Effect of growth hormone on dawn phenomenon in patients with type 2 diabetes.

We aimed to investigate the involvement of growth hormone in dawn phenomenon and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). On six occasions separated by intervals of at least 3 days, subjects received early evening (16:00 hours) or late night (23:00 hours) pretreatment with subcutaneous injection of normal saline, human growth hormone, or octreotide. Modified euglycemic insulin clamp test was done 16 hours later and variable glucose infusion (M values) was determined. Plasma glucose, serum insulin, insulin-like growth factor-1, non-esterified fatty acids, and metabolic clearance rate of insulin (MCRI) were measured. Early evening application of growth hormone decreased MCRI 16 hours later, suggesting reduction in insulin sensitivity. Exogenous growth hormone injection reduced insulin sensitivity in T2DM patients. Results provide direct evidence for the role of growth hormone in regulating the insulin sensitivity in insulin-resistant patients.

Prunellae spica extract contains antagonists for human endothelin receptors.

Endothelin-1 (ET-1) is a powerful vasoconstrictor that contributes to blood pressure elevation. The biological effects of ETs are mediated by two receptors, namely, endothelin type A receptor (ET(A)R) and endothelin type B receptor (ET(B)R). Chinese herbal medicines (CHM) with antagonist activity for these two receptors were screened by establishing stable clones of CHO-K1 cells expressing high levels of human ET(A)R and ET(B)R, namely CHO-ET(A)R and CHO-ET(B)R.The aqueous extract of Prunellae Spica (P1) inhibited the binding of (125)I-ET-1 to ET(A)R and ET(B)R in CHO-ET(A)R and CHO-ET(B)R cells, respectively. P1 suppressed the ET-1-induced mobilization of intracellular Ca(2+) . Through the alcohol fractionation of P1, the antagonists of human ET(A)R and ET(B)R were found to belong to different, separable ingredients and the antagonist of ET(A)R is more soluble in alcohol. The two antagonists were also effective in the test on human primary cells, HASMC and HUVEC. P1 successfully prevented the development of ET-1-associated hypertension in rats without further purification. These results indicate the presence of anti-hypertensive ingredients in P. Spica extract, at least through the inactivation of ET(A)R and/or ET(B)R.

Lower intake of magnesium and dietary fiber increases the incidence of type 2 diabetes in Taiwanese.

BACKGROUND/PURPOSE: Several studies have indicated an inverse association between the incidence of diabetes mellitus and magnesium and dietary fiber intake. Few studies have examined both of these associations together, not to mention in Asian populations with prospective study design. We therefore aimed to study how dietary magnesium and fiber intake levels affect diabetes incidence separately or in combination, in a prospective study in Taiwan. METHODS: The study subjects were recruited for a longitudinal study, CardioVascular Disease risk FACtor Two-township Study cycle 2 from November 1990. Data from complete baseline information on dietary and biochemical profile and at least one additional follow-up visit were gathered on a total of 1604 healthy subjects aged 30 years and over. Cox proportional hazard model was used to study the association between diabetes incidence and dietary magnesium and fiber intake level estimated from a food frequency questionnaire. RESULTS: A total of 141 diabetes mellitus events were identified and confirmed during the 4.6 years of follow-up (7365.1 person-years). A significantly higher diabetes risk was observed for people in the lowest quintile of total dietary fiber intake (hazard ratio = 2.04; 95% CI = 1.17-3.53) and magnesium intake (hazard ratio = 2.61; 95% CI = 1.42-4.79) compared with the highest quintile after adjusting for traditional cardiovascular disease risk factors. Similar inverse associations for total dietary fiber were also shown for vegetable fiber and fruit fiber. CONCLUSION: Lower magnesium, lower total dietary fiber intake, or lower intake of both was associated with higher risk of diabetes in the Taiwanese population. Clinical trials are required to confirm the protective effects of the adequate intake of fiber, magnesium, and/or their combination.

Memory-based mismatch response to changes in duration of auditory stimuli: an MEG study.

