Improvement in glycated haemoglobin evaluated by baseline body mass index: a meta-analysis of the liraglutide phase III clinical trial programme.

In the liraglutide clinical trial programme, liraglutide 1.2 and 1.8 mg were found to effectively lower glycated haemoglobin (HbA1c) in patients with type 2 diabetes (T2D). It is unknown whether baseline body mass index (BMI) is a predictor of change in HbA1c observed during a clinical trial with liraglutide or placebo treatment. The present meta-analysis of patient-level data, using pooled data from seven phase III trials [LEAD-1-6 and the liraglutide versus sitagliptin trial (LIRA-DPP-4)] for liraglutide 1.2, 1.8 mg and placebo (n = 3222), identified no significant correlation between baseline BMI (<20 kg/m(2) up to 45 kg/m(2) ) and HbA1c reduction for placebo or liraglutide 1.2 mg, and a modest, clinically non-relevant, association for liraglutide 1.8 mg [-0.010 (95% confidence interval -0.020, -0.001)], whereby a 10 kg/m(2) increase in baseline BMI corresponded to 0.10%-point (1.1 mmol/mol) greater HbA1c reduction. In summary, reductions in HbA1c obtained during clinical trials with liraglutide or placebo treatment were independent of baseline BMI.

Is insulin the most effective injectable antihyperglycaemic therapy?

AIMS: The recent type 2 diabetes American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement suggested insulin is the most effective glucose-lowering therapy, especially when glycated haemoglobin (HbA1c) is very high. However, randomized studies comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide once-weekly [OW; DURATION-3 (Diabetes therapy Utilization: Researching changes in A1c, weight, and other factors Through Intervention with exenatide ONce-Weekly)] and liraglutide once-daily [OD; LEAD-5 (Liraglutide Effect and Action in Diabetes)] with insulin glargine documented greater HbA1c reduction with GLP-1RAs, from baseline HbA1c ∼8.3% (67 mmol/mol). This post hoc analysis of DURATION-3 and LEAD-5 examined changes in HbA1c, fasting glucose and weight with exenatide OW or liraglutide and glargine, by baseline HbA1c quartile. METHODS: Descriptive statistics were provided for change in HbA1c, fasting glucose, weight, and insulin dose, and subjects (%) achieving HbA1c <7.0%, by baseline HbA1c quartile. Inferential statistical analysis on the effect of baseline HbA1c quartile was performed for change in HbA1c. An analysis of covariance (ANCOVA) model was used to evaluate similarity in change in HbA1c across HbA1c quartiles. RESULTS: At 26 weeks, in both studies, HbA1c reduction, and proportion of subjects reaching HbA1c <7.0%, were similar or numerically greater with the GLP-1RAs than glargine for all baseline HbA1c quartiles. Fasting glucose reduction was similar or numerically greater with glargine. Weight decreased with both GLP-1RAs across all quartiles; subjects taking glargine gained weight, more at higher baseline HbA1c. Adverse events were uncommon although gastrointestinal events occurred more frequently with GLP-1RAs. CONCLUSIONS: HbA1c reduction with the GLP-1RAs appears at least equivalent to that with basal insulin, irrespective of baseline HbA1c. This suggests that liraglutide and exenatide OW may be appropriate alternatives to basal insulin in type 2 diabetes, including when baseline HbA1c is very high (≥9.0%).

Estimation of rat muscle blood flow by microdialysis probes perfused with ethanol, [14C]ethanol, and 3H2O.

We used the perfused rat hindquarter to evaluate whether the microdialysis ethanol technique can be used to qualitatively estimate nutritive skeletal muscle blood flow. Four microdialysis probes were inserted in different hindlimb muscles in each of 16 rats. Hindquarters were perfused at blood flow rates ranging from 0 to 21 ml. 100 g-1. min-1. The microdialysis probes were perfused at 2 microliter/min with perfusate containing ethanol, [14C]ethanol, and 3H2O. Within and between experiments outflow-to-inflow ratios (o/i) generally varied inversely with blood flow. When a low flow or no flow was maintained in hindquarters, o/i ratios first increased with time (for at least 60 min) and then leveled off. The long time constant impaired detection of rapid oscillations in blood flow, especially at low blood flow rates. Contractions per se apparently decreased o/i ratios independent of blood flow. Ethanol and [14C]ethanol o/i ratios did not differ. 3H2O o/i paralleled ethanol and [14C]ethanol o/i ratios but it was significantly lower. In conclusion, differences in skeletal muscle blood flow can be detected by the microdialysis technique. However, the slow changes in o/i, in particular at low blood flow rates, limit the usefulness of the technique for measuring dynamic changes in blood flow; caution must also be exerted during muscle contractions. 3H2O and [14C]ethanol are good alternatives to ethanol in the determination of blood flow by microdialysis.

Low-intensity training dissociates metabolic from aerobic fitness.

