bluuebunny/crossref_metadata_2025 huggingface dataset:
Theoretical Proof and Empirical Confirmation of a Continuous Labeling Method Using Naturally 13C‐Depleted Carbon Dioxide
Authors: Cheng Weixin , Dijkstra Feike A.
Published: March 2007

Continuous isotope labeling and tracing is often needed to study the transformation, movement, and allocation of carbon in plant‐soil systems. However, existing labeling methods have numerous limitations. The present study introduces a new continuous labeling method using naturally 13C‐depleted CO2. We theoretically proved that a stable level of 13C‐CO2 abundance in a labeling chamber can be maintained by controlling the rate of CO2‐free air injection and the rate of ambient airflow with coupling of automatic control of CO2 concentration using a CO2 analyzer. The theoretical results were tested and confirmed in a 54 day experiment in a plant growth chamber. This new continuous labeling method avoids the use of radioactive 14C or expensive 13C‐enriched CO2 required by existing methods and therefore eliminates issues of radiation safety or unaffordable isotope cost, as well as creating new opportunities for short‐ or long‐term labeling experiments under a controlled environment.
Comparison of Vegetation Indices and Red‐edge Parameters for Estimating Grassland Cover from Canopy Reflectance Data
Authors: Liu Zhan‐Yu , Huang Jing‐Feng , Wu Xin‐Hong , Dong Yong‐Ping
Published: March 2007

There has been a great deal of interests in the estimation of grassland biophysical parameters such as percentage of vegetation cover (PVC), aboveground biomass, and leaf‐area index with remote sensing data at the canopy scale. In this paper, the percentage of vegetation cover was estimated from vegetation indices using Moderate Resolution Imaging Spectroradiometer (MODIS) data and red‐edge parameters through the first derivative spectrum from in situ hypserspectral reflectance data. Hyperspectral reflectance measurements were made on grasslands in Inner Mongolia, China, using an Analytical Spectral Devices spectroradiometer. Vegetation indices such as the difference, simple ratio, normalized difference, renormalized difference, soil‐adjusted and modified soil‐adjusted vegetation indices (DVI, RVI, NDVI, RDVI, SAVIL = 0.5 and MSAVI2) were calculated from the hyperspectral reflectance of various vegetation covers. The percentage of vegetation cover was estimated using an unsupervised spectral‐contextual classifier automatically. Relationships between percentage of vegetation cover and various vegetation indices and red‐edge parameters were compared using a linear and second‐order polynomial regression. Our analysis indicated that MSAVI2 and RVI yielded more accurate estimations for a wide range of vegetation cover than other vegetation indices and red‐edge parameters for the linear and second‐order polynomial regression, respectively.
Isolation and Characterization of a Putative Class E Gene from Taihangia rupestris
Authors: Wang Yong‐Qiang , Tian Hui‐Yu , Du Xiao‐Qiu , Lü Shan‐Hua , Lu Wen‐Liang , Chong Kang , Meng Zheng
Published: March 2007

Studies in model plants showed that SEPALLATA(SEP) genes are required for the identification of floral organs and the determination of floral meristems in Arabidopsis. In this paper a SEP homolog, TrSEP3, was isolated from a China‐specific species, Taihangia rupestrisi Yü et Li. Phylogenetic analysis showed that the gene belongs to the SEP3‐clade of SEP (previous AGL2) subfamily. In situ hybridization was used to reveal the potential functional specification, and the results showed that TrSEP3 expression was first observed in floral meristems and then confined to the floral primordia of the three inner whorls. In the matured flower, TrSEP3 was strongly expressed in the tips of pistils and weak in stamens and petals. The evolution force analysis shows that TrSEP3 might undergo a relaxed negative selection. These results suggested that TrSEP3 may not only function in determining the identity of floral meristems and the primordia of three inner whorls, but also function in matured reproductive organs.
Over 75 years of acoustics at the National Research Council of Canada
Authors: Daigle Gilles A. , Stinson Michael R.
Published: March 2007

The first Director of the Division of Applied Physics brought with him a strong interest in ultrasonics, thereby opening a line of research in acoustics, which has continued unbroken even since. It was George J. Thiessen, Section Head from 1950 to 1975, who rebuilt the acoustics section after the war effort and charted the course the laboratory follows today. It was in the early 50s that Edgar Shaw and Tony Embleton joined the laboratory. They were both students of R. W. B. Stephens, a research supervisor who has taught and inspired a generation of acoustics students and guided them in the attainment of excellence. During the over 50 intervening years, several generations of acousticians have studied and been mentored in the laboratory. Most of the students and post-docs that have spent time in the laboratory now hold faculty, government, or industry positions in acoustics.
Artificial selection for high-capacity endurance running is protective against high-fat diet-induced insulin resistance
Authors: Noland Robert C. , Thyfault John P. , Henes Sarah T. , Whitfield Brian R. , Woodlief Tracey L. , Evans Jasper R. , Lust Jennifer A. , Britton Steven L. , Koch Lauren G. , Dudek Ronald W. , Dohm G. Lynis , Cortright Ronald N. , Lust Robert M.
Published: March 2007

