The ever increasing burden of an ageing population and pandemic of metabolic syndrome worldwide demands further understanding of the modifiable risk factors in reducing disability and morbidity associated with these conditions. Disuse skeletal muscle atrophy (sometimes referred to as “simple” atrophy) and insulin resistance are ‘non-pathological’ events resulting from sedentary behaviour and periods of enforced immobilization e.g. due to fractures or elective orthopaedic surgery. Yet, the processes and drivers regulating disuse atrophy and insulin resistance and the associated molecular events remain unclear – especially in humans. The aim of this review is to present current knowledge of relationships between muscle protein turnover, insulin resistance and muscle atrophy during disuse, principally in humans. Immobilisation lowers fasted state muscle protein synthesis (MPS) and induces fed-state ‘anabolic resistance’. While a lack of dynamic measurements of muscle protein breakdown (MPB) precludes defining a definitive role for MPB in disuse atrophy, some proteolytic “marker” studies (e.g. MPB genes) suggest a potential early elevation. Immobilisation also induces muscle insulin resistance (IR). Moreover, the trajectory of muscle atrophy appears to be accelerated in persistent IR states (e.g. Type II diabetes), suggesting IR may contribute to muscle disuse atrophy under these conditions. Nonetheless, the role of differences in insulin sensitivity across distinct muscle groups and its effects on rates of atrophy remains unclear. Multifaceted time-course studies into the collective role of insulin resistance and muscle protein turnover in the setting of disuse muscle atrophy, in humans, are needed to facilitate the development of appropriate countermeasures and efficacious rehabilitation protocols.

Introduction While the beneficial effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on cardiovascular and renal outcomes are recognized, their direct effects on endothelial function remain unclear. We, therefore, undertook a systematic review to evaluate the current literature in this area. Methods Electronic databases (PubMed, EMBASE, and Medline) were systematically searched using PRISMA guidelines for studies involving the in vitro, in vivo, or ex vivo administration of SGLT-2 inhibitors to animals, vascular tissue, or vascular endothelial cells. Results Of 144 retrieved publications, 24 experimental studies met the inclusion criteria. Reporting of possible sources of bias were poor, making the overall risk of bias difficult to assess. Within the 24 studies, the SGLT-2 inhibitors canagliflozin, ipragliflozin, empagliflozin, dapagliflozin, tofogliflozin, and luseogliflozin were assessed as interventions. Animal model studies (n = 17) demonstrated that all SGLT-2 inhibitors prevented endothelial dysfunction and enhanced endothelium-dependent vasorelaxation in diabetic and non-diabetic models. In vitro studies (n = 9) using human endothelial cells indicated a direct anti-inflammatory effect of dapagliflozin (1–100 nM) and canagliflozin, (10 µM), while empagliflozin (1 and 10 µM) improved viability of hyperglycemic cells. Potential mechanisms of action of the SGLT-2 inhibitors include a reduction in oxidative stress, modulation of adhesion molecules and reductions in pro-inflammatory cytokines. Conclusions Preclinical studies indicate that SGLT-2 inhibitors attenuate vascular dysfunction in preclinical models via a combination of mechanisms that appear to act independently of glucose-lowering benefits.

Introduction: Recent studies have concluded that elevated circulating branched chain amino acids (BCAA) are associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and obesity. However, the development of this association over time and the quantification of the strength of this association for individual BCAAs prior to T2DM diagnosis remains unexplored. Methods: A systematic search was conducted using the Healthcare Databases Advance Search (HDAS) via the National Institute for Health and Care Excellence (NICE) website. The data sources included EMBASE, MEDLINE and PubMed for all papers from inception until November 2021. Nine studies were identified in this systematic review and meta-analysis. Stratification was based on follow-up times (0–6, 6–12 and 12 or more years) and controlling of body mass index (BMI) through the specific assessment of overweight cohorts was also undertaken. Results: The meta-analysis revealed a statistically significant positive association between BCAA concentrations and the development of T2DM, with valine OR = 2.08 (95% CI = 2.04–2.12, p < 0.00001), leucine OR = 2.25 (95% CI = 1.76–2.87, p < 0.00001) and isoleucine OR = 2.12, 95% CI = 2.00–2.25, p < 0.00001. In addition, we demonstrated a positive consistent temporal association between circulating BCAA levels and the risk of developing T2DM with differentials in the respective follow-up times of 0–6 years, 6–12 years and ≥12 years follow-up for valine (OR = 2.08, 1.86 and 2.14, p < 0.05 each), leucine (OR = 2.10, 2.25 and 2.16, p < 0.05 each) and isoleucine (OR = 2.12, 1.90 and 2.16, p < 0.05 each) demonstrated. Conclusion: Plasma BCAA concentrations are associated with T2DM incidence across all temporal subgroups. We suggest the potential utility of BCAAs as an early biomarker for T2DM irrespective of follow-up time.

