Fumitaka Okajima

Association of serum apolipoprotein B48 level with the presence of carotid plaque in type 2 diabetes mellitus

AIMS The atherogenicity of chylomicron remnants has been discussed. We examined whether serum apoB48 level is associated with the presence of carotid plaque in type 2 diabetic patients. METHOD Forty type 2 diabetic patients (21 males and 19 females, 52.8+/-11.8 years old; mean+/-S.D.) were divided into two groups by the presence or absence of carotid plaque. The diurnal change of serum apoB48 level was measured by enzyme-linked immunosorbent assay. RESULTS Fasting serum apoB48 level was higher in the subjects with carotid plaque than those without (6.5+/-3.8vs. 4.1+/-1.9 microg/ml, p=0.01). Age- and gender-adjusted analysis showed that the presence of carotid plaque was associated with fasting apoB48 (OR 1.43; 95% CI, 1.07-2.09, p=0.04) and triglyceride (OR 1.14; 95% CI, 1.02-1.32, p=0.04) levels. In normal LDL-cholesterol (<140 mg/dl) subjects, the presence of carotid plaque was associated with fasting apoB48 level (OR 2.16; 95% CI, 1.22-5.32, p=0.04), but not associated with fasting triglyceride level (OR 1.11; 95% CI, 0.99-1.30, p=0.13). CONCLUSIONS Serum apoB48 level was strongly associated with the presence of carotid plaque in type 2 diabetic patients.

Comparison of three α‐glucosidase inhibitors for glycemic control and bodyweight reduction in Japanese patients with obese type 2 diabetes

α‐Glucosidase inhibitors (αGIs) are widely used for the primary treatment of type 2 diabetes. We compared the clinical effects of three αGIs (miglitol, acarbose and voglibose) in patients with obese type 2 diabetes.

Involvement of Rac GTPase activation in phosphatidylcholine hydroperoxide-induced THP-1 cell adhesion to ICAM-1.

Increasing evidence indicates that phospholipid oxidation plays important roles in atherosclerosis. Here, we investigated the involvement of Rho-family GTPases inphosphatidylcholine hydroperoxide (PCOOH)-induced THP-1 cell adhesion to ICAM-1. Isoprenoid depletion by fluvastatin and geranylgeranyltransferase inhibition by GGTI-286 suppressed PCOOH-induced cell adhesion to ICAM-1 and F-actin-rich membrane protrusion formation. Pull-down assays demonstrated the activation of Rac1 and Rac2 in PCOOH-treated cells. Pan-Rho-family GTPase inhibitor Clostridium difficile toxin B, Rac-specific inhibitor NSC23776, and RNA interference of the Rac isoforms suppressed the cell adhesion. These findings indicate the involvement of Rac GTPase activation in PCOOH-induced cell adhesion to ICAM-1 via actin reorganization.

Selective breeding of mice for different susceptibilities to high fat diet-induced glucose intolerance : Development of two novel mouse lines, Selectively bred Diet-induced Glucose intolerance-Prone and -Resistant

Aims/Introduction:  The development of type 2 diabetes is primarily due to lifestyle and environmental factors, as well as genetics, as shown by familial clustering. To establish mouse lines for evaluating heritable factors determining susceptibility to diet‐induced diabetes, we performed selective breeding for differences in high fat diet (HFD)‐induced glucose intolerance.

