GLP-1 does not acutely affect insulin sensitivity in healthy man

Summary Previous studies have suggested that glucagon-like peptide-1 (GLP-1) (7–36 amide) may have the direct effect of increasing insulin sensitivity in healthy man. To evaluate this hypothesis we infused GLP-1 in seven lean healthy men during a hyperinsulinaemic (0.8 mU · kg⁻¹ · min⁻¹), euglycaemic (5 mmol/l) clamp. Somatostatin (450 μg/h) was infused to suppress endogenous insulin secretion, and growth hormone (3 ng · kg⁻¹ · min⁻¹) and glucagon (0.8 ng · kg⁻¹ · min⁻¹) were infused to maintain basal levels. GLP-1 (50 pmol · kg⁻¹ · h⁻¹) or 154 mmol/l NaCl (placebo) was infused after 3 h of equilibration, i.e. from 180-360 min. GLP-1 infusion resulted in GLP-1 levels of approximately 40 pmol/l. Plasma glucose, insulin, growth hormone, and glucagon levels were similar throughout the clamps. The rate of glucose infusion required to maintain euglycaemia was similar with or without GLP-1 infusion (7.69±1.17 vs 7.76±0.95 mg · kg⁻¹ · min⁻¹ at 150–180 min and 8.56±1.13 vs 8.55±0.68 mg · kg⁻¹ · min⁻¹ at 330–360 min) and there was no difference in isotopically determined hepatic glucose production rates (− 0.30±0.23 vs −0.16±0.22 mg · kg⁻¹ · min⁻¹ at 330–360 min). Furthermore, arteriovenous glucose differences across the forearm were similar with or without GLP-1 infusion (1.43±0.23 vs 1.8±0.29 mmol/l), (ANOVA;p>0.60, in all instances). In conclusion, GLP-1 (7–36 amide) administered for 3 h, leading to circulating levels within the physiological range, does not affect insulin sensitivity in healthy man.     

Macrophage migration inhibitory factor promotes intestinal tumorigenesis

BACKGROUND & AIMS: The cytokine macrophage migration inhibitory factor (MIF) is expressed throughout the human gastrointestinal tract. Recently, protumorigenic activity of MIF has been described in several cancer models. Therefore, we investigated the expression and function of MIF during the early stages of intestinal tumorigenesis. METHODS: MIF messenger RNA, protein, and tautomerase activity were measured in normal intestinal mucosa and adenomas from patients with sporadic colorectal adenomas and in the adenomatous polyposis coli (Apc)Min/+ mouse model of intestinal tumorigenesis. MIF function was investigated by using VACO-235 human colorectal adenoma cells in vitro and by testing the effect of genetic deletion of Mif on ApcMin/+ mouse intestinal tumorigenesis. RESULTS: MIF expression and tautomerase activity were increased in human and ApcMin/+ mouse intestinal adenomas compared with adjacent normal mucosa. Up-regulation of MIF occurred mainly in epithelial cells (associated with an increasing grade of dysplasia), but also in stromal plasma cells. Exogenous MIF inhibited apoptosis and promoted anchorage-independent growth of VACO-235 cells (maximal at 100 ng/mL). Homozygous deletion of Mif was associated with a reduction in the number and size of ApcMin/+ mouse adenomas (P = .025 for the difference in large [>7-mm] tumors) and decreased angiogenesis (43% decrease in mean tumor microvessel density), but there was no alteration in epithelial cell apoptosis or proliferation. CONCLUSIONS: MIF expression is increased in sporadic human colorectal adenomas, and exogenous MIF drives tumorigenic behavior of epithelial cells in vitro. Mif also promotes intestinal tumorigenesis (predominantly via angiogenesis) in the ApcMin/+ mouse. Therefore, MIF is a potential colorectal cancer chemoprevention target.     

