Effect of various treatments on leptin,adiponectin, ghrelin and neuropeptide Y in patients with type 2 diabetes mellitus

Introduction: Several peptides are involved in the regulation of food intake and energy expenditure, among which are leptin, adiponectin, ghrelin and neuropeptide Y (NPY). These peptides may be implicated in the obesity seen in the majority of patients with type 2 diabetes mellitus (T2DM).

Areas covered: The present review considers: i) the role of leptin, adiponectin, ghrelin and NPY in patients with T2DM, and, ii) the effect of insulin as well as oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet agents on these peptides in patients with T2DM.

Expert opinion: Patients with T2DM have either lower or similar leptin levels, decreased adiponectin and ghrelin levels, and increased NPY circulating levels compared with nondiabetic controls. Treatment with insulin, oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet drugs may influence the levels of these peptides. It is not widely appreciated that several drugs commonly administered to patients with T2DM can influence adipokine levels. The clinical relevance of these effects needs to be evaluated.     

77th Scientific Sessions of the American Heart Association

Nearly 4000 abstracts were selected for presentation at the 77th Scientific Sessions of the American Heart Association, held in New Orleans, Louisiana, USA. The sessions were divided into basic, clinical and population science. The abstracts have been published in a supplement to Circulation (2004) 110(7).     

Novel factors as therapeutic targets to treat diabetes. Focus on leptin and ghrelin

Background: Obesity is the major cause of type 2 diabetes. In the mid 1990s interest in adipose tissue was revived by the discovery of leptin. The association of obesity and diabetes emphasizes their shared physiopathological features. At the end of the 1990s, ghrelin, a potent gastric orexigenic factor, was found to be involved in obesity. Leptin and ghrelin have opposite actions in several tissues including the regulation of feeding in the brain. Objective/methods: To survey the role of leptin and ghrelin in glucose metabolism. We summarize the current state of research and discuss the roles of ghrelin and leptin in glucose homeostases and the potential application of drugs targeting leptin and ghrelin signalling to prevent and treat diabetes. Results/conclusions: A pressing challenge is to determine how leptin, ghrelin and other adipokines or gastric factors are involved in metabolic disorders. Answering these questions will require the development of new pharmacological tools that target specific adipokine systems. Hopefully, new therapeutic targets will be identified.     

Circulating ghrelin levels in obese women: a possible association with hypertension

Objective. The orexigenic hormone ghrelin induces weight gain by stimulating food intake. Ghrelin has been shown to modulate sympathetic activity, to exert vasodilative effects and to counterreact with leptin on both food intake and blood pressure. Of these two hormones, ghrelin levels are decreased in obesity, whereas leptin levels are increased. In this cross‐sectional study, differences in serum ghrelin and leptin levels were examined in normotensive and hypertensive obese women. Material and methods. Sixty‐one normotensive and hypertensive women were classified according to the body mass indices as follows: (a) 18 healthy subjects with BMI 21.5–27.5?kg/m²; (b) 22 normotensive subjects with BMI 30–47?kg/m²; (c) 21 hypertensive obese subjects (BMI 30–48?kg/m²) with systolic blood pressure ?140?mmHg or diastolic blood pressure ?90?mmHg. Anthropometric measurements including height, weight, BMI, waist and hip circumferences and blood pressure were recorded. The levels of ghrelin and leptin were determined in sera using the commercial ELISA kits. Results. In normotensive obese subjects, ghrelin levels were significantly lower than in controls (0.21±0.13 vs 0.60±0.3?ng/mL), whereas hypertensive obese women had elevated ghrelin levels (0.64±0.36?ng/mL). Ghrelin concentration was decreased despite the presence of hypertension in the patients who had BMIs above 35?kg/m². Leptin levels were significantly higher in both normotensive and hypertensive obese groups (19.54±11.19 and 21.61±12.7?ng/mL, respectively) than in controls (7.61±3.3?ng/mL), and were not affected by the presence of hypertension in obese subjects. Conclusion. Ghrelin was positively associated with hypertension in obese women and this association was inversely influenced by the increase of BMI.     