Sodium-glucose cotransporter-2 inhibitors (SGLT2Is) reduce cardio-metabolic and renal outcomes in patients with type 2 diabetes (T2D) but their efficacy and safety in older or frail individuals remains unclear. We searched PubMed, Scopus, Web of Science, Cochrane CENTRA and Google Scholar and selected randomised controlled trials and observational studies comparing SGLT2Is versus placebo/other glucose-lowering agent for people with frailty or older individuals (>65 years) with T2D and heart failure (HF). Extracted data on the change in HbA1c % and safety outcomes were pooled in a random-effects meta-analysis model. We included data from 20 studies (22 reports; N = 77,083 patients). SGLT2Is did not significantly reduce HbA1c level (mean difference −0.13, 95%CI: −0.41 to 0.14). SGLT2Is were associated with a significant reduction in the risk of all-cause mortality (risk ratio (RR) 0.81, 95%CI: −0.69 to 0.95), cardiac death (RR 0.80, 95%CI: −0.94 to 0.69) and hospitalisation for heart failure (HHF) (RR 0.69, 95%CI: 0.59–0.81). However, SGLT2Is did not demonstrate significant effect in reducing in the risk of macrovascular events (acute coronary syndrome or cerebral vascular occlusion), renal progression/composite renal endpoint, acute kidney injury, worsening HF, atrial fibrillation or diabetic ketoacidosis. In older or frail patients with T2D and HF, SGLT2Is are consistently linked with a decrease in total mortality and the overall burden of cardiovascular (CV) events, including HHF events and cardiac death, but not protective for macrovascular death or renal events. Adverse events were more difficult to quantify but the risk of diabetic ketoacidosis or acute kidney injury was not significantly increase.

Fracture risk is higher in older adults with Type 2 diabetes mellitus (T2DM). Oral glucose-lowering medications have different effects on bone metabolism. The purpose of this study is to appraise the evidence from literature and determine the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor on the risk of developing bone fractures. Using Boolean search terms, the search strategy combined synonyms of 'fracture' and 'DPP-4 inhibitor'. Comprehensive electronic databases which include EMBASE, MEDLINE, the EMA and the WHO ICTRP databases were searched for randomised controlled trial (RCT) studies which compared a DPP-4 inhibitor with an active comparator or placebo amongst patients with T2DM. Meta-analysis was performed to compare DPP-4 inhibitor with either an active comparator or a placebo. The outcome measure was the presence or absence of fracture. The search yielded 5061 records relating to fractures and DPP-4 inhibitor, from which 51 eligible RCTs were selected for meta-analysis (N=36,402). Thirty-seven (37) studies compared DPP-4 inhibitor with placebo (n=23,974), while fourteen (14) studies (n=12,428) compared DPP-4 inhibitor with an active comparator. The mean age of patients was 57.5±5.4years, the average glycated haemoglobin (HbA1c) was 8.2%, while the average BMI was 30±2kg/m(2). Overall, there was no significant association of fracture events with the use of DPP-4 inhibitor when compared with placebo (OR; 0.82, 95% CI 0.57-1.16, P=0.9) or when DPP-4 inhibitor was compared against an active comparator (OR; 1.59, 95% CI 0.91-2.80, P=0.9). This study offers a larger, up-to-date review of the subject. The meta-analysis showed that there was no significant association between DPP-4 inhibitor use and the incidence of fractures.