Kozo Shimakawa

Overexpression of GPR40 in Pancreatic β-Cells Augments Glucose-Stimulated Insulin Secretion and Improves Glucose Tolerance in Normal and Diabetic Mice

OBJECTIVE GPR40 is a G protein–coupled receptor regulating free fatty acid–induced insulin secretion. We generated transgenic mice overexpressing the hGPR40 gene under control of the mouse insulin II promoter and used them to examine the role of GPR40 in the regulation of insulin secretion and glucose homeostasis. RESEARCH DESIGN AND METHODS Normal (C57BL/6J) and diabetic (KK) mice overexpressing the hGPR40 gene under control of the insulin II promoter were generated, and their glucose metabolism and islet function were analyzed. RESULTS In comparison with nontransgenic littermates, hGPR40 transgenic mice exhibited improved oral glucose tolerance with an increase in insulin secretion. Although islet morphologic analysis showed no obvious differences between hGPR40 transgenic and nontransgenic mice, isolated islets from hGPR40 transgenic mice had enhanced insulin secretion in response to high glucose (16 mmol/l) compared with those from nontransgenic mice, and they both had similar low glucose (3 mmol/l)-stimulated insulin secretion. In addition, hGPR40 transgenic islets significantly increased insulin secretion against a naturally occurring agonist palmitate in the presence of 11 mmol/l glucose. hGPR40 transgenic mice were also found to be resistant to high-fat diet–induced glucose intolerance, and hGPR40 transgenic mice harboring KK background showed augmented insulin secretion and improved oral glucose tolerance compared with nontransgenic littermates. CONCLUSIONS Our results suggest that GPR40 may have a role in regulating glucose-stimulated insulin secretion and plasma glucose levels in vivo and that pharmacological activation of GPR40 may provide a novel insulin secretagogue beneficial for the treatment of type 2 diabetes.

MANAGEMENT AND DESIGN OF THE MAINTENANCE OF SAM MOUSE STRAINS : AN ANIMAL MODEL FOR ACCELERATED SENESCENCE AND AGE-ASSOCIATED DISORDERS

The Senescence-Accelerated Mouse (SAM) was established by inbreeding and pedigree selection based on the life span, degree of senescence, as well as the incidence and degree of several age-associated disorders. At first, SAM strains were developed under conventional conditions, but now some strains are also maintained under specific pathogen-free conditions. There are many methods used to maintain such strains of mice; our methods will be introduced as one example of how to develop and maintain strains of mice used in aging research.

Characterization of transgenic rats constitutively expressing vitamin D-24-hydroxylase gene.

Vitamin D-24-hydroxylase (CYP24) is one of the enzymes responsible for vitamin D metabolism. CYP24 catalyzes the conversion of 25-hydroxyvitamin D(3) [25(OH)D(3)] to 24,25-dihydroxyvitamin D(3) [24,25(OH)(2)D(3)] in the kidney. CYP24 is also involved in the breakdown of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the active form of vitamin D(3). In this study, we generated transgenic (Tg) rats constitutively expressing CYP24 gene to investigate the biological role of CYP24 in vivo. Surprisingly, the Tg rats showed a significantly low level of plasma 24,25(OH)(2)D(3). Furthermore, the Tg rats developed albuminuria and hyperlipidemia shortly after weaning. The plasma lipid profile revealed that all lipoprotein fractions were elevated in the Tg rats. Also, the Tg rats showed atherosclerotic lesions in the aorta, which greatly progressed with high-fat and high-cholesterol feeding. These unexpected results suggest that CYP24 is involved in functions other than the regulation of vitamin D metabolism.

The antiobesity action of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124)

The antiobesity effects of (S)-(+)-1-(4-chlorophenylthiomethyl)-N-methylethylamine fumarate (AO-124) were examined in rats and dogs. AO-124 suppressed food intake dose dependently in normal, Zucker fatty and VMH-obese rats, and beagle dogs. Its anorectic activity was not altered by pretreatment with methysergide, a serotonin receptor blocker. AO-124 also reduced the hyperphagia induced by 2-deoxy-D-glucose but not that induced by insulin, noradrenaline or muscimol, suggesting that the anoretic mechanism of AO-124 may be implicated in a glucostatic regulatory system of feeding. In addition, AO-124 decreased insulin secretion in response to an oral, but not an intravenous, glucose load. Such a suppression in insulin secretion may be explained by slow absorption of glucose from the intestine: AO-124 delayed the gastric emptying time of glucose and inhibited the active transport of glucose as observed in the everted small intestine. Two week administration of AO-124 to Zucker fatty rats resulted in a significant reduction of plasma insulin levels, body weight gain, and body lipid without exerting any changes in body protein. These findings indicate that AO-124 may be useful as an antibesity agent on the basis of its unique mechanisms of action.