Familial partial lipodystrophy (FPLD) 3 is a rare genetic disorder caused by peroxisome proliferator-activated receptor γ gene (PPARG) mutations. Most cases have been reported in Western patients. Here, we describe a first pedigree of FPLD 3 in Japanese. The proband was a 51-year-old woman. She was diagnosed with fatty liver at age 32 years, dyslipidemia at age 37 years, and diabetes mellitus at age 41 years. Her body mass index was 18.5 kg/m2, and body fat percentage was 19.2%. On physical examination, she had less subcutaneous fat in the upper limbs than in other sites. On magnetic resonance imaging, atrophy of subcutaneous adipose tissue was seen in the upper limbs and lower legs. Fasting serum C-peptide immunoreactivity was high (3.4 ng/mL), and the plasma glucose disappearance rate was low (2.07%/min) on an insulin tolerance test, both suggesting apparent insulin resistance. The serum total adiponectin level was low (2.3 μg/mL). Mild fatty liver was seen on abdominal computed tomography. On genetic analysis, a P495L mutation in PPARG was identified. The same mutation was also seen in her father, who had non-obese diabetes mellitus, and FPLD 3 was diagnosed. Modest increases in body fat and serum total adiponectin were seen with pioglitazone treatment. Attention should be paid to avoid overlooking lipodystrophy syndromes even in non-obese diabetic patients if they show features of insulin resistance.
To date, familial partial lipodystrophy (FPLD) has been known to consist of seven types, and FPLD type 3 is a rare autosomal dominant genetic disorder caused by mutations of peroxisome proliferator-activated receptor γ gene. In this issue, Dr. Iizaka and colleague report the first pedigree of FPLD 3 in Japanese exemplifying prolonged insulin resistant diabetes mellitus, liver steatosis and hypertriglyceridemia with a relatively low degree of BMI and percentage of body fat. For all endocrinologists, attention should be paid to avoid overlooking lipodystrophy syndromes.
The thyrotropin receptor (TSHR) plays critical roles in thyroid growth and function and in the pathogenesis of several thyroid diseases including Graves’ hyperthyroidism and ophthalmopathy, non-autoimmune hyperthyroidism and thyroid cancer. Several low-molecular weight compounds (LMWCs) and anti-TSHR monoclonal antibodies (mAbs) with receptor antagonistic and inverse agonistic activities have been reported. The former binds to the pocket formed by the receptor transmembrane bundle, and the latter to the extracellular TSH binding site. Both are effective inhibitors of TSH/thyroid stimulating antibody-stimulated cAMP and/or hyaluronic acid production in TSHR-expressing cells. Anti-insulin-like growth factor 1 inhibitors are also found to inhibit TSHR signaling. Each agent has advantages and disadvantages; for example, mAbs have a higher affinity and longer half-life but are more costly than LMWCs. At present, mAbs appear most promising, yet the development of more efficacious LMWCs is desirable. These agents are anticipated to be efficacious not only for the above-mentioned diseases but also for resistance to thyroid hormone and have utility for thyroid cancer radionuclide scintigraphy/therapy as a new theranostic.
Molecular research on agonists / antagonists / inverse agonists in a variety of G-protein coupled receptors (GPCRs) has long attracted robust attention of endocrinologists. In this issue, Dr. Nagayama and Dr. Nishihara contributes an encyclopedic, well-organized article on the update of antagonists / inverse agonists research around the thyrotropin receptor (TSHR), providing us with promising therapeutic potential for Graves’ hyperthyroidism, non-autoimmune hyperthyroidism, thyroid cancer and resistance to thyroid hormone.
Findings of preclinical studies and recent phase I/II clinical trials have shown that mesenchymal stem cells (MSCs) play a significant role in the development of diabetic kidney disease (DKD). Thus, MSCs have attracted increasing attention as a novel regenerative therapy for kidney diseases. This review summarizes recent literature on the roles and potential mechanisms, including hyperglycemia regulation, anti-inflammation, anti-fibrosis, pro-angiogenesis, and renal function protection, of MSC-based treatment methods for DKD. This review provides novel insights into understanding the pathogenesis of DKD and guiding the development of biological therapies.
It has long been recognized that uncontrolled high blood pressure, dysmetabolism of glucose and lipids, and sustained inflammation and fibrosis are involved in the pathophysiology and progression of diabetic kidney disease (DKD) in an extremely complexed manner. It is therefore exactly a herculean issue to accurately identify patients with higher risks than we would imagine for end-stage renal diseases (ESRDs). In the October issue, Dr. Xu Ning and colleague provide an attractive review article focusing on potentials of mesenchymal stem cells (MSCs) for the treatment of such an intractable medical condition.
Cushing’s disease is an endocrine disorder characterized by hypercortisolism, mainly caused by autonomous production of ACTH from pituitary adenomas. Autonomous ACTH secretion results in excess cortisol production from the adrenal glands, and corticotroph adenoma cells disrupt the normal cortisol feedback mechanism. Pan-histone deacetylase (HDAC) inhibitors inhibit cell proliferation and ACTH production in AtT-20 corticotroph tumor cells. A selective HDAC6 inhibitor has been known to exert antitumor effects and reduce adverse effects related to the inhibition of other HDACs. The current study demonstrated that the potent and selective HDAC6 inhibitor tubastatin A has inhibitory effects on proopiomelanocortin (Pomc) and pituitary tumor-transforming gene 1 (Pttg1) mRNA expression, involved in cell proliferation. The phosphorylated Akt/Akt protein levels were increased after treatment with tubastatin A. Therefore, the proliferation of corticotroph cells may be regulated through the Akt-Pttg1 pathway. Dexamethasone treatment also decreased the Pomc mRNA level. Combined tubastatin A and dexamethasone treatment showed additive effects on the Pomc mRNA level. Thus, tubastatin A may have applications in the treatment of Cushing’s disease.
