A novel oral form of sCT showed antidiabetic effects in DIO rats by improving glycaemic control, glucose homeostasis, insulin sensitivity and body weight.

Background and aim:The current study utilized a carbon tetrachloride (CCl4)-induced liver fibrosis model to measure levels of the MMP9-mediated collagen type III degradation fragment CO3-610 (site of cleavage: KNGETGPQGP), during disease progression and regression, and to investigate a potential prognostic role of the biomarker.Materials and methods:72 female Sprague-Dawley rats aged 6 months old were injected with CCl4 twice a week over different periods of time to induce varying degrees of liver fibrosis. After 4, 6 and 8 weeks of treatment, administration of CCl4 was stopped. The 6- and 8-week treatment groups were left to regress for a further 6 or 12 weeks at which point they were sacrificed and livers removed and sectioned. Liver fibrosis was quantified using Visiopharm software to analyse Sirius red-stained sections. Serum levels of CO3-610 were measured in all animals using an ELISA assay as described by Barascuk et al.1Results:Quantitative histology revealed total collagen deposition in the liver increased as fibrosis progressed. In animals treated with CCl4 for 4 weeks, collagen comprised on average 4.94% of the total tissue in liver sections, while after 6 weeks the mean was 8.25%, and after 8 weeks, 9.11%. During the regression phase, the total collagen deposition gradually decreased to a mean of 6.9% and 5.09% for animals regressing 6 and 12 weeks respectively after 6 weeks treatment, and 6.27% for animals regressed 12 weeks after 8 weeks treatment. CO3-610 values increased progressively in rats treated for 4 weeks (by a mean of 55.0 ng/ml), 6 weeks (mean 61.1 ng/ml) and 8 weeks (mean 70.2 ng/ml). During the regression phase, CO3-610 values rapidly decreased by a mean of 28.9 ng/ml at 6 weeks and 21.6 ng/ml at 12 weeks in animals previously treated for 6 weeks, and by a mean of 19.52 ng/ml in animals treated for 8 weeks and regressed for 12 weeks. CO3-610 levels were statistically significantly correlated with total collagen during disease progression (r = 0.5701, P < 0.0001). No statistically significant correlation was observed during regression (r = 0.2081, P = 0.1138).Conclusion:Levels of the MMP-9 generated fragment of collagen type III, CO3-610, correlated with the degree of liver fibrosis in rats during the progression phase, but were not correlated with total collagen levels during regression. CO3-610 seems to be produced only under the CCL4 stimulus, and signifies CO3-610 as a potential marker of progression rather than regression. The corresponding steep elevations in levels of CO3-610 total collagen and collagen type III during liver fibrosis progression underline a potential prognostic capacity of the biomarker.

BACKGROUND AND PURPOSE Oral salmon calcitonin (sCT), a dual‐action amylin and calcitonin receptor agonist, improved glucose homeostasis in diet‐induced obese rats. Here, we have evaluated the anti‐diabetic efficacy of oral sCT using parameters of glycaemic control and beta‐cell morphology in male Zucker diabetic fatty (ZDF) rats, a model of type 2 diabetes. EXPERIMENTAL APPROACH Male ZDF rats were treated with oral sCT (0.5, 1.0 or 2 mg·kg−1) or oral vehicle twice daily from age 8 to 18 weeks. Zucker lean rats served as control group. Fasting and non‐fasted blood glucose, glycosylated haemoglobin (HbA1c) and levels of pancreas and incretin hormones were determined. Oral glucose tolerance test and i.p. glucose tolerance test were compared, and beta‐cell area and function were evaluated. KEY RESULTS Oral sCT treatment dose‐dependently attenuated fasting and non‐fasted hyperglycaemia during the intervention period. At the end of the study period, oral sCT treatment by dose decreased diabetic hyperglycaemia by ∼9 mM and reduced HbA1c levels by 1.7%. Furthermore, a pronounced reduction in glucose excursions was dose‐dependently observed for oral sCT treatment during oral glucose tolerance test. In addition, oral sCT treatment sustained hyperinsulinaemia and attenuated hyperglucagonaemia and hypersecretion of total glucagon‐like peptide‐1 predominantly in the basal state. Lastly, oral sCT treatment dose‐dependently improved pancreatic beta‐cell function and beta‐cell area at study end. CONCLUSIONS AND IMPLICATIONS Oral sCT attenuated diabetic hyperglycaemia in male ZDF rats by improving postprandial glycaemic control, exerting an insulinotropic and glucagonostatic action in the basal state and by preserving pancreatic beta‐cell function and beta‐cell area.

Aim:To measure levels of the collagen V formation marker CO5-1230 during liver fibrosis progression and regression.Methods:Monoclonal antibodies were raised against the sequence TAALGDIMGH located at the start of the C-terminal propeptide between amino acid position 1230′ and 1239′ (CO5-1230). An assay developed using the biotin-streptavidin system was evaluated in a rat reversible model of fibrosis. Animals were treated for duration of 4, 6 and 8 weeks. Animals that were treated for 8 weeks were left to regress for a period of 14, 20 and 26 weeks.Results:Mean CO5-1230 level for control animals was found to be 8.7 ng/mL. CO5-1230 marker levels, at termination points, for CCl4 treated animals was be 8.7 ng/mL at 4 weeks (P < 0.05, ROC: 0.83), 11.4 ng/mL at 6 weeks (P < 0.001, ROC: 0.93) and 10.8 ng/mL at 8 weeks (P < 0.05, ROC: 0.82). During regression phase, marker levels were statistically significantly decreased when compared with the marker levels at 8 weeks of treatment. Marker levels were found to be 5.9 ng/mL (P < 0.001, ROC: 0.8) after 14 weeks of regression, 3.9 ng/mL (P < 0.001, ROC: 0.95) after 20 weeks and 4.5 ng/mL (P < 0.001, ROC: 0.97) after 26 weeks of regression.Conclusions:The data indicates that CO5-1230 levels are statistically significantly increased when CCl4 intoxication stimulus is applied in all treatment time points. CO5-1230 levels return back to control levels when the stimulus is removed. The above finding adds to our previous evaluation of the marker and suggests that CO5-1230 may be a promising potential marker for liver fibrosis staging and monitoring in both disease progression and regression.

A novel oral form of salmon calcitonin (sCT) was recently demonstrated to improve both fasting and postprandial glycemic control and induce weight loss in diet-induced obese and insulin-resistant rats. To further explore the glucoregulatory efficacy of oral sCT, irrespective of obesity and metabolic dysfunction, the present study investigated the effect of chronic oral sCT treatment on fasting and postprandial glycemic control in male lean healthy rats. 20 male rats were divided equally into a control group receiving oral vehicle or an oral sCT (2 mg/kg) group. All rats were treated twice daily for 5 weeks. Body weight and food intake were monitored during the study period and fasting blood glucose, plasma insulin and insulin sensitivity were determined and an oral glucose tolerance test (OGTT) performed at study end. Compared with the vehicle group, rats receiving oral sCT had improved fasting glucose homeostasis and insulin resistance, as measured by homeostatic model assessment of insulin resistance index (HOMA-IR), with no change in body weight or fasting plasma insulin. In addition, the rats receiving oral sCT had markedly reduced glycemia and insulinemia during OGTT. This is the first report showing that chronic oral sCT treatment exerts a glucoregulatory action in lean healthy rats, irrespective of influencing body weight. Importantly, oral sCT seems to exert a dual treatment effect by improving fasting and postprandial glycemic control and insulin sensitivity. This and previous studies suggest oral sCT is a promising agent for the treatment of obesity-related insulin resistance and type 2 diabetes.