Elevated oxidative capacity, such as occurs via endurance exercise training, is believed to protect against the development of obesity and diabetes. Rats bred both for low (LCR)- and high (HCR)-capacity endurance running provide a genetic model with inherent differences in aerobic capacity that allows for the testing of this supposition without the confounding effects of a training stimulus. The purpose of this investigation was to determine the effects of a high-fat diet (HFD) on weight gain patterns, insulin sensitivity, and fatty acid oxidative capacity in LCR and HCR male rats in the untrained state. Results indicate chow-fed LCR rats were heavier, hypertriglyceridemic, less insulin sensitive, and had lower skeletal muscle oxidative capacity compared with HCR rats. Upon exposure to an HFD, LCR rats gained more weight and fat mass, and their insulin resistant condition was exacerbated, despite consuming similar amounts of metabolizable energy as chow-fed controls. These metabolic variables remained unaltered in HCR rats. The HFD increased skeletal muscle oxidative capacity similarly in both strains, whereas hepatic oxidative capacity was diminished only in LCR rats. These results suggest that LCR rats are predisposed to obesity and that expansion of skeletal muscle oxidative capacity does not prevent excess weight gain or the exacerbation of insulin resistance on an HFD. Elevated basal skeletal muscle oxidative capacity and the ability to preserve liver oxidative capacity may protect HCR rats from HFD-induced obesity and insulin resistance.
Plasma adiponectin concentration in healthy pre- and postmenopausal women: relationship with body composition, bone mineral, and metabolic variables
Authors: Jürimäe Jaak , Jürimäe Toivo
Published: March 2007

The aim of the current investigation was to determine the possible relationships of fasting adiponectin level with body composition, bone mineral, insulin sensitivity, leptin, and cardiorespiratory fitness parameters in 153 women. Subjects were classified as premenopausal ( n = 42; 40.8 ± 5.7 yr) if they had regular menstrual periods, early postmenopausal ( n = 49; 56.7 ± 3.6 yr) if they had been postmenopausal for more than >1 yr but <7 yr (5.5 ± 1.3 yr), and postmenopausal ( n = 62; 72.2 ± 4.5 yr) if they had been postmenopausal for >7 yr. All women studied had a body mass index (BMI) <30 kg/m2. Adiponectin values were higher ( P < 0.05) in middle-aged (12.0 ± 5.1 μg/ml) and older (15.3 ± 7.3 μg/ml) postmenopausal women compared with middle-aged premenopausal women (8.4 ± 3.2 μg/ml). Mean plasma adiponectin concentration in the total group of women ( n = 153) was 12.2 ± 6.3 μg/ml and was positively related ( P < 0.05) to age, indexes of overall obesity (BMI, body fat mass), and cardiorespiratory fitness (PWC) values. In addition, a negative association ( P < 0.05) between adiponectin with central obesity (waist-to-hip and waist-to-thigh ratio), fat-free mass, bone mineral (bone mineral content, total and lumbar spine bone mineral density), and leptin and insulin resistance (insulin, fasting insulin resistance index) values was observed. However, multivariate regression analysis revealed that only age, fasting insulin resistance index, and leptin were independent predictors of adiponectin concentration. In conclusion, circulating adiponectin concentrations increase with age in normal-weight middle-aged and older women. It appears that adiponectin is independently related to age, leptin, and insulin resistance values in women across the age span and menstrual status.
Regulation of human organic anion transporter 4 by progesterone and protein kinase C in human placental BeWo cells
Authors: Zhou Fanfan , Hong Mei , You Guofeng
Published: March 2007

Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti-tumor drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the placenta. In the current study, we examined the regulation of hOAT4 by pregnancy-specific hormones progesterone (P4) and 17β-estradiol (E2) and by protein kinase C (PKC) in human placental BeWo cells. P4 induced a time- and concentration-dependent downregulation of hOAT4 transport activity, whereas E2 had no effect on hOAT4 function. The downregulation of hOAT4 activity by P4 mainly resulted from a decreased cell surface expression without a change in total cell expression of the transporter, kinetically revealed as a decreased Vmax without significant change in Km. Activation of PKC by phorbol 12,13-dibutyrate also resulted in an inhibition of hOAT4 activity through a decreased cell surface expression of the transporter. However, P4-induced downregulation of hOAT4 activity could not be prevented by treating hOAT4-expressing cells with the PKC inhibitor staurosporine. We concluded that both P4 and activation of PKC inhibited hOAT4 activity through redistribution of the transporter from cell surface to the intracellular compartments. However, P4 regulates hOAT4 activity by mechanisms independent of PKC pathway.
Depolarization of the macula densa induces superoxide production via NAD(P)H oxidase
Authors: Liu Ruisheng , Garvin Jeffrey L. , Ren YiLin , Pagano Patrick J. , Carretero Oscar A.
Published: March 2007

Superoxide (O2−) enhances tubuloglomerular feedback by scavenging nitric oxide at the macula densa. However, the singling pathway of O2−production in the macula densa is not known. We hypothesized that the increase in tubular NaCl concentration that initiates tubuloglomerular feedback induces O2−production by the macula densa via NAD(P)H oxidase, which is activated by macula densa depolarization. We isolated and microperfused the thick ascending limb of the loop of Henle and attached macula densa in rabbits. A fluorescent dye, dihydroethidium, was used to detect O2−production at the macula densa. When luminal NaCl was switched from 10 to 80 mM, a situation of initiating maximum tubuloglomerular feedback response, O2−production significantly increased. To make sure that the shifts in the oxyethidium/dihydroethidium ratio were due to changes in O2−, we used tempol (10−4M), a stable membrane-permeant superoxide dismutase mimetic. With tempol present, when we switched from 10 to 80 mM NaCl, the increase in oxyethidium/dihydroethidium ratio was blocked. To determine the source of O2−, we used the NAD(P)H oxidase inhibitor apocynin. When luminal NaCl was switched from 10 to 80 mM in the presence of apocynin, O2−production was inhibited by 80%. To see whether the effect of increasing luminal NaCl involves Na-K-2Cl cotransporters, we inhibited them with furosemide. When luminal NaCl was switched from 10 to 80 mM in the presence of furosemide, O2−production was blocked. To test whether depolarization of the macula densa induces O2−production, we artificially induced depolarization by adding valinomycin (10−6M) and 25 mM KCl to the luminal perfusate. Depolarization alone significantly increases O2−production. We conclude that increasing luminal NaCl induces O2−production during tubuloglomerular feedback. O2−generated by the macula densa is primarily derived from NAD(P)H oxidase and is induced by depolarization.
Losartan-hydrochlorothiazide association promotes lasting blood pressure normalization and completely arrests long-term renal injury in the 5/6 ablation model
Authors: Fujihara Clarice Kazue , Malheiros Denise M. A. C. , Zatz Roberto
Published: March 2007

The possible long-term renoprotective effects of treatment with thiazides, either as monotherapy or associated with renin-angiotensin suppressors, have not been assessed. We investigated the effect of hydrochlorothiazide (H), alone or combined with losartan (L), in the 5/6 renal ablation model (Nx). Adult male Munich-Wistar rats underwent Nx, remaining untreated for 1 mo. At this time, functional and morphological studies were performed in 21 rats (group Nxpre). The remaining rats were distributed among groups: Nx, no treatment; Nx+L, receiving L, 50 mg·kg−1·day−1in the drinking water; Nx+H, receiving H, 6 mg·kg−1·day−1in drinking water; and Nx+L+H, receiving both L and H as described. At 30 days of treatment, systemic and glomerular pressures were markedly elevated in group Nx. Both H and L attenuated hypertension, whereas combined L+H treatment completely normalized both pressures. Eight months after Nx, mortality approached 70% in untreated rats, whereas severe albuminuria, hypertension, glomerulosclerosis, and interstitial expansion were observed. H and L attenuated, but did not prevent, mortality, hypertension, and renal injury. Combined L+H treatment completely prevented mortality, normalized albuminuria and blood pressure, and arrested renal injury at levels found 1 mo after ablation, despite the unusually long period of observation. Combined L+H treatment may represent an effective therapeutic alternative to prevent progression of chronic nephropathies.
Neonatal Treatment With Beta‐Cell Stimulatory Agents Reduces the Incidence of Diabetes in BB Rats
Authors: Buschard Karsten , Bock Troels , Pedersen Charlotte R. , Hansen Susanne V. , Aaen Kim , JØrgensen Merete , Hansen Michael WØllike , Kjaer Troels W. , Hageman Ida , Josefsen Knud
Published: March 2007