A non-acromegalic case of multiple endocrine neoplasia type 1 accompanied by a growth hormone-releasing hormone-producing pancreatic tumor

Cases of acromegaly due to GHRH-producing pancreatic endocrine tumors have been reported. Here we present a case of a 31-yr-old nonacromegalic man with hyperparathyroidism and elevated serum IGF-I with normal serum GH levels. Serum GH was not suppressed below 1 ng/ml by the glucose tolerance test and increased in response to TRH and GHRH administration. Magnetic resonance imaging (MRI) revealed pituitary hyperplasia and an abdominal computed tomography (CT) scan showed a tumor in the pancreatic tail. Plasma concentration of GHRH was elevated. Based on these clinical data, multiple endocrine neoplasia (MEN) type 1 was suspected. Three enlarged parathyroid glands were removed and a distal pancreatectomy was performed. Pathological examination of the parathyroid glands and pancreatic tumor showed nodular hyperplasia and a well-differentiated endocrine tumor, respectively, both compatible with MEN features. Immuno-histochemistry revealed positive immunoreactivity for GHRH, SS, insulin, glucagon, chromogranin A, and pancreatic polypeptide in the pancreatic tumor. After pancreatic surgery, elevated levels of GHRH and IGF-I were normalized and pituitary hyperplasia definitely decreased in size. In cases of pituitary hyperplasia with elevated IGF-I, ectopic GHRH syndrome must be considered even if physical features of acromegaly are absent. It is also important to measure plasma GHRH concentrations in order to give a diagnosis.

Comparison of pituitary-adrenal responsiveness between insulin tolerance test and growth hormone-releasing peptide-2 test: a pilot study.

Insulin tolerance test (ITT) is the gold standard for assessing the hypothalamic-pituitary-adrenal (HPA) function. GH-releasing peptide (GHRP)-2, which has a strong GH-stimulating activity, is useful for diagnosing GH deficiency as well as ITT. Additionally, GHRP-2 is also known to activate HPA axis. There have been no comparative studies of pituitary-adrenal responsiveness between GHRP-2 test and ITT in patients with hypothalamic/pituitary disease. To assess whether GHRP-2 test could be an alternative to ITT for diagnosing HPA axis failure, both ITT and GHRP-2 test were performed in 15 patients suspected of hypopituitarism. A 100mug dose of GHRP-2 was administered intravenously and plasma ACTH and serum cortisol concentrations were measured. In ITT, a peak cortisol value over 18mug/dl is considered normal. Nine patients were diagnosed as HPA axis failure by ITT. Their median peak cortisol in GHRP-2 test was 11.4mug/ml. In 6 patients diagnosed as normal HPA axis status by ITT, their median peak cortisol in response to GHRP-2 test was 21.4mug/dl, significantly higher (p=0.0032) than seen in patients diagnosed as HPA axis failure. There was a strong correlation between the peak cortisol in GHRP-2 test and ITT (r=0.817; p<0.0001). When the cut-off value for the peak cortisol in GHRP-2 test was set to 13-14mug/dl for diagnosing HPA axis failure, the specificity and sensitivity were 100% and 88.9%, respectively. Although further studies that include normal subjects are needed, these preliminary results suggest the possibility that GHRP-2 test may be an alternative to ITT for assessing HPA axis function.

Preventive effect of ipragliflozin on nocturnal hypoglycemia in patients with type 2 diabetes treated with basal-bolus insulin therapy: An open-label, single-center, parallel, randomized control study.

The efficacy of the administration of sodium‐glucose co‐transporter 2 inhibitor or the co‐administration of sodium‐glucose co‐transporter 2 inhibitor and dipeptidyl peptidase‐4 inhibitor to insulin therapy is not well known. A total of 58 patients with type 2 diabetes, admitted for glycemic control, were randomized to basal–bolus insulin therapy (BBT) alone or BBT plus 50 mg ipragliflozin and/or 20 mg teneligliptin. Insulin doses were adjusted to maintain normal blood glucose levels. Plasma glucose profiles were estimated by continuous glucose monitoring before discharge. Required insulin doses were not significantly different among the treatment groups. The frequency of nocturnal hypoglycemia was significantly lower in the groups treated with ipragliflozin (6.5 ± 10.6%) and ipragliflozin plus teneligliptin (6.9 ± 14.3%) than in the group treated with BBT alone (42 ± 43.6%). The administration of sodium‐glucose co‐transporter 2 inhibitor with or without dipeptidyl peptidase‐4 inhibitor prevented nocturnal hypoglycemia in type 2 diabetes patients with BBT.