OBJECTIVE: Differences in physical features and occurrence probability between standards and deviants in oddball paradigms provide contributions to magnetic mismatch negativity (MMNm). We aimed to reduce these influential factors and extract memory-based MMNm by adding a control paradigm. METHODS: Magnetoencephalographic responses were recorded in 13 healthy adults with an oddball paradigm (125-ms standard and 50-ms deviant tones) and an equiprobable control paradigm (50-ms control and four other duration-varying tones). The stimulus onset asynchrony was 500 ms. Controlled MMNm was obtained by subtracting control-evoked responses from deviant-evoked responses. RESULTS: With respect to the onset of stimulus difference, the peak latency of controlled MMNm was compatible with previous intracranial MMN recordings. Both controlled and traditional MMNm were generated around the superior temporal cortex, whereas the controlled MMNm amplitude was about 70% of traditional MMNm amplitude. Right-hemispheric dominance was observed in traditional MMNm but not in controlled MMNm. N100m amplitude was smaller in standard-evoked than in deviant- or control-evoked responses. CONCLUSIONS: Controlled MMNm reflects memory-based processing of duration changes, whereas traditional MMNm additionally involves non-memory activations related to differential refractoriness states and physical properties between standard and deviant stimuli. SIGNIFICANCE: The memory-based processing of auditory deviants may be preferentially extracted by adding a control paradigm.

Green tea epigallocatechin gallate inhibits insulin stimulation of adipocyte glucose uptake via the 67-kilodalton laminin receptor and AMP-activated protein kinase pathways.

Insulin and (-)-epigallocatechin gallate (EGCG) are reported to regulate obesity and fat accumulation, respectively. This study investigated the pathways involved in EGCG modulation of insulin-stimulated glucose uptake in 3T3-L1 and C3H10T1/2 adipocytes. EGCG inhibited insulin stimulation of adipocyte glucose uptake in a dose- and time-dependent manner. The concentration of EGCG that decreased insulin-stimulated glucose uptake by 50-60% was approximately 5-10 µM for a period of 2 h. At 10 µM, EGCG and gallic acid were more effective than (-)-epicatechin, (-)-epigallocatechin, and (-)-epicatechin 3-gallate. We identified the EGCG receptor [also known as the 67-kDa laminin receptor (67LR)] in fat cells and extended the findings for this study to clarify whether EGCG-induced changes in insulin-stimulated glucose uptake in adipocytes could be mediated through the 67LR. Pretreatment of adipocytes with a 67LR antibody, but not normal rabbit immunoglobulin, prevented the effects of EGCG on insulin-increased glucose uptake. This suggests that the 67LR mediates the effect of EGCG on insulin-stimulated glucose uptake in adipocytes. Moreover, pretreatment with an AMP-activated protein kinase (AMPK) inhibitor, such as compound C, but not with a glutathione (GSH) activator, such as N-acetyl-L-cysteine (NAC), blocked the antiinsulin effect of EGCG on adipocyte glucose uptake. These data suggest that EGCG exerts its anti-insulin action on adipocyte glucose uptake via the AMPK, but not the GSH, pathway. The results of this study possibly support that EGCG mediates fat content.

Theta oscillation during auditory change detection: An MEG study.

To study the phase and power characteristics of brain oscillations during the preattentive detection of auditory deviance, we recorded magnetoencephalographic responses in 10 healthy subjects with an oddball paradigm. As the subject was watching a silent movie, standard tones (1000-Hz frequency, 100-ms duration) and their duration deviants (50-ms duration, probability of 15%) were randomly delivered binaurally. In addition to localizing the magnetic counterpart of mismatch negativity (MMNm) with equivalent current dipole modeling, we also measured the phase-locking value (PLV) and power change of the oscillatory responses to standard and deviant stimuli by employing the Morlet wavelet-based analysis. The MMNm signals peaking at 150-200ms after the onset of deviant were localized in bilateral temporal regions with larger amplitudes in the right hemisphere. Then 50ms after the onset of either standard or deviant stimuli, we observed an increase of PLV and power of theta and alpha oscillations in bilateral temporal regions. PLVs of theta and alpha activities to deviant stimuli were significantly larger in the right than left hemisphere (P<0.001). Compared with standard stimuli, deviants elicited a larger theta PLV (P<0.001) at 150-300ms and a larger theta power change (P<0.05) at 50-300ms for the responses in the right temporal region. In addition, a prominent theta phase-locking of deviant-elicited responses was found in the right frontal area at 110-250ms (P<0.01). Our current data suggest that a pronounced phase and power modulation on sound-elicited theta oscillations might characterize the change detection processing in the temporo-frontal network as reflected by the mismatch negativity.

