Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP's pancreatic function in vivo, we generated transgenic mice overexpressing PACAP in the pancreas under the control of human insulin promoter. Northern blot and immunohistochemical analyses showed that PACAP is overexpressed in pancreatic islets, specifically in transgenic mice. Plasma glucose and glucagon levels during a glucose tolerance test were not different between PACAP transgenic mice and nontransgenic littermates. However, plasma insulin levels in transgenic mice were higher after glucose loading. Also, increases of streptozotocin-induced plasma glucose were attenuated in transgenic compared with nontransgenic mice. Notably, an increase in 5-bromo-2-deoxyuridine-positive ␤-cells in the streptozotocin-treated transgenic mice was observed but without differences in the staining patterns by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Morphometric analysis revealed that total islet mass tends to increase in 12-month-old transgenic mice but showed no difference between 12-weekold transgenic and nontransgenic littermates. This is the first time that PACAP has been observed to play an important role in the proliferation of ␤-cells. Diabetes

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an intraislet neuropeptide and shares insulinotropic and insulinsensitizing properties with glucagon-like peptide-1 (GLP-1); however, the pathophysiological significance of PACAP in diabetes remains largely unknown. To assess this, we crossed our recently developed transgenic mice overexpressing PACAP in pancreatic ␤-cells (Tg/ϩ), with lethal yellow agouti (KKA y ) mice (A y /ϩ), a genetic model for obesity-diabetes, and examined the metabolic and morphological phenotypes of F 1 animals. Tg/ϩ mice with the A y allele (Tg/ϩ:A y /ϩ) developed maturity-onset obesity and diabetes associated with hyperglycemia, hyperlipidemia, and hyperphagia, similar to those of A y /ϩ mice, but hyperinsulinemia was significantly ameliorated in Tg/ϩ:A y /ϩ mice. Although A y /ϩ mice exhibited a marked increase in islet mass resulting from hyperplasia and hypertrophy, this increase was significantly attenuated in Tg/ϩ:A y /ϩ mice. Size frequency distribution analysis revealed that the very large islets comprising one-fourth of islets of A y /ϩ mice were selectively reduced in Tg/ϩ:A y /ϩ mice. Because functional defects have been demonstrated in the large islets of obese animal models, together these findings suggest that PACAP regulates hyperinsulinemia and the abnormal increase in islet mass that occurs during the diabetic process.PACAP, which exists in two molecular forms, either with 27 (PACAP27) or 38 (PACAP38) amino acid residues, belongs to the vasoactive intestinal polypeptide/secretin/glucagon superfamily (Arimura, 1998;Vaudry et al., 2000). Some members of this group, such as the gastrointestinal hormones glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide, stimulate ␤-cell growth, differentiation, and cell survival, in addition to their well documented nutrient-stimulated secretion of insulin (so-called "incretin effect") (Kieffer and Habener, 1999;Pospisilik et al., 2003). GLP-1 and glucose-dependent insulinotropic polypeptide are secreted postprandially from the L-cells of the lower small intestine and from the K-cells of the upper small intestine, respectively, and released into the circulatory system. In comparison, PACAP is a neuropeptide in pancreatic islets, where it may act as a parasympathetic and sensory neurotransmitter, and stimulate secretion of insulin in a glucosedependent manner (Kieffer and Habener, 1999;Sherwood et al., 2000;Filipsson et al., 2001). In addition, PACAP has been shown to be expressed in islet ␤-cells (Yada et al., 1997;Portela-Gomes et al., 2003). PACAP stimulates insulin secretion from insulin-secreting ␤-cell lines (Klinteberg et al., 1996;Straub and Sharp, 1996), isolated pancreas (Yokota et al., 1993;Yada et al., 1994;Bertrand et al., 1996), and intact animals (Fridolf et al., 1992). There is recent evidence to suggest that PACAP exerts not only insulinotropic effects but also insulin-sensitizing properties like GLP-1. Yada et al. (2000) showed that intraperitoneal administration of PACAP...

Glucose is a major energy source consumed by proliferating mammalian cells. Therefore, in general, proliferating cells have the preference of high glucose contents in extracellular environment. Here, we showed that high glucose concentrations impede the proliferation of satellite cells, which are muscle-specific stem cells, under adherent culture conditions. We found that the proliferation activity of satellite cells was higher in glucose-free DMEM growth medium (low-glucose medium with a glucose concentration of 2 mM) than in standard glucose DMEM (high-glucose medium with a glucose concentration of 19 mM). Satellite cells cultured in the high-glucose medium showed a decreased population of reserve cells, identified by staining for Pax7 expression, suggesting that glucose concentration affects cell fate determination. In conclusion, glucose is a factor that decides the cell fate of skeletal muscle-specific stem cells. Due to this unique feature of satellite cells, hyperglycemia may negatively affect the regenerative capability of skeletal muscle myofibers and thus facilitate sarcopenia.

The Shimokita Peninsula in Aomori Prefecture, Japan, which is inhabited by Japanese monkeys (Macaca fuscata), is the northernmost habitat for wild primates in the world. This study was the first to determine the conception dates of specific individuals and estimate the pregnancy rate of wild populations in this region. The pregnancy rate of animals aged 5 years or more at delivery was estimated to be 40.9% (27/66). Conception dates of each fetus were also estimated using a regression line of Pig-tail monkeys (Macaca nemestrina), which are taxonomically related to Japanese monkeys and have a similar physique. The conception dates were distributed across 90 days between September 24th and December 23rd, with a mean conception date of November 4th (SD = 22.3 days, n = 53).Using these findings, the mean birth date was estimated as April 25th, more than two weeks earlier than the mean birth date in previous research determined using direct observations carried out over the past 20 years ago. Global warming due to climate change is thought to be one of the main causes of this difference.