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  • 刊频： Twice monthly, Feb. 2012-
  • NLM标题： Am J Physiol Endocrinol Metab
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  • 1.

    【2hr】MiR-206 is expressed in pancreatic islets and regulates glucokinase activity

    包量

    机译 MiR-206在胰岛中表达并调节葡萄糖激酶活性
    摘要：Glucose homeostasis is a complex indispensable process, and its dysregulation causes hyperglycemia and type 2 diabetes mellitus. Glucokinase (GK) takes a central role in these pathways and is thus rate limiting for glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Several reports have described the transcriptional regulation of Gck mRNA, whereas its posttranscriptional mechanisms of regulation, especially those involving microRNAs (miR), are poorly understood. In this study, we investigated the role of miR-206 as a posttranscriptional regulator of Gck. In addition, we examined the effects of miR-206 on glucose tolerance, GSIS, and gene expression in control and germ line miR-206 knockout (KO) mice fed either with chow or high-fat diet (HFD). MiR-206 was found in Gck-expressing tissues and was differentially altered in response to HFD feeding. Pancreatic islets showed the most profound induction in the expression of miR-206 in response to HFD. Chow- and HFD-fed miR-206KO mice have improved glucose tolerance and GSIS but unaltered insulin sensitivity. In silico analysis of Gck mRNA revealed a conserved 8-mer miR-206 binding site. Hence, the predicted regulation of Gck by miR-206 was confirmed in reporter and GK activity assays. Concomitant with increased GK activity, miR-206KO mice had elevated liver glycogen content and plasma lactate concentrations. Our findings revealed a novel mechanism of posttranscriptional regulation of Gck by miR-206 and underline the crucial role of pancreatic islet miR-206 in the regulation of whole body glucose homeostasis in a murine model that mimics the metabolic syndrome.
  • 2.

    【2hr】Neonatal programming of innate immune function

    包量

    机译 天然免疫功能的新生儿编程
    摘要：The early life environment can be crucial in influencing the development of an animal’s long-term physiology. There is now much evidence to suggest that perinatal challenges to an animal’s immune system will result in changes in adult rat behavior, physiology, and molecular pathways following a single inflammatory event during development caused by the bacterial endotoxin lipopolysaccharide (LPS). In particular, it is now apparent that neonatal LPS administration can influence the adult neuroimmune response to a second LPS challenge through hypothalamic-pituitary-adrenal axis modifications, some of which are caused by alterations in peripheral prostaglandin synthesis. These pronounced changes are accompanied by a variety of alterations in a number of disparate aspects of endocrine physiology, with significant implications for the health and well-being of the adult animal. In this review, we discuss the newly elucidated mechanisms by which neonatal immune challenge can permanently alter an animal’s endocrine and metabolic physiology and the implications this has for various disease states.
  • 3.

    【2hr】Leucine or carbohydrate supplementation reduces AMPK and eEF2 phosphorylation and extends postprandial muscle protein synthesis in rats

    包量

    机译 补充白氨酸或碳水化合物可减少大鼠的AMPK和eEF2磷酸化并延长餐后肌肉蛋白的合成
    摘要：Muscle protein synthesis (MPS) increases after consumption of a protein-containing meal but returns to baseline values within 3 h despite continued elevations of plasma amino acids and mammalian target of rapamycin (mTORC1) signaling. This study evaluated the potential for supplemental leucine (Leu), carbohydrates (CHO), or both to prolong elevated MPS after a meal. Male Sprague-Dawley rats (~270 g) trained to consume three meals daily were food deprived for 12 h, and then blood and gastrocnemius muscle were collected 0, 90, or 180 min after a standard 4-g test meal (20% whey protein). At 135 min postmeal, rats were orally administered 2.63 g of CHO, 270 mg of Leu, both, or water (sham control). Following test meal consumption, MPS peaked at 90 min and then returned to basal (time 0) rates at 180 min, although ribosomal protein S6 kinase and eIF4E-binding protein-1 phosphorylation remained elevated. In contrast, rats administered Leu and/or CHO supplements at 135 min postmeal maintained peak MPS through 180 min. MPS was inversely associated with the phosphorylation states of translation elongation factor 2, the “cellular energy sensor” adenosine monophosphate-activated protein kinase-α (AMPKα) and its substrate acetyl-CoA carboxylase, and increases in the ratio of AMP/ATP. We conclude that the incongruity between MPS and mTORC1 at 180 min reflects a block in translation elongation due to reduced cellular energy. Administering Leu or CHO supplements ~2 h after a meal maintains cellular energy status and extends the postprandial duration of MPS.
  • 4.