The aim of the study was to investigate whether
various beta‐cell stimulatory drugs, given neonatally,
influence the incidence of diabetes in BB rats.
Newborn BB rats were treated twice daily for 6 days
and diabetes development was observed during the
following 200‐day study period. Compared to a
diabetes incidence of 63.8% in 163 control BB rats
which received saline or were untreated, the percentage
of experimental BB rats that developed diabetes
was as follows in the different subgroups: arginineglucose:
47% (n= 73, p < 0.02); glucagon: 37% (n =
93, p < 0.0001); tolbutamide‐glucose: 36% (n = 58,
p < 0.0005); and theophylline‐glucose: 39% (n = 41,
p < 0.005). A long‐term arginine‐glucose treatment
was not superior to the shorter neonatal treatment.
Histological examination revealed a higher degree of
insulitis in diabetic than in non‐diabetic animals
but no difference according to the kind of treatment
was observed. Finally, we found that the diabetes
incidence in BB rats was higher in the first litter
compared to subsequent litters (p = 0.04). Thus,
neonatal treatment with various beta‐cell stimulatory
agents reduces diabetes incidence in BB rats.
The theory behind the study, that the treatment
accelerates beta‐cell maturation leading to increased
immunological tolerance towards beta cells, is
discussed.
Aminoguanidine Exerts a β‐Cell Function‐preserving Effect in High Glucose‐cultured β‐Cells (INS‐1)
Authors: Tajiri Yuji , Grill Valdemar
Published: March 2007

We investigated the effects of aminoguanidine (AG)
on β‐cell functions in an insulin secreting cell line
(INS‐1). Culture with 27 mM glucose for one week markedly decreased both insulin release and insulin content compared to culture in 0.8 mM or 3.3 mM glucose. Relative to culture at 27 mM glucose alone, the co‐exposure to 1 mM AG almost doubled basal as well as glucose or 25 mM KCl‐stimulated insulin release and increased insulin content by 42%. AG failed to affect release and content in cells cultured at 0.8 or 3.3 mM glucose. Preproinsulin mRNA content in 27 mM glucose‐cultured cells was 52% suppressed compared to 0.8 mM glucose‐cultured cells, and AG treatment partially counteracted this decline. Advanced glycosylation end product (AGE)‐associated fluorescence (370 nm excitation and 440 nm emission) of cells′ extracts did not differ between 27 mM and 0.8 mM glucose‐cultured cells after 1 week of culture and fluorescence was unaffected
by AG. Accumulation of nitrite into culture media was markedly increased from 27 mM glucose‐cultured cells, and this accumulation was 33% suppressed by AG. In conclusion, AG partially protects against glucotoxic effects in INS‐1 cells. These beneficial effects may involve a decrease in early glycation products and/or nitric oxide synthase (NOS) activity. The effects which were obtained after one week of high glucose exposure may supplement AGE‐associated effects seen after chronically elevated glucose.
Impaired Relaxation in Aorta from Streptozotocin‐diabetic Rats: Effect of Aminoguanidine (AMNG) Treatment
Authors: Özyazgan Sibel , Unlucerci Yesim , Bekpinar Selda , Akkan Ahmet Gökhan
Published: March 2007

Aim The effect of 8 weeks′ streptozotocin (STZ)‐
induced diabetes and aminoguanidine (AMNG), the
inhibitor of advanced glycosylation reaction, treatment
on arteriolar reactivity to vasoactive substances
was investigated in vitro.
Materials and Methods Studies were performed in
untreated control rats (n = 10), STZ‐induced (60 mg/kg
i.v.) diabetic rats (n = 10), AMNG‐treated (600 mg/l
given in drinking water throughout 8 weeks) control
rats (n = 10) and AMNG‐treated (600 mg/l given in
drinking water, beginning at 72h after STZ and
throughout 8 weeks of diabetes) diabetic rats (n = 10).
Results are expressed as the mean ±s.e. Relaxant
responses are expressed as a percentage (%) relaxation
of noradrenaline‐induced tone. Statistical comparisons
were made by one‐way analysis of variance
(ANOVA) followed by Tukey–Kramer multiple
comparisons test.
Results 1. The decreased body weights (205 ± 6 g)
and increased blood glucose levels (583 ± 8 mg/dl) of
diabetic rats were partially restored by treatment of
aminoguanidine (253 ± 6 g, p < 0.05 and 480 ± 14 mg/dl, p < 0.001, respectively). 2. Diabetes caused a 71%
deficit in maximal endothelium‐dependent relaxation
to acetylcholine for noradrenaline precontracted
aortas (p < 0.001). AMNG treatment prevented the
diabetes‐induced impairment in endothelium dependent
relaxation (58 ± 8%) to acetylcholine, maximum
relaxation remaining in the non‐diabetic range
(78 ± 4%). 3. Neither diabetes nor treatment affected endothelium‐independent relaxation (pD2 and max.
Relax.) to sodium nitroprusside. 4. Vasoconstrictor
responses (pD2 and Max. Contraction) to noradrenaline
and KCl were not influenced by the diabetic
state and treatment.
Conclusion Our data suggest that 8 weeks of
experimental diabetes is associated with a decreased
endothelium‐dependent vasodilatation. AMNG
treatment may prevent diabetes‐induced endothelial
dysfunction. This may be mediated via the prevention
of advanced glycosylation end product formation,
the enhanced release of vasodilator substances
such as prostacyclin, the increased elasticity of blood
vessels, the antioxidant activity and inhibitor activity
of enzyme aldose‐reductase by AMNG.
Streptozotocin and Alloxan‐based Selection Improves Toxin Resistance of Insulin‐Producing RINm Cells
Authors: Bloch Konstantin O. , Zemel Romy , Bloch Olga V. , Grief Hagar , Vardi Pnina
Published: March 2007