Quantification of electroacupuncture-induced neural activity by analysis of functional neural imaging with monocrystalline iron oxide nanocolloid enhancement.

The purpose of this study was to investigate the neural activity of electroacupuncture (EA) quantitatively. The responses of Sprague-Dawley rats' brain to EA on acupoints--Hegu (LI 4) and Neiguan (PC 6)--were detected by monocrystalline iron oxide nanoparticle (MION)-enhanced functional magnetic resonance imaging (MION-fMRI), which is a 1.5 T horizontal spectrometer equipped with a circular polarized extremity coil. During EA at LI 4, neural activities were analyzed by analysis of functional neural images (AFNI). Neural activation was detected at the structures of hypothalamus, thalamus, hippocampus, and the cortex, while neural deactivation existed at the areas adjacent to the activated sites. EA on PC 6 activated the structures of thalamus and the cortex but deactivated the structures of hypothalamus and hippocampus. The brain responses to EA existed in different areas of activation and deactivation despite stimulating the same acupoint. Additionally, distinct brain neuroimages were produced through stimulating different acupoints. This study suggests that fMRI with AFNI is a good approach to quantifying brain activities. This innovative method brings new perspective into the mechanisms of acupuncture.

Zinc deficiency increases platelet oxidative stress in nephrectomized rats.

We previously reported that reduced platelet endogenous antioxidant enzymes activities are related to the low plasma zinc level in patients with end-stage renal failure (ESRF). In this study, we attempt to evaluate whether dietary zinc deprivation reduces the activities of endogenous antioxidant and then enhances oxidative stress in the unstimulated platelet of normal and 5/6 nephrectomized (Nx) rats because increased platelet oxidative stress is suggested to involve in the incidence of thrombotic and atherosclerotic diseases. Male Sprague-Dawley rats (n = 48) were fed a zinc-deficient diet and deionized distilled water for 1 week to induce reduction of plasma zinc level. Half of the rats continued on this diet for 4 weeks as zinc-deplete group, and the other half were maintained on the same diet but with zinc-supplemented water (120 mg/L zinc sulfate solution) to correct the reduction of plasma zinc level as zinc-replete group. Half of each group underwent 5/6 Nx, while the other half underwent sham operation. Another 12 normal rats were fed standard rat chow (containing 23.4% protein and 50 ppm zinc) and drank deionized distilled water as normal control rats. In zinc-deplete rats including sham-operated and 5/6 Nx rats exhibited lower endogenous antioxidant enzymes activities such as reduced glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase (GPX) and higher malondialdehyde (MDA) levels than normal control rats in the unstimulated platelets. However, in zinc-replete rats including sham-operated and 5/6 Nx rats have a normal endogenous antioxidant enzymes activity and normal MDA levels in the unstimulated platelets. We suggest that in uremia, the low plasma zinc level may be a risk factor for thrombotic and atherosclerotic diseases because it reduces the activities of endogenous antioxidant enzymes and increases oxidative stress in the unstimulated platelet.

Side of the stimulated ear influences the hemispheric balance in coding tonal stimuli.