    【2hr】Dietary manipulation reveals an unexpected inverse relationship between fat mass and adipose 11β-hydroxysteroid dehydrogenase type 1

    包量

    机译 饮食管理揭示了脂肪与脂肪1β-羟类固醇脱氢酶1型之间存在意想不到的逆向关系
    摘要：Increased dietary fat intake is associated with obesity, insulin resistance, and metabolic disease. In transgenic mice, adipose tissue-specific overexpression of the glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) exacerbates high-fat (HF) diet-induced visceral obesity and diabetes, whereas 11β-HSD1 gene knockout ameliorates this, favoring accumulation of fat in nonvisceral depots. Paradoxically, in normal mice HF diet-induced obesity (DIO) is associated with marked downregulation of adipose tissue 11β-HSD1 levels. To identify the specific dietary fats that regulate adipose 11β-HSD1 and thereby impact upon metabolic disease, we either fed mice diets enriched (45% calories as fat) in saturated (stearate), monounsaturated (oleate), or polyunsaturated (safflower oil) fats ad libitum or we pair fed them a low-fat (11%) control diet for 4 wk. Adipose and liver mass and glucocorticoid receptor and 11β-HSD1 mRNA and activity levels were determined. Stearate caused weight loss and hypoinsulinemia, partly due to malabsorption, and this markedly increased plasma corticosterone levels and adipose 11β-HSD1 activity. Oleate induced pronounced weight gain and hyperinsulinemia in association with markedly low plasma corticosterone and adipose 11β-HSD1 activity. Weight gain and hyperinsulinemia was less pronounced with safflower compared with oleate despite comparable suppression of plasma corticosterone and adipose 11β-HSD1. However, with pair feeding, safflower caused a selective reduction in visceral fat mass and relative insulin sensitization without affecting plasma corticosterone or adipose 11β-HSD1. The dynamic depot-selective relationship between adipose 11β-HSD1 and fat mass strongly implicates a dominant physiological role for local tissue glucocorticoid reactivation in fat mobilization.
  • 5.

    【2hr】High β-cell mass prevents streptozotocin-induced diabetes in thioredoxin-interacting protein-deficient mice

    包量

    机译 高β细胞可预防与硫氧还蛋白相互作用的蛋白质缺陷型小鼠的链脲佐菌素诱导的糖尿病
    摘要：Thioredoxin-interacting protein (TxNIP) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. Diabetic mice exhibit increased expression of TxNIP in pancreatic islets, and recent studies suggest that TxNIP is a proapoptotic factor in β-cells that may contribute to the development of diabetes. Here, we examined the role of TxNIP deficiency in vivo in the development of insulin-deficient diabetes and whether it impacted on pancreatic β-cell mass and/or insulin secretion. TxNIP-deficient (Hcb-19/TxNIP−/−) mice had lower baseline glycemia, higher circulating insulin concentrations, and higher total pancreatic insulin content and β-cell mass than control mice (C3H). Hcb-19/TxNIP−/− did not develop hyperglycemia when injected with standard multiple low doses of streptozotocin (STZ), in contrast to C3H controls. Surprisingly, although β-cell mass remained higher in Hcb-19/TxNIP−/− mice compared with C3H after STZ exposure, the relative decrease induced by STZ was as great or even greater in the TxNIP-deficient animals. Consistently, cultured pancreatic INS-1 cells transfected with small-interfering RNA against TxNIP were more sensitive to cell death induced by direct exposure to STZ or to the combination of inflammatory cytokines interleukin-1β, interferon-γ, and tumor necrosis factor-α. Furthermore, when corrected for insulin content, isolated pancreatic islets from TxNIP−/− mice exhibited reduced glucose-induced insulin secretion. These data indicate that TxNIP functions as a regulator of β-cell mass and influences insulin secretion. In conclusion, the relative resistance of TxNIP-deficient mice to STZ-induced diabetes appears to be because of an increase in β-cell mass. However, TxNIP deficiency is associated with sensitization to STZ- and cytokine-induced β-cell death, indicating complex regulatory roles of TxNIP under different physiological and pathological conditions.
  • 6.

