Growth hormone (GH) can increase milk production in cattle, and this effect was thought to be mediated by an indirect mechanism because traditional ligand binding assays failed to detect GH binding sites in the mammary gland. However, recent findings that GH receptor (GHR) mRNA and protein are expressed in the epithelial cells of the bovine mammary gland suggest that GH may directly act on these cells to affect milk production. Therefore, the objective of this study was to determine whether GH could affect milk protein gene expression, nutrient uptake, and cell proliferation in bovine mammary epithelial cells using the bovine mammary epithelial cell-derived MAC-T cells as a model. Native MAC-T cells had low expression of GHR. Thus, we transfected them with expression plasmids for GHR and signal transducer and activator of transcription 5 (STAT5), 2 key components of GHR signaling, to maximize their GH response. Growth hormone increased the expression of alphaS1-casein, alphaS2-casein, beta-casein, and alpha-lactalbumin mRNA 16- to 117-fold in the transfected MAC-T cells, whereas it had no effect on the expression of kappa-casein, beta-lactoglobulin, or insulin-like growth factor I mRNA. Cotransfection analyses showed that GH also strongly induced reporter gene expression from alphaS1-casein, alphaS2-casein, beta-casein, and alpha-lactalbumin gene promoters. Growth hormone had no effect on the uptake of 2-deoxyglucose, an unmetabolizable glucose analog, amino acids, or oleic acid; neither did it affect cell proliferation or death. These observations together with the fact that GH receptor mRNA and protein are expressed in the epithelial cells of the bovine mammary gland raise the possibility that GH might act directly on the mammary epithelial cells in cows to stimulate transcription of major milk protein genes, as part of the mechanism by which GH stimulates milk production.

As a first-line treatment for diabetes, the insulin-sensitizing biguanide, metformin, regulates glucose levels and positively affects cardiovascular function in patients with diabetes and cardiovascular complications. Endothelial dysfunction (ED) represents the primary pathological change of multiple vascular diseases, because it causes decreased arterial plasticity, increased vascular resistance, reduced tissue perfusion and atherosclerosis. Caused by “biochemical injury”, ED is also an independent predictor of cardiovascular events. Accumulating evidence shows that metformin improves ED through liver kinase B1 (LKB1)/5'-adenosine monophosphat-activated protein kinase (AMPK) and AMPK-independent targets, including nuclear factor-kappa B (NF-κB), phosphatidylinositol 3 kinase-protein kinase B (PI3K-Akt), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1), forkhead box O1 (FOXO1), krüppel-like factor 4 (KLF4) and krüppel-like factor 2 (KLF2). Evaluating the effects of metformin on endothelial cell functions would facilitate our understanding of the therapeutic potential of metformin in cardiovascular diabetology (including diabetes and its cardiovascular complications). This article reviews the physiological and pathological functions of endothelial cells and the intact endothelium, reviews the latest research of metformin in the treatment of diabetes and related cardiovascular complications, and focuses on the mechanism of action of metformin in regulating endothelial cell functions.

Atherosclerosis is an immuno-metabolic disease involving chronic inflammation, oxidative stress, epigenetics, and metabolic dysfunction. There is compelling evidence suggesting numerous modifications including the change of the size, density, and biochemical properties in the low-density lipoprotein (LDL) within the vascular wall. These modifications of LDL, in addition to LDL transcytosis and retention, contribute to the initiation, development and clinical consequences of atherosclerosis. Among different atherogenic modifications of LDL, oxidation represents a primary modification. A series of pathophysiological changes caused by oxidized LDL (oxLDL) enhance the formation of foam cells and atherosclerotic plaques. OxLDL also promotes the development of fatty streaks and atherogenesis through induction of endothelial dysfunction, formation of foam cells, monocyte chemotaxis, proliferation and migration of SMCs, and platelet activation, which culminate in plaque instability and ultimately rupture. This article provides a concise review of the formation of oxLDL, enzymes mediating LDL oxidation, and the receptors and pro-atherogenic signaling pathways of oxLDL in vascular cells. The review also explores how oxLDL functions in different stages of endothelial dysfunction and atherosclerosis. Future targeted pathways and therapies aiming at reducing LDL oxidation and/or lowering oxLDL levels and oxLDL-mediated pro-inflammatory responses are also discussed.

