m6A Modification Prevents Formation of Endogenous Double-Stranded RNAs and Deleterious Innate Immune Responses during Hematopoietic Development.

N6-methyladenosine (m6A) is the most abundant RNA modification, but little is known about its role in mammalian hematopoietic development. Here, we show that conditional deletion of the m6A writer METTL3 in murine fetal liver resulted in hematopoietic failure and perinatal lethality. Loss of METTL3 and m6A activated an aberrant innate immune response, mediated by the formation of endogenous double-stranded RNAs (dsRNAs). The aberrantly formed dsRNAs were long, highly m6A modified in their native state, characterized by low folding energies, and predominantly protein coding. We identified coinciding activation of pattern recognition receptor pathways normally tasked with the detection of foreign dsRNAs. Disruption of the aberrant immune response via abrogation of downstream Mavs or Rnasel signaling partially rescued the observed hematopoietic defects in METTL3-deficient cells in vitro and in vivo. Our results suggest that m6A modification protects against endogenous dsRNA formation and a deleterious innate immune response during mammalian hematopoietic development.

Comparison of Protocols to Reduce Diabetic Ketoacidosis in Patients With Type 1 Diabetes Prescribed a Sodium-Glucose Cotransporter 2 Inhibitor.

OBJECTIVE | Sodium-glucose cotransporter 2 (SGLT2) inhibitors are approved for type 1 diabetes in Europe and Japan, with off-label use in type 1 diabetes in the United States. Although there were no consistent approaches to risk mitigation in clinical trials of these agents, protocols have been developed to try to reduce the risk of diabetic ketoacidosis (DKA). However, a validated risk mitigation strategy does not exist. We reviewed available DKA risk mitigation protocols to better understand the various strategies currently in use. METHODS | We conducted a search of the published medical literature and other medical information sources, including conference presentations, for protocols. We then categorized the information provided into guidance on patient selection, initiation of SGLT2 inhibitors, ketone monitoring, necessary patient action in the event of ketosis or DKA, and inpatient treatment of ketosis or DKA. RESULTS | Patient selection is generally similar among the protocols, although some require a minimum BMI and insulin dose. All protocols advocate routine measurement of ketones, although some insist on blood ketone tests. Although action steps for ketosis varies, all protocols advocate rapid patient intervention. The importance of evaluating ketones and acid-base balance even in the absence of hyperglycemia is emphasized by all protocols, as is the need to continue administering insulin until ketosis has resolved. CONCLUSION | DKA risk mitigation must be pursued systematically in individuals with type 1 diabetes, although the best strategy remains to be determined. Given the ongoing need for adjunctive therapies in type 1 diabetes and current use of SGLT2 inhibitors for this purpose, additional education and research are crucial, especially in the hospital environment, where DKA may not be diagnosed promptly and treated appropriately.

Diabetes news.

Ursula Biba, Rhea W. Teng, Martin J. Kurian, Ann M. Carracher, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Biba, Teng, Kurian, Carracher, and Close review the latest developments relevant to researchers and clinicians.

Practical ways to achieve targets in diabetes care conference.

Ursula Biba, Rhea W. Teng, Martin J. Kurian, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Biba, Teng, Kurian, and Close review the latest developments relevant to researchers and clinicians.