    【2hr】Differential modulation of L-type calcium channel subunits by oleate

    包量

    机译 油酸对L型钙通道亚基的差异调节
    摘要：Nonesterified fatty acids such as oleate and palmitate acutely potentiate insulin secretion from pancreatic islets in a glucose-dependent manner. In addition, recent studies show that fatty acids elevate intracellular free Ca2+ and increase voltage-gated Ca2+ current in mouse β-cells, although the mechanisms involved are poorly understood. Here we utilized a heterologous system to express subunit-defined voltage-dependent L-type Ca2+ channels (LTCC) and demonstrate that β-cell calcium may increase in part from an interaction between fatty acid and specific calcium channel subunits. Distinct functional LTCC were assembled in both COS-7 and HEK-293 cells by expressing either one of the EYFP-tagged L-type α1-subunits (β-cell Cav1.3 or lung Cav1.2) and ERFP-tagged islet β-subunits (iβ2a or iβ3). In COS-7 cells, elevations in intracellular Ca2+ mediated by LTCC were enhanced by an oleate-BSA complex. To extend these findings, Ca2+ current was measured in LTCC-expressing HEK-293 cells that revealed an increase in peak Ca2+ current within 2 min after addition of the oleate complex, with maximal potentiation occurring at voltages <0 mV. Both Cav1.3 and Cav1.2 were modulated by oleate, and the presence of different auxiliary β-subunits resulted in differential augmentation. The potentiating effect of oleate on Cav1.2 was abolished by the pretreatment of cells with triacsin C, suggesting that long-chain CoA synthesis is necessary for Ca2+ channel modulation. These results show for the first time that two L-type Ca2+ channels expressed in β-cells (Cav1.3 and Cav1.2) appear to be targeted by nonesterified fatty acids. This effect may account in part for the acute potentiation of glucose-dependent insulin secretion by fatty acids.
  • 7.

    【2hr】EFFECT OF OVARIAN SUPPRESSION WITH GONADOTROPIN-RELEASING HORMONE AGONIST ON GLUCOSE DISPOSAL AND INSULIN SECRETION

    包量

    机译 促性腺激素释放激素激动剂对卵巢的抑制作用对葡萄糖沉积和胰岛素分泌的影响
    摘要：Several lines of evidence suggest that ovarian hormones influence glucose homeostasis, although their exact role in humans has not been clearly defined. In the present study, we sought to test the hypothesis that ovarian hormones regulate glucose homeostasis by examining the effect of pharmacologically-induced ovarian hormone deficiency on glucose disposal and insulin secretion. Young, healthy women with regular menstrual patterns were studied during the follicular and luteal phases of their cycle at baseline and after two months of treatment with gonadotropin-releasing hormone agonist (GnRHa; n=7) or placebo (n=6). Using hyperglycemic clamps, in combination with stable isotope-labeled (i.e., 13C and 2H) glucose tracers, we measured glucose disposal and insulin secretion. Additionally, we assessed body composition and regional fat distribution using radiologic imaging techniques, as well as glucoregulatory hormones. Ovarian hormone suppression with GnRHa did not alter body composition, abdominal fat distribution or thigh tissue composition. There was no effect of ovarian suppression on total, oxidative or non-oxidative glucose disposal expressed relative to plasma insulin level. Similarly, no effect of ovarian hormone deficiency was observed on first- or second phase insulin secretion or insulin clearance. Finally, ovarian hormone deficiency was associated with an increase in circulating adiponectin levels, but no change in leptin concentration. Our findings suggest that a brief period of ovarian hormone deficiency in young, healthy eugonadal women does not alter glucose disposal index or insulin secretion, supporting the conclusion that ovarian hormones play a minimal role in regulating glucose homeostasis. Our data do, however, support a role for ovarian hormones in the regulation of plasma adiponectin levels.
  • 8.