OBJECTIVE: To evaluate whether the side of stimulated ear affects the hemispheric asymmetry of auditory evoked cortical activations. METHODS: Using a whole-head neuromagnetometer, we recorded neuromagnetic approximately 100 ms responses (N100m) in 21 healthy right-handers to 100 ms 1 kHz tones delivered alternatively to left and right ear. RESULTS: Although the peak latencies of N100m were shorter in contralateral than in ipsilateral hemisphere, the difference was significant only for the left ear stimulation. Based on the relative N100m amplitudes across hemispheres, the laterality evaluation showed a rightward predominance of N100m activation to tone stimuli, but the lateralization toward the right hemisphere was more apparent by the left than by the right ear stimulation (laterality index: -0.27 versus -0.10, p=0.008). Within the right hemisphere, the N100m was 2-4 mm more posterior for left ear than for right ear stimulation. CONCLUSIONS: The hemispheric asymmetry in auditory processing depends on the side of the stimulated ear. The more anterior localization of right N100m responses to ipsilateral than to contralateral ear stimulation suggests that there might be differential neuronal populations in the right hemisphere for processing spatially different auditory inputs.

Plastic phase-locking and magnetic mismatch response to auditory deviants in temporal lobe epilepsy.

The magnetic equivalent (MMNm) of mismatch negativity may reflect auditory discrimination and sensory memory. To study whether temporal lobe epilepsy (TLE) affects automatic central auditory-change processing, we recorded magnetoencephalographic (MEG) responses to standard and duration-deviant sounds in 12 TLE patients and 12 age-matched controls, and repeated MEG measurement in 8 patients 6-30 months following epilepsy surgery and in 6 controls 3-8 months after their first measurement. We compared the MMNm between patients and controls, and also evaluated intertrial phase coherences as indexed by phase-locking factors (PLF) using wavelet-based analyses. We observed longer MMNm latencies for patients than for controls. Dipole modeling and minimum-current estimates together showed bi-frontotemporal sources for MMNm. The phase locking across trials was dominant at the 4- to 14-Hz band, and the main difference in PLF between deviant- and standard-evoked responses occurred in the time frame of 150-250 ms after stimulus onset. Notably, in the 5 patients who became seizure free after removal of right temporal epileptic focus, the phase-locking phenomena resulting from deviant stimuli were enhanced, and even more distributed in the frontotemporal regions. We conclude that mesial TLE might affect auditory-change detection, and a successful surgery causes a possible plastic change in phase locking of deviant-evoked signals.

Hemispheric balance in coding speech and non-speech sounds in Chinese participants.

To study the role of neuromagnetic auditory approximately 100-ms responses (N100m) in phonetic processing, we recorded N100m in 24 right-handed Chinese participants using a whole-head neuromagnetometer. The stimuli included vowel /a/ and consonant-vowels /ba/ and /da/, spoken by one Chinese speaker, and a 1-kHz tone. N100m to tones was larger in the right hemisphere, whereas that to speech sounds was bilaterally similar. The amplitude ratio of speech to non-speech N100m was larger in the left hemisphere. N100m dipoles in the left hemisphere were approximately 2 mm more anterior for speech than for tone stimuli. The results suggest that N100m reflects both acoustics and phonetic processing. Moreover, the ratio of speech to non-speech activation in individual hemispheres may be useful for language lateralization.

Green tea supplementation ameliorates insulin resistance and increases glucose transporter IV content in a fructose-fed rat model.

BACKGROUND: Sprague-Dawley rats fed a fructose-rich diet exhibit insulin resistance and hypertension, a pathologic status resembling human type II diabetes mellitus, and are an excellent laboratory animal model for research on insulin action and the development of hypertension. Since green tea has numerous beneficial effects, we tested its effect on fructose-fed rats. AIM: The present study was therefore designed to further evaluate the effects of green tea supplementation on insulin resistance, hypertension, and the glucose transporters I and IV contents in adipose tissue in the fructose-fed rat model. METHODS: The animals were divided into three groups and fed for 12 weeks with standard chow and water (control group), a high fructose diet and water (fructose group), or the same high fructose diet, but with green tea (0.5 g of lyophilized green tea powder dissolved in 100 mL of deionized distilled water) instead of water (fructose/green tea group). During the 12 weeks study period, fresh water or green tea was provided daily at 6:00 PM. Blood pressure was measured twice a week, and an oral glucose tolerance test performed after 12 weeks of diet supplementation. At the end of the experiment, plasma triglyceride (TG), free fatty acid (FFA), glucose, and insulin were assayed. The epididymal fat pads from all rats in the same group were pooled and adipocytes isolated and tested for insulin binding, glucose uptake, and their content of glucose transporters I (GLUT I) and IV (GLUT IV). RESULT: Compared to the control group, the fructose group developed fasting hyperglycemia, hyperinsulinemia, and elevated blood pressure. Insulin-stimulated glucose uptake and insulin binding of adipocytes were significantly reduced, and the glucose transporter IV content of adipocytes also decreased. The fructose/green tea group showed improvement in all of these metabolic defects and in insulin resistance and blood pressure. CONCLUSION: Based on these results, we suggest that the amelioration of insulin resistance by green tea is associated with the increased expression of GLUT IV.

