Tsunekazu Umekawa

Effects of Trp64Arg mutation in the β3-adrenergic receptor gene on weight loss, body fat distribution, glycemic control, and insulin resistance in obese type 2 diabetic patients

OBJECTIVE To investigate the effects of Trp64Arg mutation in the β3-adrenergic receptor gene on weight loss, body fat distribution, glycemic control, and insulin resistance in obese type 2 diabetic patients. RESEARCH DESIGN AND METHODS We measured body weight, waist-to-hip ratio (WHR), adjusted resting metabolic rate, fasting blood glucose, fasting serum insulin levels, insulin resistance index (fasting glucose × fasting insulin/22.5), and HbA1c levels before and after 12 weeks of obesity treatment in 61 obese women with type 2 diabetes. The Mval polymorphism of the β3-adrenergic receptor gene was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS Of obese type 2 diabetic patients, those with the mutation (n = 24) had a higher WHR (P < 0.001), a lower adjusted metabolic rate, and higher blood glucose levels, serum insulin levels, insulin resistance index (P < 0.001), and HbA1c levels (P = 0.016). Furthermore, patients with the mutation had smaller decreases in body weight, WHR, insulin resistance index, and HbA1c levels after the weight-loss program compared with patients without the mutation (n = 37), even though food intake, exercise, and serum thyroid hormone levels were similar in both groups. CONCLUSIONS These present findings show that the Trp64Arg allele of the β3-adrenergic receptor gene may predict difficulty in losing body weight, lowering WHR, and improving glycemic control and insulin resistance in obese patients with type 2 diabetes.

Anti-obesity and anti-diabetic effects of CL 316, 243, a highly specific β3-adrenoceptor agonist, in yellow KK mice

The anti-obesity and anti-diabetic effects of CL 316,243, a highly specific beta 3-adrenoceptor agonist (beta 1: beta 2: beta 3 = 0:1:100,000), were evaluated in obese diabetic yellow KK mice and C57Bl control mice. The study compound was fed through a gastric tube at a rate of 0.1 mg/kg/day for 2 weeks. The following parameters were compared in the treated and control animals given distilled water: brown adipose tissue thermogenesis, resting metabolic rate, insulin receptors in adipocytes, and blood glucose and serum insulin levels during a glucose overloading test. CL 316,243 significantly increased brown adipose tissue thermogenesis and resting metabolic rate in both yellow KK mice and C57Bl controls. The amount of white adipose tissue decreased, although food intake was not affected. The effects contributed to the mitigation of obesity in yellow KK mice. CL 316,243 also increased the concentration of insulin receptors and decreased the levels of serum insulin and blood glucose during the glucose overloading test in yellow KK mice. These observations suggest that CL 316,243 possesses anti-obesity and anti-diabetic effects and consequently may be useful for treating obesity as well as non-insulin-dependent diabetes mellitus in obese persons, without causing excessive side effects.

Effects of caffeine on the uncoupling protein family in obese yellow KK mice.

1. The hypothesis that caffeine upregulates uncoupling protein (UCP)‐1, UCP‐2 and UCP‐3 expression, which contribute to thermogenesis, was investigated in obese mice.

Effect of nicotine on sympathetic nervous system activity of mice subjected to immobilization stress

We tested the hypothesis that nicotine possesses an antistress action by measuring the turnover of norepinephrine (NE), a reliable indicator of sympathetic nervous system activity, in the interscapular brown adipose tissue (IBAT) and heart of mice treated with nicotine injections, immobilization stress, or nicotine + immobilization stress, vs. untreated controls. Nicotine enhanced the sympathetic activity in the IBAT and heart, and induced a loss of body weight. Immobilization-related stress accelerated sympathetic activity in the IBAT and heart more strongly than did nicotine loading alone. Pretreatment with nicotine suppressed the sympathetic activity induced by immobilization stress to the same extent as that observed after administering nicotine alone. Thus, these results appeared to support our hypothesis.