Epigenome-based drugs such as inhibitors against DNA methyltransferases (DNMTs) and histone deacetylase (HDACs) have long been employed for the treatment of a variety of malignancy and pre-cancer status. In this issue, Dr. Rie Hagiwara and colleague provide a convincing data set of in vitro experiments demonstrating a selective HDAC6 inhibitor, tubastatin A substantially suppresses the growth of as well as the ACTH secretion from a murine corticotroph cell line, AtT-20. The present study may open a fresh avenue for brand-new therapeutics in humans on pituitary neuroendocrine tumors including Cushing’s disease.
Inorganic phosphate (Pi) in the mammalian body is balanced by its influx and efflux through the intestines, kidneys, bones, and soft tissues, at which several sodium/Pi co-transporters mediate its active transport. Pi homeostasis is achieved through the complex counter-regulatory feedback balance between fibroblast growth factor 23 (FGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone. FGF23, which is mainly produced by osteocytes in bone, plays a central role in Pi homeostasis and exerts its effects by binding to the FGF receptor (FGFR) and αKlotho in distant target organs. In the kidneys, the main target, FGF23 promotes the excretion of Pi and suppresses the production of 1,25(OH)2D. Deficient and excess FGF23 result in hyperphosphatemia and hypophosphatemia, respectively. FGF23-related hypophosphatemic rickets/osteomalacia include tumor-induced osteomalacia and various genetic diseases, such as X-linked hypophosphatemic rickets. Coverage by the national health insurance system in Japan for the measurement of FGF23 and the approval of burosumab, an FGF23-neutralizing antibody, have had a significant impact on the diagnosis and treatment of FGF23-related hypophosphatemic rickets/osteomalacia. Some of the molecules responsible for genetic hypophosphatemic rickets/osteomalacia are highly expressed in osteocytes and function as local regulators of FGF23 production. A number of systemic factors also regulate FGF23 levels. Although the mechanisms responsible for Pi sensing in mammals have not yet been elucidated in detail, recent studies have suggested the involvement of FGFR1. The further clarification of the mechanisms by which osteocytes detect Pi levels and regulate FGF23 production will lead to the development of better strategies to treat hyperphosphatemic and hypophosphatemic conditions.
Science and clinics on phosphate homeostasis are no doubt an authentic, royal road to endocrinology. As most of readers of Endocrine Journal well recognize, basic scientists and endocrinologists in Japan have made a huge contribution to the molecular medicine on fibroblast growth factor 23 (FGF 23) in this academic field. To STATE-OF-THE-ART REVIEW IN ENDOCRINOLOGY in this issue, Dr. Michigami contributes an extensive, well-organized article on the recent research progress in phosphate homeostasis and related disorders with a particular emphasis on FGF 23, providing us with an invaluable perspective for cutting-edge area of bone-mineral endocrinology.
Effects of pre- and post-pubertal dihydrotestosterone treatment on penile length in 5α-reductase type 2 deficiency
Released on J-STAGE: September 28, 2019 | Volume 66 Issue 9 Pages 837-842
Goro Sasaki, Tomohiro Ishii, Naoaki Hori, Naoko Amano, Keiko Homma, Seiji Sato, Tomonobu Hasegawa
Views: 1,930
Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men
Released on J-STAGE: February 28, 2020 | Volume 67 Issue 2 Pages 153-160
Junichiro Irie, Emi Inagaki, Masataka Fujita, Hideaki Nakaya, Masanori Mitsuishi, Shintaro Yamaguchi, Kazuya Yamashita, Shuhei Shigaki, Takashi Ono, Hideo Yukioka, Hideyuki Okano, Yo-ichi Nabeshima, Shin-ichiro Imai, Masato Yasui, Kazuo Tsubota, Hiroshi Itoh
Views: 565
Update on subclinical thyroid dysfunction
Released on J-STAGE: July 28, 2022 | Volume 69 Issue 7 Pages 725-738
Koshi Hashimoto
Views: 457
Effects of berberine on blood glucose in patients with type 2 diabetes mellitus: a systematic literature review and a meta-analysis
Released on J-STAGE: January 28, 2019 | Volume 66 Issue 1 Pages 51-63
Yaping Liang, Xiaojia Xu, Mingjuan Yin, Yan Zhang, Lingfeng Huang, Ruoling Chen, Jindong Ni
Views: 242
Impairment of CRH in the intestinal mucosal epithelial barrier of pregnant Bama miniature pig induced by restraint stress
Released on J-STAGE: April 28, 2021 | Volume 68 Issue 4 Pages 485-502
Wenjiao Xu, Jiayin Lu, Yaoxing Chen, Zixu Wang, Jing Cao, Yulan Dong
Views: 226