Effectiveness and Safety of Sotagliflozin in Slowing Kidney Function Decline in Persons With Type 1 Diabetes and Moderate to Severe Diabetic Kidney Disease

Powerful new drugs that can prevent or delay end stage kidney disease (ESKD) - so called sodium-glucose cotransporter-2 inhibitors (SGLT2i) - are now available for patients with type 2 diabetes. Whether these drugs have similar effects in patients with type 1 diabetes (T1D) remains unknown because of the few studies in this population, due to concerns about the increase in risk of diabetic ketoacidosis (DKA, a serious, potentially fatal acute complication of diabetes due to the accumulation of substances called ketone bodies) observed with SGLT2i therapy in T1D. One of the few T1D studies conducted to date showed that implementing an enhanced DKA prevention plan can reduce the risk of DKA associated with the SGLT2i sotagliflozin (SOTA) to very low levels. In the present study, a similar DKA prevention program will be used to carry-out a 3-year trial to test the kidney benefit of SOTA in 150 persons with T1D and moderate to advanced DKD. After a 2-month period, during which diabetes care will be standardized and education on monitoring and minimizing DKA implemented, eligible study subjects will be randomly assigned (50/50) to take one tablet of SOTA (200 mg) or a similarly looking inactive tablet (placebo) every day for 3 years followed by 2-months without treatment. Neither the participants nor the study staff will know whether a person was assigned to taking SOTA or the inactive tablet. Kidney function at the end of the study will be compared between the two treatment groups to see whether SOTA prevented kidney function loss in those treated with this drug as compared to those who took the inactive tablet. The DKA prevention program will include participant education, close follow-up with study staff, continuous glucose monitoring, and systematic ketone body self-monitoring with a meter provided by the study. If successful, this study will provide efficacy and safety data that could be used to seek FDA approval of SOTA for the prevention of kidney function decline in patients with T1D and DKD.

开始日期2024-10-15

申办/合作机构

Joslin Diabetes Center, Inc.

[+24]

NCT06069583 / Not yet recruitingN/AIIT

Using the Support Online Platform for Self-management Education of Adults Living With Type 1 Diabetes as Part of Usual Care or Independently: an Implementation Study

The investigators will conduct a trial to evaluate if an online training and support platform can help adults living with type 1 diabetes (T1D) in their diabetes self-management. Investigators will compare a group that has access to the "Support" platform through their usual medical care to a group that accesses the platform independently. The first group will be recruited through four participating clinics in the province of Quebec (Canada). The second group will be composed of adults living with T1D across Canada. Participants will have access to the platform for 12 months and will be asked to complete online questionnaires at the beginning and after 6 and 12 months, and share their glucose reader data with the research team. A subgroup of participants as well as healthcare professionals from the four clinics will be invited to participate in an individual interview aiming to understand the barriers and facilitators of integration "Support" in clinical care.

开始日期2024-01-05

申办/合作机构

McGill University

[+2]

NCT06158503 / Not yet recruitingN/AIIT

GLYcemic COntrol and OSTEOhealth: Impact of Short-Term Glycemic Control on Skeletal Outcomes in Adults With Type 1 Diabetes

Bone damage is frequently observed in type 1 diabetes, and hyperglycemia is associated with an increased risk of fracture. This pilot study in 25 people living with type 1 diabetes aims to determine whether the introduction of an automated insulin delivery (AID) system improves bone markers through rapide optimization of glycemic control. Measurements will be taken before the start of AID, 2 months and 4 months afterwards.

开始日期2024-01-01

申办/合作机构

Institut de recherches cliniques de Montréal

[+1]

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2024-11-01·JOURNAL OF BIOLOGICAL CHEMISTRY

GDF10 is a negative regulator of vascular calcification

Article

作者: Krepinsky, Joan C. ; Seidah, Nabil G. ; Igdoura, Suleiman A. ; Krepinsky, Joan C ; Platko, Khrystyna ; Gyulay, Gabriel ; Byun, Jae Hyun ; Igdoura, Suleiman A ; Holden, Rachel M ; Lynn, Edward G. ; Lebeau, Paul F. ; Holden, Rachel M. ; MacDonald, Melissa E ; Lynn, Edward G ; Austin, Richard C ; Roubtsova, Anna ; Austin, Richard C. ; MacDonald, Melissa E. ; Seidah, Nabil G ; Lebeau, Paul F

