Valine Pyrrolidide Preserves Intact Glucose-Dependent Insulinotropic Peptide and Improves Abnormal Glucose Tolerance in Minipigs With Reduced β-Cell Mass

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation.However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced β-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)–treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg).VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 ± 1880 to 9208 ± 3267 pM × min; P<.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 ± 480 to 1582 ± 353 mM × min;P = .05).VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 ± 42 to 192 ± 108; P < .05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced β-cell mass

High-fat but not sucrose intake is essential for induction of dyslipidemia and non-alcoholic steatohepatitis in guinea pigs

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and dyslipidemia are closely related. Diet plays an important role in the progression of these diseases, but the role of specific dietary components is not completely understood. Therefore, we investigated the role of dietary sucrose and fat/cholesterol on the development of dyslipidemia and NAFLD. METHODS: Seventy female guinea pigs were block-randomized (based on weight) into five groups and fed a normal chow diet (control: 4 % fat), a very high-sucrose diet (vHS: 4 % fat, 25 % sucrose), a high-fat diet (HF: 20 % fat, 0.35 % cholesterol), a high-fat/high-sucrose diet (HFHS: 20 % fat, 15 % sucrose, 0.35 % cholesterol) or a high-fat/very high-sucrose diet (HFvHS: 20 % fat, 25 % sucrose, 0.35 % cholesterol) for 16 and 25 weeks. RESULTS: All three high-fat diets induced dyslipidemia with increased concentrations of plasma cholesterol (p < 0.0001), LDL-C (p < 0.0001) and VLDL-C (p < 0.05) compared to control and vHS. Contrary to this, plasma triglycerides were increased in control and vHS compared to high-fat fed animals (p < 0.01), while circulating levels of free fatty acids were even between groups. Histological evaluation of liver sections revealed non-alcoholic steatohepatitis (NASH) with progressive inflammation and bridging fibrosis in high-fat fed animals. Accordingly, hepatic triglycerides (p < 0.05) and cholesterol (p < 0.0001) was increased alongside elevated levels of alanine and aspartate aminotransferase (p < 0.01) compared to control and vHS. CONCLUSION: Collectively, our results suggest that intake of fat and cholesterol, but not sucrose, are the main factors driving the development and progression of dyslipidemia and NAFLD/NASH. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12986-016-0110-1) contains supplementary material, which is available to authorized users

Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics

Abstract In the apolipoprotein E–deficient mouse, the gut microbiota has an impact on the development of atherosclerosis, but whether such correlations are also present in rats requires investigation. Therefore, we studied female SD-Apoe tm1sage (Apoe −/−) rats fed either a Western diet or a low-fat control diet with or without gluten, which is known to promote gut microbiota changes, until 20 weeks of age. We hypothesized that the manifestation of atherosclerosis would be more severe in Apoe −/− rats fed the Western high-fat diet, as compared with rats fed the low-fat diet, and that atherosclerosis would be accelerated by gluten. Both Western diet-feeding and gluten resulted in significant changes in gut microbiota, but the microbiota impact of gluten was transient. Compared with Apoe −/− rats fed a low-fat diet, Western diet-fed Apoe −/− rats were heavier and became glucose intolerant with increased levels of oxidative stress. They developed early fatty streak lesions in their aortic sinus, while there was no evidence of atherosclerosis in the thoracic aorta. No conclusions could be made on the impact of gluten on atherosclerosis. Although Western diet-fed Apoe −/− rats exhibited a more human-like LDL dominated blood lipid profile, signs of obesity, type 2 diabetes and cardiovascular disease were modest

Semaglutide treatment attenuates vessel remodelling in ApoE-/- mice following vascular injury and blood flow perturbation.

