Osteoporosis and type 2 diabetes mellitus (T2DM) are now prevalent in aging and westernized societies, and adversely affect the health of the elderly people by causing fractures and vascular complications, respectively. Recent experimental and clinical studies show that both disorders are etiologically related to each other through the actions of osteocalcin and adiponectin. Meta-analyses of multiple clinical studies show that hip fracture risk of T2DM patients is increased to 1.4 to 1.7-folds, although BMD of the patients is not diminished. Vertebral fracture risk of T2DM patients is also increased, and BMD is not useful for assessing its risk. These findings suggest that bone fragility in T2DM depends on bone quality deterioration rather than bone mass reduction. Thus, surrogate markers are needed to replace the insensitivity of BMD in assessing fracture risks of T2DM patients. Markers related to advanced glycation end products as well as insulin-like growth factor-I may be such candidates, because these substances were experimentally shown to modulate bone quality in DM. In practice, it is important for physicians to assess fracture risk in T2DM patients by evaluating prior VFs and fracture histories using spine X-ray and interview, respectively, until the usefulness of surrogate markers is established.
Ghrelin has been shown to be associated with feeding behavior in humans and rodents. It has been suggested that ghrelin may play a role behind the effect of bariatric surgery. Inbred rats were made into parabiotic pairs so that they shared a single abdominal cavity. A further operation is performed later in which the small intestines are transected and re-connected so that one rat continually lost nutrition to its partner. Changes in food intake and body weight were recorded. Seven weeks later, content of ghrelin in the plasma, stomach and upper intestines were measured in the paired rats. Rats which lost nutrients to its counterpart (Loss rats) ingested significantly more food than sham control rats (p<0.001). Rats which gained nutrient (Gain rats) ingested less than controls (p<0.001). There was no significant difference in body weight, blood glucose, insulin, free fatty acids and triglycerides between the paired rats. There was significantly higher levels of ghrelin in the plasma (p<0.008) and the intestine of the Loss rats (p<0.02). There were no difference in ghrelin in the stomach between parabiotic rats and sham operated controls. The ghrelin content of the plasma and intestines were significantly higher in the Loss rats, which ate more, and normal in the Gain rats, which ate less than controls. Because no remarkable changes in the ghrelin content were observed in the stomach, difference in the quality of the chime may affect the local synthesis and release of ghrelin.
It had been observed that some cystic nodules change morphologically with ultrasonographic (US) features suspicious for malignancy. The aim of this study was to evaluate the US characteristics of benign cystic nodules mimicking papillary thyroid carcinoma (PTC) during interval changes. Between January 2009 and October 2009, 26 patients with benign cystic nodules showing marked hypoechogenicity in US during the follow-up period were enrolled. During the same period, 38 patients with marked hypoechogenicity in US were enrolled for the PTC group. We evaluated the differences in US characteristics between the 2 groups. Nodule size, margin, echogenic dot and vascularity were not significantly different between the 2 groups. Nodule shape was significantly different between the 2 groups with a lower prevalence of taller than wide in the benign cystic group (11.5% vs. 39.5%, P=0.022). Other coexisting cystic nodules were more frequently observed in benign cystic group (48.3% vs. 5.3%, P=0.001). If echogenic dot was detected in benign cystic nodule, it was more than 1 mm in size without posterior acoustic shadowing unlike echogenic dots in the PTC group. In conclusion, some of the benign cystic nodules may have suspicious malignant features on US during interval changes. A careful assessment of US findings and a previous history may be of value in discriminating them from PTC.
Visceral adipose tissue-derived serpin (vaspin) is a novel adipokine that is thought to have insulin-sensitizing effects. We investigated vaspin mRNA expression in abdominal adipose tissue and examined how gene expression related to abdominal fat distribution and metabolic parameters in Korean women. We measured anthropometric variables, metabolic parameters, serum vaspin concentration, and vaspin mRNA expression in abdominal adipose tissue obtained from women who underwent abdominal gynecological surgery and were aged 18-67 years (n = 85). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) area were measured in 40 subjects using computed tomography (CT). Vaspin expression was analyzed by real-time quantitative RT-PCR according to abdominal fat distribution. Vaspin mRNA expression was greater in adipocytes than in stroma/vascular cells. In the total subjects, vaspin expression was significantly higher in SAT than in VAT. Vaspin expression in SAT in subcutaneous fat type (VSR ≤ 0.3) was significantly higher than in visceral fat type (VSR > 0.3), although vaspin expression in VAT was similar between subcutaneous and visceral fat type. There was a significant negative correlation between vaspin expression in SAT and VAT area (r = -0.55, p = 0.001). Serum vaspin concentration was significantly correlated with fasting insulin (r = 0.30, p = 0.02), HOMA-IR (r = 0.29, p = 0.02), and the ratio of vaspin expression in VAT to vaspin expression in SAT (r = 0.41, p = 0.04). Vaspin expression in abdominal adipose tissue was adipocyte-specific and vaspin expression in SAT decreased as VAT area increased.
