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Nearly nine years ago, new mechanism that bone secretes a hormone called osteocalcin and regulates glucose/energy metabolism was discovered. To date the study of osteocalcin as the bone hormone was progressed well, and the new roles in various tissues, such as glucose metabolism, male fertility, and development of the brain, are demonstrated. On the other hand, signaling pathway of osteocalcin has not yet been fully understood, though its receptor was reported. This review focuses on the diverse roles of osteocalcin and also on the future task that should be solved.

Gender-difference is thought to be an important factor in the pathogenesis of glucose metabolism. Imbalances in sex hormones, such as increasing levels of progesterone or testosterone, are associated with systemic insulin resistance. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. On the other hand, insulin resistance caused excess secretion of androgen, leading to menstrual disorder in obese young female. For the better management of glucose intolerance in pregnancy, the diagnostic criteria for gestational diabetes was revised in Japan. Although glucose intolerance in pregnancy is usually recovered after delivery, the subjects who diagnosed gestational diabetes need to be followed for an early detection of type 2 diabetes development. In addition, gender-differences in living practice and attitude are related to their lifestyle, including diet and exercise, therefore, gender-specific medicine increasingly plays key roles in the treatment of diabetes.

Insomnia disorder is one of the most prevalent conditions comorbid with diabetes and has been shown to have a possible role in the development of diabetes. Insomnia is characterized by a state of excessive physiological and cognitive arousal with alterations in autonomic and hypothalamic-pituitary-adrenal function. The chronic neuroendocrine activation in insomnia may predispose insomniacs to the development of metabolic disorders including glucose intolerance. In contrast, diabetic complications, in combination with the disruption of a sleep-wake homeostatic and circadian process, can be key factors precipitating insomnia symptoms and involve several subtypes of insomnia. Furthermore, inappropriate lifestyles are also likely responsible for the exacerbation of insomnia and diabetes. Thus, the pathogenesis of insomnia disorder and diabetes could mutually interact to develop each disease with a vicious cycle, accounting for the high comorbidity between the diseases.

Cyclodextrins (CyDs) are cyclic oligosaccharides composed of 6, 7, or 8 glucopyranoside units, named α-, β-, or γ-CD, respectively. CyDs consist of a hydrophobic cavity in which hydrophobic molecules are encapsulated to form an inclusion complex. CyDs are widely used in pharmaceutical applications because they function as nanocapsules to improve the stability and solubility of drugs. Recently, CyDs have attracted much attention as for use as components of supramolecular nanostructures that are particularly attractive because of their unique structures. We modified CyDs with phenylboronic acid (PBA), which forms covalent bonds with the diol groups of sugar, and used the resulting PBA-CyDs to prepare supramolecular nanomachines that undergo structural transformation in the presence of a chemical signal in the form of a sugar. PBA-α-CyD formed a supramolecular polymer that showed consecutive intermolecular interactions between PBA and the cavity of another PBA-α-CyD, whereas PBA-β-CyD formed head-to-head dimers in which one PBA moiety was encapsulated in the other. These supramolecular nanostructures disintegrated in the presence of sugars because of the structural change in the PBA moiety and loss of the driving force of the supramolecular assembly. These features of disintegration can be potentially used to prepare a nanomachine that would act as a sugar-responsive insulin release system. Currently, we are studying sugar-responsive nanomachines composed of PEGylated insulin and PBA-γ-CyD.

It is reported that shortage of oral magnesium intake increase the incidence of diabetes. In addition, magnesium replacement therapy improves insulin resistance and glycemic control. Low levels of magnesium in the venous blood induce the disturbances of auto-phosphylation on the insulin receptor and deteriorate insulin resistance. Since magnesium is closely related to evolution and development of metabolic syndrome including diabetes mellitus and so on, magnesium is expected as potentially effective ingredient of drug therapy in the future perspectives.

Number of diabetic patients has continued to increase in the world, disturbance of sleep habits have been pointed out as one of the factor recently. Sleep habits are categorized into quantity and quality of sleep. Inappropriate sleep duration and decline in quality of sleep have caused the exacerbation and onset of diabetes. On the other hand, it is known that many patients with diabetes have already suffered from sleep disorders. Here, we will give an outline of the relationship between sleep habits and diabetes.