Ghrelin and Obestatin Levels in Rheumatoid Arthritis

Background: Ghrelin is a powerful, endogenous orexigenic peptide. In addition, ghrelin has anti-inflammatory effects, and it has been reported that ghrelin down-regulates pro-inflammatory cytokines, including interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Obestatin appears to decrease food intake and appetite, and its potential role in inflammation is not yet clear. The aims of this study were to assess total and acylated (active) ghrelin and obestatin serum levels and their relations with inflammatory status in rheumatoid arthritis (RA) patients. Design: Fasting blood samples were obtained from 37 patients with RA, 29 patients with Behçet’s disease (BD) and 28 healthy controls (HC). Total ghrelin and obestatin levels were measured by radioimmunoassay and acylated ghrelin was quantified by enzyme-linked immunosorbent assay. Results: Patients with RA had lower total ghrelin, but higher obestatin levels than patients with BD (p < 0.05 for both), but when compared with HC group differences were not significant. There was no difference across groups in terms of acylated ghrelin. Total ghrelin level was not correlated with any study parameters in the all groups. Obestatin level correlated with erythrocyte sedimentation rate and DAS-28 in the RA group, the level of IL-6 in the BD group, and with the level of TNF-α in the HC group (r = 0.400, p < 0.05; r = 0.412, p < 0.05, r = 0.543, p < 0.01 and r = 0.528, p < 0.05, respectively). Conclusions: Our results did not show a significant correlation between circulating ghrelin and clinical or laboratory markers of disease activity in RA. Surprisingly, obestatin correlated with some inflammatory markers. So, obestatin seems to be more valuable than ghrelin in the pathogenesis of RA.     

A single night of sleep deprivation increases ghrelin levels and feelings of hunger in normal-weight healthy men

Sleep loss is currently proposed to disturb endocrine regulation of energy homeostasis leading to weight gain and obesity. Supporting this view, a reduction of sleep duration to 4 h for two consecutive nights has recently been shown to decrease circulating leptin levels and to increase ghrelin levels, as well as self-reported hunger. We hypothesized that similar endocrine alterations occur even after a single night of sleep restriction. In a balanced order, nine healthy normal-weight men spent three nights in our sleep laboratory separated by at least 2 weeks: one night with a total sleep time of 7 h, one night with a total sleep time of 4.5 h and one night with total sleep deprivation (SD). On a standard symptom-rating scale, subjects rated markedly stronger feelings of hunger after total SD than after 7 h sleep (3.9 ± 0.7 versus 1.7 ± 0.3; P  = 0.020) or 4.5 h sleep (2.2 ± 0.5; P  = 0.041). Plasma ghrelin levels were 22 ± 10% higher after total SD than after 7 h sleep (0.85 ± 0.06 versus 0.72 ± 0.04 ng mL⁻¹; P  = 0.048) with intermediate levels of the hormone after 4.5 h sleep (0.77 ± 0.04 ng mL⁻¹). Serum leptin levels did not differ between conditions. Feelings of hunger as well as plasma ghrelin levels are already elevated after one night of SD, whereas morning serum leptin concentrations remain unaffected. Thus, our results provide further evidence for a disturbing influence of sleep loss on endocrine regulation of energy homeostasis, which on the long run may result in weight gain and obesity.     

ghreIin在大鼠急性坏死性胰腺炎肺损伤中的作用及机制

目的探讨ghrelin在大鼠急性坏死性胰腺炎肺损伤中的作用和机制。方法 54只SD大鼠随机分为假手术（SO）组、急性坏死性胰腺炎（ANP）组和ghrelin干预组,采用胰胆管逆行注射5%牛磺胆酸钠诱导大鼠ANP模型,ghrelin干预组于模型制作前30 min和造模后3 h腹腔注射ghrelin,SO组开腹后翻动胰腺后关腹。观察各组大鼠血清淀粉酶的变化,ELISA检测血清肿瘤坏死因子-α（TNF-α）,光镜观察胰腺和肺组织的病理改变,Western blot检测肺组织核因子-κB（NF-κB）蛋白的表达,酶化学法测定肺组织髓过氧化物酶（MPO）的变化。结果 ANP组大鼠胰腺和肺组织随着时间延长病变加重;ANP组血清淀粉酶、TNF-α、肺组织MPO均较SO组明显升高（均P〈0.05）,表达水平与肺病理严重程度成正相关。ghrelin干预组各检测指标均较ANP组明显降低（均P〈0.05）,胰腺及肺组织病理损伤明显减轻。结论 ghrelin可减轻大鼠ANP后的肺损伤,并对MPO和TNF-α有明显的抑制作用,其机制可能与影响了NF-κB的表达,从而干预了炎症信号传导过程有关。     

Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Background Levodopa (l ‐dopa) is the most commonly used treatment for alleviating symptoms of Parkinson’s disease. However, l ‐dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents l ‐dopa action on gastric emptying and enhances circulating l ‐dopa in rats. Methods Gastric emptying of non‐nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) l ‐dopa, or intravenous (i.v.) ghrelin 10 min before orogastric l ‐dopa. Plasma l ‐dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 μg kg^?1) 10 min before i.p. l ‐dopa. Key Results Levodopa (5 and 15 mg kg^?1) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 μg kg^?1, i.v.) completely prevented l ‐dopa’s (15 mg kg^?1, orogastrically) inhibitory action on gastric emptying and enhanced plasma l ‐dopa and dopamine levels compared with vehicle 15 min after orogastric l ‐dopa. Levodopa (5 mg kg^?1) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg^?1, i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. Conclusions & Inferences Ghrelin counteracts l ‐dopa‐induced delayed gastric emptying but not Fos induction in the brain and enhances circulating l ‐dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson’s disease patients treated with l ‐dopa remain to be investigated.