    【2hr】Exercise-induced alterations in intramyocellular lipids and insulin resistance: the athlete’s paradox revisited

    包量

    机译 运动引起的肌细胞内脂质和胰岛素抵抗的改变：重新审视了运动员的悖论
    摘要：We previously reported an “athlete’s paradox” in which endurance-trained athletes, who possess a high oxidative capacity and enhanced insulin sensitivity, also have higher intramyocellular lipid (IMCL) content. The purpose of this study was to determine whether moderate exercise training would increase IMCL, oxidative capacity of muscle, and insulin sensitivity in previously sedentary overweight to obese, insulin-resistant, older subjects. Twenty-five older (66.4 ± 0.8 yr) obese (BMI = 30.3 ± 0.7 kg/m2) men (n = 9) and women (n = 16) completed a 16-wk moderate but progressive exercise training program. Body weight and fat mass modestly but significantly (P < 0.01) decreased. Insulin sensitivity, measured using the euglycemic hyperinsulinemic clamp, was increased (21%, P = 0.02), with modest improvements (7%, P = 0.04) in aerobic fitness (V̇O2peak). Histochemical analyses of IMCL (Oil Red O staining), oxidative capacity [succinate dehydrogenase activity (SDH)], glycogen content, capillary density, and fiber type were performed on skeletal muscle biopsies. Exercise training increased IMCL by 21%. In contrast, diacylglycerol and ceramide, measured by mass spectroscopy, were decreased (n = 13; −29% and −24%, respectively, P < 0.05) with exercise training. SDH (19%), glycogen content (15%), capillary density (7%), and the percentage of type I slow oxidative fibers (from 50.8 to 55.7%), all P ≤ 0.05, were increased after exercise. In summary, these results extend the athlete’s paradox by demonstrating that chronic exercise in overweight to obese older adults improves insulin sensitivity in conjunction with favorable alterations in lipid partitioning and an enhanced oxidative capacity within muscle. Therefore, several key deleterious effects of aging and/or obesity on the metabolic profile of skeletal muscle can be reversed with only moderate increases in physical activity.
  • 9.

    【2hr】Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway

    包量

    机译 氧化应激通过磷脂酰肌醇3激酶依赖性途径刺激骨骼肌葡萄糖摄取
    摘要：We determined the acute effects of oxidative stress on glucose uptake and intracellular signaling in skeletal muscle by incubating muscles with reactive oxygen species (ROS). Xanthine oxidase (XO) is a superoxide-generating enzyme that increases ROS. Exposure of isolated rat extensor digitorum longus (EDL) muscles to Hx/XO (Hx/XO) for 20 min resulted in a dose-dependent increase in glucose uptake. To determine whether the mechanism leading to Hx/XO-stimulated glucose uptake is associated with the production of H2O2, EDL muscles from rats were preincubated with the H2O2 scavenger catalase or the superoxide scavenger superoxide dismutase (SOD) prior to incubation with Hx/XO. Catalase treatment, but not SOD, completely inhibited the increase in Hx/XO-stimulated 2-deoxyglucose (2-DG) uptake, suggesting that H2O2 is an intermediary leading to Hx/XO-stimulated glucose uptake with incubation. Direct H2O2 also resulted in a dose-dependent increase in 2-DG uptake in isolated EDL muscles, and the maximal increase was threefold over basal levels at a concentration of 600 μmol/l H2O2. H2O2-stimulated 2-DG uptake was completely inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, but not the nitric oxide inhibitor NG-monomethyl-L-arginine. H2O2 stimulated the phosphorylation of Akt Ser473 (7-fold) and Thr308 (2-fold) in isolated EDL muscles. H2O2 at 600 μmol/l had no effect on ATP concentrations and did not increase the activities of either the α1 or α2 catalytic isoforms of AMP-activated protein kinase. These results demonstrate that acute exposure of muscle to ROS is a potent stimulator of skeletal muscle glucose uptake and that this occurs through a PI3K-dependent mechanism.
  • 10.

    【2hr】Prototypical anti-inflammatory cytokine IL-10 prevents loss of IGF-I-induced myogenin protein expression caused by IL-1β

