprised of the same receptor type. We present unmatched bivalent ligands (UmBLs) to study the asymmetric function of melanocortin homodimers. UmBLs contain one agonist and one antagonist pharmacophore designed to target a melanocortin homodimer such that one receptor is occupied by an agonist and the other receptor by an antagonist pharmacophore. First-in-class biased UmBLs (BUmBLs) targeting the human melanocortin-4 receptor (hMC4R) were discovered. The BUmBLs displayed biased agonism by potently stimulating cAMP signaling (EC50 ∼ 2-6 nM) but minimally activating the ß-arrestin recruitment pathway (≤55% maximum signal at 10 µM). To our knowledge, we report the first single-compound strategy to pharmacologically target melanocortin receptor allosteric signaling that occurs between homodimers that can be applied straightforwardly in vitro and in vivo to other GPCR systems.

Differentiating Antiproliferative and Chemopreventive Modes of Activity for Electron-Deficient Aryl Isothiocyanates against Human MCF-7 Cells.

The consumption of Brassica vegetables provides beneficial effects through organic isothiocyanates (ITCs), products of the enzymatic hydrolysis of glucosinolate secondary metabolites. The ITC l-sulforaphane (l-SFN) is the principle agent in broccoli that demonstrates several modes of anticancer action. While the anticancer properties of ITCs like l-SFN have been extensively studied and l-SFN has been the subject of multiple human clinical trials, the scope of this work has largely been limited to those derivatives found in nature. Previous studies have demonstrated that structural changes in an ITC can lead to marked differences in a compound's potency to 1) inhibit the growth of cancer cells, and 2) alter cellular transcriptional profiles. This study describes the preparation of a library of non-natural aryl ITCs and the development of a bifurcated screening approach to evaluate the dose- and time-dependence on antiproliferative and chemopreventive properties against human MCF-7 breast cancer cells. Antiproliferative effects were evaluated using a commercial MTS cell viability assay. Chemopreventive properties were evaluated using an antioxidant response element (ARE)-promoted luciferase reporter assay. The results of this study have led to the identification of 1) several key structure-activity relationships and 2) lead ITCs for continued development.

Discovery of Melanocortin Ligands via a Double Simultaneous Substitution Strategy Based on the Ac-His-dPhe-Arg-Trp-NH2 Template.

The melanocortin system regulates an array of diverse physiological functions including pigmentation, feeding behavior, energy homeostasis, cardiovascular regulation, sexual function, and steroidogenesis. Endogenous melanocortin agonist ligands all possess the minimal messaging tetrapeptide sequence His-Phe-Arg-Trp. Based on this endogenous sequence, the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide has previously been shown to be a useful scaffold when utilizing traditional positional scanning approaches to modify activity at the various melanocortin receptors (MC1-5R). The study reported herein was undertaken to evaluate a double simultaneous substitution strategy as an approach to further diversify the Ac-His1-dPhe2-Arg3-Trp4-NH2 tetrapeptide with concurrent introduction of natural and unnatural amino acids at positions 1, 2, or 4, as well as an octanoyl residue at the N-terminus. The designed library includes the following combinations: (A) double simultaneous substitution at capping group position (Ac) together with position 1, 2, or 4, (B) double simultaneous substitution at positions 1 and 2, (C) double simultaneous substitution at positions 1 and 4, and (D) double simultaneous substitution at positions 2 and 4. Several lead ligands with unique pharmacologies were discovered in the current study including antagonists targeting the neuronal mMC3R with minimal agonist activity and ligands with selective profiles for the various melanocortin subtypes. The results suggest that the double simultaneous substitution strategy is a suitable approach in altering melanocortin receptor potency or selectivity or converting agonists into antagonists and vice versa.

Human ß-Defensin 1 and ß-Defensin 3 (Mouse Ortholog mBD14) Function as Full Endogenous Agonists at Select Melanocortin Receptors.

