Compound K attenuates glucose intolerance and hepatic steatosis through AMPK-dependent pathways in type 2 diabetic OLETF rats

BACKGROUND/AIMS: Non-alcoholic fatty liver disease is associated with insulin resistance. Compound K (CK) is the final metabolite of panaxadiol ginsenosides that have been shown to exert antidiabetic effects. However, the molecular mechanism of the antidiabetic effects in the liver have not been elucidated; further, whether CK has beneficial effects in hepatosteatosis remains unclear. Therefore, we evaluated the effect of CK on hepatosteatosis as well as its mechanism in high-fat diet (HFD)-fed type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS: Twenty-four-week-old male OLETF rats were assigned to four groups: control (saline), CK 10 mg/kg, CK 25 mg/kg, or metformin 300 mg/kg (positive control); all treatments were administered orally for 12 weeks. RESULTS: Fasting glucose levels of the CK25 group were significantly lower than those of the control group during the 12 weeks. The results of the oral glucose tolerance test showed that both the glucose concentration after glucose loading and the fasting insulin levels of the CK25 group were significantly lower than those of the control. Hepatosteatosis was significantly improved by CK25. CK25 and metformin significantly increased the phosphorylation of hepatic adenosine monophosphate-activated protein kinase (AMPK). CK25 significantly inhibited the expression of sterol regulatory element-binding protein-1c and fatty acid synthase, while upregulating that of peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1. CONCLUSIONS: CK improved glucose intolerance and hepatosteatosis in HFD-fed OLETF rats through AMPK activation, which has dual mode of action that involves decreasing the synthesis of fatty acids and increasing fatty acid oxidation.

The Role of Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Understanding How Data Can Inform Clinical Practice in Korea

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce glycosylated hemoglobin (HbA1c, 0.5% to 1.0%), and are associated with moderate weight loss and a relatively low risk of hypoglycemia. There are differences between Asian and non-Asian populations. We reviewed available data on GLP-1RAs, focusing on Korean patients, to better understand their risk/benefit profile and help inform local clinical practice. Control of postprandial hyperglycemia is important in Asians in whom the prevalence of post-challenge hyperglycemia is higher (vs. non-Asians). The weight lowering effects of GLP-1RAs are becoming more salient as the prevalence of overweight and obesity among Korean patients increases. The higher rate of gastrointestinal adverse events amongst Asian patients in clinical trials may be caused by higher drug exposure due to the lower body mass index of the participants (vs. non-Asian studies). Data on the durability of weight loss, clinically important health outcomes, safety and optimal dosing in Korean patients are lacking. Use of GLP-1RAs is appropriate in several patient groups, including patients whose HbA1c is uncontrolled, especially if this is due to postprandial glucose excursions and patients who are overweight or obese due to dietary problems (e.g., appetite control). The potential for gastrointestinal adverse events should be explained to patients at treatment initiation to facilitate the promotion of better compliance.

Serum Bisphenol A Concentration in Postmenopausal Women with Osteoporosis

OBJECTIVES: Bishphenol A (BPA) is a representative endocrine disruptor and is also known as a xenoestrogen. The objective of the present study is to investigate how many patients are exposed to BPA and to analyze the relationships between serum BPA concentration, bone mineral density (BMD) and biochemical bone markers in postmenopausal women with osteoporosis. METHODS: Total 51 patients were enrolled for measuring BPA and clinical variables including BMD and bone markers. The relationship between BPA and clinical variables were analyzed by the Pearson's correlation test and the Kruskal-Wallis test. Serum BPA concentration was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: BPA was detected in all samples. The mean BPA concentration was 1.44 +/- 0.52 ng/mL. There was no statistically significant correlation between BPA and clinical variables. CONCLUSION: There was no statistical significance between serum BPA concentration and clinical variables related to bone metabolism. To clarify the effect of BPA on bone metabolism, further large scaled and high risk group investigation may be needed.

Inhibition of NF-kappaB prevents high glucose-induced proliferation and plasminogen activator inhibitor-1 expression in vascular smooth muscle cells