    包量

    机译 典型的抗炎细胞因子IL-10可防止由IL-1β引起的IGF-I诱导的肌生成素蛋白表达的丧失
    摘要：Prolonged and excessive inflammation is implicated in resistance to the biological actions of IGF-I and contributes to the pathophysiology of neurodegenerative, metabolic, and muscle-wasting disorders. IL-10 is a critical anti-inflammatory cytokine that restrains inflammatory responses in macrophages and T cells by inhibiting cytokine and chemokine synthesis and reducing expression of their receptors. Here we demonstrate that IL-10 plays a protective role in nonhematopoietic cells by suppressing the ability of exogenous IL-1β to inhibit IGF-I-induced myogenin and myosin heavy chain expression in myoblasts. This action of IL-10 is not caused by impairment of IL-1β-induced synthesis of IL-6 or the ability of IL-1β to activate two members of the MAPK family, ERK1/2 and p38. Instead, this newly defined protective role of IL-10 occurs by specific reversal of IL-1β activation of the JNK kinase pathway. IL-10 blocks IL-1β-induced phosphorylation of JNK, but not ERK1/2 or p38, indicating that only the JNK component of the IL-1β-induced MAPK signaling pathway is targeted by IL-10. This conclusion is supported by the finding that a specific JNK inhibitor acts similarly to IL-10 to restore IGF-I-induced myogenin expression, which is suppressed by IL-1β. Collectively, these data demonstrate that IL-10 acts in a novel, nonclassical, protective manner in nonhematopoietic cells to inhibit the IL-1β receptor-induced JNK kinase pathway, resulting in prevention of IGF-I resistance.
  • 11.

    【2hr】Chronic Late Gestation Hypoglycemia Up-Regulates Hepatic PEPCK Associated with Increased PGC1α mRNA and pCREB in Fetal Sheep

    包量

    机译 慢性晚期妊娠低血糖会上调胎羊的肝PEPCK与PGC1αmRNA和pCREB的增加
    摘要：Hepatic glucose production is normally activated at birth, but has been observed in response to experimental hypoglycemia in fetal sheep. The cellular basis for this process remains unknown. We determined the impact of 2 weeks of fetal hypoglycemia during late gestation on enzymes responsible for hepatic gluconeogenesis, focusing on the insulin signaling pathway, transcription factors, and coactivators which regulate gluconeogenesis. Hepatic PEPCK and glucose-6-phosphatase mRNA increased 12-fold and 7-fold respectively following chronic hypoglycemia with no change in hepatic glycogen. Chronic hypoglycemia decreased fetal plasma insulin with no change in glucagon, but increased plasma cortisol 3.5-fold. PGC1 mRNA and phosphorylation of CREB at serine 133 were both increased, with no change in Akt, FOXO1, HNF4α, or C/EBPβ. These results demonstrate that chronic fetal hypoglycemia triggers signals which can activate gluconeogenesis in the fetal liver.
  • 12.

    【2hr】Expression and Regulation of Kruppel-like factors 4, 9 and 13 and the steroidogenic genes LDLR, StAR and CYP11A in ovarian granulosa cells

    包量

    机译 Kruppel样因子4、9和13以及类固醇生成基因LDLR，StAR和CYP11A在卵巢颗粒细胞中的表达和调控
    摘要：Kruppel-like factors (KLF's) are important Sp1-like eukaryotic transcriptional proteins, which mediate cell growth, differentiation and apoptosis. The LDLR, StAR and CYP11A genes exhibit GC-rich Sp1-like sites, which have the potential to bind KLF's in multiprotein complexes. We now report that KLF4, KLF9 and KLF13 transcripts and cognate proteins are expressed in and regulate ovarian cells. KLF4 and 13, but not KLF9, mRNA expression was induced and then repressed over time (P < 0.001). Combined LH and IGF-I stimulation increased KLF4 mRNA at 2 h (P < 0.01), whereas LH decreased KLF13 mRNA at 6 h (P < 0.05) and IGF-I did the so at 24 h (P < 0.01) compared with untreated controls. KLF9 was not regulated by either hormone. Transient transfection of KLF4, KLF9 and KLF13 suppressed LDLR/luc, StAR/luc and CYP11A/luc by 80 to 90% (P < 0.001). Histone-deacetylase (HDAC) inhibitors stimulated LDLR/luc by 5-6 fold and StAR/luc and CYP11A/luc activity by 2-fold (P < 0.001), and partially reversed suppression by all 3 KLF's (P < 0.001). Deletion of the zinc-finger domain of KLF13 abrogated repression of LDLR/luc. Lentiviral overexpression of the KLF13 gene suppressed LDLR mRNA (P < 0.001) and CYP11A mRNA (P = 0.003), but increased StAR mRNA (P = 0.007). Collectively, these data suggest that KLF's may recruit inhibitory complexes containing HDAC corepressors, thereby repressing LDLR and CYP11A transcription. Conversely, KLF13 may recruit unknown coactivators or stabilize StAR mRNA, thereby explaining enhancement of in situ StAR gene expression. These data introduce a new cohort of potent gonadal regulator of genes encoding proteins that mediate sterol uptake and steroid biosynthesis.
  • 13.

