Gremlin1 has a distinct preference for which bone morphogenetic protein it binds to in kidney epithelial cells. Grem1–BMP-2 complexes are favoured over other BMPs, and this may play an important role in fibrotic kidney disease.

Gremlin1 (Grem1), an antagonist of bone morphogenetic proteins, plays a key role in embryogenesis. A highly specific temporospatial gradient of Grem1 and bone morphogenetic protein signaling is critical to normal lung, kidney, and limb development. Grem1 levels are increased in renal fibrotic conditions, including acute kidney injury, diabetic nephropathy, chronic allograft nephropathy, and immune glomerulonephritis. We demonstrate that a small number of grem1−/− whole body knockout mice on a mixed genetic background (8%) are viable, with a single, enlarged left kidney and grossly normal histology. The grem1−/− mice displayed mild renal dysfunction at 4 wk, which recovered by 16 wk. Tubular epithelial cell-specific targeted deletion of Grem1 (TEC-grem1-cKO) mice displayed a milder response in the acute injury and recovery phases of the folic acid model. Increases in indexes of kidney damage were smaller in TEC-grem1-cKO than wild-type mice. In the recovery phase of the folic acid model, associated with renal fibrosis, TEC-grem1-cKO mice displayed reduced histological damage and an attenuated fibrotic gene response compared with wild-type controls. Together, these data demonstrate that Grem1 expression in the tubular epithelial compartment plays a significant role in the fibrotic response to renal injury in vivo.

Background Digital therapeutics are evidence-based therapeutic interventions driven by high-quality software programs for the treatment, prevention, or management of a medical disorder or disease. Many studies in the western population have shown the effectiveness of mobile app–based digital therapeutics for improving glycemic control in patients with type 2 diabetes (T2D). However, few studies have assessed similar outcomes in the South Asian population. Objective This study aims to investigate the real-world effectiveness of the Wellthy CARE digital therapeutic for improving glycemic control among the South Asian population of Indian origin. Methods We analyzed deidentified data from 102 patients with T2D from India enrolled in a 16-week structured self-management program delivered using the Wellthy CARE mobile app. Patients recorded their meals, weight, physical activity, and blood sugar in the app, and they received lessons on self-care behaviors (healthy eating, being active, monitoring, medication adherence, problem solving, healthy coping, and reducing risks); feedback provided by an artificial intelligence–powered chatbot; and periodic interactions with certified diabetes educators via voice calls and chats. The primary outcome of the program was a change in glycated hemoglobin A1c (HbA1c). Secondary outcomes included the difference between preintervention and postintervention fasting blood glucose (FBG) and postprandial blood glucose (PPBG) levels; changes in BMI and weight at the completion of 16 weeks; and the association between program engagement and the changes in HbA1c, FBG, and PPBG levels. Results At the end of 16 weeks, the average change in HbA1c was –0.49% (n=102; 95% CI −0.73 to 0.25; P<.001). Of all the patients, 63.7% (65/102) had improved HbA1c levels, with a mean change of −1.16% (n=65; 95% CI −1.40 to −0.92; P<.001). The mean preintervention and postintervention FBG levels were 145 mg/dL (n=51; 95% CI 135-155) and 134 mg/dL (n=51; 95% CI 122-146; P=.02) and PPBG levels were 188 mg/dL (n=51; 95% CI 172-203) and 166 mg/dL (n=51; 95% CI 153-180; P=.03), respectively. The mean changes in BMI and weight were –0.47 kg/m2 (n=59; 95% CI −0.22 to −0.71; P<.001) and –1.32 kg (n=59; 95% CI −0.63 to −2.01; P<.001), respectively. There was a stepwise decrease in HbA1c, FBG, and PPBG levels as the program engagement increased. Patients in the highest tertile of program engagement had a significantly higher reduction in HbA1c (−0.84% vs −0.06%; P=.02), FBG (−21.4 mg/dL vs −0.18 mg/dL; P=.02), and PPBG levels (−22.03 mg/dL vs 2.35 mg/dL; P=.002) than those in the lowest tertile. Conclusions The use of the Wellthy CARE digital therapeutic for patients with T2D showed a significant reduction in the levels of HbA1c, FBG, and PPBG after 16 weeks. A higher level of participation showed improved glycemic control, suggesting the potential of the Wellthy CARE platform for better management of the disease.

The polyketide natural product borrelidin 1 is a potent inhibitor of angiogenesis and spontaneous metastasis. Affinity biopanning of a phage display library of colon tumor cell cDNAs identified the tandem WW domains of spliceosome-associated protein formin binding protein 21 (FBP21) as a novel molecular target of borrelidin, suggesting that borrelidin may act as a modulator of alternative splicing. In support of this idea, 1, and its more selective analog 2, bound to purified recombinant WW domains of FBP21. They also altered the ratio of vascular endothelial growth factor (VEGF) isoforms in retinal pigmented endothelial (RPE) cells in favour of anti-angiogenic isoforms. Transfection of RPE cells with FBP21 altered the ratio in favour of pro-angiogenic VEGF isoforms, an effect inhibited by 2. These data implicate FBP21 in the regulation of alternative splicing and suggest the potential of borrelidin analogs as tools to deconvolute key steps of spliceosome function.

Background: High out of pocket expenses have led to poor diabetes self-management and glycemic control in India. This study evaluates the impact of an iPDM (integrated personalized diabetes management) on blood glucose (BG) control. Methods: Study participants (n=286) used an iPDM consisting of the Accu-Chek® Active BG meter and the Wellthy Care™ digital therapeutic platform (WDTx), which allowed them to log BG values while receiving artificial intelligence-powered real-time feedback and self-management education. The BG values at baseline (M0), month 2 (M2), month 4 (M4), and month 6 (M6) were analyzed. Mean BG (MBG), Fasting BG (FBG), Post-meal BG (PBG), number of hypoglycemia logs (&lt;70 mg/dl), and in-range logs (FBG: 70-130 mg/dl; MBG/PBG: 70-180 mg/dl) were evaluated. Results: The average number of active days and BG logs by the participants was 75.9 days (95% CI: 66.0-85.7 days) and 73 logs (95% CI: 67-79 logs), respectively. The BG values and logs are summarized in Table 1. There was a significant reduction in BG from M0 to M2 after which the BG was stable over M4 and M6. There was also a reduction in the number of hypoglycemia logs and a corresponding increase in the number of in-range BG logs from M0 through M6. Conclusion: This study shows that an iPDM using SMBG and WDTx can be an effective and affordable tool for improving glycemic control and reducing hypoglycemia events in resource limited countries like India. Disclosure A. Krishnakumar: Employee; Self; Wellthy Therapeutics. V. Kumar: None. B.D. Saboo: None. V. Khatry: None. S. Joshi: Consultant; Self; Wellthy Therapeutics. R.R. Adhikary: Employee; Self; Wellthy Therapeutics. S. Kolwankar: Employee; Self; Wellthy Therapeutics. V. Mattoo: None.