The aim of our study was to develop a method for
selection of subpopulations of insulin producing
RINm cells with higher resistance to beta cell toxins.
Cells, resistant to streptozotocin (RINmS) and
alloxan (RINmA), were obtained by repeated exposure
of parental RINm cells to these two toxins,
while the defense capacity, was estimated by the
MTT colorimetric method, and [ 3H]‐thymidine incorporation
assay. We found that RINmS and
RINmA displayed higher resistance to both streptozotocin
(STZ) and alloxan (AL) when compared to
the parental RINm cells. In contrast, no differences
in sensitivity to hydrogen peroxide were found
between toxin selected and parental cells. Partial
protection from the toxic effect of STZ and AL was
obtained only in the parental RINm cells after
preincubation of cells with the unmetabolizable 3‐
O‐methyl‐glucose. The possibility that GLUT‐2 is
involved in cell sensitivity to toxins was confirmed
by Western blot analysis, which showed higher
expression of GLUT‐2 in parental RINm compared
to RINmS and RINmA cells. In addition to the
higher cell defense property evidenced in the
selected cells, we also found higher insulin content
and insulin secretion in both RINmS and RINmA
cells when compared to the parental RINm cells. In
conclusion, STZ and AL treatment can be used for
selection of cell sub‐populations with higher cell defense properties and hormone production. The
different GLUT‐2 expression in parental and re
sistant cells suggest involvement of GLUT‐2 in
mechanisms of cell response to different toxins.
High Glucose‐enhanced Acetylcholine Stimulated CGMP Masks Impaired Vascular Reactivity in Tail Arteries from Short‐Term Hyperglycemic Rats
Authors: Hamaty Marwan , Guzmán Cristina B. , Walsh Mary F. , Bode Ann M. , Levy Joseph , Sowers James R.
Published: March 2007

Impaired vascular endothelium‐dependent relaxation
and augmented contractile responses have been
reported in several models of long‐term hyperglycemia.
However, the effects of short‐term ambient
hyperglycemia are poorly understood. Since oxidative
stress has been implicated as a contributor to
impaired vascular function, we investigated the
following:

Aims: (1) the effects of high glucose exposure in vitro (7 – 10 days) on vascular relaxation to acetylcholine
(Ach) and contractility to norepinephrine (NE)
and KCl; (2) if NO‐dependent cGMP generation is
affected under these conditions; and (3) aortic redox
status.

Methods: Non‐diabetic rat tail artery rings were
incubated in normal (5mM) (control NG) or high
(20mM) glucose buffer (control HG). Vascular responses
to Ach, NE and KCl were compared to
those of streptozotocin (SZ) diabetic animals in
the same buffers (diabetic NG, diabetic HG). Ach stimulated
cGMP levels were quantitated as an indirect
assessment of endothelial nitric oxide (NO)
production and oxidative stress evaluated by
measuring vascular glutathione and oxidized
glutathione.

Results: Rings from diabetic rats in NG showed
impaired relaxation to Ach (P = 0.002) but relaxed
normally, when maintained in HG. Similarly, contractile
responses to NE were attenuated in diabetic
rings in NG but similar to controls in HG. HG
markedly augmented maximal contraction to KCl
compared to control and diabetic vessels in NG
(P < 0.0001). Diabetic vessels in a hyperosmolar, but
normoglycemic, milieu respond like those in HG.
in vitro, HG for 2 hours changed neither relaxation
nor contractile responses to NE and KCl in control
rings. Basal cGMP levels were lower in aortae
from diabetic animals pre‐incubated in NG than in
HG/LG or in control rings in NG (P < 0.05). cGMP
responses to Ach were exaggerated in diabetic vessels
in HG (P = 0.035 vs. control NG, P = 0.043 vs.
diabetic NG) but not different between control
and diabetic rings in NG. Vessels from diabetic
animals had lower levels of GISH (P < 0.0001) and
higher levels of GSSG (P < 0.0001) indicating oxidative
stress.