It has been recognized that chromium is an essential trace element associated with carbohydrate metabolism, and chromium deficiency causes an impaired glucose tolerance. Recently, however, Vincent et al. have reported that chromium is not an essential trace element. In the present report, the author evaluated the nutritional essentiality of chromium by reviewing several previous reports. In almost all previous reports, the chromium concentration in the animal feed used was higher than 0.1 μg/g, and it is difficult to consider that the experimental animals were in a low-chromium state. In addition, the amount of chromium administered to the animals for the improvement of glucose tolerance was at a pharmacological level, and corresponded to a level that far exceeded the human daily chromium intake (20 to 80 μg/day). On the other hand, recent research has clearly shown that feeding with a severely low-chromium diet (0.016 μg/g) does not impair glucose tolerance. The amount of chromium absorbed in humans estimated from chromium intake (20 to 80 μg/day), chromium absorption rate (1%), and urinary chromium excretion (<1 μg/day) is less than 1 μg/day, which is much lower than those of other essential trace elements. In addition, because there is an inconsistency between the chromium concentration in food and chromium intake, chromium intake seems to be dependent on chromium contamination during food processing and cooking. It is concluded that there is a high possibility that chromium is not an essential trace element.

Preoperative oral hydration is an important component of "enhanced recovery after surgery" strategies. This was originally developed for patients undergoing colon surgery. The Obstetric Anesthesia Practice Guideline issued by American Society of Anesthesiologists states that intake of minimum amount of clear fluid 2 hours prior to surgery may be safe. However, anesthesiologists have to consider physiological changes that parturients undergo during pregnancy, such as increased risk of aspiration and impaired glucose tolerance. We also have to consider the potential effect of glucose loading on neonates. Mothers are more likely to develop ketosis by glucose loading. It also stimulates insulin release in the fetus, which can result in neonatal hypoglycemia. In addition, sodium overloading may deteriorate intra-vascular dehydration and cause lung edema to mothers. On the other hand, oral hydration can alleviate a sense of thirst and increase maternal satisfaction. Our data showed that maternal urinal ketone body at delivery tended to decrease with oral hydration during labor. Moreover, some articles suggest that oral hydration may improve utero-placental perfusion. Therefore, we have to balance risks and benefits of oral hydration in parturients. Further investigations are needed among this specific subgroup of patients in order to establish the safe application of preoperative oral hydration.

It is well known that insulin plays an important role in bone metabolism. In addition, resent reports have demonstrated that adipocytokine and peroxisome proliferator-activated receptors (PPARs) , which are involved in insulin resistance, dramatically affect bone metabolism. In particular, Food and Drug Administration of the United States Department of Health and Human Service (FDA) noted that rosiglitazone and pioglitazone, PPAR gamma agonists, have an increased risk of bone fractures. This review focuses on the relationship between molecules involved in insulin resistance and bone metabolism.

Trastuzumab is a recombinant humanized monoclonal antibody directed against the human epidermal growth factor receptor 2(HER2). ADCC is considered to be a major mechanism of anti-tumor effect of trastuzumab. The difference in subtype and gene polymorphism of Fcgamma receptor of effecter cells causes difference in affinity to Fc fragment of antibody and in ADCC activity. Consequently, it may cause the difference of trastuzumab treatment efficacy. These findings suggest the importance of gene polymorphism in strategy of new therapeutic antibody development and predict of treatment efficacy.

Bone mineral metabolism and bone remodeling involve a variety of molecules, for instance, bone morphogenetic proteins (BMPs) , fibroblast growth factors (FGFs) , insulin growth factors (IGFs) , interleukin-1 (IL-1) , prostagrandin E(2) (PGE(2)) , and tumor necrosis factor-alpha (TNF-alpha) . Most of them are also involved in lipid and glucose metabolism. Recent in vitro and in vivo studies have reported that therapeutic agents for diabetes and hyperlipidemia, such as insulin, thiazolidinediones, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have pleiotropic effects on bone mineral metabolism. These agents may be useful tools for treatment of bone and mineral disorders.

Two adiponectin receptors were recently identified, AdipoR1 and R2. AdipoR1 expression was increased approximately 2.5-fold in muscle tissues from insulin-deficient diabetic mice, but normalized with insulin administration. AdipoR1 expression was decreased by 44% in insulin-resistant obese, as compared to lean, mice. These results indicate AdipoR1 expression to correlate inversely with plasma insulin levels. Insulin treatment for 24 h decreased AdipoR1 expression by approximately 60% in C2C12 myocytes. In addition, this effect was mediated by the phosphatidylinositol-3 kinase/Foxo 1 dependent pathway. In contrast, AdipoR2 expression was not significantly altered in diabetic states. Our results indicate that regulation of AdipoR1, but not AdipoR2, may be involved in glucose and lipid metabolism in diabetic states.

