Abstract. Impaired secretion of glucagon-like peptide 1 (GLP-1) has been suggested to contribute to the deficient incretin effect in patients with type 2 diabetes mellitus (t2Dm). Recent studies, however, have not always supported this notion. Since Japanese patients with t2Dm usually have severe impairment in the early-phase of insulin secretion, the measurement of incretin secretions in Japanese t2Dm patients would be useful for assessing the association between incretin levels and insulin secretion. We conducted an oral glucose tolerance test (75 g) (oGtt) and meal tolerance test (480 kcal) (mtt) for subjects with normal glucose tolerance (NGt, n=12), subjects with impaired glucose tolerance (iGt, n=7), and t2Dm patients (n=21). the tests were carried out over 120-min study periods on separate occasions. intact GLP-1, GiP, and dipeptidyl peptidase (DPP)-iV were measured by eLiSa. t2Dm exhibited an impaired early phase of insulin secretion and a reduction in glucagon suppression. There were no significant differences in GLP-1 or GIP levels at each sampling time among NGt, iGt, and t2Dm after the ingestions; hence the incremental areas under the curve (iauc) for the three groups were quite similar. the levels of DPP-iV, a limiting enzyme for the degradation of incretins, were comparable among the three groups. the GLP-1-iauc was not correlated with iaucs of insulin, c-peptide, or glucagon determined by the oGtt or the mtt. We concluded that intact GLP-1 levels are comparable between non-diabetics and t2Dm, suggesting that impaired insulin secretion in Japanese t2Dm is not attributable to defect in GLP-1 secretion.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert potent glucose-lowering effects without increasing risks for hypoglycemia and weight gain. Preclinical studies have demonstrated direct antiatherogenic effects of GLP-1RAs in normoglycemic animal models; however, the underlying mechanisms in hyperglycemic conditions have not been fully clarified. Here we aimed to elucidate the role of AMP-activated protein kinase (AMPK) in antiatherogenic effects of GLP-1RAs in hyperglycemic mice. Streptozotocin-induced hyperglycemic apolipoprotein E-null mice were treated with vehicle, low-dose liraglutide (17 nmol·kg−1·day−1), or high-dose liraglutide (107 nmol·kg−1·day−1) in experiment 1 and the AMPK inhibitor dorsomorphin, dorsomorphin + low-dose liraglutide, or dorsomorphin + high-dose liraglutide in experiment 2. Four weeks after treatment, aortas were collected to assess atherosclerosis. In experiment 1, metabolic parameters were similar among the groups. Assessment of atherosclerosis revealed that high-dose liraglutide treatments reduced lipid deposition on the aortic surface and plaque volume and intraplaque macrophage accumulation at the aortic sinus. In experiment 2, liraglutide-induced AMPK phosphorylation in the aorta was abolished by dorsomorphin; however, the antiatherogenic effects of high-dose liraglutide were preserved. In cultured human umbilical vein endothelial cells, liraglutide suppressed tumor necrosis factor-induced expression of proatherogenic molecules; these effects were maintained under small interfering RNA-mediated knockdown of AMPKα1 and in the presence of dorsomorphin. Conversely, in human monocytic U937 cells, the anti-inflammatory effects of liraglutide were abolished by dorsomorphin. In conclusion, liraglutide exerted AMPK-independent antiatherogenic effects in hyperlipidemic mice with streptozotocin-induced hyperglycemia, with the possible involvement of AMPK-independent suppression of proatherogenic molecules in vascular endothelial cells.

IntroductionTo compare the effect of dulaglutide and liraglutide on oxidative stress and endothelial function in patients with type 2 diabetes mellitus (T2DM).MethodsTwenty-two patients with T2DM who received treatment with liraglutide for at least 12 weeks were randomized to either continue liraglutide or receive dulaglutide for 24 weeks. The primary end points were changes in the diacron-reactive oxygen metabolite (d-ROMs) test, as a marker of oxidative stress, and endothelial function, as determined by the reactive hyperemia index (RHI). The secondary end points were changes in body weight (BW), glucose variability, diabetes treatment satisfaction questionnaire (DTSQ) score, and eating behavior.ResultsThere were no significant differences in changes in d-ROMs and logarithmic-scaled RHI (L-RHI) between the two groups after 24 weeks of treatment. Notably, the treatment with dulaglutide was superior to that with liraglutide in terms of mean glucose levels and mean amplitude of glycemic excursions following the 24-week treatment. However, in this regard, the outcome following the treatment with dulaglutide was maintained, whereas that with the treatment with liraglutide was aggravating. The DTSQ score for “convenience” improved in the dulaglutide group. No statistically significant changes in fasting plasma glucose, hemoglobin A1c, and BW were observed between the two groups.ConclusionWe showed that once-weekly dulaglutide was comparable to once-daily liraglutide in terms of oxidative stress and endothelial function. Switching from liraglutide to dulaglutide improved convenience by decreasing the number of injections without deteriorating glucose metabolism.Trial RegistrationThis trial was registered with the University Hospital Medical Information Network (UMIN no. 000034353) on 10 October 2018.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-018-0560-8) contains supplementary material, which is available to authorized users.

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. We performed shotgun liquid chromatography (LC)/tandem mass spectrometry (MS/MS) analysis on pooled protein extracts from patients with PTC and compared the results with those from normal thyroid tissue validated by real-time (RT) PCR and immunohistochemistry (IHC). We detected 524 types of protein in PTC and 432 in normal thyroid gland. Among these proteins, 145 were specific to PTC and 53 were specific to normal thyroid gland. We have also identified two important new markers, nephronectin (NPNT) and malectin (MLEC). Reproducibility was confirmed with several known markers, but the one of two new candidate markers such as MLEC did not show large variations in expression levels. Furthermore, IHC confirmed the overexpression of both those markers in PTCs compared with normal surrounding tissues. Our protein data suggest that NPNT and MLEC could be a characteristic marker for PTC.

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