X-linked hypophosphatemic rickets (XLH) is caused by inactivating mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene. Deletion of Phex leads to increased serum fibroblast growth factor23 (FGF23) levels in mouse. The aim is to assure the clinical usefulness of FGF23 determination in the diagnosis of XLH. Participants were 21 patients with XLH having abnormalities in PHEX from 13 kindred (PtPHEX: 1 to 42 years old; 10 males, 11 females) and 55 healthy controls (1 month to 18 years old; 27 males, 28 females). Temporal changes in FGF23 were determined by a single oral phosphate administration in PtPHEX and an ad lib diet in controls. Reference ranges of intact FGF23 (iFGF23) for children were determined. iFGF23 level which distinguish between controls and PtPHEX were validated. Correlations between iFGF23 and the severity of XLH (gender, age of onset, bone deformity, The ratio of maximum rate of renal tubular reabsorption of phosphate to glomerular filtration rate (TmPO4/GFR), inorganic phosphate (IP), Alkaline Phosphatase (ALP), therapeutic dose) were investigated. Increasing tendency after phosphate administration and no general tendency after breakfast in iFGF23 were observed. Reference range (5th and 95th percentiles) of iFGF23 for children (12.9 and 51.2 pg/mL) was similar to that for adults. iFGF23 were above the reference range in 19 of 21 PtPHEX (40 to 4710 pg/mL). iFGF23 did not correlate with any index of severity of XLH. Relatively high iFGF23 despite hypophosphatemia is one of the clinical indicators to diagnose XLH.
Postprandial hyperglycemia is an established risk factor for atherosclerotic vascular diseases, and it is frequently observed in gastrectomized subjects. This study sought to examine whether other atherosclerotic risk factors are also common among gastrectomized subjects. The study population comprised of 44 non-diabetic men who previously underwent gastrectomy. The age- and body mass index-matched control population comprised of 278 non-diabetic men without gastrectomy. In addition to traditional atherosclerotic risk factors for atherosclerosis, high sensitivity C-reactive protein (hsCRP) and brachial-ankle pulse wave velocity (baPWV) were also compared between the groups. Fasting plasma glucose was not different between both groups, while glycated hemoglobin (HbA1c) was significantly higher in the gastrectomized men than in the control men. Systolic and diastolic blood pressures and high density lipoprotein cholesterol (HDL-C) were significantly higher, whereas low density lipoprotein cholesterol (LDL-C) was lower in the gastrectomized men than in the control men. baPWV, hsCRP, triglycerides and insulin resistance (as per the homeostasis model assessment) were not different between groups. While levels of certain atherosclerotic risk factors, including HbA1c and blood pressure are higher among gastrectomized men, HDL-C and LDL-C were actually favorable. Additionally, levels of more emerging risk factors, such as hsCRP and baPWV were not altered among gastrectomized men.
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. Rosuvastatin effectively reduced total cholesterol, LDL-C, triglycerides, non-high density lipoprotein cholesterol (non-HDL-C) levels, and the LDL-C/HDL-C ratio. Although there was no significant change in the estimated glomerular filtration rate (eGFR), serum cystatin C levels and urinary albumin/creatinine ratio were significantly decreased. Subjects were divided into 2 groups: with and without diabetes mellitus (DM). Percent changes of HDL-C, C-reactive protein (CRP), and malondialdehyde-modified (MDA)-LDL were significantly higher in the DM group than in the non-DM group. Furthermore, when the subjects were divided into 2 groups based on eGFR levels (60 mL/min/1.73 m2 or more, normal-GFR group; less than 60 mL/min/1.73 m2, 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.
Recurrent autoimmune hypophysitis is a rare autoimmune endocrine disease involving lymphocytic infiltration and chronic pituitary inflammation. It is even more rare than primary hypophysitis. The objective of the study was to evaluate the efficacy of glucocorticoid treatment combined with azathioprine for treating three cases of recurrent autoimmune lymphocytic hypophysitis encountered within a two-year period. The clinical features and follow-up data of these cases were analyzed, including results of treatment with glucocorticoids combined with azathioprine. All three patients were female and presented with the following clinical characteristics: case 1 was a 22-year-old with headache and diplopia; case 2 was a 70-year-old with dry mouth, polydipsia, and polyuria; case 3, a 32-year-old, with polydipsia, polyuria and menstrual disorders with headache and dizziness. Regarding recurrence, case 1 recurred 4 months after surgery and again 14 months after discontinuing prednisone; case 2 relapsed 16 months after receiving high-dose methylprednisolone pulse therapy; and case 3 recurred during the period of prednisone dose reduction. The patients were treated with glucocorticoids plus azathioprine, and positive responses were seen in all three cases. Symptoms were relieved, and MRI revealed significant reduction of lesions during follow-up. Pituitary function resumed in cases 1 and 3; permanent hypopituitarism was present in case 2. At last follow-up, MRI showed no further recurrence of disease in any patient. Treatment and responses of these patients with autoimmune hypophysitis suggest that glucocorticoid therapy combined with azothioprine is effective treatment for recurrent autoimmune hypophysitis. Endocrine and radiologic studies are an essential part of follow-up.
