Evaluating glucose‐lowering treatment in older people with diabetes : lessons from the IMPERIUM trial

Understanding the benefits and risks of treatments to be used by older individuals (≥65 years old) is critical for informed therapeutic decisions. Glucose‐lowering therapy for older patients with diabetes should be tailored to suit their clinical condition, comorbidities and impaired functional status, including varying degrees of frailty. However, despite the rapidly growing population of older adults with diabetes, there are few dedicated clinical trials evaluating glucose‐lowering treatment in older people. Conducting clinical trials in the older population poses multiple significant challenges. Despite the general agreement that individualizing treatment goals and avoiding hypoglycaemia is paramount for the therapy of older people with diabetes, there are conflicting perspectives on specific glycaemic targets that should be adopted and on use of specific drugs and treatment strategies. Assessment of functional status, frailty and comorbidities is not routinely performed in diabetes trials, contributing to insufficient characterization of older study participants. Moreover, significant operational barriers and problems make successful enrolment and completion of such studies difficult. In this review paper, we summarize the current guidelines and literature on conducting such trials, as well as the learnings from our own clinical trial (IMPERIUM) that assessed different glucose‐lowering strategies in older people with type 2 diabetes. We discuss the importance of strategies to improve study design, enrolment and attrition. Apart from summarizing some practical advice to facilitate the successful conduct of studies, we highlight key gaps and needs that warrant further research

Nitrogen-centered radicals in functionalization of sp2 systems : generation, reactivity, and applications in synthesis

The chemistry of nitrogen-centered radicals (NCRs) has plentiful applications in organic synthesis, and they continue to expand as our understanding of these reactive species increases. The utility of these reactive intermediates is demonstrated in the recent advances in C-H amination and the (di)amination of alkenes. Synthesis of previously challenging structures can be achieved by efficient functionalization of sp2 moieties without prefunctionalization, allowing for faster and more streamlined synthesis. This Review addresses the generation, reactivity, and application of NCRs, including, but not limited to, iminyl, aminyl, amidyl, and aminium species. Contributions from early discovery up to the most recent examples have been highlighted, covering radical initiation, thermolysis, photolysis, and, more recently, photoredox catalysis. Radical-mediated intermolecular amination of (hetero)arenes can occur with a variety of complex amine precursors, generating aniline derivatives, an important class of structures for drug discovery and development. Functionalization of olefins is achievable in high anti-Markovnikov regioselectivity and allows access to difunctionalized structures when the intermediate carbon radicals are trapped. Additionally, the reactivity of NCRs can be harnessed for the rapid construction of N-heterocycles such as pyrrolidines, phenanthridines, quinoxalines, and quinazolinones

Pancreas-enriched miRNAs are altered in the circulation of subjects with diabetes: a pilot cross-sectional study

The clinical presentation of diabetes sometimes overlaps, contributing to ambiguity in the diagnosis. Thus, circulating pancreatic islet-enriched microRNAs (miRNAs) might be useful biomarkers of β-cell injury/dysfunction that would allow more accurate subtyping of diabetes. We measured plasma levels of selected miRNAs in subjects with prediabetes (n = 12), type 2 diabetes (T2D, n = 31), latent autoimmune diabetes of adults (LADA, n = 6) and type 1 diabetes (T1D, n = 16) and compared them to levels in healthy control subjects (n = 27). The study was conducted at the Translational Research Institute for Metabolism and Diabetes (TRI-MD), Florida Hospital. MiRNAs including miR-375 (linked to β-cell injury), miR-21 (associated with islet inflammation), miR-24.1, miR-30d, miR-34a, miR-126, miR-146, and miR-148a were significantly elevated in subjects with various forms of diabetes compared to healthy controls. Levels of several miRNAs were significantly correlated with glucose responses during oral glucose tolerance testing, HbA[subscript 1c], β-cell function, and insulin resistance in healthy controls, prediabetes, and T2D. These data suggest that miRNAs linked to β-cell injury and islet inflammation might be useful biomarkers to distinguish between subtypes of diabetes. This information could be used to predict progression of the disease, guide selection of optimal therapy and monitor responses to interventions, thus improving outcomes in patients with diabetes.Translational Research Institute for Metabolism and Diabetes (TRI

