Endocrine journal
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A number of whole-genome association studies show the cdk5 regulatory associated protein 1-like 1 (cdkal1) gene to be one of the most reproducible risk genes in type 2 diabetes (T2D). Variations in the gene are associated with impaired insulin secretion but not insulin resistance or obesity. Although the physiological functions of Cdkal1 had been unclear, recent studies show that it is a tRNA modification enzyme, a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N(6)-threonylcarbamoyladenosine (ms(2)t(6)A) at position 37 of tRNA(Lys)(UUU). The ms(2)t(6)A modification in tRNA(Lys)(UUU) is important for preventing the misreading of its cognate codons, especially when the rate of translation is relatively high. In both general and pancreatic β-cell-specific cdkal1-deficient mice, impaired mitochondrial ATP generation and first-phase insulin secretion are observed. Moreover, the β-cell-specific knockout mice show pancreatic islet hypertrophy and impaired blood glucose control. The mice are also hypersensitive to high-fat diet-induced ER stress. In this review, we provide an overview of the physiological functions of Cdkal1 and the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.
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Ghrelin functions as a neuroprotective agent and rescues neurons from various insults. However, the molecular mechanisms underlying ghrelin neuroprotection remains to be elucidated. An accumulation of unfolded proteins in the endoplasmic reticulum (ER) leads to ER stress and then induces ER stress-mediated cell death. ⋯ In addition, phospho-Akt was translocated to the nucleus in response to ghrelin and PI3K inhibition by LY294002 prevented ghrelin-induced effect on phospho-Akt localization. Our study suggests that suppression of CHOP activation via the inhibition of PERK/eIF2α/ATF4 pathway and prevention of Foxo1 activation and nuclear translocation may contribute to ghrelin-mediated neuroprotection during ER stress responses. Our data also suggest that PI3K/Akt-mediated inactivation of GSK-3β, BAD and Foxo1 may be associated with the anti-apoptotic effect of ghrelin.
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In vitro studies in isolated pancreas and islets have shown that glucagon-like peptide-1 (GLP-1) promotes insulin release in a typical concentration-dependent manner. In contrast, the relationship between plasma GLP-1 and insulin concentrations in vivo is complicated, because GLP-1-promoted insulin release lowers blood glucose, which influences glucose-dependent insulinotropic ability of GLP-1. GLP-1 also stimulates insulin release via hepatoportal neuronal mechanism. ⋯ In contrast, bell-shaped dose responses were observed for both the 2nd phase and total insulin AUCs, in which a significant increase was obtained only with 11 pmol/l of active GLP-1 for total insulin AUC. A statistically significant reduction in the plasma glucose AUC was observed when active GLP-1 concentration was 11 pmol/l and 21 pmol/l. These results indicate that GLP-1 markedly enhances the 1st phase insulin release while less potently the 2nd phase insulin release, possibly due to a negative feedback regulation of β-cells via reduced plasma glucose levels by the enhanced 1st phase insulin release.
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We report a 21-year-old man with severe fatigue due to hypopituitarism. At the age of 6 years, he was diagnosed with short stature due to a GH deficiency accompanied by a sphenoid cystic lesion. Laboratory findings and provocative tests for pituitary hormone function revealed ACTH, LH, FSH, TSH, and GH deficiency. ⋯ At 6 years, he only had severe GH deficiency and poor response of LH to LHRH. Hypothalamic-pituitary dysfunction and pituitary herniation have progressed subsequently; we observed a longitudinal progression of hypothalamic-pituitary dysfunction caused by transsphenoidal cephalocele. This dysfunction requires the selection of a treatment that will not aggravate the condition further.
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Clinical Trial
Efficacy analysis of the lipid-lowering and renoprotective effects of rosuvastatin in patients with chronic kidney disease.
We aimed to assess the effects of rosuvastatin treatment on lipid levels, albuminuria, and kidney function in patients with chronic kidney disease (CKD). We conducted a prospective, open-label, study of 91 patients with CKD, low-density lipoprotein cholesterol (LDL-C) levels > 120 mg/dL, and well-controlled blood pressure who were undergoing treatment with renin-angiotensin system inhibitors. Subjects were treated with 2.5 mg/day rosuvastatin, which was increased to 10 mg/day for the 24-week study period. ⋯ Furthermore, when the subjects were divided into 2 groups based on eGFR levels (60 mL/min/1.73 m(2) or more, normal-GFR group; less than 60 mL/min/1.73 m(2), decreased-GFR group), the percent reduction of non-HDL-C, CRP, MDA-LDL levels, and albuminuria of DM subjects in the decreased-GFR group were significantly higher than those in the non-DM subjects. Multivariate analysis identified a change in cystatin C to be associated with decreased albuminuria during rosuvastatin treatment. Rosuvastatin administration reduced albuminuria, serum cystatin C levels, and inflammation, and improved lipid profiles, regardless of the presence or absence of DM, and the degree of the eGFR.