A new perspective on metformin therapy in type 1 diabetes

Metformin is quite frequently used off-label in type 1 diabetes to limit insulin dose requirement. Guidelines recommend that it can improve glucose control in those who are overweight and obese but evidence in support of this is limited. Recently-published findings from the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial suggest that metformin therapy in type 1 diabetes can reduce atherosclerosis progression, weight and LDL-cholesterol levels. This provides a new perspective on metformin therapy in type 1 diabetes and suggests a potential role for reducing the long-term risk of cardiovascular disease

Cardiovascular benefits of GLP-1 agonists in type 2 diabetes: a comparative review

Type 2 diabetes (T2D) carries risks of both cardiovascular (CV) (myocardial infarction, stroke, and peripheral vascular disease) and microvascular (retinopathy/nephropathy/neuropathy) complications. Glucose-lowering is an effective strategy for preventing microvascular complications, but the extent to which it can reduce CV complications is less certain. Glucagon-like peptide-1 (GLP-1) agonists are potent glucose-lowering agents but also have potentially beneficial effects on other traditional (body weight, blood pressure (BP), and LDL cholesterol) and non-traditional risk factors (low grade inflammation and endothelial dysfunction). The results of four large CV outcome trials with GLP-1 agonists are now available. These have compared lixisenatide (ELIXA), liraglutide (LEADER), semaglutide (SUSTAIN-6), and long-acting exenatide (EXSCEL) with placebo and standard of care over 2–4 years; four others (including with dulaglutide and albiglutide) are ongoing. LEADER and SUSTAIN-6 have demonstrated reductions in rates of major adverse CV events with active GLP-1 treatment but ELIXA and EXSCEL have not. In this review, we discuss the mechanisms by which GLP-1 receptor agonists act on the CV system and the design and conduct of these trials. Contrary to the assertions that (a) all GLP-1 agonists reduce CV disease in T2D but to different extents or (b) the magnitude of CV protection is predominantly related to glucose-lowering, we argue that CV benefit is specific to agents that provide longer acting agonism at the GLP-1 receptor. The mechanisms involve reduction in body weight and BP, and lowering of LDL-cholesterol and glucose, but pleiotropic effects—including suppression of low grade inflammation, vasodilation, and natriuresis—are also likely relevant

Readily available sources of long-chain omega-3 oils: Is farmed australian seafood a better source of the good oil than wild-caught seafood?

Seafood consumption enhances intake of omega-3 long-chain (≥C20) polyunsaturated fatty acids (termed LC omega-3 oils). Humans biosynthesize only small amounts of LC-omega-3, so they are considered semi-essential nutrients in our diet. Concern has been raised that farmed fish now contain lower LC omega-3 content than wild-harvested seafood due to the use of oil blending in diets fed to farmed fish. However, we observed that two major Australian farmed finfish species, Atlantic salmon (Salmo salar) and barramundi (Lates calcifer), have higher oil and LC omega-3 content than the same or other species from the wild, and remain an excellent means to achieve substantial intake of LC omega-3 oils. Notwithstanding, LC omega-3 oil content has decreased in these two farmed species, due largely to replacing dietary fish oil with poultry oil. For Atlantic salmon, LC omega-3 content decreased ~30%-50% between 2002 and 2013, and the omega-3/omega-6 ratio also decreased (>5:1 to <1:1). Australian consumers increasingly seek their LC omega-3 from supplements, therefore a range of supplement products were compared. The development and future application of oilseeds containing LC omega-3 oils and their incorporation in aquafeeds would allow these health-benefitting oils to be maximized in farmed Australian seafood. Such advances can assist with preventative health care, fisheries management, aquaculture nutrition, an innovative feed/food industry and ultimately towards improved consumer health

