Shiko Asai

Evaluation of whole-abdominal fat volume by 700-slice CT scanning and comparison with the umbilical fat area anthropometric indices

SUMMARY BACKGROUND The fat area at the umbilical region on CT scans is widely used to identify visceral obesity. However, whether it precisely represents the abdominal visceral fat volume is uncertain, because of technical difficulty in evaluating whole-abdominal visceral fat volume. In this study, we compared the whole-abdominal visceral fat and subcutaneous fat volumes with the visceral fat area at the umbilical region and anthropometric indices. METHODS The study population consisted of 131 Japanese diabetic and non-diabetic subjects (72 males and 59 females) who underwent anthropometric measurements (height, weight, waist circumference, and hip circumference) and CT scanning from the top of the liver to the pelvic floor (about 700 slices) to analyze the whole-abdominal and umbilical contents of visceral and subcutaneous fat. RESULTS The visceral fat volume of the male group was 1.3-fold higher than that of the female group, while the subcutaneous fat volume of the female group was 1.3-fold higher than that of the male group. The visceral fat area at the umbilical region was strongly correlated with visceral fat volume (r = 0.921 in males and 0.931 in females). Both visceral and subcutaneous fat volumes were strongly correlated with the waist circumference (r = 0.768 and 0.809 in males and 0.744 and 0.803 in females), but not with the BMI or waist/hip ratio. CONCLUSION The visceral fat area at the umbilical region is an optimal indicator for whole-abdominal visceral fat volume, and the waist circumference is the anthropometric index that reflects visceral obesity more closely than BMI or the waist/hip ratio.

Intrahepatic lipid content is linked to insulin resistance in obese subjects

SUMMARY BACKGROUND Abdominal visceral fat (VAT) and intrahepatic lipid (IHL) are associated with insulin resistance in obese subjects, but VAT is usually measured on CT scans at the umbilical level or on MRI images of the partial abdomen. Thus, the association of the total abdominal visceral fat volume (VFV) with insulin resistance is unclear. In this study, we evaluated the correlations of obesity-related factors, including VFV and IHL, with clinical markers of insulin resistance (HOMA-R and the MATSUDA Index), and then assessed the effect of weight loss on these factors and markers. METHODS The study population consisted of 30 obese Japanese subjects with a BMI > 25 kg/m(2) (13 men and 17 women) who underwent a 75-g oral glucose tolerance test to calculate HOMA-R and the MATSUDA Index, dual energy X-ray absorptiometry (DEXA) for measurement of body fat (%-Fat), proton magnetic resonance spectroscopy ((1)H MRS) to assess IHL, and whole abdominal CT scanning (from the top of the liver to the floor of the pelvic cavity = about 700 slices) to determine the total abdominal subcutaneous fat volume (SFV) and VFV. Seven subjects from the original population were placed on a diet and exercise program, and these indices were examined again after 5% reduction of body weight. RESULTS Abdominal SFV, VFV, and IHL were mutually independent, but BMI and %-Fat were not independent of the other factors. According to multiple regression analysis, IHL (but not SFV or VFV) was significantly correlated with both HOMA-R and the MATSUDA Index in obese patients. Weight reduction by 5% led to improvement of the MATSUDA Index and decreased the number of subjects with metabolic syndrome, and the reduction of IHL was greater than that of SFV or VFV. These results suggest that IHL may be a superior marker of insulin resistance.

Effect of sitagliptin on glycemic control and beta cell function in Japanese patients given basal-supported oral therapy for type 2 diabetes