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Aims: Our aim was to investigate the impact of glycemic variability (GV) on the relationship between glucose management indicator (GMI) and laboratory glycated hemoglobin A1c (HbA1c). Methods: Adult patients with type 1 diabetes mellitus (T1D) were enrolled from five hospitals in China. All subjects wore the iPro™2 system for 14 days before HbA1c was measured at baseline, 3 months and 6 months. Data derived from iPro™2 sensor was used to calculate GMI and GV parameters [standard deviation (SD), glucose coefficient of variation (CV), and mean amplitude of glycemic excursions (MAGE)]. Differences between GMI and laboratory HbA1c were assessed by the absolute value of the hemoglobin glycation index (HGI). Results: A total of 91 sensor data and corresponding laboratory HbA1c, as well as demographic and clinical characteristics were analyzed. GMI and HbA1c were 7.20 ± 0.67% and 7.52 ± 0.73%, respectively. The percentage of subjects with absolute HGI 0 to lower than 0.1% was 21%. GMI was significantly associated with laboratory HbA1c after basic adjustment (standardized β = 0.83, p < 0.001). Further adjustment for SD or MAGE reduced the standardized β for laboratory HbA1c from 0.83 to 0.71 and 0.73, respectively (both p < 0.001). In contrast, the β remained relatively constant when further adjusting for CV. Spearman correlation analysis showed that GMI and laboratory HbA1c were correlated for each quartile of SD and MAGE (all p < 0.05), with the corresponding correlation coefficients decreased across ascending quartiles. Conclusions: This study validated the GMI formula using the iPro™2 sensor in adult patients with T1D. GV influenced the relationship between GMI and laboratory HbA1c.

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Early intensive insulin therapy improves insulin sensitivity in type 2 diabetic patients; while the underlying mechanism remains largely unknown. Pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, is believed to be involved in the pathogenesis of insulin resistance. Here, we hypothesize that PEDF might be down regulated by insulin and then lead to the improved insulin resistance in type 2 diabetic patients during insulin therapy. We addressed this issue by investigating insulin regulation of PEDF expression in diabetic conditions. The results showed that serum PEDF was reduced by 15% in newly diagnosed type 2 diabetic patients after insulin therapy. In adipose tissue of diabetic Sprague-Dawley rats, PEDF expression was associated with TNF-α elevation and it could be decreased both in serum and in adipose tissue by insulin treatment. In adipocytes, PEDF was induced by TNF-α through activation of NF-κB. The response was inhibited by knockdown and enhanced by over expression of NF-κB p65. However, PEDF expression was indirectly, not directly, induced by NF-κB which promoted 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) expression in adipocytes. 11β-HSD1 is likely to stimulate PEDF expression through production of active form of glucocorticoids as dexamethasone induced PEDF expression in adipose tissue. Insulin inhibited PEDF by down-regulating 11β-HSD1 expression. The results suggest that PEDF activity is induced by inflammation and decreased by insulin through targeting 11β-HSD1/glucocorticoid pathway in adipose tissue of diabetic patients.

Growth hormone (GH), also known as somatotropin, stimulates milk production in cows. At the tissue level, the action of GH is mediated by the GH receptor (GHR) and the receptor-activated intracellular signaling pathway involving Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). A T/A nucleotide variation in exon 8 of the bovine GHR gene, resulting in a phenylalanine to tyrosine change in the transmembrane domain of the GHR protein, has been reported to be associated with a major effect on milk yield in cows. The objective of this study was to determine whether the 2 versions of GHR differ in mediating GH-induced STAT5 activation of gene expression. We created cDNA expression plasmids for the 2 versions of GHR and cotransfected each of them with a STAT5 expression plasmid and a luciferase reporter gene construct containing STAT5 binding sites into 2 different cell lines. Treatment of the transfected cells with various concentrations of GH triggered a dose-dependent increase in luciferase activity. However, the GH-induced luciferase activity was not different between the 2 GHR expression plasmids, indicating that the 2 GHR forms did not differ in mediating GH-induced STAT5 activation of gene expression. Thus, if the T/A polymorphism in exon 8 of the GHR gene has a causative effect on milk production, this effect is unlikely to be mediated by the JAK2-STAT5 pathway, the currently known major signaling pathway from the growth hormone receptor.