ß-Defensin 3 (BD3) was identified as a ligand for the melanocortin receptors (MCRs) in 2007, although the pharmacology activity of BD3 has not been clearly elucidated. Herein, it is demonstrated that human BD3 and mouse BD3 are full micromolar agonists at the MCRs. Furthermore, mouse ß-defensin 1 (BD1) and human BD1 are also MCR micromolar agonists. This work identifies BD1 as an endogenous MCR ligand and clarifies the controversial role of BD3 as a micromolar agonist.

1,2,3-Triazole Rings as a Disulfide Bond Mimetic in Chimeric AGRP-Melanocortin Peptides: Design, Synthesis, and Functional Characterization.

The melanocortin system is involved in the regulation of complex physiological functions, including energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. The five melanocortin receptors that belong to the superfamily of G protein-coupled receptors (GPCRs) are regulated by endogenously expressed agonists and antagonists. The aim of this study was to explore the potential of replacing the disulfide bridge in chimeric AGRP-melanocortin peptide Tyr-c[Cys-His-d-Phe-Arg-Trp-Asn-Ala-Phe-Cys]-Tyr-NH2 (1) with 1,2,3-triazole moieties. A series of 1,2,3-triazole-bridged peptidomimetics were designed, synthesized, and pharmacologically evaluated at the mouse melanocortin receptors. The ligands possessed nanomolar to micromolar agonist cAMP signaling potency. A key finding was that the disulfide bond in peptide 1 can be replaced with the monotriazole ring with minimal effect on the functional activity at the melanocortin receptors. The 1,5-disubstituted triazole-bridged peptide 6 showed equipotent functional activity at the mMC3R and modest 5-fold decreased agonist potency at the mMC4R compared to those of 1. Interestingly, the 1,4- and 1,5-disubstituted isomers of the triazole ring resulted in different selectivities at the receptor subtypes, indicating subtle structural features that may be exploited in the generation of selective melanocortin ligands. Introducing cyclic and acyclic bis-triazole moieties into chimeric AGRP template 1 generally decreased agonist activity. These results will be useful for the further design of neuronal chemical probes for the melanocortin receptors as well as in other receptor systems.

Comparative in Vivo Investigation of Intrathecal and Intracerebroventricular Administration with Melanocortin Ligands MTII and AGRP into Mice.

Central administration of melanocortin ligands has been used as a critical technique to study energy homeostasis. While intracerebroventricular (ICV) injection is the most commonly used method during these investigations, intrathecal (IT) injection can be equally efficacious for the central delivery of ligands. Importantly, intrathecal administration can optimize exploration of melanocortin receptors in the spinal cord. Herein, we investigate comparative IT and ICV administration of two melanocortin ligands, the synthetic MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2) MC4R agonist and agouti-related peptide [AGRP(87-132)] MC4R inverse agonist/antagonist, on the same batch of age-matched mice in TSE metabolic cages undergoing a nocturnal satiated paradigm. To our knowledge, this is the first study to test how central administration of these ligands directly to the spinal cord affects energy homeostasis. Results showed, as expected, that MTII IT administration caused a decrease in food and water intake and an overall negative energy balance without affecting activity. As anticipated, IT administration of AGRP caused weight gain, increase of food/water intake, and increase respiratory exchange ratio (RER). Unexpectantly, the prolonged activity of AGRP was notably shorter (2 days) compared to mice given ICV injections of the same concentrations in previous studies (7 days or more).1-4 It appears that IT administration results in a more sensitive response that may be a good approach for testing synthetic compound potency values ranging in nanomolar to high micromolar in vitro EC50 values. Indeed, our investigation reveals that the spine influences a different melanocortin response compared to the brain for the AGRP ligand. This study indicates that IT administration can be a useful technique for future metabolic studies using melanocortin ligands and highlights the importance of exploring the role of melanocortin receptors in the spinal cord.

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016.

The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress. This article is part of a Special Issue entitled: Melanocortin Receptors - edited by Ya-Xiong Tao.

A Direct in Vivo Comparison of the Melanocortin Monovalent Agonist Ac-His-DPhe-Arg-Trp-NH2 versus the Bivalent Agonist Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2: A Bivalent Advantage.