Conclusions: Our data indicate that endothelium dependent relaxation is altered early in the diabetic state and that increased NO responses may compensate for augmented oxidative stress but the lack of effect of short‐term exposure of normal vessels to HG suggests that short‐term hyperglycemia per se does not cause abnormal vascular responses.
Decreased Expression Of apM1 in Omental and Subcutaneous Adipose Tissue of HumansWith Type 2 Diabetes
Authors: Statnick Michael A. , Beavers Lisa S. , Conner Laura J. , Corominola Helena , Johnson Dwayne , Hammond Craig D. , Rafaeloff-Phail Ronit , Seng Thomas , Suter Todd M. , Sluka James P. , Ravussin Eric , Gadski Robert A. , Caro Jose F.
Published: March 2007

We have screened a subtracted cDNA library in
order to identify differentially expressed genes in
omental adipose tissue of human patients with
Type 2 diabetes. One clone (#1738) showed a marked
reduction in omental adipose tissue from patients
with Type 2 diabetes. Sequencing and BLAST analysis
revealed clone #1738 was the adipocyte‐specific
secreted protein gene apM1 (synonyms ACRP30,
AdipoQ, GBP28). Consistent with the murine orthologue,
apM1 mRNA was expressed in cultured
human adipocytes and not in preadipocytes.
Using RT‐PCR we confirmed that apM1 mRNA
levels were significantly reduced in omental adipose
tissue of obese patients with Type 2 diabetes compared
with lean and obese normoglycemic subjects.
Although less pronounced, apM1 mRNA levels
were reduced in subcutaneous adipose tissue of
Type 2 diabetic patients. Whereas the biological
function of apM1 is presently unknown, the tissue
specific expression, structural similarities to TNFα
and the dysregulated expression observed in obese
Type 2 diabetic patients suggest that this factor
may play a role in the pathogenesis of insulin resistance
and Type 2 diabetes.
A New Spontaneously Diabetic Non‐obese Torii Rat Strain With Severe Ocular Complications
Authors: Shinohara Masami , Masuyama Taku , Shoda Toshiyuki , Takahashi Tadakazu , Katsuda Yoshiaki , Komeda Kajuro , Kuroki Masatoshi , Kakehashi Akihiro , Kanazaw Yasunori
Published: March 2007

A new spontaneously diabetic strain of the Sprague‐Dawley rat was established in 1997 and named
the SDT (Spontaneously Diabetic Torii) rat. In this
research, we investigated the characteristics of the
disease condition in the SDT rats. The time of onset
of glucosuria was different between male and
female SDT rats; glucosuria appeared at approximately
20 weeks of age in male rats and at approximately
45 weeks of age in female rats. A cumulative
incidence of diabetes of 100% was noted by 40
weeks of age in male rats, while it was only 33.3%
even by 65 weeks of age in female rats. The survival
rate up to 65 weeks of age was 92.9% in male
rats and 97.4% in female rats. Glucose intolerance
was observed in male rats from 16 weeks of age.
The clinical characteristics of the male SDT rats
were (1) hyperglycemia and hypoinsulinemia (from
25 weeks of age); (2) long‐term survival without insulin
treatment; (3) hypertriglyceridemia (by 35
weeks of age); however, no obesity was noted in
any of the male rats. The histopathological characteristics
of the male rats with diabetes mellitus
(DM) were (1) fibrosis of the pancreatic islets (by
25 weeks of age); (2) cataract (by 40 weeks of age);
(3) tractional retinal detachment with fibrous proliferation
(by 70 weeks of age) and (4) massive hemorrhaging
in the anterior chamber (by 77 weeks of age).
These clinical and histopathological characteristics
of the disease in SDT rats resemble those of human
Type 2 diabetes with insulin hyposecretion. In conclusion,
SDT rat is considered to be a potentially
useful model for studies of diabetic retinopathy
encountered in humans.
Placental Transfer of Lactate, Glucose and 2‐deoxyglucose in Control and Diabetic Wistar Rats
Authors: Thomas Chris R. , Oon Beryl B. , Lowy Clara
Published: March 2007

