Summary Recent studies show that liquid-liquid phase separation plays a key role in the assembly of diverse intracellular structures. However, the biophysical principles by which phase separation can be precisely localized within subregions of the cell are still largely unclear, particularly for low-abundance proteins. Here we introduce an oligomerizing biomimetic system, “Corelets”, and utilize its rapid and quantitative light-controlled tunability to map full intracellular phase diagrams, which dictate the concentrations at which phase separation occurs, and the mode of phase separation. Surprisingly, both experiments and simulations show that while intracellular concentrations may be insufficient for global phase separation, sequestering protein ligands to slowly diffusing nucleation centers can move the cell into a different region of the phase diagram, resulting in localized phase separation. This diffusive capture mechanism liberates the cell from the constraints of global protein abundance and is likely exploited to pattern condensates associated with diverse biological processes.

Sodium–glucose cotransporter (SGLT) inhibitors are new oral antidiabetes medications shown to effectively reduce glycated hemoglobin (A1C) and glycemic variability, blood pressure, and body weight without intrinsic properties to cause hypoglycemia in people with type 1 diabetes. However, recent studies, particularly in individuals with type 1 diabetes, have demonstrated increases in the absolute risk of diabetic ketoacidosis (DKA). Some cases presented with near-normal blood glucose levels or mild hyperglycemia, complicating the recognition/diagnosis of DKA and potentially delaying treatment. Several SGLT inhibitors are currently under review by the U.S. Food and Drug Administration and European regulatory agencies as adjuncts to insulin therapy in people with type 1 diabetes. Strategies must be developed and disseminated to the medical community to mitigate the associated DKA risk. This Consensus Report reviews current data regarding SGLT inhibitor use and provides recommendations to enhance the safety of SGLT inhibitors in people with type 1 diabetes.

In the originally published version of this article, the label for the vertical axis at the bottom of Figure 7H mistakenly referred to the state where D core < D IDR . The correct label should read D core R D IDR . The corrected Figure 7 is shown here and this error has now been corrected in the article online. We apologize for any confusion this error may have caused.

Suspensions of paramagnetic colloids are driven to phase separate and self-assemble in toggled magnetic fields. At field strengths above 575 A/m and toggle frequencies between 0.66 and 2 Hz, an initial gel-like, arrested network collapses into condensed, ellipsoidal aggregates. The evolution to this equilibrium structure occurs via a Rayleigh-Plateau instability. The toggle frequency ν determines the fluidity of the breakup process. At frequencies between 0.66 and 1.5 Hz, the suspension breaks up similar to a viscous, Newtonian fluid. At frequencies ν > 1.5 Hz, the network ruptures like a viscoplastic material. The field strength alters the onset time of the instability. A power law relationship emerges as the scaled frequency and field strength can be used to predict the onset of breakup. These results further aid in understanding the mechanics and dynamics of the phase separation process of suspensions of polarizable colloids in toggled external fields.

Suspensions of superparamagnetic colloids that equilibrate in a toggled magnetic field undergo a Rayleigh-Plateau instability with a characteristic wavelength λ = 600 μm for the toggle frequency ν = 0.66 Hz. The instability is suppressed when the chamber length L in the field direction is less than 2λ. The final size of the magnetic domains perpendicular to the field, D, follows a power law relation of D ∼ L(0.71±0.07). These results demonstrate the structural differences of field-directed suspensions when confined to lengths scale set by the phase separation process and can potentially be used to create self-assembled colloidal crystals with well-defined size and shape.

Recent studies show that liquid-liquid phase separation plays a key role in the assembly of diverse intracellular structures. However, the biophysical principles by which phase separation can be precisely localized within subregions of the cell are still largely unclear, particularly for lowabundance proteins. Here we introduce a biomimetic optogenetic system, "Corelets", and utilize its rapid and quantitative tunability to map the first full intracellular phase diagrams, which dictate whether phase separation occurs, and if so by nucleation and growth or spinodal decomposition. Surprisingly, both experiments and simulations show that while intracellular concentrations may be insufficient for global phase separation, sequestering protein ligands to slowly diffusing nucleation centers can move the cell into a different region of the phase diagram, resulting in localized phase separation. This diffusive capture mechanism liberates the cell from the constraints of global protein abundance and is likely exploited to pattern condensates associated with diverse biological processes.

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.

Cardiovascular disease (CVD) is a leading cause of death in people with type 2 diabetes (T2D). Recent cardiovascular (CV) outcomes trials have shown CV benefits for several GLP-1 receptor agonists and SGLT2 inhibitors. We aimed to evaluate T2D patients’ awareness, perceptions, and behaviors regarding CVD and cardioprotective T2D drugs. An online survey was completed by 927 T2D patients of diverse socioeconomic backgrounds from an opted-in patient research panel in the U.S. Median respondent age was 64 and median duration of diabetes was 15 years. Half were taking a GLP-1 or SGLT2, a statistically robust sample of patients on these therapies. Questions covered perceptions of CVD disease; awareness of and interest in diabetes drugs that reduce CVD risk; knowledge of their own health metrics; physicians seen and frequency of discussions about CVD; self-assigned ‘grades’ on lifestyle behaviors known to reduce CVD risk. Most patients recognized the link between T2D and CVD: 61% strongly agreed that T2D increases CVD risk. Yet, only 29% think often about their risk of CVD. Awareness of CV benefits from some T2D therapies was also low (34% overall; 42% for those on SGLT2 or GLP-1). Interest in taking an additional cardioprotective diabetes agent aligned with awareness (37% overall; 42% for those on SGLT2 or GLP-1). While almost all knew their HbA1c and blood pressure, over 25% did not know their LDL cholesterol or other lipid levels. In the prior year, 31% of patients had seen a cardiologist and 17% had discussed CVD risk with an endocrinologist. Respondents generally ranked themselves ‘average’ to ‘below average’ on heart-healthy behaviors like exercise, weight, sleep, diet, and stress management. Although a majority of T2D patients are aware of the link between T2D and CVD, most are not actively managing their CV health, and few know that some T2D therapies are cardioprotective. These data suggest a need to better inform T2D patients about their risk for CVD, and steps they can take to reduce that risk. Disclosure K.C. Stoner: Other Relationship; Self; Multiple companies and organizations in the diabetes field (greater than 10). E.N. Fitts: Other Relationship; Self; Various diabetes companies. D. Gopisetty: Other Relationship; Self; Various diabetes companies. A. Carracher: Other Relationship; Self; Other. C.S. Florissi: Other Relationship; Self; dQ&A has several clients (&gt;10) in the diabetes field. M.J. Kurian: Other Relationship; Self; Other Company. J. Kwon: Other Relationship; Self; Various diabetes companies. P. Marathe: Consultant; Self; Close Concerns. P. Rentzepis: Other Relationship; Self; Various Diabetes Companies. J.B. Rost: Other Relationship; Self; dQ&A has several clients (&gt;10) in the diabetes field. K.L. Close: Other Relationship; Self; Various diabetes companies. I.B. Hirsch: Consultant; Self; Abbott, Becton, Dickinson and Company, Big Foot, Roche Diabetes Care. Research Support; Self; Medtronic. M.N. Kosiborod: Consultant; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eisai Co., Ltd., GlaxoSmithKline plc., Glytec, LLC, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. R. Wood: Other Relationship; Self; Multiple companies in the diabetes field (&gt;10 companies). Funding AstraZeneca