Recent developments in adjunct therapies for type 1 diabetes

Introduction: There have been many recent advances in the treatment of type 1 diabetes (T1D) including in insulin formulations, continuous glucose monitoring (CGM) technology and automated insulin delivery. However, long-term optimal glycemic control is still only achieved in a minority. Areas covered: Adjunct therapy – the use of therapeutic agents other than insulin – is one strategy aimed at improving outcomes. An ideal adjunct agent would improve glycemic control, reduce weight (or weight gain), reduce insulin requirement and prevent complications (e.g. cardiorenal) without increasing hypoglycemia. The amylin analogue pramlintide has been licensed in the USA, while the sodium glucose co-transporter-2 inhibitor (SGLT2i) dapagliflozin, was briefly (2019 − 2021) licensed for type 1 diabetes in Europe and the UK. However, other agents from the type 2 diabetes (T2D) arena including metformin, other SGLT2is, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-IV (DPP-4) inhibitors have been investigated. Expert opinion: As evidence emerges for cardiorenal protection by SGLT2is and GLP-1RAs in T2D, it has become increasingly important to know whether people with T1D can also benefit. Here, we review recent trials of adjunct agents in T1D and discuss the efficacy and safety of these agents (alone and in combination) in an era in which continuous glucose monitoring is becoming standard of care

Barley heads east: Genetic analyses reveal routes of spread through diverse Eurasian landscapes

One of the world’s most important crops, barley, was domesticated in the Near East around 11,000 years ago. Barley is a highly resilient crop, able to grown in varied and marginal environments, such as in regions of high altitude and latitude. Archaeobotanical evidence shows that barley had spread throughout Eurasia by 2,000 BC. To further elucidate the routes by which barley cultivation was spread through Eurasia, simple sequence repeat (SSR) analysis was used to determine genetic diversity and population structure in three extant barley taxa: domesticated barley (Hordeum vulgare L. subsp. vulgare), wild barley (H. vulgare subsp. spontaneum) and a six-rowed brittle rachis form (H. vulgare subsp. vulgare f. agriocrithon (Åberg) Bowd.). Analysis of data using the Bayesian clustering algorithm InStruct suggests a model with three ancestral genepools, which captures a major split in the data, with substantial additional resolution provided under a model with eight genepools. Our results indicate that H. vulgare subsp. vulgare f. agriocrithon accessions and Tibetan Plateau H. vulgare subsp. spontaneum are closely related to the H. vulgare subsp. vulgare in their vicinity, and are therefore likely to be feral derivatives of H. vulgare subsp. vulgare. Under the eight genepool model, cultivated barley is split into six ancestral genepools, each of which has a distinct distribution through Eurasia, along with distinct morphological features and flowering time phenotypes. The distribution of these genepools and their phenotypic characteristics is discussed together with archaeological evidence for the spread of barley eastwards across Eurasia

Expanding the docosahexaenoic acid food web for sustainable production: engineering lower plant pathways into higher plants

This article describes current progress in the engineering of oilseed crops for the production of long-chain omega-3 fatty acids such as DHA. This example highlights the importance of algal genetic resources to the future of agricultural biotechnology

Coronary-artery bypass surgery in patients with ischemic cardiomyopathy

BACKGROUND The survival benefit of a strategy of coronary-artery bypass grafting (CABG) added to guideline-directed medical therapy, as compared with medical therapy alone, in patients with coronary artery disease, heart failure, and severe left ventricular systolic dysfunction remains unclear. METHODS From July 2002 to May 2007, a total of 1212 patients with an ejection fraction of 35% or less and coronary artery disease amenable to CABG were randomly assigned to undergo CABG plus medical therapy (CABG group, 610 patients) or medical therapy alone (medical-therapy group, 602 patients). The primary outcome was death from any cause. Major secondary outcomes included death from cardiovascular causes and death from any cause or hospitalization for cardiovascular causes. The median duration of follow-up, including the current extended-follow-up study, was 9.8 years. RESULTS A primary outcome event occurred in 359 patients (58.9%) in the CABG group and in 398 patients (66.1%) in the medical-therapy group (hazard ratio with CABG vs. medical therapy, 0.84; 95% confidence interval [CI], 0.73 to 0.97; P=0.02 by log-rank test). A total of 247 patients (40.5%) in the CABG group and 297 patients (49.3%) in the medical-therapy group died from cardiovascular causes (hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006 by log-rank test). Death from any cause or hospitalization for cardiovascular causes occurred in 467 patients (76.6%) in the CABG group and in 524 patients (87.0%) in the medical-therapy group (hazard ratio, 0.72; 95% CI, 0.64 to 0.82; P<0.001 by log-rank test). CONCLUSIONS In a cohort of patients with ischemic cardiomyopathy, the rates of death from any cause, death from cardiovascular causes, and death from any cause or hospitalization for cardiovascular causes were significantly lower over 10 years among patients who underwent CABG in addition to receiving medical therapy than among those who received medical therapy alone. (Funded by the National Institutes of Health; STICH [and STICHES] ClinicalTrials.gov number, NCT00023595.