We evaluated the effect of sitagliptin on glycemic control, endogenous insulin secretion, and beta cell function in Japanese patients with type 2 diabetes mellitus (T2DM) receiving a combination of oral antidiabetics and basal insulin analog glargine (basal-supported oral therapy [BOT]). Twenty-one patients showing inadequate glycemic control with BOT were given dipeptidylpeptidase-4 inhibitor (DPP-4I) sitagliptin at 50 mg/day for 12 weeks. Clinical markers of glycemic control, HbA1c, glycated albumin (GA), and 1,5-anhydroglucitol (1,5-AG), were measured before and 4 and 12 weeks after the start of sitagliptin. A 2-hour morning meal test was performed upon enrollment and at 12 weeks, and plasma glucose (PG), serum C-peptide, and plasma intact proinsulin (PI) were measured. HbA1c, GA, and 1,5-AG at 4 and 12 weeks were significantly improved over enrollment levels. The area under the PG concentration curve (AUC-PG) during the meal test at 12 weeks was significantly reduced (from 350 ± 17 mg ･ hr/dL before sitagliptin treatment to 338 ± 21 mg ･ hr/dL [mean ± SE], P < 0.05,); the AUC-C-peptide was unchanged (from 3.4 ± 0.4 ng ･ hr/mL to 3.6 ± 0.5 ng ･ hr/mL). However, both fasting and 2-hour PI/C-peptide ratios at 12 weeks were significantly decreased (from 13.3 ± 2.3 to 11.1 ± 2.0 [P < 0 .05] and from 9.5 ± 1.6 to 5.3 ± 0.9 [P < 0.01], respectively). Adding sitagliptin to BOT in Japanese T2DM patients appears to improve glycemic control without increasing endogenous insulin secretion and to reduce fasting and 2-hour postprandial PI/C-peptide ratios.

Differing effects of liraglutide on gastric emptying in Japanese patients with type 2 diabetes

This study was performed to clarify the influence of liraglutide on gastric emptying in Japanese patients with type 2 diabetes. In 16 patients, the [13C]‐acetate breath test was performed to compare gastric emptying before and after liraglutide treatment. We found two patterns of response, with gastric emptying being delayed by liraglutide in seven patients (delayers) and not delayed in nine patients (non‐delayers). The mean increase of the maximum gastric emptying time was 31 ± 4 min (p < 0.01 vs. baseline) in the delayers, while it was only 2 ± 3 min (p = 0.60 vs. baseline) in the non‐delayers. The delayers showed a greater early decrease of AUC‐PG from 0 to 60 min, despite no increase of the plasma insulin level compared with non‐delayers. In conclusion, the effect of liraglutide treatment on gastric emptying shows heterogeneity, and patients can be classified as delayers or non‐delayers.

In the overnight dexamethasone suppression test, 1.0 mg loading is superior to 0.5 mg loading for diagnosing subclinical adrenal Cushing’s syndrome based on plasma dexamethasone levels determined using liquid chromatography-tandem mass spectrometry

The low-dose dexamethasone suppression test (DST) is one of the commonly used initial tests for endogenous Cushings syndrome (CS). However, there are two loading dose regimens (0.5-mg and 1-mg), which may cause some confusion in daily practice in Japan; furthermore, there are no reports regarding whether 0.5-mg DST is a better loading dose for detecting adrenal subclinical CS (SCS) based on the plasma dexamethasone (DEX) levels. Therefore, the aims of this study were (a) to develop a novel assay to measure DEX by using liquid chromatography tandem-mass spectrometry (LC-MS/MS) and (b) to compare between the 0.5-mg and 1-mg DST for SCS diagnosis based on the DEX levels. The study retrospectively analyzed 52 consecutive subjects hospitalized for diagnosis of adrenal incidentaloma but who did not exhibit an overt CS phenotype; eight (15.4%) patients were affected with adrenal SCS. Inter-individual variability of DEX levels after the DST was high, but intra-individual variability was low. DEX levels after 1-mg loading in each patient was around two times higher than those after 0.5-mg loading (ρ = 0.853 and p < 0.001). There were 45 (86.5%) and 17 (32.7%) subjects with DEX levels ≤2.2 ng/mL after the 0.5-mg and 1-mg DST, respectively (p < 0.001). Twenty-eight (93.3%) of 30 subjects and four (21.1%) of 19 subjects with detectable ACTH levels after the 0.5-mg and 1.0-mg DST, respectively, did not exhibit DEX levels >2.2 ng/mL. These results clearly indicate that the 1-mg DST is superior to 0.5-mg loading for the diagnosis of adrenal SCS.

Immunohistochemical analysis of insulin-like growth factor 1 and its receptor in sporadic schwannoma/peripheral nerve sheath tumour.

