Mari Kimura

T lymphopaenia in relation to body mass index and TNF‐α in human obesity: adequate weight reduction can be corrective

Although individuals with obesity are susceptible to infection, the underlying causes have not been fully identified. To investigate whether obesity affects immunity, we studied subjects with isolated obesity.

DEHYDROEPIANDROSTERONE DECREASES SERUM TUMOR NECROSIS FACTOR-? AND RESTORES INSULIN SENSITIVITY: INDEPENDENT EFFECT FROM SECONDARY WEIGHT REDUCTION IN GENETICALLY OBESE ZUCKER FATTY RATS

Dehydroepiandrosterone (DHEA) and its sulfate ester are the most abundant circulating adrenal steroids in humans. Administration of DHEA has been reported to have beneficial effects on obesity, hyperlipidemia, diabetes, and atherosclerosis in obese rodents, although its effects on insulin resistance have not been fully elucidated. In this study, the effects of DHEA treatment on insulin sensitivity were investigated in genetically obese Zucker rats, an animal model of insulin resistance, using the euglycemic clamp technique. After 0.4% DHEA was administered for 10 days to female obese Zucker rats aged 16 weeks, body weight and plasma insulin decreased and glucose disposal rate (GDR), which was normally reduced in obese rats, rose significantly compared with age- and sex-matched control obese rats. On the other hand, although the pair-fed obese rats also showed levels of weight reduction similar to those of DHEA-treated rats, the increase in GDR of DHEA-treated rats was significantly greater than in pair-fe...

Reduced serum dehydroepiandrosterone levels in diabetic patients with hyperinsulinaemia.

To elucidate the interaction between insulin and dehydroepi‐androsterone (DHEA) concentrations, we evaluated serum DHEA and DHEA‐sulphate (DHEA‐S) levels in diabetic patients with hyperinsulinaemia.

T LYMPHOPENIA IN OBESE DIABETIC (DB/DB) MICE IS NON-SELECTIVE AND THYMUS INDEPENDENT

Although C57BL/KsJ db/db mice, an animal model of non-insulin-dependent diabetes mellitus (NIDDM), develop T lymphopenia in association with the progression of NIDDM, the T lymphopenia has not been fully investigated. In this study, to elucidate how and why T lymphopenia develops in db/db mice, T-lymphocyte subsets in spleen and thymus were longitudinally examined by flow cytometry and the effects of thymectomy and dietary restriction on the development of T lymphopenia were evaluated. After 8 weeks of age, when obese diabetes progresses, T lymphopenia in both spleen and thymus developed and all T-lymphocyte subsets examined were similarly reduced compared to lean (-/X) littermates, indicating non-selective T lymphopenia in db/db mice. Thymectomy performed at 5 wk of age, when neither T lymphopenia nor NIDDM yet presents, had no significant effect on the development of T lymphopenia. Furthermore, pair feeding until 30 weeks of age produced normal body weight and normoglycemia with still marked hyperinsulinemia, but failed to correct T lymphopenia in db/db mice. In conclusion, our results suggest that T lymphopenia may develop non-selectively and independently of either thymic dysfunction or obese diabetes in db/db mice.

Antibody responses raised against a conformational V3 loop peptide of HIV-1.

The amino acid sequence of the principal neutralizing determinant (PND) of 224 cases of human immunodeficiency virus type 1 (HIV‐1) was determined and the most frequently occurring sequence was used as a peptide antigen for studying virus‐specific antibody responses. In our present study, a linear peptide of the most frequent PND was first synthesized and then oxidized to create a disulfide‐bridged loop conformation. Then, in order to construct a macromolecular structure for the purpose of increasing anti‐genicity, the synthetic peptide was conjugated to a core peptide. We compared the immunogenicity of the disulfide‐bridged loop PND peptide antigen (AG4) and the linear PND peptide antigen (AG5). After immunizing rabbits 5 and 6 times with both peptides, the results obtained using ELISA revealed that AG4 (conformational‐loop type) was more capable of inducing a high titer of antigen‐specific antibodies than was AG5 (linear type). Despite an amino acid sequence homology of 72%, a 1:8 dilution of serum raised against AG4 inhibited 81.9% of HIV‐1IIIB‐mediated cell fusion, suggesting that conformational V3 loop peptide is able to elicit an antibody response which is strongly HIV‐1‐specific.