Estimating extragalactic Faraday rotation

(abridged) Observations of Faraday rotation for extragalactic sources probe magnetic fields both inside and outside the Milky Way. Building on our earlier estimate of the Galactic contribution, we set out to estimate the extragalactic contributions. We discuss the problems involved; in particular, we point out that taking the difference between the observed values and the Galactic foreground reconstruction is not a good estimate for the extragalactic contributions. We point out a degeneracy between the contributions to the observed values due to extragalactic magnetic fields and observational noise and comment on the dangers of over-interpreting an estimate without taking into account its uncertainty information. To overcome these difficulties, we develop an extended reconstruction algorithm based on the assumption that the observational uncertainties are accurately described for a subset of the data, which can overcome the degeneracy with the extragalactic contributions. We present a probabilistic derivation of the algorithm and demonstrate its performance using a simulation, yielding a high quality reconstruction of the Galactic Faraday rotation foreground, a precise estimate of the typical extragalactic contribution, and a well-defined probabilistic description of the extragalactic contribution for each data point. We then apply this reconstruction technique to a catalog of Faraday rotation observations. We vary our assumptions about the data, showing that the dispersion of extragalactic contributions to observed Faraday depths is most likely lower than 7 rad/m^2, in agreement with earlier results, and that the extragalactic contribution to an individual data point is poorly constrained by the data in most cases.Comment: 20 + 6 pages, 19 figures; minor changes after bug-fix; version accepted for publication by A&A; results are available at http://www.mpa-garching.mpg.de/ift/faraday

Receipt of Diabetes Specialty Care and Management Services by Older Adults With Diabetes in the United States, 2015-2019: An Analysis of Medicare Fee-for-Service Claims.

OBJECTIVE: We characterized the receipt of diabetes specialty care and management services among older adults with diabetes. RESEARCH DESIGN AND METHODS: Using a 20% random sample of fee-for-service Medicare beneficiaries aged ≥65 years, we analyzed cohorts of type 1 diabetes (T1D) or type 2 diabetes (T2D) with history of severe hypoglycemia (HoH), and all other T2D annually from 2015 to 2019. Outcomes were receipt of office-based endocrinology care, diabetes education, outpatient diabetes health services, excluding those provided in primary care, and any of the aforementioned services. RESULTS: In the T1D cohort, receipt of endocrinology care and any service increased from 25.9% and 29.2% in 2015 to 32.7% and 37.4% in 2019, respectively. In the T2D with HoH cohort, receipt of endocrinology care and any service was 13.9% and 16.4% in 2015, with minimal increases. Age, race/ethnicity, residential setting, and income were associated with receiving care. CONCLUSIONS: These findings suggest that many older adults may not receive specialty diabetes care and underscore health disparities

Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor Alogliptin in Patients With Type 2 Diabetes and Inadequate Glycemic Control: A randomized, double-blind, placebo-controlled study

OBJECTIVE—To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drug-naïve patients with inadequately controlled type 2 diabetes

Changes in Prandial Glucagon Levels After a 2-Year Treatment With Vildagliptin or Glimepiride in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy

OBJECTIVE - To determine if the dipeptidyl peptidase-4 inhibitor vildagliptin more effectively inhibits glucagon levels than the sulfonylurea glimepiride during a meal. RESEARCH DESIGN AND METHODS - Glucagon responses to a standard meal were measured at baseline and study end point (mean 1.8 years) in a trial evaluating add-on therapy to metformin with 50 mg vildagliptin bid. compared with glimepiride up to 6 mg q.d. in type 2 diabetes (baseline MC 7.3 +/- 0.6%). RESULTS - A1C and prandial glucose area under the curve (AUC)(0-2 h) were reduced similarly in both groups, whereas prandial insulin AUC(0-2 h) increased to a greater extent by glimepiride. Prandial glucagon AUC(0-2 h) (baseline 66.6 +/- 2.3 pmol . h(-1) . l(-1)) decreased by 3.4 +/- 1.6 pmol . h(-1) . l(-1) by vildagliptin (n = 137) and increased by 3.8 +/- 1.7 pmol . h(-1) . l(-1) by glimepiride (n = 121). The between-group difference was 7.3 +/- 2.1 pmol . h(-1) . l(-1) (P < 0.001). CONCLUSIONS - Vildagliptin therapy but not glimepiride improves postprandial a-cell function, which persists for at least 2 years