    【2hr】Leucine-enriched essential amino acid and carbohydrate ingestion following resistance exercise enhances mTOR signaling and protein synthesis in human muscle

    包量

    机译 抵抗运动后富含亮氨酸的必需氨基酸和碳水化合物的摄入增强了人类肌肉中的mTOR信号传导和蛋白质合成
    摘要：We recently showed that resistance exercise and ingestion of essential amino acids with carbohydrate (EAA+CHO) can independently stimulate mammalian target of rapamycin (mTOR) signaling and muscle protein synthesis in humans. Providing an EAA+CHO solution postexercise can further increase muscle protein synthesis. Therefore, we hypothesized that enhanced mTOR signaling might be responsible for the greater muscle protein synthesis when leucine-enriched EAA+CHOs are ingested during postexercise recovery. Sixteen male subjects were randomized to one of two groups (control or EAA+CHO). The EAA+CHO group ingested the nutrient solution 1 h after resistance exercise. mTOR signaling was assessed by immunoblotting from repeated muscle biopsy samples. Mixed muscle fractional synthetic rate (FSR) was measured using stable isotope techniques. Muscle protein synthesis and 4E-BP1 phosphorylation during exercise were significantly reduced (P < 0.05). Postexercise FSR was elevated above baseline in both groups at 1 h but was even further elevated in the EAA+CHO group at 2 h postexercise (P < 0.05). Increased FSR was associated with enhanced phosphorylation of mTOR and S6K1 (P < 0.05). Akt phosphorylation was elevated at 1 h and returned to baseline by 2 h in the control group, but it remained elevated in the EAA+CHO group (P < 0.05). 4E-BP1 phosphorylation returned to baseline during recovery in control but became elevated when EAA+CHO was ingested (P < 0.05). eEF2 phosphorylation decreased at 1 and 2 h postexercise to a similar extent in both groups (P < 0.05). Our data suggest that enhanced activation of the mTOR signaling pathway is playing a role in the greater synthesis of muscle proteins when resistance exercise is followed by EAA+CHO ingestion.
  • 14.

    【2hr】Palmitate action to inhibit glycogen synthase and stimulate protein phosphatase 2A increases with risk factors for type 2 diabetes

    包量

    机译 棕榈酸酯抑制糖原合酶和刺激蛋白磷酸酶2A的作用随2型糖尿病的危险因素而增加
    摘要：Recent studies have suggested that abnormal regulation of protein phosphatase 2A (PP2A) is associated with Type 2 diabetes in rodent and human tissues. Results with cultured mouse myotubes support a mechanism for palmitate activation of PP2A, leading to activation of glycogen synthase kinase 3. Phosphorylation and inactivation of glycogen synthase by glycogen synthase kinase 3 could be the mechanism for long-chain fatty acid inhibition of insulin-mediated carbohydrate storage in insulin-resistant subjects. Here, we test the effects of palmitic acid on cultured muscle glycogen synthase and PP2A activities. Palmitate inhibition of glycogen synthase fractional activity is increased in subjects with high body mass index compared with subjects with lower body mass index (r = −0.43, P = 0.03). Palmitate action on PP2A varies from inhibition in subjects with decreased 2-h plasma glucose concentration to activation in subjects with increased 2-h plasma glucose concentration (r = 0.45, P < 0.03) during oral glucose tolerance tests. The results do not show an association between palmitate effects on PP2A and glycogen synthase fractional activity. We conclude that subjects at risk for Type 2 diabetes have intrinsic differences in palmitate regulation of at least two enzymes (PP2A and glycogen synthase), contributing to abnormal insulin regulation of glucose metabolism.
  • 15.

    【2hr】Phospholipid hydrolysis and insulin secretion: a step toward solving the Rubik’s cube

    包量

    机译 磷脂水解和胰岛素分泌：迈向魔方的一步
    • 作者：Vincent Poitout
    • 刊名：American Journal of Physiology - Endocrinology and Metabolism
    • 2008年第2期
    摘要：
  • 16.