Chronic fatigue occurring in previously healthy children and adolescents is a vexing problem encountered by pediatric practitioners and the impact of fatigue in youngsters should not be underestimated. In its severe form, it is often associated with mood disorders. Findings in children and adolescent cases suggest that severe unexplained fatigue might precede the development of fatigue-related illness, such as childhood chronic fatigue syndrome (CCFS). This is a disabling condition characterized by severe disabling fatigue and a combination of symptoms, the prominent features being self-reported impairments in concentration and short-term memory, sleep disturbances and autonomic symptoms that cannot be explained by medical or psychiatric illness. We have encountered such patients with these complaints; their major symptoms include: general fatigue, fever, headache (not migraine), and memory disturbance. From our clinical experience, we have inferred that patients with CCFS might experience changes in brain function levels, which induce an autonomic imbalance and engender symptoms such as general fatigue, higher-order level cognitive dysfunction, and memory disturbance.

Nonalcoholic fatty liver disease(NAFLD) is recognized as a cause of potentially progressive liver damage. NAFLD is often associated with metabolic syndrome that comprises central obesity, insulin resistance, and hyperlipidemia. Among these, severer forms with histopathological features of increasing ballooned hepatocytes and fibrosis are defined as nonalcoholic steatohepatitis (NASH). The natural history of NASH is only partly known, the disease is slowly progressive and therapeutic outcomes are difficult to define. Since central obesity and insulin resistance are most likely involved in the pathogenesis, justification of life style including physical exercise and nutritional counseling is essential for the treatment of NASH.

When the numbers of mutations per 1,000 bases of mitochondrial DNA were compared among three groups of Al-Hep, NASH and FL, there were significantly more mutations in ND1 and COII of Al-Hep and NASH than in FL. When details of the base mutation were investigated by group, the transition type of mutation between T:A and C:G occurred in control and coding regions. In FLS and FLS-ob mice, mutations in the D-loop and coding regions of mitochondrial DNA were investigated by sequencing analysis. The average number of mutations per clone in each region was more than 5-fold higher in FLS-ob than in FLS. In addition, the mutations were mostly transition-type mutations. These data indicate that nitric oxide plays an important role in mitochondrial DNA mutations.

Acute pancreatitis has been reported in several studies to increase the catabolism and proteolysis of skeletal muscle in comparison with normal controls. Decreased levels of total plasma proteins and rapid turnover proteins and a marked decrease of the ratio of branched-chain to aromatic amino acid further characterize the hypercatabolic state. Significant decreases in plasma essential amino acids, with marked reductions of almost all amino acids in the liver and increased uptake of endogenous amino acids by the skeletal muscle mass, have been reported clinically and experimentally. Gluconeogenesis increases, and glucose clearance and oxidation diminish, leading to glucose intolerance in 40% to 90% of cases. As a consequence, insulin canbe required in as many as 81% of patients.

Living bodies may experience oxidative stress induced by reactive oxygen species and heavy metal ions, which may damage components in the body and cause aging and disorders. In addition to the known defense systems against oxidative damage, the author describes new defense systems. Lipid peroxidation in living bodies, which has hitherto been thought to increase oxidative damage, was found to attenuate oxidative stress-induced DNA damage. Red blood cells become senescent due to oxidative stress during circulation, where membrane band 3 becomes aggregated to anti-band 3 IgG and macrophages attached through poly-N-acetyllactosaminyl sugar chains, and the sugar chain attachment to macrophages is stimulated by oxidative stress in macrophages. Oxidized protein hydrolase that preferentially hydrolyzes proteins damaged by oxidative stress was newly discovered, which may play an important role in saving cells from oxidative damage.

The worldwide epidemic of type 2 diabetes and impaired glucose tolerance is a crucial health problem. Since disorder of carbohydrate metabolism causes arteriosclerosis in combination with other metabolic abnormalities such as hypertension, hyperlipidemia and obesity, it has now been recognized as one manifestation of the metabolic syndrome, a condition characterized by insulin resistance. In this article, we summarize the current our knowledge on how disorder of carbohydrate metabolism influences insulin resistance and arteriosclerosis in part of metabolic syndrome.