This study investigated the effect of prolonged whole-body low-intensity exercise on blood lipids, skeletal muscle adaptations and aerobic fitness. Seven male subjects completed a 32-day crossing of the Greenland icecap on cross-country skies and before and after this arm or leg cranking was performed on two separate days and biopsies were obtained from arm and leg muscle, and venous blood was sampled. During the crossing, subjects skied for 342+/-42 min/day and body mass was decreased by 7.1+/-0.7 kg. Peak leg oxygen uptake (4.6+/-0.2 L/min) was decreased (P<0.05) by 7% whereas peak arm oxygen uptake (3.0+/-0.2 L/min) remained unchanged. Total and low-density lipoprotein cholesterol (5.0+/-0.2 and 3.20.2 mmol/L) were decreased by 8% and 20%, respectively. Muscle beta-hydroxy-acyl-CoA dehydrogenase activity was increased with 22% in arm (P=0.08) and remained unchanged in leg muscle. Hormone sensitive lipase activity was similar in arm and leg muscle prior to the expedition and was not significantly affected by the crossing. In conclusion, an improved blood lipid profile and thus metabolic fitness was present after prolonged low-intensity training and this occurred in spite of a decreased aerobic fitness and an unchanged arm and leg muscle hormone-sensitive lipase activity.

Additivity of adrenaline and contractions on hormone-sensitive lipase, but not on glycogen phosphorylase, in rat muscle.

AIM: Hormone-sensitive lipase (HSL) has been proposed to regulate triacylglycerol (TG) breakdown in skeletal muscle. In muscles with different fibre type compositions the influence on HSL of two major stimuli causing TG mobilization was studied. METHODS: Incubated soleus and extensor digitorum longus (EDL) muscles from 70 g rats were stimulated by adrenaline (5.5 microm, 6 min) or contractions (200 ms tetani, 1 Hz, 1 min) in maximally effective doses or by both adrenaline and contractions. RESULTS: Hormone-sensitive lipase activity was increased significantly by adrenaline as well as contractions, and the highest activity (P < 0.05) was seen with combined stimulation [Soleus: 0.40 +/- 0.03 (SE) m-unit mg protein(-1) (basal), 0.65 +/- 0.02 (adrenaline), 0.65 +/- 0.03 (contractions), 0.78 +/- 0.03 (adrenaline and contractions); EDL: 0.18 +/- 0.01, 0.30 +/- 0.02, 0.26 +/- 0.02, 0.32 +/- 0.01]. Glycogen phosphorylase activity was always increased more by adrenaline compared with contractions [Soleus: 60 +/- 4 (a/a + b)% vs. 46 +/- 3 (P < 0.05); EDL: 60 +/- 5 vs. 39 +/- 6 (P < 0.05)]. After combined stimulation glycogen phosphorylase activity in soleus [59 +/- 3 (a/a + b)%] was identical to and in EDL [45 +/- 4 (a/a + b)%] smaller (P < 0.05) than the activity after adrenaline only. CONCLUSIONS: In slow-twitch oxidative as well as in fast-twitch glycolytic muscle HSL is activated by both adrenaline and contractions. These stimuli are partially additive indicating at least partly different mechanisms of action. Contractions may impair the enhancing effect of adrenaline on glycogen phosphorylase activity in muscle.

Hormone-sensitive lipase in skeletal muscle: regulatory mechanisms.

AIM: The enzymatic regulation of intramuscular triacylglycerol (TG) breakdown has until recently not been well understood. Our aim was to elucidate the role of hormone-sensitive lipase (HSL), which controls TG breakdown in adipose tissue. METHODS: Isolated rat muscle as well as exercising humans were studied. RESULTS: The presence of HSL was demonstrated in all muscle fibre types by Western blotting of muscle fibres isolated by collagenase treatment or after freeze-drying. The content of HSL varies between fibre types, being higher in oxidative than in glycolytic fibres. Analysed under conditions optimal for HSL, neutral lipase activity in muscle can be stimulated by adrenaline as well as by contractions. These increases are abolished by presence of anti-HSL antibody during analysis. Moreover, immunoprecipitation with affinity-purified anti-HSL antibody causes similar reductions in muscle HSL protein concentration and in measured neutral lipase responses to contractions. The immunoreactive HSL in muscle is stimulated by adrenaline via beta-adrenergic activation of protein kinase A (PKA). From findings in adipocytes it is likely that PKA phosphorylates HSL at residues Ser563, Ser659 and Ser660. Contraction probably also enhances muscle-HSL activity by phosphorylation, because the contraction-induced increase in HSL activity is increased by the protein phosphatase inhibitor okadaic acid and reversed by alkaline phosphatase. A novel signalling pathway in muscle by which HSL activity may be stimulated by protein kinase C (PKC) via extracellular signal regulated kinase (ERK) has been demonstrated. In contrast to previous findings in adipocytes, in muscle activation of ERK is not necessary for stimulation of HSL by adrenaline. However, contraction-induced HSL activation is mediated by PKC, at least partly via the ERK pathway. In fat cells ERK is known to phosphorylate HSL at Ser600. So, phosphorylation of different sites may explain that in muscle the effects of contractions and adrenaline on HSL activity are partially additive. In line with the view that the two stimuli act by different mechanisms, training increases the contraction-mediated, but diminishes the adrenaline mediated HSL activation in muscle. CONCLUSION: The existence and regulation of HSL in skeletal muscle indicate a role of HSL in muscle TG metabolism.