    【2hr】Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo

    包量

    机译 急性生理性高胰岛素血症对人体骨骼肌基因表达的影响
    摘要：This study was undertaken to test the hypothesis that short-term exposure (4 h) to physiological hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response independently of glycemic status. Twelve normal glucose tolerant subjects received a 4-h euglycemic hyperinsulinemic clamp with biopsies of the vastus lateralis muscle. Microarray analysis identified 121 probe sets that were significantly altered in response to physiological hyperinsulinemia while maintaining euglycemia. In normal, healthy human subjects insulin increased the mRNAs of a number of inflammatory genes (CCL2, CXCL2 and THBD) and transcription factors (ATF3, BHLHB2, HES1, KLF10, JUNB, FOS, and FOSB). A number of other genes were upregulated in response to insulin, including RRAD, MT, and SGK. CITED2, a known coactivator of PPARα, was significantly downregulated. SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to fasting plasma insulin concentrations. We independently validated the mRNA expression changes in an additional five subjects and closely paralleled the results observed in the original 12 subjects. A saline infusion in healthy, normal glucose-tolerant subjects without family history of diabetes demonstrated that the genes altered during the euglycemic hyperinsulinemic clamp were due to hyperinsulinemia and were unrelated to the biopsy procedure per se. The results of the present study demonstrate that insulin acutely regulates the levels of mRNAs involved in inflammation and transcription and identifies several candidate genes, including HES1 and BHLHB2, for further investigation.
  • 17.

    【2hr】The selective serotonin reuptake inhibitor sertraline enhances counterregulatory responses to hypoglycemia

    包量

    机译 选择性5-羟色胺再摄取抑制剂舍曲林增强对低血糖的反调节反应
    摘要：Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for patients with comorbid diabetes and depression. Clinical case studies in diabetic patients, however, suggest that SSRI therapy may exacerbate hypoglycemia. We hypothesized that SSRIs might increase the risk of hypoglycemia by impairing hormonal counterregulatory responses (CRR). We evaluated the effect of the SSRI sertraline on hormonal CRR to single or recurrent hypoglycemia in nondiabetic rats. Since there are time-dependent effects of SSRIs on serotonin neurotransmission that correspond with therapeutic action, we evaluated the effect of 6- or 20-day sertraline treatment on hypoglycemia CRR. We found that 6-day sertraline (SERT) treatment specifically enhanced the epinephrine response to a single bout of hypoglycemia vs. vehicle (VEH)-treated rats (t = 120: VEH, 2,573 ± 448 vs. SERT, 4,202 ± 545 pg/ml, P < 0.05). In response to recurrent hypoglycemia, VEH-treated rats exhibited the expected impairment in epinephrine secretion (t = 60: 678 ± 73 pg/ml) vs. VEH-treated rats experiencing first-time hypoglycemia (t = 60: 2,081 ± 436 pg/ml, P < 0.01). SERT treatment prevented the impaired epinephrine response in recurrent hypoglycemic rats (t = 60: 1,794 ± 276 pgl/ml). In 20-day SERT-treated rats, epinephrine, norepinephrine, and glucagon CRR were all significantly elevated above VEH-treated controls in response to hypoglycemia. Similarly to 6-day SERT treatment, 20-day SERT treatment rescued the impaired epinephrine response in recurrent hypoglycemic rats. Our data demonstrate that neither 6- nor 20-day sertraline treatment impaired hormonal CRR to hypoglycemia in nondiabetic rats. Instead, sertraline treatment resulted in an enhancement of hypoglycemia CRR and prevented the impaired adrenomedullary response normally observed in recurrent hypoglycemic rats.
  • 18.

    【2hr】Mechanisms of high-glucose/insulin-mediated desensitization of acute insulin-stimulated glucose transport and Akt activation