Identification of functional prolactin (PRL) receptor gene expression: PRL inhibits lipoprotein lipase activity in human white adipose tissue

During lactation serum levels of prolactin (PRL) are elevated, and the activity of lipoprotein lipase (LPL) is decreased in the adipose tissue and increased in the mammary gland. However, PRL has been suggested to affect the adipose tissue in an indirect fashion during lactation. In the present study, we demonstrated expression of four PRL receptor (PRLR) mRNA isoforms (L, I, S1(a), and S1(b)) in human sc abdominal adipose tissue and breast adipose tissue using RT-PCR/Southern blot analysis. In addition, L-PRLR [relative molecular mass (M(r)) 90,000] and I-PRLR (M(r) 50,000) protein expression was detected in human sc abdominal adipose tissue and breast adipose tissue using immunoblot analysis. Two additional protein bands with the molecular weight M(r) 40-35,000 were also detected. The direct effect of PRL on the regulation of LPL activity in human abdominal adipose tissue cultured in vitro was investigated. PRL (500 ng/ml) reduced the LPL activity in human adipose tissue to 31 +/- 7.7%, compared with control. GH (100 ng/ml) also reduced the LPL activity, to 45 +/- 8.6%, compared with control. In agreement with previous studies, cortisol increased the LPL activity and GH inhibited cortisol-induced LPL activity. Furthermore, we found that PRL also inhibited the cortisol-induced LPL activity. Taken together, these results demonstrate a direct effect of PRL, via functional PRLRs, in reducing the LPL activity in human adipose tissue, and these results suggest that LPL might also be regulated in this fashion during lactation.     

Atherosclerosis in coronary arteries and aorta among Greenlanders: an autopsy study

In a cross-sectional autopsy study of 107 Inuit in Greenland, the extent of arterial surface involvement with atherosclerosis was evaluated in the presence of known or estimated environmental risk factors for coronary heart disease (CHD): age, gender, obesity, serum lipids, smoking, and hypertension. Mean, median, and range values for all of the risk factor variables and for the extent of atherosclerosis in the thoracic aorta, abdominal aorta, right coronary artery, and left anterior descending coronary artery are reported by age strata, along with the results of covariant analysis of the dependence of the extent of atherosclerosis upon the risk factors. No significant differences between females and males were found in either the risk factors or prevalence and extent of atherosclerosis in the aorta and in the coronary arteries. It appears that the extent of advanced atherosclerotic lesions in Greenlanders appears to be the same as that previously reported in a similar study in Alaska Natives.     

Prevalence, prognostic significance, and treatment of atrial fibrillation in congestive heart failure with particular reference to the DIAMOND-CHF study

Atrial fibrillation is a growing health problem and the most common cardiac arrhythmia, affecting 5% of persons above the age of 65 years. The number of hospital discharges for atrial fibrillation has more than doubled in the past decade. It occurs very often in patients with congestive heart failure and the prevalence increases with the severity of the disease. These two conditions seem to be linked together, and congestive heart failure may either be the cause or the consequence of atrial fibrillation. The prognosis of atrial fibrillation is controversial, but studies indicate that atrial fibrillation is a risk factor in congestive heart failure patients. In the last 10-15 years, significant advances in the treatment of heart failure have improved survival, whereas effective management of atrial fibrillation in heart failure patients still awaits similar progress. Empirically, two strategies have evolved for treatment of atrial fibrillation: 1) rhythm control, which means conversion to sinus rhythm and maintenance of sinus rhythm; and 2) rate control, which means reduction of heart rate to an acceptable frequency. It is unknown whether one of these strategies is better than the other. In this review the authors discuss the prevalence, impact, and treatment of atrial fibrillation in heart failure patients.     