Objective To investigate the immunohistochemical localization of insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R) in archival specimens of sporadic schwannoma. Method This study retrospectively analysed the immunolocalization of IGF-1 and IGF-1R in schwannoma specimens collected from all patients with sporadic schwannoma that were treated by two institutions in Japan. The study also evaluated the association between the extent of the IGF-1 and IGF-1R immunoreactivity and several clinicopathological characteristics (age, sex and maximum tumour dimension). Results The study examined a total of 29 sporadic schwannoma specimens. IGF-1 and IGF-1R immunoreactivity was detected in the majority of the specimens regardless of their anatomical location. IGF-1 and IGF-1R were not co-localized. There was no association between the extent of the IGF-1 and IGF-1R immunoreactivity and the clinicopathological characteristics of the patients. Conclusions As IGF-1 and IGF-1R immunoreactivity was detected in the majority of sporadic schwannoma specimens regardless of their anatomical location, these findings suggest that an IGF-1/IGF-1R loop could play a role in the tumorigenesis and progression of schwannomas via an autocrine–paracrine mechanism.

Contralateral adrenal suppression on adrenocortical scintigraphy provides good evidence showing subclinical cortisol overproduction from unilateral adenomas

Unilateral and/or predominant uptake on adrenocortical scintigraphy (ACS) may be related to autonomous cortisol overproduction in patients with subclinical Cushings syndrome (SCS). However, there is no information regarding whether increased tracer uptake on the tumor side or decreased uptake on the contralateral side on ACS is more greatly associated with inappropriate cortisol production. Therefore, we evaluated the relationship between quantitative 131I-6β-iodomethyl-norcholesterol (131I-NP-59) uptake in both adrenal glands and parameters of autonomic cortisol secretion and attempted to set a cut off for SCS detection. The study included 90 patients with unilateral adrenal adenoma who fulfilled strict criteria. The diagnosis of SCS was based on serum cortisol ≥3.0 μg/dL after 1-mg dexamethasone suppression test (DST) with at least 1 other hypothalamus-pituitary-adrenal axis function abnormality. Twenty-two (27.7%) subjects were diagnosed with SCS. The uptake rate on the affected side in the SCS group was comparable to that in the non-functioning adenoma group. In contrast, the uptake rate on the contralateral side was lower and the laterality ratio significantly higher in the SCS group. The two ACS indices were correlated with serum cortisol levels after a 1-mg DST, but uptake on the tumor side was not. Tumor size was also important for the functional statuses of adrenal tumors and NP-59 imaging patterns. The best cut-off point for the laterality ratio to detect SCS was 3.07. These results clearly indicate that contralateral adrenal suppression in ACS is good evidence showing subclinical cortisol overproduction.

In Silico Analysis Identification of a Novel Germ-Line VHL Mutation in a Patient of Malignant Pheochromocytoma

OBJECTIVE Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited tumor syndrome caused by a VHL gene mutation. Here we report a novel mutation of VHL in a patient diagnosed with malignant pheochromocytoma at the age of 17. METHODS A 17-year-old female was referred for paroxysmal supraventricular tachycardia and anemia. She was diagnosed with a left adrenal pheochromocytoma based on biochemical and imaging studies. A left adrenalectomy was performed. Six months after surgery, metastatic lesions were suspected in the lung. The histopathologic findings of thoracoscopic lung biopsy specimens confirmed metastasis of the malignant pheochromocytoma. RESULTS Genetic analysis of VHL showed a novel missense mutation at codon 194 (V194G) in exon 3. This mutation was inherited from the paternal allele, and a loss of heterozygosity was noted in 3 of the patients distinct tumors. Two independent in silico analyses suggested that this amino acid substitution was pathogenic. CONCLUSION We identified a novel missense mutation of VHL in a young patient with malignant pheochromocytoma.

An interesting case with obese and ketosis-prone type 2 diabetes suggesting metformin action on the adipose tissue

We report a 63-year-old obese ketosis-prone diabetic woman who was being treated with metformin and a low dose of insulin. We performed two hyperinsulinemic-euglycemic clamp studies followed by an oral glucose load (clamp-OGL) with and without administration of metformin. These clamp studies revealed that her splanchnic glucose uptake (SGU) was increased from 27.6 to 64.4% by metformin administration, though the glucose infusion rate (GIR) was not altered. Further investigation indicated that the intrahepatic lipid (IHL) content was low in this patient. After she stopped metformin, the fasting plasma glucose, free fatty acid, and ketone body levels were elevated, while these were decreased by re-administration of the drug. Our results suggest that metformin might not only act on the liver, but also on adipose tissue, and it could be an adjunctive treatment for obese patients with ketosis-prone type 2 diabetes.