A Close Companion Search Around L Dwarfs Using Aperture Masking Interferometry and Palomar Laser Guide Star Adaptive Optics

We present a close companion search around 16 known early L dwarfs using aperture masking interferometry with Palomar laser guide star adaptive optics (LGS AO). The use of aperture masking allows the detection of close binaries, corresponding to projected physical separations of 0.6-10.0 AU for the targets of our survey. This survey achieved median contrast limits of ΔK ~ 2.3 for separations between 1.2λ/D-4λ/D and ΔK ~ 1.4 at 2/3λ/D. We present four candidate binaries detected with moderate-to-high confidence (90%-98%). Two have projected physical separations less than 1.5 AU. This may indicate that tight-separation binaries contribute more significantly to the binary fraction than currently assumed, consistent with spectroscopic and photometric overluminosity studies. Ten targets of this survey have previously been observed with the Hubble Space Telescope as part of companion searches. We use the increased resolution of aperture masking to search for close or dim companions that would be obscured by full aperture imaging, finding two candidate binaries. This survey is the first application of aperture masking with LGS AO at Palomar. Several new techniques for the analysis of aperture masking data in the low signal-to-noise regime are explored

Increased DHA Production in Seed Oil Using a Selective Lysophosphatidic Acid Acyltransferase

Metabolic engineering of the omega-3 (ω3) long chain polyunsaturated fatty acid biosynthesis pathway has generated fish oil-like levels of pharmaceutically and nutritionally important docosahexaenoic acid (DHA) in plant seeds. However, the majority of DHA has been accumulated at the sn-1 and sn-3 positions of triacylglycerol (TAG) in these engineered seeds, leaving only a minor amount (∼10%) at sn-2 position and indicating a strong discrimination (or, a very poor specificity) for DHA by seed lysophosphatidic acid acyltransferases (LPAATs), which mediate the acylation of sn-2 position of glycerol backbone. In order to increase the level of DHA at sn-2 position of TAG and to increase overall DHA level in seeds, we attempted to discover DHA-preferring LPAATs. Several LPAATs for acylation of the sn-2 position of the TAG glycerol backbone were investigated for substrate preference for DHA. In transiently expressing these LPAATs in Nicotiana benthamiana, a Mortierella alpina LPAAT had the highest substrate specificity for accumulating DHA onto oleoyl-lysophosphatidic acid (oleoyl-LPA), while the plant LPAATs tested showed lower preference for DHA. In a competition assay with a pool of four ω3 acyl-Coenzyme A (CoA) substrates involved in the DHA biosynthesis pathway, LPAATs from both M. alpina and Emiliania huxleyi showed a high preference for DHA-CoA acylation onto oleoyl-LPA. When docosahexaenoyl-LPA was used as the acyl receiver, M. alpina LPAAT also showed a high preference for DHA-CoA. Stable overexpression of M. alpina LPAAT in an Arabidopsis line that expressed the DHA biosynthesis pathway significantly increased both the total DHA levels and the distribution of DHA onto the sn-2 position of seed TAG. LC-MS analysis of the seed TAG species also confirmed that overexpression of M. alpina LPAAT increased di-DHA and tri-DHA TAGs, suggesting that the M. alpina LPAAT could enrich DHA at the TAG sn-2 position, leading to a metabolic engineering of oil seed for channeling DHA into the sn-2 position of TAG and to a higher DHA level