Cardiovascular mortality is particularly high and increasing in patients with chronic kidney disease, with vascular calcification (VC) as a major pathophysiologic feature. VC is a highly regulated biological process similar to bone formation involving osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). We have previously demonstrated that loss of T-cell death-associated gene 51 (TDAG51) expression leads to an attenuation of medial VC. We now show a significant induction of circulating levels of growth differentiation factor 10 (GDF10) in TDAG51^-/- mice, which was of interest due to its established role as an inhibitor of osteoblast differentiation. The objective of this study was to examine the role of GDF10 in the osteogenic transdifferentiation of VSMCs. Using primary mouse and human VSMCs, as well as ex vivo aortic ring cultures, we demonstrated that treatment with recombinant human (rh) GDF10 mitigated phosphate-mediated hydroxyapatite (HA) mineral deposition. Furthermore, ex vivo aortic rings from GDF10^-/- mice exhibited increased HA deposition compared to C57BL/6J controls. To explain our observations, we identified that rhGDF10 treatment reduced protein expression of runt-related transcription factor 2, a key driver of osteogenic transdifferentiation of VSMCs and VC. In support of these findings, in vivo treatment with rhGDF10 attenuated VD₃-induced VC. Furthermore, we demonstrated an increase in circulating GDF10 in patients with chronic kidney disease with clinically defined severe VC, as assessed by coronary artery calcium score. Thus, our studies identify GDF10 as a novel inhibitor of mineral deposition and as such, may represent a potential novel biomarker and therapeutic target for the detection and management of VC.

2024-10-01·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Paracrine FGF1 signaling directs pituitary architecture and size

Article

作者: Kmita, Marie ; Christian, Helen ; Mollard, Patrice ; Lafont, Chrystel ; Gouhier, Arthur ; Khetchoumian, Konstantin ; Drouin, Jacques ; Kherdjemil, Yacine ; Bemmo, Amandine ; Le Tissier, Paul ; Sochodolsky, Kevin

Organ architecture is established during development through intricate cell–cell communication mechanisms, yet the specific signals mediating these communications often remain elusive. Here, we used the anterior pituitary gland that harbors different interdigitated hormone-secreting homotypic cell networks to dissect cell–cell communication mechanisms operating during late development. We show that blocking differentiation of corticotrope cells leads to pituitary hypoplasia with a major effect on somatotrope cells that directly contact corticotropes. Gene knockout of the corticotrope-restricted transcription factor Tpit results in fewer somatotropes, with less secretory granules and a loss of cell polarity, resulting in systemic growth retardation. Single-cell transcriptomic analyses identified FGF1 as a corticotrope-specific Tpit dosage-dependent target gene responsible for these phenotypes. Consistently, genetic ablation of FGF1 in mice phenocopies pituitary hypoplasia and growth impairment observed in Tpit -deficient mice. These findings reveal FGF1 produced by the corticotrope cell network as an essential paracrine signaling molecule participating in pituitary architecture and size.

2024-10-01·MOLECULAR CELL

Integrated multi-omics analysis of zinc-finger proteins uncovers roles in RNA regulation

Article

作者: Uddin Syed, Easin ; Lécuyer, Eric ; Jovanovic, Marko ; Graveley, Brenton R ; Gosztyla, Maya L ; Cavazos, Francisco F ; Zhan, Lijun ; Olson, Sara ; Nguyen, Grady ; Kofman, Eric ; Li, Allison ; Street, Lena ; Kwon, Eunjeong ; Jain, Manya ; Dominguez, Daniel ; Yeo, Gene W ; Wei, Xintao ; Gonzalez, Valerie ; Jin, Wenhao ; Goda, Grant A ; Schmok, Jonathan C ; Naritomi, Jack ; Tankka, Alexandra T

RNA interactome studies have revealed that hundreds of zinc-finger proteins (ZFPs) are candidate RNA-binding proteins (RBPs), yet their RNA substrates and functional significance remain largely uncharacterized. Here, we present a systematic multi-omics analysis of the DNA- and RNA-binding targets and regulatory roles of more than 100 ZFPs representing 37 zinc-finger families. We show that multiple ZFPs are previously unknown regulators of RNA splicing, alternative polyadenylation, stability, or translation. The examined ZFPs show widespread sequence-specific RNA binding and preferentially bind proximal to transcription start sites. Additionally, several ZFPs associate with their targets at both the DNA and RNA levels. We highlight ZNF277, a C2H2 ZFP that binds thousands of RNA targets and acts as a multi-functional RBP. We also show that ZNF473 is a DNA/RNA-associated protein that regulates the expression and splicing of cell cycle genes. Our results reveal diverse roles for ZFPs in transcriptional and post-transcriptional gene regulation.

