Spexin (SPX) and kisspeptin (KISS) are novel peptides relevant in the context of regulation of metabolism, food intake, puberty and reproduction. Here, we studied changes of serum SPX and KISS levels in female non-obese volunteers (BMI<25 kg/m2) and obese patients (BMI>35 kg/m2). Correlations between SPX or KISS with BMI, McAuley index, QUICKI, HOMA IR, serum levels of insulin, glucagon, leptin, adiponectin, orexin-A, obestatin, ghrelin and GLP-1 were assessed. Obese patients had lower SPX and KISS levels as compared to non-obese volunteers (SPX: 4.48±0.19 ng/ml vs. 6.63±0.29 ng/ml; p<0.001, KISS: 1.357±0.15 nmol/l vs. 2.165±0.174 nmol/l; p<0.01). SPX negatively correlated with BMI, HOMA-IR, insulin, glucagon, active ghrelin and leptin. Positive correlations were found between SPX and QUICKI index, McAuley index, serum levels of obestatin, GLP-1 and adiponectin and orexin-A Serum KISS negatively correlated with BMI, HOMA-IR, serum levels of insulin, glucagon, active ghrelin and leptin. KISS positively correlated with QUICKI index, McAuley index and adiponectin. In summary, SPX and KISS show negative correlations with obesity, insulin resistance indices, and hormones known to affect insulin sensitivity in females. Both, SPX and KISS could be therefore relevant in the pathophysiology of obesity and insulin resistance.

Aims/hypothesis Glucagon reduces body weight by modifying food intake, glucose/lipid metabolism and energy expenditure. All these physiological processes are also controlled by fibroblast growth factor 21 (FGF-21), a circulating hepatokine that improves the metabolic profile in obesity and type 2 diabetes. Animal experiments have suggested a possible interaction between glucagon and FGF-21 however, the metabolic consequences of this crosstalk are not understood. Methods The effects of exogenous glucagon on plasma FGF-21 levels and lipolysis were evaluated in healthy volunteers and humans with type 1 diabetes, as well as in rodents with streptozotocin (STZ)-induced insulinopenic diabetes. In vitro, the role of glucagon on FGF-21 secretion and lipolysis was studied using isolated primary rat hepatocytes and adipocytes. Fgf-21 expression in differentiated rat pre-adipocytes was suppressed by small interfering RNA and released FGF-21 was immunoneutralised by polyclonal antibodies. Results Glucagon induced lipolysis in healthy human volunteers, patients with type 1 diabetes, mice and rats with STZ-induced insulinopenic diabetes, and in adipocytes isolated from diabetic and non-diabetic animals. In addition, glucagon increased circulating FGF-21 in healthy humans and rodents, as well as in patients with type 1 diabetes, and insulinopenic rodents. Glucagon stimulated FGF-21 secretion from isolated primary hepatocytes and adipocytes derived from animals with insulinopenic diabetes. Furthermore, FGF-21 stimulated lipolysis in primary adipocytes isolated from non-diabetic and diabetic rats. Reduction of Fgf-21 expression (by approximately 66%) or immunoneutralisation of released FGF-21 markedly attenuated glucagon-stimulated lipolysis in adipocytes. Conclusions/interpretation These results indicate that glucagon increases circulating FGF-21 independently of endogenous insulin levels. FGF-21 participates in glucagon-induced stimulation of lipolysis.

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Background Chronic obstructive pulmonary disease (COPD) is associated with an increased risk for thromboembolic events. We investigated thrombin generation profiles in COPD patients and their dependence on plasma factor/inhibitor composition. Methods Factors (f) (fII, fV, fVII, fVIII, fIX, fX), antithrombin, protein C (PC) and free tissue factor pathway inhibitor (fTFPI) from 60 COPD patients (aged 64.2±10.1 years; a mean forced expiratory volume in 1 second [FEV1], 55.6 ± 15.8% of predicted values) were compared with those for 43 controls matched for age, sex, weight and smoking. Patients receiving anticoagulation were excluded. Using each individual’s plasma coagulation protein composition, tissue factor-initiated thrombin generation was assessed computationally. Results COPD patients had higher fII (115±16 vs 102±10%, p<0.0001), fV (114±19 vs 102±12%, p=0.0002), fVII (111±15 vs 102±17%, p=0.002), fVIII (170±34 vs 115±27%, p<0.0001), and fIX (119±21 vs 107±17%, p=0.003), and lower fTFPI (17.7±3.2 vs 18.9±3.2 ng/ml, p=0.047) compared with controls, while fX, antithrombin, and PC were similar in both groups. Computational thrombin generation profiles showed that compared with controls, COPD patients had higher maximum thrombin levels (+28.3%, p<0.0001), rates of thrombin generation (+46.1%, p<0.0001) and total thrombin formation (+14.4%, p<0.001), together with shorter initiation phase of thrombin generation (p<0.0001) and the time to maximum thrombin levels (p<0.0001). Thrombin generation profiles in COPD patients can be normalized via correction of fII, fVIII, fIX and TFPI. The severity of COPD and inflammatory markers were not associated with thrombin generation profiles. Conclusions Prothrombotic phenotype in COPD patients is largely driven by increased prothrombin, fVIII, fIX, and lower fTFPI.

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Background: An increased glucagon/insulin ratio is known to contribute to hyperglycemia in diabetes.Results: NOX-G15, a mirror-image mixed DNA/RNA glucagon-neutralizing aptamer, was identified. It improved glucose tolerance in models of type 1 and 2 diabetes.Conclusion: NOX-G15 may be useful for treatment of type 1 and 2 diabetes.Significance: The new therapeutic candidate may help to reduce insulin need in diabetes.

Genistein and daidzein belong to a large group of compounds called phytooestrogens present in several plants consumed by animals. Apart from oestrogenic activity, these compounds influence on many different processes in the organism. Their effect on metabolic processes was previously observed, however, it is poorly understood. In the performed experiment the effect of genistein (5 mg/kg BW) or daidzein (5 mg/kg BW) administered intragastrically for three days to growing male rats was studied and compared to oestradiol (0.1 mg/kg BW). Both phytooestrogens and oestradiol caused slight increase in blood glucose content with concomitant drop in insulin level. Blood cholesterol and HDL-cholesterol were not statistically altered. However, a slight reduction in total cholesterol with simultaneous slight rise in HDL-cholesterol in rats receiving oestradiol and phytooestrogens caused that HDL-cholesterol/total cholesterol ratio was significantly higher in these animals. The tested substances had no influence on blood free fatty acids and triglycerides. All these compounds caused substantial diminution in muscle triglycerides content. Liver glycogen, triglycerides and cholesterol contents were augmented only by daidzein.Our results indicate that genistein and daidzein evoked many similar metabolic changes. These changes were comparable to those caused by oestradiol and to changes induced by genistein and observed previously in ovariectomized rats.