Recent epidemiologic studies clearly showed that early intensive glucose control has a legacy effect for preventing diabetic macrovascular complications. However, the cellular and molecular processes by which high glucose leads to macrovascular complications are poorly understood. Vascular smooth muscle cell (VSMC) dysfunction due to high glucose is a characteristic of diabetic vascular complications. Activation of nuclear factor-kappaB (NF-kappaB) may play a key role in the regulation of inflammation and proliferation of VSMCs. We examined whether VSMC proliferation and plasminogen activator inhibitor-1 (PAI-1) expression induced by high glucose were mediated by NF-kappaB activation. Also, we determined whether selective inhibition of NF-kappaB would inhibit proliferation and PAI-1 expression in VSMCs. VSMCs of the aorta of male SD rats were treated with various concentrations of glucose (5.6, 11.1, 16.7, and 22.2 mM) with or without an inhibitor of NF-kappaB or expression of a recombinant adenovirus vector encoding an IkappaB-alpha mutant (Ad-IkappaBalphaM). VSMC proliferation was examined using an MTT assay. PAI-1 expression was assayed by real-time PCR and PAI-1 protein in the media was measured by ELISA. NF-kappaB activation was determined by immunohistochemical staining, NF-kappaB reporter assay, and immunoblotting. We found that glucose stimulated VSMC proliferation and PAI-1 expression in a dose-dependent manner up to 22.2 mM. High glucose (22.2 mM) alone induced an increase in NF-kappaB activity. Treatment with inhibitors of NF-kappaB such as MG132, PDTC or expression of Ad-IkappaB-alphaM in VSMCs prevented VSMC proliferation and PAI-1 expression induced by high glucose. In conclusion, inhibition of NF-kappaB activity prevented high glucose-induced VSMC proliferation and PAI-1 expression.

A Case of Cushing's Syndrome Complicating Pregnancy Adrenalectomized after Delivery / 대한내분비학회지

Pregnancy is rare in women with Cushing's syndrome, as the associated infertility is related to excess cortisol and/or androgen. However, approximately 100 such cases have been reported, with 50% due to an adrenal cortical adenoma. Establishing a diagnosis and cause can be difficult. Clinically, striae, hypertension and gestational diabetes are common features in pregnancy, with hypertension and diabetes being the most common signs of Cushing's syndrome in pregnant women. Furthermore, biochemically, a normal pregnancy is associated with a several fold increase in plasma cortisol, as the increased cortisol production rate also increases the cortisol binding protein. Untreated, the condition results in high maternal and fetal morbidity and mortality. An adrenal or pituitary adenoma should be excised, but a metyrapone, which is not teratogenic, has been effective in controlling many cases of excess cortisol. Here, a case of Cushing's syndrome, complicating a pregnancy due to an adrenal cortical adenoma, with thorough obstetric and medical management, including a metyrapone, which was adrenalectomized after delivery, is reported.

Frequency of Vertebral Compression Fractures in Spinal Osteoarthritis Patients in Relation to Bone Mineral Density / 대한류마티스학회지

OBJECTIVE: To investigate the association between bone mineral density (BMD) and osteoporotic compression fractures in radiographic spinal osteoarthritis (OA) patients. METHODS: Subjects were 382 female patients (ages 45 to 85) from outpatient clinic for osteoporosis and rheumatic diseases. BMD was measured at lumbar spine and hip by dual X-ray absorptiometry (Hologic QDR 2000). The standard anteroposterior and lateral plain radiographs of thoracic and lumbar spine were taken to define spinal OA and vertebral compression fractures. Radiographic spinal OA was defined by grade of disc degeneration and facet joint degeneration. Frequency of vertebral fractures was compared between spinal OA and control patients in relation to their BMD, age, weight, body mass index (BMI) and years post menopause. RESULTS: Higher proportion of fracture cases were observed in spinal OA patients than non-spinal OA patients (34.1%, 44/129 vs. 18.2%, 46/253, p<0.001) despite comparable mean BMD (0.836+/-0.152 vs. 0.834+/-0.185, p=0.89) and older mean age (65.8+/-8.5 vs. 57.8+/-10.3, p<0.001). In subjects of ages from 65 to 74, spinal OA patients showed significantly higher BMD than non-spinal OA patients (0.784+/-0.125 vs. 0.719+/-0.119, p=0.007), but the frequency of fractures seems to be higher than that of non-spinal OA patients (44.9%, 22/50 patients vs. 34%,19/55 patients, p=0.58). When all study subjects were stratified according to their spine BMD (normal, osteopenia, and osteoporosis), significantly higher proportion of vertebral compression fractures was noted in spinal OA than non-spinal OA patients in osteopenia group (38.5% vs. 13.5%, p<0.001). CONCLUSION: Higher BMD does not seem to be translated directly into decreased risk of osteoporotic compression fractures in spinal OA patients. Careful assessment of risk factors for osteoporotic fractures and newer methods for assessing bone strength in this group of patients are needed.

