Weight change with liraglutide and comparator therapies: an analysis of seven phase 3 trials from the liraglutide diabetes development programme.

AIM: We investigated the relationship between weight change and related factors in subjects with type 2 diabetes mellitus (T2DM) treated with liraglutide versus comparator diabetes therapies. METHODS: Twenty-six-week data from seven phase 3, randomized trials in the liraglutide T2DM development programme were analysed by trial and treatment group: liraglutide (1.2 and 1.8 mg), active comparator and placebo. Outcome measures included proportions of subjects in various weight change categories and their percentage weight change from baseline; impact of body mass index (BMI) and gastrointestinal (GI) adverse events (AEs) on weight change and correlation of weight change with change in glycosylated haemoglobin (HbA1c). RESULTS: A number of subjects experienced >5% weight loss during the trials (24.4% liraglutide 1.8 mg and 17.7% liraglutide 1.2 mg; 17.7% exenatide, 10.0% sitagliptin, 3.6-7.0% sulphonylurea, 2.6% thiazolidinedione and 2.6% glargine; 9.9% placebo). More weight loss was seen with liraglutide 1.2 and 1.8 mg than with active comparators except exenatide. Across trials, higher initial BMI was associated with slightly greater weight loss with liraglutide. Mean weight loss increased slightly the longer GI AEs persisted. Although HbA1c reduction was slightly larger in higher weight loss categories across treatments (including placebo), sample sizes were small and no clear correlation could be determined. Liraglutide-treated subjects experienced additional HbA1c reduction beyond that which appeared weight induced; thus, not all HbA1c-lowering effect appears weight mediated. CONCLUSIONS: The majority of liraglutide-treated T2DM subjects experienced weight loss in this analysis. Weight loss was greater and occurred more in glucagon-like peptide-1 receptor agonist-treated subjects than in active comparator-treated subjects.

Effects of eccentric cycling exercise on IGF-I splice variant expression in the muscles of young and elderly people.

Recovery from micro damage resulting from intensive exercise has been shown to take longer in older muscles. To investigate the factors that may contribute to muscle repair, we have studied the expression of two splice variants of the insulin-like growth factor-I (IGF-I) gene. IGF-IEa and mechano growth factor (MGF) were studied in response to 1 h of eccentric cycling exercise in young and old individuals. Subjects (nine young, aged 20-27 years and eight elderly, aged 67-75 years) completed an eccentric exercise protocol that consisted of 60 min of reverse pedal cycling. Workloads were chosen to give the same relative increases in oxygen uptake (VO2max) and heart rate in young and old subjects. Muscle biopsy samples were obtained from the quadriceps muscle before and 2 1/4 h after completion of the exercise bout and were analyzed for IGF-IEa and MGF mRNA levels using real-time quantitative PCR. No difference was observed between the baseline levels of the two splice variants between the two subject groups. Eccentric cycling exercise resulted in a significant increase in the mean MGF mRNA in both young and old subjects but did not alter IGF-IEa mRNA levels in either age group. As reported previously (Toft et al., 2002), the levels of serum creatine kinase and myoglobin, markers of muscle damage, were increased significantly from baseline and to 5 days after exercise in both young and old subjects. This supports previous research in suggesting that the MGF splice variant is sensitive to muscle damage-inducing exercise and is differentially regulated compared with IGF-IEa.

Controversies in radioiodine therapy: relation to ophthalmopathy, the possible radioprotective effect of antithyroid drugs, and use in large goitres.

In routine use for more than 50 years, radioiodine ((131)I) is generally considered safe and devoid of major side effects. Therefore, it is surprising that relatively many aspects of radioiodine therapy are controversial, as illustrated by recent international questionnaire studies. Our review aims at highlighting three of these areas - namely, the influence of (131)I on the course of Graves' ophthalmopathy, the possible radioprotective effects of antithyroid drugs, and the use of (131)I in large goitres. (131)I therapy carries a small (but definite) risk of causing progression of Graves' ophthalmopathy. Identification of risk factors (thyroid dysfunction, high level of thyroid-stimulating hormone (TSH) receptor antibodies, cigarette smoking) allows the identification of patients at risk and the institution of concomitant glucocorticoid treatment, thereby hindering progression of eye disease. On the basis, largely, of retrospective data, it appears that carbimazole (or methimazole), if stopped 3-5 days before treatment, does not influence the outcome of (131)I therapy. Simultaneous thyrostatic medication most probably reduces the efficacy of (131)I, as does restarting it within 7 days. Propylthiouracil seems to have a more prolonged radioprotective effect than carbimazole. Surgery is the treatment of first choice in patients with a large goitre. However, in the case of patient ineligibility or preference, (131)I therapy may be an option. The treatment has a favourable effect on tracheal compression and inspiratory capacity, but the reduction in thyroid volume is only 30-40%. Inpatient treatment, necessitated by the large doses, makes the treatment cumbersome. Controversy related to radioiodine therapy is mainly based on the lack of adequate prospective randomised studies comparing efficacy, side effects, cost and patient satisfaction.

