Leptin is a circulating hormone that is expressed abundantly and specifically in the adipose tissue. It is involved in the regulation of energy homeostasis, as well as the neuroendocrine and ...reproductive systems. Here, we demonstrate production of leptin by nonadipose tissue, namely, placental trophoblasts and amnion cells from uteri of pregnant women. We show that pregnant women secrete a considerable amount of leptin from the placenta into the maternal circulation as compared with nonpregnant obese women. Leptin production was also detected in a cultured human choriocarcinoma cell line, BeWo cells, and was augmented during the course of forskolin-induced differentiation of cytotrophoblasts into syncytiotrophoblasts. Plasma leptin levels were markedly elevated in patients with hydatidiform mole or choriocarcinoma and were reduced after surgical treatment or chemotherapy. Leptin is also produced by primary cultured human amnion cells and is secreted into the amniotic fluid. The present study provides evidence for leptin as a novel placenta-derived hormone in humans and suggests the physiologic and pathophysiologic significance of leptin in normal pregnancy and gestational trophoblastic neoplasms.
Turner syndrome (TS) is a chromosomal abnormality attributed to a total or partial loss of the X chromosome. While TS is characterized clinically by short stature and primary ovarian insufficiency, ...those with a deletion of Xq often have ovarian insufficiency but no other features of TS. We herein report a case of a young adult patient with Xq partial deletion accompanied by diabetes mellitus. The patient was a 30-year-old woman who had begun hormone replacement therapy for primary ovarian insufficiency with a diagnosis of TS at 16 years of age. She was admitted to our hospital because her fasting blood sugar and HbA1c had increased to 212 mg/dL and 10.4 %, respectively. A physical examination revealed no short stature, but she was overweight, with a body mass index of 28.3 kg/m2. Her anti-GAD antibody titer was negative, and he urine C-peptide level was 76.3 μg/day. Diet restriction, exercise, and the administration of metformin and dulaglutide improved her glucose level. Karyotype determination revealed the partial deletion of the long arm. TS patients have a high prevalence of diabetes mellitus, but whether or not TS patients with Xq deletion are prone to diabetes mellitus is still unknown. This case suggests that even TS patients with an atypical phenotype and karyotype should receive ongoing care with monitoring for comorbidities.
A number of studies have demonstrated that insulin resistance in the skeletal muscle plays a pivotal role in the insulin resistance associated with obesity and type 2 diabetes. A decrease in GLUT4 ...translocation from the intracellular pool to the plasma membranes in skeletal muscles has been implicated as a possible cause of insulin resistance. Herein, we examined the effects of an insulin-sensitizing drug, troglitazone (TGZ), on glucose uptake and the translocation of GLUT4 in L6 myotubes. The prolonged exposure (24 h) of L6 myotubes to TGZ (10(-5) mol/l) caused a substantial increase in the 2-deoxy-3HD-glucose (2-DG) uptake without changing the total amount of the glucose transporters GLUT4, GLUT1, and GLUT3. The TGZ-induced 2-DG uptake was completely abolished by cytochalasin-B (10 micromol/l). The ability of TGZ to translocate GLUT4 from light microsomes to the crude plasma membranes was greater than that of insulin. Both cycloheximide treatment (3.5 x 10(-6) mol/l) and the removal of TGZ by washing reversed the 2-DG uptake to the basal level. Moreover, insulin did not enhance the TGZ-induced 2-DG uptake additively. The TGZ-induced 2-DG uptake was only partially reversed by wortmannin to 80%, and TGZ did not change the expression and the phosphorylation of protein kinase B; the expression of protein kinase C (PKC)-lambda, PKC-beta2, and PKC-zeta; or 5'AMP-activated protein kinase activity. a-Tocopherol, which has a molecular structure similar to that of TGZ, did not increase 2-DG uptake. We conclude that the glucose transport in L6 myotubes exposed to TGZ for 24 h is the result of an increased translocation of GLUT4. The present results imply that the effects of troglitazone on GLUT4 translocation may include a new mechanism for improving glucose transport in skeletal muscle.
Uncoupling protein 3 (UCP3), which uncouples electron transport
from ATP synthesis, is expressed at high levels in the skeletal muscle,
an important organ in glucose and lipid metabolism. Because ...several
reports proposed that fatty acids induced UCP3 gene expression in
skeletal muscle in vivo, in the present study we
examined the regulation of UCP3 gene expression by various fatty acids
using L6 myotubes. UCP3 gene expression was increased in L6 myotubes by
various fatty acids or by α-bromopalmitate, a nonmetabolized
derivative of palmitic acid. Because fatty acids are also known as
agonists for PPARs, we examined the involvement of PPARs in the
regulation of the UCP3 gene expression. L-165041, a PPARδ agonist,
increased UCP3 gene expression in L6 myotubes, whereas neither Wy
14,643, a PPARα agonist, nor Pioglitazone, a PPARγ
agonist, increased it. Therefore, we conclude that UCP3 gene expression
is increased by the activation of PPARδ in L6 myotubes and postulate
that PPARδ mediates at least some part of the increased UCP3
gene expression by fatty acids in skeletal muscle in
vivo.
In type 2 diabetes, macroangiopathy manifests as atherosclerosis like in nondiabetic patients, characterized by formation of plaques that follows in stages but with an accelerated course due to the ...several risk factors. Atherosclerosis in diabetes begins earlier, is more markedly pronounced and progresses more rapidly. It is still a debated question whether antidiabetic therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with advanced type 2 diabetes. New findings result from ACCORD Study reveal that microvascular and macrovascular effects of intensive glucose lowering have to be considered separately. On the other hand, our NICE Study yielded better cardiovascular outcomes for those patients with intensive glucose-lowering therapy using rapid-acting insulin analogue reducing postprandial glucose levels with less hypoglycemia.
Thiazolidinediones, insulin-sensitizing agents, have been reported to increase glucose uptake along with the expression of glucose transporters in adipocytes and cardiomyocytes. Recently, we have ...further suggested that the translocation of GLUT4 is stimulated by thiazolidinediones in L6 myocytes. However, the direct effects of thiazolidinediones on translocation of glucose transporters have not yet been determined. In this study, using hemagglutinin epitope-tagged GLUT4 (GLUT4-HA), we provide direct evidence of the effect of troglitazone on the translocation of GLUT4 in rat epididymal adipocytes. Primary cultures of rat adipocytes were transiently transfected with GLUT4-HA and overexpressed eightfold compared with endogenous GLUT4 in transfected cells. A total of 24 h of treatment with troglitazone (10(-4) mol/l) increased the cell surface level of GLUT4-HA by 1.5 +/- 0.03-fold (P < 0.01) without changing the total amount of GLUT4-HA, whereas it increased the protein level of endogenous GLUT4 (1.4-fold) without changing that of GLUT1. Thus, the direct effect on the translocation can be detected apart from the increase in endogenous GLUT4 content using GLUT4-HA. Troglitazone not only increased the translocation of GLUT4-HA on the cell surface in the basal state but also caused a leftward shift in the dose-response relations between GLUT4-HA translocation and insulin concentration in the medium (ED(50): from approximately 0.1 to 0.03 nmol/l). These effects may partly contribute to the antidiabetic activity of troglitazone in patients with obesity and type 2 diabetes.
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