Recent epidemiological surveys have revealed that diabetes is a risk factor for bone fracture. The mechanism for this presumably relates to the various factors associated with diabetics (e.g., insulin deficiency or resistance and/or continuous hyperglycemia). We, therefore, studied the effects of high glucose and tumor necrosis factorα(TNFα) on osteoblasts and osteoclasts; TNFα has been shown to be a key factor responsible for insulin resistance. High glucose concentrations (60 mM) did not affect alkaline phosphatase (ALP) activity in mouse primary osteoblasts (OBs), whereas TNFα decreased ALP activity. Treatment of OBs with TNFα showed an increased number of apoptotic cells. When mouse OBs and bone marrow cells were cultured in the presence of PGE₂ and 1,25(OH) ₂D₃, osteoclasts (OCs) were formed under high glucose concentrations (5.6-60 mM), while TNFα inhibited OC formation in the co-cultures. When mature OCs were studied with respect to bone resorbing function, it was found that bone resorption was inhibited by exposure to high glucose (15-60 mM). TNFα also inhibited bone resorbing capacity. The effects of decreased bone resorption were, at least partly, due to the deranged actin ring formation of OCs. Although OC formation and function was modified, these agents did not influence the expression of receptor activator of nuclear factor κB ligand and osteoprotegerin in OBs nor the expression of receptor activator of nuclear factor κB in OC progenitors. These results indicate that the functions of OBs and OCs could be modified to some extent by TNFα, together with high glucose. This study also supports our recent observation that rats with type 2 diabetes showed low turnover of bone, which resulted in deranged mechanical properties of bone.

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 Both uncoupling proteins, UCP2 and UCP3, show high homologies to UCP1, a mitochondrial carrier protein, which has been shown to play a role in the regulation of energy metabolism. UCP3 gene is expressed abundantly in the skeletal muscles while UCP2 gene is expressed in the white adipose cells in various tissues of the body. Based on their homologies to UCP1, UCP2 and UCP3 are believed to be involved in the regulation of energy balance. In this paper, we examined whether the expression of UCP2 and UCP3 is affected in obese and hyperglycemic mice, since obesity is associated with disturbed energy and glucose metabolism. We generated obese and hyperglycemic mice by using gold thioglucose (GTG) at the age of 6 weeks. Body weight were significantly increased at the age of 11, 16 and 26 weeks in GTG mice in comparison with control mice. Plasma glucose and insulin levels of GTG mice at the age of 11 weeks increased more than those of control mice. Pancreatic beta cell mass also increased significantly in GTG mice at the age of 16 weeks. We found that UCP2 mRNA levels in skeletal muscle of GTG mice were higher than those of control mice by 5.2-fold (16 weeks) and 2.9-fold (26 weeks), respectively. We also found that UCP3 mRNA levels in the skeltal muscle of GTG mice were higher than those of control mice by 2.7-fold (16 weeks) and 2.3-fold (26 weeks), respecively. Thus, the present study supports the concept that UCP2 and UCP3 may profoundly contribute to improvement of obesity and glucose metabolism in GTG induced obese mice via thrifty effects on heat production.

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  α-isoproterenol was administrated to study its effect on the soleus and tibialis anterior muscles after sciatic nerve crush injury.
  ICR mice were divided into 3 groups; nerve crush injury (NC group), α-isoproterenol administration after nerve crush injury (NC・IPR group) and control (CNT group). At three weeks following crush injury, soleus and tibialis anterior muscles were sampled for light and electron microscopic observation. Irregular banding pattern of myofilaments was seen in NC group. Administration of α-isoproterenol induced prevention of muscular atrophy in all muscles in NC group. Notably, the size of cross-sectional area in the red muscle dominant soleus muscle in NC・IPR group was significantly larger than that in NC group. However, there was no significant difference in the white muscle dominant tibialis anterior muscle. The result suggested a substantial effect of α-isoproterenol on red muscles in prevention of muscular atrophy after nerve crush injury.
  Investigated also was the influence of α-isoproterenol on the submandibular gland in Wistar rats in addition to the same mice as above. Electron density of secretory granules in the granular duct cells differed between α-isoproterenol administrated group and control group. Whereas control group showed many secretory granules equally with high electron density, α-isoproterenol administrated group showed variability in electron density among secretory granules with reduction in the number of secretory granules with high electron density. GS-II displayed little reactivity in secretory granules of the granular duct in both groups, while WGA induced intensive effect in the granules with high electron density in the both groups. These results indicated that lectin staining in the granular ducts derived from sialic acid within the electron-dense granules. Hypertrophy of acinar cells of the submandibular gland was observed in both species. The rat acinar cells developed peculiar lamellar inclusions in the secretory granules, which exhibited WGA reactivity.
  In the application of α-isoproterenol for prevention muscular atrophy, one should be consider its side effects on the submandibular gland as observed in the present study.

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 We investigated the effects of various concentrations of halothane (0.2, 0.5 and 1.0%) on the excitation and inhibition of dorsal horn wide dynamic range (WDR) neuronal activity induced by bradykinin (BK) in spinal cordtransected cat. Extracellular activity was recorded from a single WDR neuron in the dorsal horn when noxious and non-noxious stimuli were applied to the cutaneous receptive fields on the left hind paw footpads of decerebrate, and spinal cord-transected (L_1-2) cats. Injection of 10 μg of BK (used as the noxious stimulus) into the femoral artery ipsilateral to the recording site resulted in excitatory response in 13 of 13 (100%) WDR neurons. On the other hand, when the same dose of BK was injected into the femoral artery contralateral to the recording site, 7 of 13 (54%) WDR neurons showed inhibitory responses and 6 showed no response. Halothane at 1.0% concentration, but not at lower concentrations (0.2 or 0.5%) significantly depressed the excitatory neuronal activity recorded in WDR neurons. Furthermore, halothane at 0.2, 0.5 and 1.0% significantly depressed the inhibitory neuronal activity in WDR neurons. Our results indicated that halothane reduces the excitation as well as inhibition of dorsal horn WDR neuronal activity induced by BK injection, suggesting that this anesthetic agent reduces the excitatory and inhibitory responses produced by noxious stimuli at spinal cord level.

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