Strenuous exercise decreases the percentage of type 1 T cells in the circulation.

Prolonged strenuous exercise is followed by a temporary functional immune impairment. Low numbers of CD4+ T helper (Th) and CD8+ T cytotoxic (Tc) cells are found in the circulation. These cells can be divided according to their cytokine profile into type 1 (Th1 and Tc1), which produce interferon-gamma and interleukin (IL)-2, and type 2 (Th2 and Tc2) cells, which produce IL-4. The question addressed in the present study was whether exercise affected the relative balance between the circulating levels of these cytokine-producing T cells. Nine male runners performed treadmill running for 2.5 h at 75% of maximal oxygen consumption. The intracellular expression of cytokines was detected following stimulation with ionomycin and phorbol 12-myristate 13-acetate in blood obtained before, during, and after exercise. The percentage of type 1 T cells in the circulation was suppressed at the end of exercise and 2 h after exercise, whereas no changes were found in the percentage of type 2 T cells. Plasma epinephrine correlated negatively with the percentage of circulating CD8+ T cells producing IL-2, whereas peak IL-6 correlated with the percentage of CD8+ IL-4-producing T cells in the circulation. Peak plasma IL-6 correlated with plasma cortisol postrunning. In conclusion, the postexercise decrease in T lymphocyte number is accompanied by a more pronounced decrease in type 1 T cells, which may be linked to high plasma epinephrine. Furthermore, IL-6 may stimulate type 2 T cells, thereby maintaining a relatively unaltered percentage of these cells in the circulation compared with total circulating lymphocyte number.

Plasma interleukin-6 during strenuous exercise: role of epinephrine.

Exercise induces increased levels of plasma interleukin-6 (IL-6) as well as changes in the concentration of lymphocytes and neutrophils. The aim of this study was to investigate a possible role for epinephrine. Seven healthy men participated in an exercise experiment. One month later they received an epinephrine infusion. The exercise consisted of treadmill running at 75% of maximal O(2) consumption for 2.5 h. The infusion trial consisted of 2.5 h of epinephrine infusion calculated to reach the same plasma epinephrine levels seen during the exercise experiment. The plasma concentration of IL-6 increased 29-fold during exercise, with peak levels at the end of exercise. The increase in plasma IL-6 during epinephrine infusion was only sixfold, with the peak value at 1 h after infusion. The lymphocyte concentration increased to the same levels during exercise and epinephrine infusion. The lymphocyte count decreased more in the postexercise period than after epinephrine infusion. The neutrophil concentration was elevated threefold in response to exercise, whereas no change was found in response to epinephrine infusion. In conclusion, the exercise-induced increase in plasma IL-6 could not be mimicked by epinephrine infusion. However, epinephrine induced a small increase in IL-6 and may, therefore, partly influence the plasma levels of IL-6 during exercise. In addition, the results support the idea that epinephrine plays a role in exercise-induced changes in lymphocyte number, whereas epinephrine does not mediate exercise-induced neutrocytosis.

Evidence for a Graves' disease susceptibility locus at chromosome Xp11 in a United Kingdom population.