Effect of green tea supplementation on insulin sensitivity in Sprague-Dawley rats.

Epidemiological observations and laboratory studies have shown that green tea has a variety of health effects, including antitumor, antioxidative, and hypolipidemic activities. The aim of this study was to examine whether it had an effect on glucose tolerance and insulin sensitivity in Sprague-Dawley rats. In experiment 1 (in vivo study), rats were divided into two groups: a control group fed standard chow and deionized distilled water and a "green tea" group fed the same chow diet but with green tea instead of water (0.5 g of lyophilized green tea powder dissolved in 100 mL of deionized distilled water). After 12 weeks of green tea supplementation, the green tea group had lower fasting plasma levels of glucose, insulin, triglyceride, and free fatty acid than the control rats. Insulin-stimulated glucose uptake of, and insulin binding to, adipocytes were significantly increased in the green tea group. In experiment 2 (in vitro study), a tea polyphenol extract was used to determine its effect on insulin activity in vitro. Green tea polyphenols (0.075%) significantly increased basal and insulin-stimulated glucose uptake of adipocytes. Results demonstrated that green tea increases insulin sensitivity in Sprague-Dawley rats and that green tea polyphenol is one of the active components.

Hypoxic preconditioning prevents cortical infarction by transient focal ischemia-reperfusion.

One of the proposed pathologic actions underlying brain infarction is excess free radicals resulting from reoxygenation. In this paper we report an investigation of the neuroprotective effect of hypoxic preconditioning on transient focal ischemia-reperfusion injuries in rat brain. Female Wistar rats were subjected to 380 mmHg in an altitude chamber for 15 hours/day. Our ex vivo studies showed that auto-oxidation and iron-induced lipid peroxidation of brain homogenates of the four-week hypoxia-preconditioned rats were significantly lower than those of the normoxic rats. A focal infarction in the cerebral cortex of normoxic rats was consistently observed 24 hours after a 60-minute transient ischemic occlusion of the right middle cerebral artery and bilateral common carotid arteries. Hypoxic preconditioning in fact attenuated cortical infarction in a duration-dependent manner. Induction of the neuroprotection required two weeks of hypoxic preconditioning. Four weeks of hypoxic preconditioning significantly reduced the cortical infarcted area, the elevated lipid peroxidation, and resulted in an acute increase in cytosolic cytochrome c in the infarcted cortex of normoxic rats. The protective effect of four weeks of hypoxic preconditioning lasted seven days under a renormoxic condition. Our data suggest that oxidative stress may result in apoptosis in the transient focal ischemia-reperfusion injuries. Furthermore, hypoxic preconditioning attenuated cortical infarction in the rat brain. Although supplementation of antioxidants may encounter difficulty at the blood-brain barrier, hypoxic preconditioning is very likely to protect CNS targets from oxidative injuries without any barrier.

Different central manifestations in response to electroacupuncture at analgesic and nonanalgesic acupoints in rats: a manganese-enhanced functional magnetic resonance imaging study.