项与 Institut de recherches cliniques de Montréal 相关的新闻（医药）

2024-08-14

·Business Wire

RAMQ Expands Provincial Coverage to Include Dexcom G7, Bringing the Next-Generation CGM System to More Québec Residents

BURNABY, British Columbia--( BUSINESS WIRE )--Dexcom, Inc. (NASDAQ: DXCM), a global leader in real-time continuous glucose monitoring (rtCGM) for people with diabetes, announced today that its latest innovation, the Dexcom G7 Continuous Glucose Monitoring (CGM) System, will be added to the Régie de l'assurance maladie du Québec (RAMQ) Public Prescription Drug Insurance Plan. Québec residents living with type 1 diabetes who meet the eligibility criteria will now be able to receive coverage for Dexcom G7.* “Today’s announcement from RAMQ showcases its commitment to improving the lives of those living with type 1 diabetes across the province. We are thrilled that more Québec residents will be able to experience the Dexcom difference,” said André Côté, Vice President and General Manager of Dexcom Canada. Launched in Canada in 2023, Dexcom G7 is the most accurate CGM system available, †,1 clinically proven to lower A1C and increase time in range. 2-6 Designed to take the guesswork out of day-to-day diabetes management, Dexcom G7 allows the user to easily see their glucose levels and where they’re headed, so they can make informed decisions about insulin, food and activity in the moment, with no routine fingersticks ǂ or scanning required. “It is critical that we continue to provide access to the most advanced continuous glucose monitoring technology to support patients managing diabetes, and ultimately improve their health outcomes and quality of life,” says Dr. Remi Rabasa-Lhoret, Director, Metabolic Diseases Research Unit, Institut de Recherches Cliniques de Montréal. “CGM technology is a game changer. It can simplify diabetes management, giving people who live with diabetes an incredible tool to improve a condition that changes every day.” Now through RAMQ, thousands of eligible Québec residents living with type 1 diabetes will have access to the latest technology in continuous glucose monitoring systems, helping to reduce the burden of out-of-pocket costs for essential diabetes tools and make modern management solutions more accessible. The majority of Quebec’s top private insurers already cover Dexcom G7 for individuals with type 1 diabetes or type 2 diabetes on insulin. §,7 “As a Dexcom CGM user, this announcement means that I can more feasibly access the technology that has changed how I manage my type 1 diabetes for the better,” says Serge Turcotte, a Québec resident who has lived with type 1 diabetes for 8 years. “For someone as active as I am, I must say that using Dexcom G7 has been a game-changer in how I deal with diabetes and can still be me. Being able to see my glucose levels in real-time and knowing I can be alerted before a dangerous low gives me so much more peace of mind. I am so grateful that such technology exists now.” Today’s news is the latest in a series of provincial announcements regarding coverage for Dexcom CGM systems. New Brunswick, Newfoundland and Labrador, British Columbia, Saskatchewan, Manitoba, Prince Edward Island, Northwest Territories, Yukon and Nova Scotia have recently adapted their respective provincial health programs to include or expand coverage for Dexcom G7. To learn more about Dexcom G7 and the RAMQ coverage eligibility criteria , along with private insurance plans that cover Dexcom G7, visit dexcom.com. About Dexcom, Inc. Dexcom, Inc. empowers people to take control of health through innovative continuous glucose monitoring (CGM) systems. Headquartered in San Diego, Calif., and with operations across Canada, Dexcom has emerged as a leader of diabetes care technology. By listening to the needs of users, caregivers, and providers, Dexcom works to simplify and improve diabetes management around the world. For more information about Dexcom CGM, visit www.dexcom.com . _______________________________________ 1 Dexcom, data on file, 2023. 2 Beck RW, et al. JAMA. 2017;317(4):371-378. 3 Beck RW, et al. Ann Intern Med. 2017;167(6):365-374. 4 Martens T, et al. JAMA. 2021;325(22):2262-2272. 5 Laffel LM, et al. JAMA. 2020;323(23):2388-2396. 6 Welsh JB, et al. J Diabetes Sci Technol. 2024;18(1):143-7. 7 Dexcom, data on file, 2024. * Individuals who do not have a compatible smart device are eligible for a free G7 Receiver and should contact Dexcom Customer Service at 1-844-832-1810. † When compared with CGM systems commercially available in Canada as of July 2024. ǂ Fingersticks required for diabetes treatment decisions if symptoms or expectations do not match readings. § Eligibility and coverage vary by policy, plan, and payor. For details, visit www.dexcom.com/en-CA/coverage .

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