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ABSTRACT: Lipin1 protein, a product of the LPIN1 gene, is required for normal adipose tissue development and metabolism. Lipin1 deficiency results in immature adipocyte development in cases of mouse fatty liver dystrophy and human lipodystrophy. Recently, pioglitazone has been reported to increase human adipocyte lipin1 expression. We evaluated the effects of LPIN1 polymorphisms on rosiglitazone response in patients with type 2 diabetes (T2DM). A total of 262 patients were treated with 12 weeks of rosiglitazone (4 mg/day) in addition to their previous drug regimen medications. Six single nucleotide polymorphisms (SNPs) at the LPIN1 locus were genotyped: rs11693809, rs10192566, rs2278513, rs2577262, rs2716610, and rs1050800. Because rs11693809, rs10192566, and rs2278513 are in nearly complete linkage disequilibrium (D'>0.958, r(2) >0.882), we analyzed rs10192566, rs2577262, rs2716610, and rs1050800. Rs10192566 was significantly associated with rosiglitazone treatment response. Patients with the G allele in rs10192566 had a larger decrease in fasting plasma glucose, 2-h postprandial glucose, and HbA1c than those without. This genetic effect remained significant after adjustment for age, sex, and initial body weight. No other SNPs were associated with response. These data suggest that LPIN1 genetic variations can affect rosiglitazone treatment response in T2DM.
Molecular Genetics and Metabolism 08/2008; 95(1-2):96-100. · 3.19 Impact Factor
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Yongho Lee,
Mi Kyong Kwon,
Eun Seok Kang,
Young Mi Park,
Seung Ho Choi,
Chul Woo Ahn, Kyung Sub Kim,
Chul Won Park,
Bong Soo Cha,
Sung Wan Kim,
Je Kyung Sung,
Eun Jig Lee,
Hyun Chul Lee
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ABSTRACT: Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone that plays an important role in glucose homeostasis. Its functions include glucose-stimulated insulin secretion, suppression of glucagon secretion, deceleration of gastric emptying, and reduction in appetite and food intake. Despite the numerous antidiabetic properties of GLP-1, its therapeutic potential is limited by its short biological half-life due to rapid enzymatic degradation by dipeptidyl peptidase IV. The present study aimed to demonstrate the therapeutic effects of constitutively expressed GLP-1 in an overt type 2 diabetic animal model using an adenoviral vector system.
A novel plasmid (pAAV-ILGLP-1) and recombinant adenoviral vector (Ad-ILGLP-1) were constructed with the cytomegalovirus promoter and insulin leader sequence followed by GLP-1(7-37) cDNA.
The results of an enzyme-linked immunosorbent assay showed significantly elevated levels of GLP-1(7-37) secreted by human embryonic kidney cells transfected with the construct containing the leader sequence. A single intravenous administration of Ad-ILGLP-1 into 12-week-old Zucker diabetic fatty (ZDF) rats, which have overt type 2 diabetes mellitus (T2DM), achieved near normoglycemia for 3 weeks and improved utilization of blood glucose in glucose tolerance tests. Circulating plasma levels of GLP-1 increased in GLP-1-treated ZDF rats, but diminished 21 days after treatment. When compared with controls, Ad-ILGLP-1-treated ZDF rats had a lower homeostasis model assessment for insulin resistance score indicating amelioration in insulin resistance. Immunohistochemical staining showed that cells expressing GLP-1 were found in the livers of GLP-1-treated ZDF rats.
These data suggest that GLP-1 gene therapy can improve glucose homeostasis in fully developed diabetic animal models and may be a promising treatment modality for T2DM in humans.
The Journal of Gene Medicine 04/2008; 10(3):260-8. · 2.48 Impact Factor
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ABSTRACT: A partial C-terminal cDNA sequence of a novel Drosophila mitogen-activated protein kinase phosphatase (MKP), designated DMKP-3, was identified from an epitope expressed sequence tag database, and the missing N-terminal cDNA fragment was cloned from a Drosophila cDNA library. DMKP-3 is a protein of 411 amino acids, with a calculated molecular mass of 45.8 kDa; the deduced amino acid sequence is most similar to that of mammalian MKP-3. Recombinant DMKP-3 produced in Escherichia coli retained intrinsic tyrosine phosphatase activity. In addition, DMKP-3 specifically inhibited extracellular-signal-regulated kinase (ERK) activity, but was without a significant affect on c-Jun N-terminal kinase (JNK) and p38 activities, when it was overexpressed in Schneider cells. DMKP-3 interacted specifically with Drosophila ERK (DERK) via its N-terminal domain. In addition, DMKP-3 specifically inhibited Elk-1-dependent trans-reporter gene expression in mammalian CV1 cells, and dephosphorylated activated mammalian ERK in vitro. DMKP-3 is uniquely localized in the cytoplasm within Schneider cells, and gene expression is tightly regulated during development. Thus DMKP-3 is a Drosophila homologue of mammalian MKP-3, and may play important roles in the regulation of various developmental processes.
Biochemical Journal 02/2002; 361(Pt 1):143-51. · 4.90 Impact Factor