Graves' disease (GD), which has a strong female preponderance (female/male ratio, >5:1), is inherited as a complex genetic trait. Loci for GD have started to be defined using genome-wide approaches for genetic linkage. To date, 3 loci have been confirmed in at least 2 cohorts of GD patients, the strongest effect being at the cytotoxic T lymphocyte antigen-4 (CTLA-4) locus on chromosome 2q33 in our population. Two other loci for GD have recently been proposed, but not confirmed, on chromosomes Xq21 (GD3) and 14q31 (GD1). We studied a cohort of 75 sibling pairs with GD from the United Kingdom for linkage to 12 markers over a 83-cM region of the X chromosome and for 8 markers over a 36-cM region of 14q31-q33. A peak multipoint nonparametric linkage score of 2.21 (P = 0.014) was found at marker DXS8083 on Xp11, which increased to a nonparametric linkage score of 3.18 (P = 0.001) in data that had been conditioned for allele sharing at the CTLA-4 locus under an epistatic model. There was no evidence to support linkage of GD to Xq21.33-q22 (GD3) or at the 14q31-q33 (GD1) region in our population. A locus with a moderate contribution to GD susceptibility (lambda(s) = 1.4) is likely to exist in the Xp11 region, but we are unable to confirm that the GD1 or the GD3 regions contain major susceptibility loci in our United Kingdom GD population.

N-3 polyunsaturated fatty acids do not affect cytokine response to strenuous exercise.

The aim of the present study was to investigate whether fish oil supplementation was able to modulate the acute-phase response to strenuous exercise. Twenty male runners were randomized to receive supplementation (n = 10) with 6.0 g fish oil daily, containing 3.6 g n-3 polyunsaturated fatty acids (PUFA), for 6 wk or to receive no supplementation (n = 10) before participating in The Copenhagen Marathon 1998. Blood samples were collected before the race, immediately after, and 1.5 and 3 h postexercise. The fatty acid composition in blood mononuclear cells (BMNC) differed between the fish oil-supplemented and the control group, showing incorporation of n-3 PUFA and less arachidonic acid in BMNC in the supplemented group. The plasma levels of tumor necrosis factor-alpha, interleukin-6, and transforming growth factor-beta(1) peaked immediately after the run, the increase being 3-, 92-, and 1.1-fold, respectively, compared with resting samples. The level of interleukin-1 receptor antagonist peaked 1.5 h after exercise, with the increase being 87-fold. However, the cytokine levels did not differ among the two groups. Furthermore, supplementation with fish oil did not influence exercise-induced increases in leucocytes and creatine kinase. In conclusion, 6 wk of fish oil supplementation had no influence on the acute-phase response to strenuous exercise.

Effects of exercise on lymphocytes and cytokines.

OBJECTIVES: To review results on exercise induced changes in the immune system following strenuous and moderate exercise. METHODS: A literature search over the past 15 years was conducted using Medline and selected papers. RESULTS: After intense long term exercise, the immune system is characterised by concomitant impairment of the cellular immune system and increased inflammation. Thus low concentrations of lymphocytes, suppressed natural immunity, suppressed lymphocyte proliferation, and suppressed levels of secretory IgA in saliva are found simultaneously with high levels of circulating proinflammatory and antiinflammatory cytokines. The underlying mechanisms are multifactorial and include neuroendocrinological and metabolic factors. The clinical consequences of the exercise induced immune changes have not formally been identified, but the exercise effect on lymphocyte dynamics and immune function may be linked to the exercise effects on resistance to infections and malignancy and the cytokine response may be linked to muscle damage or muscle cell growth. CONCLUSIONS: Moderate exercise across the life span seems to increase resistance to upper respiratory tract infections, whereas repeated strenuous exercise suppresses immune function. It is premature to offer advice on nutrition to athletes in order to alter the exercise induced immunosuppression found after exercise.

Evidence for a new Graves disease susceptibility locus at chromosome 18q21.

Graves disease (GD) is a common autoimmune thyroid disorder that is inherited as a complex multigenic trait. By using a single microsatellite marker at each locus, we screened the type 1 diabetes loci IDDM4, IDDM5, IDDM6, IDDM8, and IDDM10 and the fucosyltransferase-2 locus for linkage in sib pairs with GD. This showed a two-point nonparametric linkage (NPL) score of 1.57 (P=.06) at the IDDM6 marker D18S41, but NPL scores were <1.0 at the other five loci. Thus, the investigation of the IDDM6 locus was extended by genotyping 11 microsatellite markers spanning 48 cM across chromosome 18q12-q22 in 81 sib pairs affected with autoimmune thyroid disease (AITD). Multipoint analysis, designating all AITD sib pairs as affected, showed a peak NPL score of 3.46 (P=.0003), at the marker D18S487. Designation of only GD cases as affected (74 sib pairs) showed a peak NPL score of 3.09 (P=.001). Linkage to this region has been demonstrated in type 1 diabetes (IDDM6), rheumatoid arthritis, and systemic lupus erythematosus, which suggests that this locus may have a role in several forms of autoimmunity.