Cribriform-morular variant (CMV) is a comparably rare histological subtype of papillary thyroid carcinoma (PTC). This can be associated with familial adenomatous polyposis (FAP) due to APC gene mutations. In this study, we investigated the difference in the biological characteristics between FAP-associated and sporadic CMV. Between 1991 and 2010, 32 patients with CMV were treated in Kuma Hospital. Thirty-one of these underwent initial surgery for CMV in Kuma Hospital. Twelve patients were FAP-associated and the remaining 19 were sporadic CMV. All patients were female. Tumors of FAP-associated CMV were more frequently multiple than those of sporadic CMV. Patient age and tumor size did not differ between the two groups. Of 12 FAP-associated CMV, 5 were detected by thyroid nodule (thyroid precedent group) and 7 were detected by FAP (polyposis precedent group) as an initial manifestation. Patient age was younger and tumor size was smaller in the polyposis group than in the thyroid nodule group. All patients lacked extrathyroid extension on intraoperative finding and were node-negative on pathological examination. To date, two patients with FAP-associated CMV who initially underwent hemithyroidectomy (one in Kuma Hospital and one in another hospital) showed recurrence to the remnant thyroid during follow-up. None of the patients showed recurrence to other regions or died of carcinoma. Taken together, CMV is considered an indolent disease in our series. FAP-associated CMV showed multiple tumors more frequently than sporadic CMV. Total thyroidectomy is recommended for FAP-associated CMV, but extensive lymph node dissection is not necessary.
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. Hence, the dynamic relationship between plasma active GLP-1 vs. insulin and glucose concentrations is obscure. In this study, we aimed to determine in vivo relationships between these parameters in rats. To mimic postprandial state, intraduodenal glucose challenge in anesthetized rats was performed, which can minimize the release of endogenous GLP-1. The glucose challenge induced the 1st phase and 2nd phase insulin release. GLP-1 infusion from jugular vein significantly and concentration-dependently enhanced area under the curve (AUC) of the 1st phase insulin, in which the minimum effective active GLP-1 concentration was 6.6 pmol/l. 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.
Cushing’s disease rarely appears as a consequence of hereditary disease. However, familial diseases with diminished glucocorticoid feedback are associated with secondary hypercorticotropinism and have been shown to give rise to pituitary adenomas. We here describe the rare case of a 30-year old female patient with congenital adrenal hyperplasia who also showed clinical signs and a typical history of hypercortisolism that was specified as Cushing’s disease. After removal of a pituitary microadenoma, serum-cortisol levels fell below normal and the symptoms improved. However, after four years the menstrual cycle was irregular again and ACTH levels were in the upper range of normal. A corticotropin challenge showed a minor cortisol response but a marked increase in 17-hydroxyprogesterone serum concentrations. Genetic analysis revealed a homozygous mutation in exon 7 of the CYP21A2 gene (CTG>TTG, p.V281L). We conclude that a marked ACTH drive was able to override insufficient 21-hydroxylation and even to cause hypercortisolism. Although we describe a rare case, the impairment of the glucocorticoid feedback system in the context of congenital adrenal hyperplasia and other diseases may contribute to the development of secondary hypercorticotropinism as well as corticotropin producing adenomas.
Ghrelin is a circulating growth hormone-releasing and appetite-inducing brain-gut peptide. It needs to be acylated on its serine-3 with octanoate for its endocrine actions. The acyl-transferase that catalyses ghrelin octanoylation has recently been identified and named as GOAT (ghrelin O-acyltransferase); GOAT enzyme is coded by the MBOAT4 gene. This study aimed to investigate GOAT expression in the human. The distribution of GOAT mRNA expression was studied in various human tissues using classical and real-time reverse transcription and polymerase chain reaction. GOAT expression was found in all tissues studied (stomach, adrenal cortex, breast, right and left colon, duodenum, jejunum, ileum, fat, Fallopian tube, gallbladder, lymph node, lymphocyte cell line, kidney, liver, lung, muscle, myocardium, pituitary, oesophagus, pancreas, ovary, placenta, prostate, testis, spleen and thyroid). The widespread expression of GOAT corresponds to the widespread distribution of ghrelin expression. GOAT expression was high in stomach and gut, the major ghrelin-secreting tissues, and in the pituitary, in which ghrelin is known to show autocrine and paracrine effects. Identification of GOAT expression in various tissues support the concept that in addition to the important endocrine effect of acylated ghrelin, the paracrine effects of locally synthetised and acylated ghrelin may be important.