Shigehisa Taketomi

Effects of 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, Ciglitazone) on glucose and lipid metabolism were examined in various animal models. ADD-3878, administered as a dietary admixture (30–186 mg/kg/day) to obese-diabetic yellow KK (KK-Ay) mice, markedly suppressed the diabetic syndromes (hyperglycemie, hypertriglyceride-mia, and hyperinsulinemia), accompanied by the reduction of insulin resistance as manifested by improvement of overall insulin sensitivity in either the insulin tolerance test òr the steady-state blood glucose test. Chronic administration of ADD-3878 for as long as 12 wk to young yellow KK mice, which were in the early stage of diabetes and obesity, depressed age-dependent rises in blood glucose, plasma triglyceride, and insulin without exerting any effect on obesity. When orally administered to obese Zucker-fatty rats, ADD-3878 decreased plasma insulin and triglyceride in a dose-dependent manner (5–100 mg/kg/day). The treated rats showed increased tolerance and decreased insulin secretion in response to oral glucose. The glycemie response to insulin and the steady-state plasma glucose were also normalized in the treated rats. Chronic administration of ADD-3878 to young fatty rats for as long as 12 wk decreased the dose-dependent rises in blood glucose, plasma triglyceride, and insulin without exerting any effect on body weight. ADD-3878 had no effect on glucose and lipid metabolism of young Sprague-Dawley rats and mild strepto-zotocin-diabetic rats. However, in old Sprague-Dawley rats that were moderately insulin resistant and hyperli-pidemic compared with young ones, ADD-3878 decreased plasma triglyceride and insulin and improved insulin sensitivity. Five-day administration of ADD-3878 to beagle dogs with slightly impaired glucose tolerance increased glucose tolerance and suppressed postprandial rises in plasma glucose, insulin, and triglyceride. Based on these results, ADD-3878 is effective on abnormal glucose and lipid metabolism associated with insulin resistance or obesity through reduction of peripheral insulin resistance. Therefore, ADD-3878 is expected to be useful in the treatment of hyperglycemie, hyperinsulinemia, and hyperlipemia in obese type II diabetes and Obesity.

Intravenous administration of human basic fibroblast growth factor (bFGF) for 2 weeks stimulated osteoblast proliferation and new bone formation in various skeletal bones in young and aged rats at dosage levels of 0.1 mg/kg/day and greater. Morphometry of the soft X-ray radiograms of cross sections of the tibia indicated about a 20% increase in the calcified bone area of the diaphysis at 0.1 mg/kg/day. The Ca and hydroxyproline contents showed statistically significant increases at this dosage. The new bone formation was found only on the endosteal side, and no periosteal bone formation was found. Similar systemic osteogenic potential was seen after intravenous administration of other growth factors of the FGF family, human acidic FGF and human heparin-binding secretory transforming protein-1. The above results suggest a potential therapeutic role for these growth factors in bone-loss diseases such as osteoporosis.

Advanced glycation end products (AGE) are formed in long-lived matrix proteins by a nonenzymatic reaction with sugar. The presence of AGE in beta 2-microglobulin-amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits, was recently demonstrated. This suggested a potential link of AGE in bone resorption and initiated this investigation of whether AGE enhance bone resorption. When mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, both AGE-modified beta 2-microglobulin and BSA increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts of those modified with the early glycation products did not. AGE proteins, however, did not increase the number of newly formed osteoclasts, even in the coculture of mouse bone marrow cells with osteoblastic cells isolated from mouse calvaria. Enhanced bone resorption was also observed when unfractionated bone cells were cultured on AGE-modified dentin slices. AGE-enhanced bone resorption was effectively inhibited by calcitonin and ipriflavone, both of which are inhibitors of bone resorption. AGE-enhanced bone resorption was further supported by in vivo evidence that rat bone particles-upon incubation with glucose for 60 days (AGE-bone particles)-when implanted subcutaneously in rats, were resorbed to a much greater extent than control bone particles upon parallel incubation without glucose. These findings suggest that AGE enhance osteoclast-induced bone resorption. Although the mechanism remains unknown, AGE are unlikely to promote differentiation of osteoclast progenitors into osteoclasts, suggesting that AGE activate osteoclasts or alter microenvironments favorable for bone resorption by osteoclasts. The modification of bone matrices with AGE might play a role in the remodeling of senescent bone matrix tissues, further implicating a pathological significance of AGE in dialysis-related amyloidosis or osteoporosis associated with diabetes and aging.

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.