| 1. |
- Bryzgalova, G, et al.
(author)
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Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice
- 2008
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 295:4, s. E904-E912
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Journal article (peer-reviewed)abstract
- The high-fat diet (HFD)-fed mouse is a model of obesity, impaired glucose tolerance, and insulin resistance. The main objective of this study was to elucidate the molecular mechanisms underlying the antidiabetogenic and weight-lowering effects of 17β-estradiol (E2) in this mouse model. C57BL/6 female mice (8 wk old) were fed on a HFD for 10 mo. E2, given daily (50 μg/kg sc) during the last month of feeding, decreased body weight and markedly improved glucose tolerance and insulin sensitivity. Plasma levels of insulin, leptin, resistin, and adiponectin were decreased. We demonstrated that E2treatment decreased the expression of genes encoding resistin and leptin in white adipose tissue (WAT), whereas adiponectin expression was unchanged. Furthermore, in WAT we demonstrated decreased expression levels of sterol regulatory element-binding protein 1c (SREBP1c) and its lipogenic target genes, such as fatty acid synthase and stearoyl-CoA desaturase 1 (SCD1). In the liver, the expression levels of transcription factors such as liver X receptor α and SREBP1c were not changed by E2treatment, but the expression of the key lipogenic gene SCD1 was reduced. This was accompanied by decreased hepatic triglyceride content. Importantly, E2decreased the hepatic expression of glucose-6-phosphatase (G-6-Pase). We conclude that E2treatment exerts antidiabetic and antiobesity effects in HFD mice and suggest that this is related to decreased expression of lipogenic genes in WAT and liver and suppression of hepatic expression of G-6-Pase. Decreased plasma levels of resistin probably also play an important role in this context.
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| 2. |
- Efanov, AM, et al.
(author)
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Insulinotropic activity of the imidazoline derivative RX871024 in the diabetic GK rat
- 2002
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 282:1, s. E117-E124
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Journal article (peer-reviewed)abstract
- The insulinotropic activity of the imidazoline derivative RX871024 was compared in pancreatic islets from nondiabetic Wistar rats and spontaneously diabetic Goto-Kakizaki (GK) rats. RX871024 significantly stimulated insulin secretion in islets from both animal groups. The insulinotropic activity of RX871024 was higher than that of the sulfonylurea glibenclamide. This difference was more pronounced in islets from GK rats compared with Wistar rat islets. More importantly, RX871024 substantially improved glucose sensitivity in diabetic β-cells, whereas glibenclamide stimulated insulin secretion about twofold over a broad range of glucose concentrations in nondiabetic and diabetic rats. RX871024 induced a faster increase in cytosolic free Ca2+concentration and faster inhibition of ATP-dependent K+channel activity in GK rat islets compared with Wistar rat islets. RX871024 also induced a more pronounced increase in diacylglycerol concentration in GK rat islets. These data support the idea that imidazoline compounds can form the basis for the development of novel drugs for treatment of type 2 diabetes, which can restore glucose sensitivity in diabetic β-cells.
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| 3. |
- Kuhl, JE, et al.
(author)
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Exercise training decreases the concentration of malonyl-CoA and increases the expression and activity of malonyl-CoA decarboxylase in human muscle
- 2006
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In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 290:6, s. E1296-E1303
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Journal article (peer-reviewed)abstract
- The study was designed to evaluate whether changes in malonyl-CoA and the enzymes that govern its concentration occur in human muscle as a result of physical training. Healthy, middle-aged subjects were studied before and after a 12-wk training program that significantly increased V̇o2 maxby 13% and decreased intra-abdominal fat by 17%. Significant decreases (25–30%) in the concentration of malonyl-CoA were observed after training, 24–36 h after the last bout of exercise. They were accompanied by increases in both the activity (88%) and mRNA (51%) of malonyl-CoA decarboxylase (MCD) in muscle but no changes in the phosphorylation of AMP kinase (AMPK, Thr172) or of acetyl-CoA carboxylase. The abundance of peroxisome proliferator-activated receptor (PPAR)γ coactivator-1α (PGC-1α), a regulator of transcription that has been linked to the mediation of MCD expression by PPARα, was also increased (3-fold). In studies also conducted 24–36 h after the last bout of exercise, no evidence of increased whole body insulin sensitivity or fatty acid oxidation was observed during an euglycemic hyperinsulinemic clamp. In conclusion, the concentration of malonyl-CoA is diminished in muscle after physical training, most likely because of PGC-1α-mediated increases in MCD expression and activity. These changes persist after the increases in AMPK activity and whole body insulin sensitivity and fatty acid oxidation, typically caused by an acute bout of exercise in healthy individuals, have dissipated.
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