Placental transfer of lactate, glucose and 2‐deoxyglucose
was examined employing the in situ perfused
placenta. Control and streptozotocin induced diabetic
Wistar rats were infused with U‐14C]‐glucose and
[3H]‐2‐deoxyglucose (2DG). The fetal side of the placenta
was perfuseci with a cell free medium and glucose
uptake was calculated in the adjacent fetuses.
Despite the 5‐fold higher maternal plasma glucose
concentration in the diabetic dams the calculated
fetal glucose metabolic index was not significantly
different between the 2 groups. Placental blood flow
was reduced in the diabetic animals compared with
controls but reduction of transfer of [U‐14C]‐glucose and [3H]‐2‐deoxyglucose and endogenously derived
[14C]‐Lactate to the fetal compartment, could not be
accounted for by reduced placental blood flow
alone. There was no significant net production or
uptake of lactate into the perfusion medium that
had perfused the fetal side of the placenta in either
group. The plasma lactate levels in the fetuses adjacent
to the perfused placenta were found to be higher
than in the maternal plasma and significantly
higher in the fetuses of the diabetic group compared
with control group. In this model the in situ perfused
placenta does not secrete significant quantities
of lactate into the fetal compartment in either
the control or diabetic group.
Diabetes in Old Male Offspring of Rat Dams Fed a Reduced Protein Diet
Authors: Petry Clive J. , Dorling Matthew W. , Pawlak Dorota B. , Ozanne Susan E. , Hales C. Nicholas
Published: March 2007

Restricted fetal growth is associated with increased
risk for the future development of Type 2 diabetes in
humans. The study aim was to assess the glucose tolerance
of old (seventeen months) male rats, which
were growth restricted in early life due to maternal
protein restriction during gestation and lactation. Rat
mothers were fed diets containing either 20% or 8%
protein and all offspring weaned onto a standard rat
diet. In old‐age fasting plasma glucose concentrations
were significantly higher in the low protein offspring:
8.4 (1.3)mmol/l v. 5.3 (1.3)mmol/l (p = 0.005),
Areas under the curves were increased by 67% for
glucose (p = 0.01) and 81% for insulin (p = 0.01) in
these rats in intravenous glucose tolerance tests, suggesting
(a degree of) insulin resistance. These results
show that early growth retardation due to maternal
protein restriction leads to the development of diabetes
in old male rat offspring. The diabetes is predominantly
associated with insulin resistance.
Differential Acute and Long Term Actions of Succinic Acid Monomethyl Ester Exposure on Insulin‐Secreting BRIN‐BD11 Cells
Authors: Picton Sally F. , Flatt Peter R. , McClenaghan Neville H.
Published: March 2007

Esters of succinic acid are potent insulin secretagogues,
and have been proposed as novel antidiabetic
agents for type 2 diabetes. This study
examines the effects of acute and chronic exposure
to succinic acid monomethyl ester (SAM) on insulin
secretion, glucose metabolism and pancreatic beta
cell function using the BRIN‐BD11 cell line. SAM
stimulated insulin release in a dose‐dependent
manner at both non‐stimulatory (1.1mM) and stimulatory
(16.7mM) glucose. The depolarizing actions
of arginine also stimulated a significant increase
in SAM‐induced insulin release but 2‐ketoisocaproic
acid (KIC) inhibited SAM induced insulin
secretion indicating a possible competition between
the preferential oxidative metabolism of these two
agents. Prolonged (18hour) exposure to SAM revealed
decreases in the insulin‐secretory responses
to glucose, KIC, glyceraldehyde and alanine.
Furthermore, SAM diminished the effects of nonmetabolized
secretagogues arginine and 3‐isobutyl‐1‐methylxanthine (IBMX). While the ability of
BRIN‐BD11 cells to oxidise glucose was unaffected
by SAM culture, glucose utilization was substantially
reduced. Collectively, these data suggest that
while SAM may enhance the secretory potential of
non‐metabolized secretagogues, it may also serve as
a preferential metabolic fuel in preference to other
important physiological nutrients and compromise
pancreatic beta cell function following prolonged
exposure.
Brain‐derived Neurotrophic Factor Regulates Energy Expenditure Through the Central NervousSystem in Obese Diabetic Mice
Authors: Nonomura Takeshi , Tsuchida Atsushi , Ono-Kishino Michiko , Nakagawa Tsutomu , Taiji Mutsuo , Noguchia Hiroshi
Published: March 2007