Evaluation of endothelial cell culture as a model system of vascular ageing

The purpose of this study was to evaluate the relevance of long-term endothelial cell culture as a model system of vascular ageing. Micro- and macrovascular endothelial cells were serially passaged until replicative senescence and their ability to form tube-like structures when cultured on Matrigel was assessed throughout their lifespan. For both cell types low passage cultures adopted a homogeneous cobblestone morphology, while senescent cultures were extremely heterogeneous. Furthermore, both cell types showed a reduction in tube formation ability with in vitro ageing, which is in accordance with the reduction in angiogenic potential observed with ageing in vivo. Examination of senescence associated β-galactosidase activity revealed an increased activity in cells forming tubes as compared to cells cultured on plastic, which could be attributed to an increased lysosomal content of cells undergoing tube formation. As this increased senescence associated β-galactosidase activity was unrelated to the replicative age of the cells, senescence associated β-galactosidase activity may not be a relevant senescence marker for differentiating endothelial cells. The age-related reduction in tube formation ability suggested that long-term culture of endothelial cells may be a valid model system of vascular ageing, which makes it an ideal platform for high throughput screening of compounds influencing angiogenesis.     

Disseminated Histoplasmosis in Persons with HIV/AIDS,Southern Brazil, 2010–2019

We evaluated disseminated histoplasmosis (DH) in HIV patients over 10 years in southern Brazil. The incidence was 12 cases/1,000 hospitalizations (2010–2019); the mortality rate was 35%. Tuberculosis frequently obscured the diagnosis of DH. We emphasize the need in our region to suspect and investigate DH using more sensitive methods.     

Auditing the Representation of Female Versus Male Athletes in Sports Science and Sports Medicine Research: Evidence-Based Performance Supplements

Although sports nutrition guidelines promote evidence-based practice, it is unclear whether women have been adequately included in the underpinning research. In view of the high usage rates of performance supplements by female athletes, we conducted a standardised audit of the literature supporting evidence-based products: β-alanine, caffeine, creatine, glycerol, nitrate/beetroot juice and sodium bicarbonate. Within 1826 studies totalling 34,889 participants, just 23% of participants were women, although 34% of studies included at least one woman. Across different supplements, 0–8% of studies investigated women exclusively, while fewer (0–2%) were specifically designed to compare sex-based responses. The annual publication of female-specific studies was ~8 times fewer than those investigating exclusively male cohorts. Interestingly, 15% of the female participants were classified as international/world-class athletes, compared with 7% of men. Most studies investigated performance outcomes but displayed poorer representation of women (16% of participants), whereas health-focussed studies had the greatest proportion of female participants (35%). Only 14% of studies including women attempted to define menstrual status, with only three studies (~0.5%) implementing best practice methodologies to assess menstrual status. New research should target the efficacy of performance supplements in female athletes, and future sports nutrition recommendations should specifically consider how well female athletes have contributed to the evidence-base.     

Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized,Double-Blind,Placebo-Controlled,Phase 2 Trial

OBJECTIVEInsulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium–glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance.RESEARCH DESIGN AND METHODSIn this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m²) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.RESULTSWe identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat.CONCLUSIONSOur results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.     

The changing landscape for the management of patients with neovascular AMD: brolucizumab in clinical practice

Untreated neovascular age-related macular degeneration (nAMD) can lead to severe and permanent visual impairment. The chronic nature of the disease can have a significant impact on patients’ quality of life and an economic and time burden on medical retina (MR) services, with the care need outweighing the growth of resources that clinical services can access. The introduction of a new treatment into clinical services can be challenging, especially for services that are already under capacity constraints. Guidance for practical implementation is therefore helpful. Roundtable meetings, facilitated by Novartis UK, between a working group of MR experts with experience of leading and managing NHS retinal services in the intravitreal era were conducted between 2020 and 2021. These meetings explored various aspects and challenges of introducing a new anti-vascular endothelial growth factor (VEGF) therapy to the UK medical retina services. Provision of clear expert recommendations and practical guidance nationally, that can be adapted locally as required to support clinicians and healthcare professionals (HCPs), is valuable in supporting the introduction of a new anti-VEGF therapy within the NHS environment. The experts provide ophthalmologic HCPs with a collation of insights and recommendations to support the introduction and delivery of brolucizumab in their local service in the face of current and projected growth in demand for retina care.Subject terms: Macular degeneration, Education