BACKGROUND AND AIMS Randomized clinical studies have shown a reduction in cardiovascular outcomes with glucagon-like peptide 1 receptor agonist (GLP-1RA) treatment with the hypothesized mechanisms being an underlying effect on atherosclerosis. Here, we aimed to assess the pharmacological effects of semaglutide in an atheroprone murine model that recapitulates central mechanisms related to vascular smooth muscle cell (VSMC) phenotypic switching and endothelial dysfunction known to operate within the atherosclerotic plaque. METHODS In study A, we employed an electrical current to the carotid artery in ApoE-/- mice to induce severe VSMC injury and death, after which the arteries were allowed to heal for 4 weeks. In study B, a constrictive cuff was added for 6 h at the site of the healed segment to induce a disturbance in blood flow. RESULTS Compared to vehicle, semaglutide treatment reduced the intimal and medial area by ∼66% (p = 0.007) and ∼11% (p = 0.0002), respectively. Following cuff placement, expression of the pro-inflammatory marker osteopontin and macrophage marker Mac-2 was reduced (p < 0.05) in the semaglutide-treated group compared to vehicle. GLP-1R were not expressed in murine carotid artery and human coronary vessels with and without atherosclerotic plaques, and semaglutide treatment did not affect proliferation of cultured primary human VSMCs. CONCLUSIONS Semaglutide treatment reduced vessel remodelling following electrical injury and blood flow perturbation in an atheroprone mouse model. This effect appears to be driven by anti-inflammatory and -proliferative mechanisms independent of GLP-1 receptor-mediated signalling in the resident vascular cells. This mechanism of action may be important for cardiovascular protection.This study was supported by a grant from the LifePharm Centre of In Vivo Pharmacology.S

The major glucagon-like peptide-1 metabolite, GLP-1-(9-36)-amide, does not affect glucose or insulin levels in mice.

Glucagon-like peptide-1 (GLP-1), a future treatment for type 2 diabetes, is efficiently degraded by the enzyme dipeptidyl peptidase IV (DPP IV), yielding the major metabolite GLP-1-(9-36)-amide. In this study, we examined the potential glucose lowering effect of GLP-1(9-36)-amide in mice and found that GLP-1-(9-36)-amide (3 and 10 nmol/kg) did not affect insulin secretion or glucose elimination when administered intravenously together with glucose (1 g/kg). This was observed both in normal mice and in transgenic mice having a complete disruption of the signalling from the GLP-1 receptor. Furthermore, after blocking insulin secretion, using diazoxide (25 mg/kg), no effect on insulin-independent glucose disposal of GLP-1-(9-36)-amide was observed. Therefore, GLP-1-(9-36)-amide does not affect glucose disposal in mice either in the presence or absence of intact GLP-1-receptors or in the presence or absence of stimulated insulin levels. This suggests that the GLP-1 metabolite is not involved in the regulation of glucose homeostasis. (C) 2004 Elsevier B.V. All rights reserved

Neutralizing Anti-IL20 Antibody Treatment Significantly Modulates Low Grade Inflammation without Affecting HbA1c in Type 2 Diabetic db/db Mice.

Low grade inflammation is present in pre-clinical and human type 2 diabetes. In this process, several cytokines like IL-1β and inflammatory cells like macrophages are activated and demonstrated to participate to the disease initiation and progression. IL-20 is a cytokine known to play non-redundant roles in progression of several inflammatory diseases. To address the therapeutic effect of inhibiting the IL-20 pathway in diabetes, diabetic db/db mice were treated with neutralizing anti-IL20 antibodies in vivo and both metabolic and inflammatory parameters were followed. Diabetic islets expressed the IL-20 cytokine and all IL-20 receptor components in elevated levels compared to resting non-diabetic islets. Islets were responsive to ex vivo IL-20 stimulation measured as SOCS induction and KC and IL-6 production. Neutralizing anti-IL20 treatment in vivo had no effect on HbA1c or weight although the slope of blood glucose increase was lowered. In contrast, anti-IL20 treatment significantly reduced the systemic low-grade inflammation and modulated the local pancreatic immunity. Significant reduction of the systemic IL-1β and MCP-1 was demonstrated upon anti-IL20 treatment which was orchestrated with a reduced RANTES, IL-16 and IL-2 but increased TIMP-1, MCP-1 and IL-6 protein expression locally in the pancreas. Interestingly, anti-IL20 treatment induced an expansion of the myeloid suppressor CD11bGr1int macrophage while reducing the number of CD8 T cells. Taken together, anti-IL20 treatment showed moderate effects on metabolic parameters, but significantly altered the low grade local and systemic inflammation. Hence, future combination therapies with anti-IL20 may provide beneficial therapeutic effects in type 2 diabetes through a reduction of inflammation