Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study.

AIMS/HYPOTHESIS: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. METHODS: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. RESULTS: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. CONCLUSIONS/INTERPRETATION: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. TRIAL REGISTRATION: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.

Adipokines and stroke: A systematic review and meta-analysis of disease risk and patient outcomes.

Obesity is reported to increase stroke risk, with adipocyte-derived cytokines or adipokines implicated as mediators. However, the relationship between adipokines and stroke is not well clarified. Thus, we aimed to evaluate the association of adipokines with stroke using fully adjusted risk estimates that incorporated body mass index in a meta-analysis. Data from 52 studies (62,428 patients) were pooled in a random-effects meta-analysis. Adiponectin was independently associated with a lower risk of pre-existing stroke (adjusted odds ratio: 0.64 [95% confidence interval: 0.46-0.88], p < 0.01), whereas leptin (1.08 [1.00-1.17], p = 0.04), resistin (1.06 [1.04-1.08], p < 0.01) and visfatin (1.04 [1.01-1.07], p = 0.01) are associated with a higher risk of stroke, but none with incident stroke. Adipokines independently associated with an ischaemic stroke subtype were adiponectin (0.48 [0.30-0.77], p < 0.01), leptin (1.10 [1.01-1.20], p = 0.04), and resistin (1.06 [1.04-1.08], p < 0.01). Fatty acid-binding protein-4 (FABP-4) independently predicted 6-month poor functional outcomes in stroke patients (adjusted hazard ratio: 1.09 [1.06-1.12], p < 0.01); whereas both FABP-4 (1.17 [1.03-1.34], p = 0.01) and visfatin (1.24 [1.00-1.55], p = 0.05) were predictive of 6-month mortality. Adipokines are associated with a greater risk of pre-existing stroke, but not with the relationship with incident stroke. Adipokines, such as FABP-4 and visfatin, may serve as biomarkers of stroke severity and worsening of stroke outcomes.

Associations between adipokines and atrial fibrillation: A systematic review and meta-analysis.

AIMS: Although overweight and obesity are associated with increased risk of atrial fibrillation (AF), the underlying mechanisms are not well characterised. Recent data suggest that this link may be partly due to abnormal adipose tissue-derived cytokines or adipokines. However, this relationship is not well clarified. To evaluate the association between adipokines and AF in a systematic review and meta-analysis. DATA SYNTHESIS: PubMed, Embase, and Web of Science Core Collection were searched from inception through 1st March 2021. Studies were included if they reported any adipokine and AF, with their quality assessed using the Newcastle-Ottawa scale. Data were independently abstracted, with unadjusted and multivariable adjusted estimates pooled in a random-effects meta-analysis. Data are presented for overall prevalent or incident AF and AF subtypes (paroxysmal, persistent, or non-paroxysmal AF). A total of 34 studies, with 31,479 patients, were included. The following adipokines were significantly associated with AF in the pooled univariate data - apelin (risk ratio for prevalent AF: 0.05 [0.00-0.50], p = 0.01; recurrent AF: 0.21 [0.11-0.42], p < 0.01) and resistin (incident AF: 2.05 [1.02-4.1], p = 0.04; prevalent AF: 2.62 [1.78-3.85], p < 0.01). Pooled analysis of multivariable adjusted effect size estimates showed adiponectin as the sole independent predictor of AF incidence (1.14 [1.02-1.27], p = 0.02). Moreover, adiponectin was associated with non-paroxysmal AF (persistent AF: 1.45 [1.08-1.94, p = 0.01; non-paroxysmal versus paroxysmal AF: 3.14 [1.87-5.27, p < 0.01). CONCLUSIONS: Adipokines, principally adiponectin, apelin, and resistin, are associated with the risk of atrial fibrillation. However, the association is not seen after multivariate adjustment, likely reflecting the lack of statistical power. Future research should investigate these relationships in larger prospective cohorts and how they can refine AF monitoring strategies. PROSPERO ID: CRD42020208879.