Bivalent ligands targeting putative melanocortin receptor dimers have been developed and characterized in vitro; however, studies of their functional in vivo effects have been limited. The current report compares the effects of homobivalent ligand CJL-1-87, Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH2, to monovalent ligand CJL-1-14, Ac-His-DPhe-Arg-Trp-NH2, on energy homeostasis in mice after central intracerebroventricular (ICV) administration into the lateral ventricle of the brain. Bivalent ligand CJL-1-87 had noteworthy advantages as an antiobesity probe over CJL-1-14 in a fasting-refeeding in vivo paradigm. Treatment with CJL-1-87 significantly decreased food intake compared to CJL-1-14 or saline (50% less intake 2-8 h after treatment). Furthermore, CJL-1-87 treatment decreased the respiratory exchange ratio (RER) without changing the energy expenditure indicating that fats were being burned as the primary fuel source. Additionally, CJL-1-87 treatment significantly lowered body fat mass percentage 6 h after administration (p < 0.05) without changing the lean mass percentage. The bivalent ligand significantly decreased insulin, C-peptide, leptin, GIP, and resistin plasma levels compared to levels after CJL-1-14 or saline treatments. Alternatively, ghrelin plasma levels were significantly increased. Serum stability of CJL-1-87 and CJL-1-14 (T1/2 = 6.0 and 16.8 h, respectively) was sufficient to permit physiological effects. The differences in binding affinity of CJL-1-14 compared to CJL-1-87 are speculated as a possible mechanism for the bivalent ligand's unique effects. We also provide in vitro evidence for the formation of a MC3R-MC4R heterodimer complex, for the first time to our knowledge, that may be an unexploited neuronal molecular target. Regardless of the exact mechanism, the advantageous ability of CJL-1-87 compared to CJL-1-14 to increase in vitro binding affinity, increase the duration of action in spite of decreased serum stability, decrease in vivo food intake, decrease mice's body fat percent, and differentially affect mouse hormone levels demonstrates the distinct characteristics achieved from the current melanocortin agonist bivalent design strategy.

Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, a 250-Fold Selective Melanocortin-4 Receptor (MC4R) Antagonist over the Melanocortin-3 Receptor (MC3R), Affects Energy Homeostasis in Male and Female Mice Differently.

The melanocortin-4 receptor (MC4R) has been indicated as a therapeutic target for metabolic disorders such as anorexia, cachexia, and obesity. The current study investigates the in vivo effects on energy homeostasis of a 15 nM MC4R antagonist SKY2-23-7, Ac-Trp-DPhe(p-I)-Arg-Trp-NH2, that is a 3700 nM melanocortin-3 receptor (MC3R) antagonist with minimal MC3R and MC4R agonist activity. When monitoring both male and female mice in TSE metabolic cages, sex-specific responses were observed in food intake, respiratory exchange ratio (RER), and energy expenditure. A 7.5 nmol dose of SKY2-23-7 increased food intake, increased RER, and trended toward decreasing energy expenditure in male mice. However, this compound had minimal effect on female mice's food intake and RER at the 7.5 nmol dose. A 2.5 nmol dose of SKY2-23-7 significantly increased female food intake, RER, and energy expenditure while having a minimal effect on male mice at this dose. The observed sex differences of SKY2-23-7 administration result in the discovery of a novel chemical probe for elucidating the molecular mechanisms of the sexual dimorphism present within the melanocortin pathway. To further explore the melanocortin sexual dimorphism, hypothalamic gene expression was examined. The mRNA expression of the MC3R and proopiomelanocortin (POMC) were not significantly different between sexes. However, the expression of agouti-related peptide (AGRP) was significantly higher in female mice which may be a possible mechanism for the sex-specific effects observed with SKY2-23-7.

An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers.

Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds, suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 possessed a functional profile that was unique from its monovalent counterpart providing evidence of the discrete effects of bivalent ligands. Lead compound 7 significantly decreased feeding in mice after intracerebroventricular administration. To the best of our knowledge, this is the first report of a melanocortin bivalent ligand's in vivo physiological effects.