    包量

    机译 高糖/胰岛素介导的急性胰岛素刺激的葡萄糖转运和Akt激活的脱敏机制
    摘要：High-glucose/low-dose insulin-mediated insulin resistance of glucose transport was studied in 3T3-L1 adipocytes. In this model, proximal insulin signaling, including insulin receptor substrate (IRS)-1-bound phosphatidylinositol 3-kinase (PI 3-kinase) activation, is preserved, but insulin-stimulated protein kinase B (Akt) activation is markedly impaired. To assess a difference in acute insulin-stimulated production of phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], cells were labeled with [32P]orthophosphate, and glycerophosphoinositides were quantified by HPLC. Although basal PtdIns(3,4,5)P3 was similar, insulin stimulated its production 33.6% more in controls (P < 0.03) than in insulin-resistant cells. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein, a lipid phosphatase that dephosphorylates PtdIns(3,4,5)P3 in the 3-position, was significantly and specifically increased in insulin-resistant cells. Treatment with rapamycin [a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1)] inhibited the increased PTEN expression and partially restored insulin-stimulated glucose transport and Akt activation to insulin-resistant cells. Acute insulin markedly stimulated Ser636/639 phosphorylation of IRS-1; this was rapamycin inhibited but was significantly decreased in cells that had been preexposed to insulin, whereas total IRS-1 was unaffected. These findings were essentially paralleled by changes in the activation of p70 S6 kinase and S6-ribosomal protein. Overexpression of uncoupling protein-1 or manganese superoxide dismutase did not prevent the development of insulin-resistant glucose transport and impaired Akt activation in high-glucose/low-insulin-pretreated cells. The insulin resistance associated with glucotoxicity in our model reflects in part decreased availability of PtdIns(3,4,5)P3, which correlates with increased PTEN protein expression. Chronic activation of mTORC1 plays a role in stimulating PTEN expression and possibly in activation or induction of a phosphoprotein phosphatase. No evidence was found for a role for increased mitochondrial superoxide production in this model.
  • 19.

    【2hr】Hypothalamic pathways linking energy balance and reproduction

    包量

    机译 连接能量平衡和再生的下丘脑途径
    摘要：During periods of metabolic stress, animals must channel energy toward survival and away from processes such as reproduction. The reproductive axis, therefore, has the capacity to respond to changing levels of metabolic cues. The cellular and molecular mechanisms that link energy balance and reproduction, as well as the brain sites mediating this function, are still not well understood. This review focuses on the best characterized of the adiposity signals: leptin and insulin. We examine their reproductive role acting on the classic metabolic pathways of the arcuate nucleus, NPY/AgRP and POMC/CART neurons, and the newly identified kisspeptin network. In addition, other hypothalamic nuclei that may play a role in linking metabolic state and reproductive function are discussed. The nature of the interplay between these elements of the metabolic and reproductive systems presents a fascinating puzzle, whose pieces are just beginning to fall into place.
  • 20.

    【2hr】Decreased clearance of serum retinol-binding protein and elevated levels of transthyretin in insulin-resistant ob/ob mice

    包量

    机译 胰岛素抵抗性ob / ob小鼠血清视黄醇结合蛋白清除率降低，运甲状腺素蛋白水平升高
    摘要：Serum retinol-binding protein (RBP4) is secreted by liver and adipocytes and is implicated in systemic insulin resistance in rodents and humans. RBP4 normally binds to the larger transthyretin (TTR) homotetramer, forming a protein complex that reduces renal clearance of RBP4. To determine whether alterations in RBP4-TTR binding contribute to elevated plasma RBP4 levels in insulin-resistant states, we investigated RBP4-TTR interactions in leptin-deficient ob/ob mice and high-fat-fed obese mice (HFD). Gel filtration chromatography of plasma showed that 88–94% of RBP4 is contained within the RBP4-TTR complex in ob/ob and lean mice. Coimmunoprecipitation with an RBP4 antibody brought down stoichiometrically equal amounts of TTR and RBP4, indicating that TTR was not more saturated with RBP4 in ob/ob mice than in controls. However, plasma TTR levels were elevated approximately fourfold in ob/ob mice vs. controls. RBP4 injected intravenously in lean mice cleared rapidly, whereas the t1/2 for disappearance was approximately twofold longer in ob/ob plasma. Urinary fractional excretion of RBP4 was reduced in ob/ob mice, consistent with increased retention. In HFD mice, plasma TTR levels and clearance of injected RBP4 were similar to chow-fed controls. Hepatic TTR mRNA levels were elevated approximately twofold in ob/ob but not in HFD mice. Since elevated circulating RBP4 causes insulin resistance and glucose intolerance in mice, these findings suggest that increased TTR or alterations in RBP4-TTR binding may contribute to insulin resistance by stabilizing RBP4 at higher steady-state concentrations in circulation. Lowering TTR levels or interfering with RBP4-TTR binding may enhance insulin sensitivity in obesity and type 2 diabetes.
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