The Change of Insulin Sensitivity and Insulin Secretion According to Glucose Metabolism Status in Patients with Cushing's Syndrome / 대한내분비학회지

BACKGROUND: Glucocorticoid plays an important role in the control of carbohydrate metabolism. Patients with Cushing's syndrome have been reported to have an increased incidence of carbohydrate intolerance due to peripheral insulin resistance and hyperinsulinemia, although the exact incidence and nature of this disorder have remained unclear. Few results have been published about insulin resistance and insulin secretion according to the level of glucose concentration, or about the reversibility of such defects in patients with Cushing's syndrome. METHODS: To assess the effect of glucocorticoid on the insulin sensitivity and insulin secretion in Cushing's syndrome, 15 patients with Cushing's syndrome were classified into 3 groups (normal glucose tolerance: NGT, impaired glucose tolerance: IGT, diabetes: DM) according to the degree of glucose tolerance based on the oral glucose tolerance test (OGTT). Insulin modified, frequentlysampled, intravenous glucose tolerance test (FSIGT) was performed before and after curative surgery on these patients and on 15 healthy control subjects. Data were evaluated by non-parametric statistical analysis. RESULTS: 1) Among the 15 patients with Cushing's syndrome, 3 (20%) were NGT, 4 (27%) IGT, and 8 (53%) DM, based on OGTT. Twenty-four hour urinary free cortisol (UFC) was significantly higher in the DM group. 2) Insulin sensitivity index (SI) of Cushing's syndrome was significantly lower than that of the control group (P=0.0024), but was not significantly different among the three Cushing's syndrome groups of NGT, IGT and DM. 3) Glucose mediated glucose disposal (SG) (Ed- confirm this abbreviation; it does not seem to match the definition) of Cushing's syndrome was not significantly different from that of the control group. 4) Insulin secretion (AIRg) of Cushing's syndrome tended to be high, but it was not significantly different from that of control. However, according to the level of glucose concentration there was significant difference in AlRg among the three Cushing's syndrome groups (P=0.0031); AIRg of DM was significantly lower than that of NGT. 5) After surgical treatment, parameters of insulin sensitivity and insulin secretion were normalized in 6 cured patients; 1 with NGT, 1 with IGT, and 4 with DM, preoperatively. Median SI of all 6 patients was significantly improved up to the normal range postoperatively (P=0.0022). Median AIRg of these 6 patients was balanced around that of normal control postoperatively (P=0.0286). CONCLUSION: Eighty percent of patients with Cushing's syndrome had abnormality of carbohydrate metabolism. Insulin sensitivity was significantly decreased in Cushing's syndrome. Insulin secretion was significantly higher only in the NGT and IGT groups of Cushing's syndrome. As the hypercortisolemia is exacerbated, insulin secretion is significantly decreased and causes DM, suggesting that glucocorticoid has a direct or indirect toxic effect on the pancreatic beta cell.

Polymorphisms of beta-2 adrenergic receptor gene in Koreans with obesity and noninsulin-dependent diabetes mellitus(NIDDM) / 대한내과학회지

OBJECTIVE: Catecholamine play a central role in the regulation of energy expenditure, in part by stimulating lipid mobilization through lipolysis in fat cells. The beta-2 adrenergic receptor(BAR-2) is a major lipolytic receptor in human fat cells. A recent study has shown that common polymorphisms occuring at codon 16 and 27 of the BAR-2 gene are significantly associated with obesity and lypolytic BAR-2 function in adipose tissue. We investigated whether the previously described human BAR-2 gene polymorphisms are associated with obesiy and NIDDM in Koreans. METHODS: All subjests were divided into two groups, non-obese and obese group, according to their body mass index. And their clinical characteristics were evaluated. The BAR-2 gene polymorphisms were analyzed by PCR-RFLP in 89 nondiabetics and 106 patients with NIDDM. RESULTS: When the allele frequency of BAR-2 gene polymorphisms was compared with that of western people, there was a significant difference. In our study, there was no significant difference in the allele frequency of BAR-2 gene polymorphisms at codons 16 and 27 between nonobese and obese group both nondiabetics and NIDDM subjects. The frequency of Glu27 homozygotes was very rare(1.1%). Body mass index(BMI), waist-hip ratio(WHR), and serum glucose and insulin secretion of the nondiabetics with polymorphism of codon 16 or codon 27 did not differ from those of the subjects without the polymorphisms. In NIDDM group, the Gly16 homozygotes had a lower BMI than Arg16 homozygotes without any difference in WHR and the other laboratory parameters. Neither clinical or laboratory parameters of the diabetics with the polymorphism at codon 27 differ from those of subjectes without the polymorphism. CONCLUSION: These findings suggest that the genetic variability in the human BAR-2 gene is not a major determinant for the development of obesity and NIDDM in Koreans.