Genetic Variation in the β3-Adrenergic Receptor in Japanese NIDDM Patients

areas as well, including retroperitoneal and subcutaneous abdominal fat (3), and these properties may be the major determinants of the pathophysiological processes related to increased central adiposity, rather than site itself. CT and MRI are not considered ideal for larger scale investigations or routine screening because of costs, radiation, and availability. However, in small studies there is a weak relationship between anthropometric measures and intraabdominal fat, or insulin resistance, despite significant correlations between waist-to-hip ratio and cardiovascular morbidity and mortality in population studies (4). Using Dual Photon Xray Absorptiometry (DEXA, Lunar DPX-Lunar Radiation Corp., Madison, WI) for measurement of central abdominal fat, we found a strong correlation with hyperinsulinemic-euglycemic clamp-measured insulin sensitivity in women at both high and low risk of diabetes (5), as reported between CT-measured intra-abdominal fat and insulin sensitivity in young men (6). Correlation of insulin sensitivity with abdominal fat was significantly better than with other fat areas, including trunk and total fat (5). DEXA accurately assesses actual fat content of heterogeneous soft tissue and has been validated against other body fatness measures (7). DEXA abdominal fat measurement correlates well with assessment by CT, accounting for 80% of the variation in intra-abdominal fat by CT in postmenopausal women (8), and DEXAmeasured total abdominal fat does not differ significantly from CT (9). We use a window (Fig. 1) from upper L2 vertebra to lower L4 (where the ratio of subcutaneous fat to intra-abdominal fat is least) (10) drawn to exclude subcutaneous fat lateral to the inner costal margins (5). This window has good reproducibility (CV -5%) and excludes 3 0 % subcutaneous fat (crosschecked by MRI, D.G.C., L.V.C., D.J.C., unpublished data). The issue of which abdominal fat domain (if any) is the greatest contributor to the pathophysiological consequences of central adiposity remains unresolved. Further research will clarify the complex interactions of the bodys fat-containing tissues, which are proving to be much more than inert storage depots. Meanwhile, while not yet proposing it for routine clinical use, we recommend DEXA measurement of regional fat as a lowFigure 1—The DEXA areas of fat with the abdominal fat window as marked between 12 and IA and the inner costal margins. • , leg fat; H, arm fat; M, trunk fat; • , central abdominal fat.

Anti-obesity and anti-diabetic effects of mazindol in yellow KK mice: its activating effect on brown adipose tissue thermogenesis.

1. The anti‐obesity and anti‐diabetic effects of mazindol were evaluated in obese diabetic yellow KK mice and C57B1 control mice.

Effect of CL316,243, a highly specific β3-adrenoceptor agonist, on sympathetic nervous system activity in mice

To examine whether long-term administration of a beta3-adrenoceptor agonist influences sympathetic nervous system (SNS) activity, norepinephrine (NE) turnover, a reliable indicator of SNS activity, in the interscapular brown adipose tissue (IBAT), the heart, and the spleen, as well as urinary excretion of NE, were measured using mice treated with CL316,243 (CL), a highly specific beta3-adrenoceptor agonist, at a dose that stimulated thermogenesis and reduced body weight. CL significantly decreased NE turnover in the IBAT, heart, and spleen and decreased urinary excretion of NE without affecting food intake over 1 to 4 weeks of treatment. These findings show that long-term administration of the beta3-adrenoceptor agonist decreases SNS activity and urinary excretion of NE.

A case of Sheehan's syndrome with delirium

Abstract A 53 year old woman was brought to a psychiatric clinic because of delirium. Upon immediate examination, severe hyponatremia (105 mEq/L) was detected. She was suspected of having internal diseases and referred to our university hospital. When she reached our hospital she was delirious and showed excitement and agitation. Her electroencephalogram showed low voltage θ waves (20 μV) in all leads. She was hospitalized and diagnosed with acute tonsillar abscess and panhypopituitarism based on various endocrine tests. Her past history suggested that Sheehans syndrome had developed after child‐bearing at age 31, resulting in panhypopituitarism. After administration of antibiotics, the fever and tonsillar abscess gradually recovered, and the correction of electrolytes improved the level of consciousness, suggesting that the hyponatremia had been closely related to the clouding of consciousness. As the subsequent administration of Cortisol kept the patients serum sodium levels within the normal range, a decrease in plasma Cortisol seemed to be the major cause of the hyponatremia. Psychological symptoms of panhypopituitarism often included abulia, apathy and occasionally coma. However, it is rare for a patient with panhypopituitarism to be misdiagnosed as having a psychiatric disease with delirium. This rare case is presented.

Effects of nicotine on norepinephrine turnover of mice subjected to emotional stress

We tested the hypothesis that nicotine suppresses the emotional and the electrical stress induced by the communication box. We measured the turnover of norepinephrine (NE), a reliable indicator of the sympathetic nervous system activity, in the brown adipose tissue (BAT) and the heart of mice that induced the electrical stress and the emotional stress by the communication box for 2 weeks, of mice treated with the same procedure 10 min after the subcutaneous injections of nicotine, and of mice treated with nicotine injections alone, vs. untreated controls. The results showed that NE turnover in BAT increased most significantly in the animals subjected to electrical stress, followed by those subjected to emotional stress, and then by those administered with nicotine alone, when compared with the control group. Pretreatment with nicotine suppressed the enhancement of NE turnover in both electrical and emotional stress. The sympathetic nervous system activity in the heart was almost the same result as the data of BAT. These results support our hypothesis that nicotine suppresses the enhancement of the emotional and the electrical stresses induced by the communication box in mice.

Effect of ultrasonic stimulation on mRNA abundance of uncoupling protein (UCP) 2 and UCP 3 in gastrocnemius muscle of rats

1. The hypothesis that ultrasonic stimulation upregulates uncoupling protein (UCP) 2 and UCP3 in gastrocnemius muscle by a different mechanism of exercise was investigated in Wister rats.