Acupuncture analgesia is an important issue in veterinary medicine. This study was designed to elucidate central modulation effects in response to electroacupuncture (EA) at different acupoints. Manganese-enhanced functional magnetic resonance imaging was performed in Sprague-Dawley rats after sham acupuncture, sham EA, or true EA at somatic acupoints. The acupoints were divided into 3 groups: group 1, analgesic acupoints commonly used for pain relief, such as Hegu (LI 4); group 2, nonanalgesic acupoints rarely used for analgesic effect such as Neiguan (PC 6); and group 3, acupoints occasionally used for analgesia, such as Zusanli (ST 36). Image acquisition was performed on a 1.5-T superconductive clinical scanner with a circular polarized extremity coil. The results showed that there was no neural activation caused by EA at a true acupoint with shallow needling and no electric current (sham acupuncture). When EA at a true acupoint was applied with true needling but no electric current (sham EA), there was only a slight increase in brain activity at the hypothalamus; when EA was applied at a true acupoint with true needling and an electric current (true EA), the primary response at the hypothalamus was enhanced. Also, there was a tendency for the early activation of pain-modulation areas to be prominent after EA at analgesic acupoints as compared with nonanalgesic acupoints. In conclusion, understanding the linkage between peripheral acupoint stimulation and central neural pathways provides not only an evidence-based approach for veterinary acupuncture but also a useful guide for clinical applications of acupuncture.

Acarbose improves glycemic control in insulin-treated Asian type 2 diabetic patients: results from a multinational, placebo-controlled study.

The purpose of the study was to determine the efficacy and tolerability of acarbose in Asian type 2 diabetic patients insufficiently controlled by insulin. Asian type 2 diabetic patients on stable insulin dosages were enrolled into a multinational, double-blind, placebo-controlled parallel arm study. After a 2-week screening phase, patients were randomly assigned to 50 mg acarbose t.i.d. or matching placebo for 6 weeks, followed by 100 mg acarbose t.i.d. or placebo for 12 weeks. The primary efficacy parameter was change from baseline in HbA(1c); secondary variables included the changes in fasting and postprandial blood glucose. After 18 weeks of treatment there was a difference in HbA(1c) levels between the two treatment groups (-0.69%, 95% CI (-1.18; -0.2), P=0.008) in favour of acarbose. Reductions in 1-h postprandial glucose levels from baseline to endpoint were observed with acarbose treatment (P=0.029). There were no differences in fasting blood glucose, total triglyceride and cholesterol between the two groups. Safety profiles were similar for both treatment arms except for the higher incidence of flatulence in the acarbose group (28.6% vs. 16.4% for placebo). Adjunctive acarbose therapy offers an efficacious and safe means for improvement of glycemic control in Asian type 2 diabetic patients insufficiently controlled by insulin.

Event-related functional MRI study on central representation of acute muscle pain induced by electrical stimulation.

Although pathological muscle pain involves a significantly larger population than any other pain condition, the central mechanisms are less explored than those of cutaneous pain. The aims of the study were to establish the pain matrix for muscle pain in the full head volume and, further, to explore the possibility of a functional segregation to nonpainful and painful stimuli within the area of the parasylvian cortex corresponding to the secondary somatosensory area. Additionally, we speculate that a randomization of nonpainful and painful stimuli may target specific structures related to stimulus salience. We used event-related functional magnetic resonance imaging (MRI) and the high sensitivity of the 3-T MRI scanner to study the central processing of acute muscle pain induced by intramuscular electrostimulation. Brief nonpainful and painful stimuli (1-ms duration, interstimulus interval = 12 s) were randomly applied to the left abductor pollicis brevis of 10 subjects. The data disclose a pain matrix for muscle pain similar to that for cutaneous pain. Individual analysis suggests separate representations within the area bounded by the upper bank of the Sylvian fissure (SF) and the circular sulcus of insula (CSI). Nonpainful stimulation activated the superficial parietal operculum adjoining the SF, while the painful condition additionally targeted the deeper parietal operculum bordering the CSI. Randomization of stimuli of different intensities likely introduces cognitive components that engage neural substrates servicing the appreciation of stimulus salience in the context of affect-laden pain imposition.