Comparison of Immunohistochemical and Clinical Characteristics in Pituitary Adenoma with Acromegaly / 대한내분비학회지

BACKGROUND: It assumed that plurihormonal pituitary adenomas in acromegaly, which were immunohistochemically stained with other pituitary hormones in addition to GH and prolactin, would be originated from poorly differentiated cells. Therefore, we speculated that they might have higher growth rates and worse prognosis than monohormonal adenomas. To verify this speculation, we analyzed the frequency of plurihormonal adenomas and compared the clinical parameters and radiological invasiveness between plurihormonal adenoma and GH-prolactin adenoma in acromegaly. METHODS: We studied 38 patients with acromegaly (22 males and 16 females, mean age 40.7 years) who were underwent surgical removal of pituitary adenomas by TSA from January 1995 to February 1998. We performed immunohistochemical staining in these tumors using avidinbiotin peroxidase complex method. An adenoma was considered as immunoreactive when above 50 percents of tumor cells were stained with anti-hormonal antibodies. Invasiveness of tumors were evaluated by preoperative MRI findings on the basis of Hardys classification. RESULTS: The frequencies of plurihormonal and GH-prolactin adenomas were 42% and 58%, respectively. Plurihormonal adenoma included an adenoma which was not stained with prolactin, but with GH and other hormones. Prolactin immunoreactivity was found in 97%(37/38) of the tumors. Immunoreactivities to FSH, ACTH, LH, and TSH were found in 37.8%, 13.1%, 2.6% and 2.7%, respectively. There were no significant differences in age, basal serum GH and IGF-1 concentrations between plurihormonal and GH-prolactin adenomas. There were also no significant differences in response to TRH & LH stimulation tests and somatostatin & bromocriptine suppression tests between two groups. There were no differences in radiological invasiveness between two groups (plurihormonal adenoma, grade I 2, grade II 3, grade III 7, grade IV 4; GH-prolactin adenoma, grade I 3, grade II 6, grade III 9, grade IV 4). CONCLUSION: Plurihormonal adenomas were 44% and immunoreactivity to prolactin was 97% in pituitary adenomas in acromegaly. There were no significant differences in clinical parameters and radiological invasiveness between plurihormonal and GH-prolactin adenomas in acromegaly.

The Responses of Pituitary Hormones to the Combined Pituitary Stimulation Test in Hypogonadotropic Hypogonadism / 대한내분비학회지

To classify the causes of hypogonadotropic hypogonadism in Korean patients, and to improve the endocrinologic evaluation for the disease, we retrospectively studied the clinical findings and result of combined pituitary stimulation test in 35 patients with hypogonadotropic hypogonadism. The following results were obtained.1) The ratio of male to female was 1.3:1, and the 50% of male patients was under 20 years of age and the 20% of female patients in 30th decades. 2) The chief complaints of male patients on the admission were the failure of secondary sexual characteristics(95.0%) and loss of hair(5.0%), those of female patients were amenorrhea(46.7%), infertility(26.7%), failure of secondary characteristics(13.3%) and loss of hair(13.3%). 3) The causes of male hypogonadotropic hypogonadism were craniopharyngioma(35.0%), idiopathic(30.0%), Kallmann's syndrome(15.0%), pituitary adenoma(10.0%) and germinoma(5.0%), and those of female hypogonadotropic hypogonadism were prolactinoma(13.3%), Sheehan's syndrome(26.6%), pituitary adenoma(6.7%), tuberculous granuloma(6.7%), germinoma(6.7%), idiopathic hypogonadotropic hypogonadism(40.0%).4) The responses of LH and FSH to GnRH test were absent or markedly blunted in diffuse pituitary diseases such as pituitary tuberculous granuloma, pituitary macroadenomas, Sheehan's syndrome. However those were also absent or blunted in Cushing's disease and hypothalamic disease such as Kallmann's syndrome, germinoma, craniopharyngioma, idiopathic hypogonadotropic hypogonadism. 5) The responses of LH, FSH increased after repeated injection of GnRH in a patient with germinoma. 6) In diffuse destructive pituitary diseases such as Sheehan's syndrome, nonfunctioning macroadenomas, tuberculous granuloma, large prolactinoma, the combined deficiency of pituitary hormones other than gonadotropins was observed. 7) In many cases with hypothalamic diseases, the combined defects of pituitary hormone response were also seen.These data suggest that GnRH test is not always useful to localize the lesion between pituitary and hypothalamus, and combined pituitary stimulation test revealed defects of pituitary hormones other than gonadotropin in various hypothalamic diseases.Therefore repeated GnRH test would be useful for the differential diagnosis, and CRH test and GRH test would be necessary to demonstrate whether pituitary abnormality is present.