Comparison of intragastric balloon therapy and intensive lifestyle modification therapy with respect to weight reduction and abdominal fat distribution in super-obese Japanese patients

This study compared the impacts of intragastric balloon (IGB) therapy and intensive lifestyle modification therapy on abdominal fat distribution. Sixteen extremely obese Japanese patients were assigned to an intensive lifestyle modification therapy group with educational hospitalisation (8 patients) or an IGB therapy group (8 patients) and were followed up for 6 months. The main outcome measures were the differences at 6 months, relative to the baseline values, in the visceral fat area (VFA), subcutaneous fat area (SFA), and liver volume as measured using computed tomography. At 0 month, the body weights (BWs) were 121.3±19.0 kg and 127.1±24.4 kg and the VFAs were 299±55 cm2 and 257±56 cm2 in the intensive lifestyle modification therapy group and the IGB therapy group, respectively. No statistically significant differences in the baseline characteristics were observed between these two groups. At 6 months, no difference in the changes in BW from the baseline value (-11.5 [-16.4, -6.6] kg vs. -11.2 [-18.9, -3.4] kg) was seen between the two groups. However, a statistically significant difference in the change in the VFA (-66 [-87, -44] cm2 vs. -22 [-70, 26]cm(2) [P=0.027]) was observed; no significant changes in the SFA or liver volume were seen. In conclusion, IGB therapy was as effective as intensive lifestyle modification therapy for weight reduction but was less effective with respect to the improvement in abdominal visceral fat accumulation and liver steatosis in super-obese Japanese patients.

Intraventricular insulin reduces the antinociceptive effect of [d-Ala2, NMePhe4, Gly-ol5]enkephalin in mice

The effects of pretreatment with insulin on the antinociception induced by intracerebroventricular (i.c.v.) administration of the mu-opioid receptor agonist [D-Ala2, NMePhe4, Gly-ol5]enkephalin (DAMGO) were studied in mice. Intracerebroventricular pretreatment with insulin (1 and 3 mU) for 60 min dose dependently attenuated the antinociception induced by i.c.v. DAMGO (5.6 ng) in mice. Intracerebroventricular pretreatment with a highly selective tyrosine kinase inhibitor, lavendustin A, at doses of 100 and 300 ng for 10 min, dose dependently reversed the antinociceptive effect of DAMGO (5.6 ng) in insulin-treated mice. The antinociceptive effect of DAMGO (5.6 ng, i.c.v.) was significantly reduced in C57BL/KsJ-db/db diabetic mice compared with that in age-matched control (C57BL/KsJ-db/ + + ) mice. When C57BL/KsJ-db/db diabetic mice were pretreated with lavendustin A (300 ng), the antinociceptive effect of DAMGO was significantly increased. These results indicate that tyrosine kinase may be involved in the reduction of DAMGO-induced antinociception by insulin in mice. Furthermore, the attenuation of DAMGO-induced antinociception in C57BL/KsJ-db/db diabetic mice may be due in part to increased tyrosine kinase activity as a result of hyperinsulinemia.

Self-Injection of Insulin Using Appropriate Supportive Devices in Handicapped Subjects with Diabetes

BACKGROUND To self-inject insulin, individuals with diabetes must be able to attach the needle to the injector, recognize the appropriate insulin dosage, detach the needle from the injector, and perform a series of operations necessary for the actual injection. These tasks require a grip strength that is strong enough to hold the necessary devices, eyesight, the use of both hands, and at least a minimum intellectual capacity. Subjects who are unable to grasp or handle the devices required for insulin injection often have difficulties with the self-injection of insulin. METHODS We treated four diabetes patients who had trouble grasping objects and using both hands. One patient had lost five fingers in an accident, two patients had suffered from ischemic cerebral infarction resulting in complete one-sided hemiplegia with no movement in one arm, and one patient had limited muscular power in an arm as a result of spinal cord disease. The plasma glucose control was poor, and the initiation of insulin therapy was necessary in each of these patients. In three cases, we used a commercially available self-injection device (HumaHelper; Eli Lilly Japan K.K., Kobe, Japan) to enable self-injection; in the fourth case, we used a newly manufactured device similar to HumaHelper. RESULTS All the patients were able to inject insulin by themselves using the appropriate supplementary devices. The blood glucose control of all the patients subsequently improved. CONCLUSION Existing or newly manufactured supportive devices can enable handicapped subjects to self-inject insulin.

Comparison of Azelnidipine and Trichlormethiazide in Japanese Type 2 Diabetic Patients with Hypertension: The COAT Randomized Controlled Trial

Objective This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension. Methods In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c ≤ 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups. Results Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 ± 0.52% and 0.19 ± 0.54%; sBP/dBP, -10.7 ± 9.6/-6.6 ± 6.6 mmHg and -7.1 ± 7.7/-3.3 ± 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period. Conclusions Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension. Trial Registration UMIN 000006081.

Plasminogen activator inhibitor-1 is associated with renal dysfunction independent of BMI and serum lipid levels in patients with type 2 diabetes

We investigated a possible association between serum plasminogen activator inhibitor-1 (PAI-1) levels and renal dysfunction in 124 type 2 diabetes patients. Multiple linear regression analyses indicated that the PAI-1 levels were significantly inversely correlated with estimated glomerular filtration rate (eGFR) independent of albuminuria, BMI, LDL-C, and triglyceride.