Rothberg, Amy E.

ABSTRACT Importance Despite the current enthusiasm for anti‐obesity medications, there is a critical need for effective lifestyle interventions that can be broadly implemented. Objective To assess the effectiveness of REWIND, an obesity and diabetes treatment program. Design Prospective cohort study. Setting Virtual, community‐based weight management program. Participants Two‐hundred and nineteen participants, BMI ≥ 30 kg/m 2 , with and without type 2 diabetes (T2D). Intervention Three phases: “induction” with meal replacement diet to promote ≥ 15% weight loss; “transition” to everyday foods; and “maintenance” to prevent weight regain. REWIND leveraged teams including community leaders, media personalities, nationally recognized athletes and participants, to disseminate information, and foster belonging, commitment, and resilience. Main Outcomes The co‐primary outcomes were the change in weight at 6‐, 12‐, and 18 months. Secondary outcomes were the proportion of patients achieving ≥ 5%, 10%, 15%, and 20% weight loss at 6, 12, and 18 months, and remission rates in T2D at 6‐, 12‐, and 18‐month, respectively. Results Two hundred and nineteen participants (mean age 49.1 [SD 10.5] years), 37% men, 12% Black, 26% with T2D. Weight decreased from: 114.4 (20.8) kg to 96.1 (18.4) kg at 6 months, to 98.5 (18.1) kg at 12 months, and to 101.1 (20.5) kg at 18 months. Weight loss percentages at 6, 12, and 18 months were ≥ 5%: 95%, 91%, 84%; ≥ 10%: 79%, 72%, 67%; ≥ 15%: 58%, 46%, 47%; and ≥ 20%: 24%, 25%, 22%. Diabetes remission was achieved by 52% and 43% of participants with T2D at 12‐ and 18‐month, respectively. Limitations Single geographic region. Weight was self‐reported. Conclusion A virtual community‐based program for individuals with obesity and T2D facilitated substantial weight loss and T2D remission. This model has the potential for wide‐scale implementation in diverse settings.

AbstractBackgroundAutonomic dysfunction can be present in patients with idiopathic and diabetic gastroparesis. The role of autonomic dysfunction relating to gastric emptying and upper gastrointestinal symptoms in patients with gastroparesis and chronic unexplained nausea and vomiting (CUNV) remains unclear. The aim of our study is to evaluate autonomic function in patients with gastroparesis and CUNV with respect to etiology, gastric emptying and symptom severity.MethodsWe studied 242 patients with chronic gastroparetic symptoms recruited at eight centers. All patients had a gastric emptying scintigraphy within 6 months of the study. Symptom severity was assessed using the gastroparesis cardinal symptom index. Autonomic function testing was performed at baseline enrollment using the ANX 3.0 autonomic monitoring system which measures heart rate variability and respiratory activity measurements.Key ResultsLow sympathetic response to challenge (Valsalva or standing) was the most common abnormality seen impacting 89% diabetic and 74% idiopathic patients. Diabetics compared to idiopathics, exhibited greater global hypofunction with sympathetic (OR = 4.7, 95% CI 2.2‐10.3; P < .001) and parasympathetic (OR = 7.2, 95% CI 3.4‐15.0; P < .001) dysfunction. Patients with delayed gastric emptying were more likely to have paradoxic parasympathetic excessive during sympathetic challenge [(Valsalva or standing) 40% vs. 26%, P = .05]. Patients with more severe symptoms exhibited greater parasympathetic dysfunction compared to those with mild‐moderate symptoms: resting sympathovagal balance [LFa/RFa 1.8 (1.0‐3.1) vs. 1.2 (0.6‐2.3), P = .006)] and standing parasympathetic activity [0.4 (0.1‐0.8) vs. 0.6 (0.2‐1.7); P = .03].ConclusionsAutonomic dysfunction was common in patients with gastroparesis and CUNV. Parasympathetic dysfunction was associated with delayed gastric emptying and more severe upper gastrointestinal symptoms. Conversely, sympathetic hypofunction was associated with milder symptoms.InferencesGastroparesis and CUNV may be a manifestation of GI autonomic dysfunction or imbalance, such that sympathetic dysfunction occurs early on in the manifestation of chronic upper GI symptoms, while parasympathetic dysfunction results in more severe symptoms and delayed gastric emptying.

Macrophage-based immune dysregulation plays a critical role in development of delayed gastric emptying in diabetic mice. Loss of anti-inflammatory macrophages and increased expression of genes associated with pro-inflammatory macrophages has been reported in full-thickness gastric biopsies from gastroparesis patients. We aimed to determine broader protein expression (proteomics) and protein-based signaling pathways in gastric biopsies of diabetic (DG) and idiopathic gastroparesis (IG) patients. Additionally, we determined correlations between protein expressions, gastric emptying, and symptoms. Full-thickness gastric antrum biopsies were obtained from nine DG patients, seven IG patients, and five nondiabetic controls. Aptamer-based SomaLogic tissue scan that quantitatively identifies 1,305 human proteins was used. Protein fold changes were computed, and differential expressions were calculated using Limma. Ingenuity pathway analysis and correlations were carried out. Multiple-testing corrected P < 0.05 was considered statistically significant. Seventy-three proteins were differentially expressed in DG, 132 proteins were differentially expressed in IG, and 40 proteins were common to DG and IG. In both DG and IG, “Role of Macrophages, Fibroblasts and Endothelial Cells” was the most statistically significant altered pathway [DG false discovery rate (FDR) = 7.9 × 10−9; IG FDR = 6.3 × 10−12]. In DG, properdin expression correlated with GCSI bloating ( r = −0.99, FDR = 0.02) and expressions of prostaglandin G/H synthase 2, protein kinase C-ζ type, and complement C2 correlated with 4 h gastric retention ( r = −0.97, FDR = 0.03 for all). No correlations were found between proteins and symptoms or gastric emptying in IG. Protein expression changes suggest a central role of macrophage-driven immune dysregulation in gastroparesis, specifically, complement activation in diabetic gastroparesis. NEW & NOTEWORTHY This study uses SOMAscan, a novel proteomics assay for determination of altered proteins and associated molecular pathways in human gastroparesis. Seventy-three proteins were changed in diabetic gastroparesis, 132 in idiopathic gastroparesis compared with controls. Forty proteins were common in both. Macrophage-based immune dysregulation pathway was most significantly affected in both diabetic and idiopathic gastroparesis. Proteins involved in the complement and prostaglandin synthesis pathway were associated with symptoms and gastric emptying delay in diabetic gastroparesis.