Association of glycated albumin with the presence of carotid plaque in patients with type 2 diabetes.

Postprandial hyperglycemia is a potent risk factor for cardiovascular disease. Serum glycated albumin (GA) has been reported to reflect postprandial blood glucose fluctuations. In the present study, we assessed the possible correlation of GA with the presence of carotid plaque to evaluate the potential clinical usefulness of GA for predicting atherosclerotic cardiovascular complications in patients with type 2 diabetes.

Frequency of Achilles Tendon Xanthoma in Patients with Acute Coronary Syndrome

Aim: We studied the frequency of Achilles tendon xanthoma (ATX) in patients with acute coronary syndrome (ACS). Furthermore, we investigated the differences in clinical findings between ACS patients with and without ATX. Methods: Patients with ACS (n = 335) were admitted to the coronary care unit of Nippon Medical School between July 2011 and December 2014. Informed consent for the measurement of Achilles tendon thickness (ATT) on a radiograph was obtained from 228 patients without tendon rupture. ATT of each side was measured on the radiograph in patients with ACS and in those with acromegaly (n = 18), non-familial hypercholesterolemia (non-FH; n = 96), and familial hypercholesterolemia (FH; n = 31). Results: ATT of the right and left side in ACS patients were 6.9 ± 1.3 and 7.0 ± 1.6 (mm; mean ± SD). In acromegaly, non-FH, and FH patients, ATT of the right/left side were 6.6 ± 1.1/6.7 ± 1.1, 6.2 ± 0.9/6.6 ± 1.0, and 9.4 ± 3.3/10.0 ± 3.1, respectively. ATX (ATT ≥ 9 mm) was found in 26 (11.4%) patients with ACS. Patients with acromegaly and non-FH had no ATX, whereas all patients with FH had ATX. No differences in age and serum lipid profiles were observed between ACS patients with and without ATX. The levels of body mass index and glycated hemoglobin of ACS patients with ATX were significantly greater than those in ACS patients without ATX (26.8 ± 4.0 vs. 23.9 ± 3.3, p < 0.05, and 6.9 ± 1.4% 6.3 ± 1.3%, p < 0.05, respectively). Conclusion: This is the first report in which the frequency of ACS patients with ATX was 11.4%. The serum lipid profiles of ACS patients with ATX were similar to those without ATX. In the future, ACS patients with ATX will be diagnosed as having FH.

A socioeconomic and behavioral survey of patients with difficult-to-control type 2 diabetes mellitus reveals an association between diabetic retinopathy and educational attainment.

Background We have recently reported that the attitude of patients toward risk could be a factor in the progression of diabetic complications. In general, risk preference is closely related to socioeconomic status (SES), which includes factors such as age, sex, income, and educational attainment. Objective We aimed to determine the effect of SES and behavioral propensity on the progress of diabetic complications in patients with type 2 diabetes mellitus (T2DM). Methods We conducted a survey of 238 patients with difficult-to-control T2DM treated at a hospital in Japan using a modified behavioral economics questionnaire that included questions related to SES. The patients had been referred by general practitioners or other departments in the hospital because of poor metabolic control or unstable complications. Results Educational attainment was significantly associated with progression of retinopathy in patients <65 years of age. Educational attainment of a high school diploma (12 years of education) or lower was a significant risk factor, but there were no differences among levels of attainment beyond high school (13–16 years or more of education). Behavioral propensities were also weakly associated with complications, but not as much as educational attainment. Personal income level and economic status did not show an association with the retinopathy levels. Conclusion Lower educational attainment is a strong risk factor for diabetic retinopathy, and it is independent of the economic status. The result suggests that cognitive function may play an important role in the progression of diabetic retinopathy in patients with T2DM.