It has been previously demonstrated that brain‐derived
neurotrophic factor (BDNF) regulates glucose
metabolism and energy expenditure in rodent
diabetic models such as C57BL/KsJ‐leprdb/leprdb (db/db) mice. Central administration of BDNF has
been found to reduce blood glucose in db/db mice,
suggesting that BDNF acts through the central nervous
system. In the present study we have expanded
these investigations to explore the effect of central
administration of BDNF on energy metabolism. Intracerebroventricular
administration of BDNF lowered blood glucose and increased pancreatic insulin
content of db/db mice compared with vehicle‐treated
pellet pair‐fed db/db mice. While body temperatures
of the pellet pair‐fed db/db mice given vehicle were
reduced because of restricted food supply in this
pair‐feeding condition, BDNF treatment remarkably
alleviated the reduction of body temperature suggesting
the enhancement of thermogenesis. BDNF
enhanced norepinephrine turnover and increased
uncoupling protein‐1 mRNA expression in the interscapular
brown adipose tissue. Our evidence indicates
that BDNF activates the sympathetic nervous
system via the central nervous system and regulates
energy expenditure in obese diabetic animals.
Albert Renold Memorial Lecture: Molecular Background of Nutritionally Induced Insulin Resistance Leadingto Type 2 Diabetes – From Animal Models to Humans
Authors: Shafrir Eleazar
Published: March 2007

Albert Renold strived to gain insight into the abnormalities
of human diabetes by defining the pathophysiology
of the disease peculiar to a given animal.
He investigated the Israeli desert‐derived spiny mice
(Acomys cahirinus), which became obese on fat‐rich
seed diet. After a few months hyperplasia and hypertrophy
of β‐cells occurred leading to a sudden rupture,
insulin loss and ketosis. Spiny mice were low
insulin responders, which is probably a characteristic
of certain desert animals, protecting against insulin
oversecretion when placed on an abundant
diet. We have compared the response to overstimulation
of several mutant diabetic species and nutritionally
induced nonmutant animals when placed on
affluent diet. Some endowed with resilient β‐cells
sustain long‐lasting oversecretion, compensating for
the insulin resistance, without lapsing into overt diabetes.
Some with labile beta cells exhibit apoptosis
and lose their capacity of coping with insulin resistance
after a relatively short period. The wide
spectrum of response to insulin resistance among
different diabetes prone species seems to represent
the varying response of human beta cells among the
populations. In search for the molecular background
of insulin resistance resulting from overnutrition we
have studied the Israeli desert gerbil Psammomys
obesus (sand rat), which progresses through hyperinsulinemia,
followed by hyperglycemia and irreversible
beta cell loss. Insulin resistance was found
to be the outcome of reduced activation of muscle insulin
receptor tyrosine kinase by insulin, in association
with diminished GLUT4 protein and DNA
content and overexpression of PKC isoenzymes, notably
of PKCε. This overexpression and translocation
to the membrane was discernible even prior to hyperinsulinemia
and may reflect the propensity to diabetes
in nondiabetic species and represent a marker
for preventive action. By promoting the phosphorylation
of serine/threonine residues on certain proteins
of the insulin signaling pathway, PKCε exerts a
negative feedback on insulin action. PKCε was also
found to attenuate the activity of PKB and to promote
the degradation of insulin receptor, as determined
by co‐incubation in HEK 293 cells. PKCε
overexpression was related to the rise in muscle diacylglycerol
and lipid content, which are prevalent
on lascivious nutrition especially if fat‐rich. Thus,
Psammomys illustrates the probable antecedents of
the development of worldwide diabetes epidemic in
human populations emerging from food scarcity to
nutritional affluence, inappriopriate to their metabolic
capacity.
Glucose‐dependent and Glucose‐sensitizing Insulinotropic Effect of Nateglinide: Comparisonto Sulfonylureas and Repaglinide
Authors: Hu Shiling , Wang Shuya , Dunning Beth E.
Published: March 2007

Nateglinide, a novel D‐phenylalanine derivative,
stimulates insulin release via closure of KATP channels
in pancreatic β‐cell, a primary mechanism of
action it shares with sulfonylureas (SUs) and
repaglinide. This study investigated (1) the influence
of ambient glucose levels on the insulinotropic
effects of nateglinide, glyburide and repaglinide,
and (2) the influence of the antidiabetic agents on
glucose‐stimulated insulin secretion (GSIS) in vitro
from isolated rat islets. The EC50 of nateglinide to
stimulate insulin secretion was 14 μM in the presence
of 3mM glucose and was reduced by 6‐fold in
8mM glucose and by 16‐fold in 16mM glucose, indicating
a glucose‐dependent insulinotropic effect.
The actions of glyburide and repaglinide failed to
demonstrate such a glucose concentration‐dependent
sensitization. When tested at fixed and equipotent
concentrations (~2x EC50 in the presence of 8mM glucose) nateglinide and repaglinide shifted
the EC50s for GSIS to the left by 1.7mM suggesting
an enhancement of islet glucose sensitivity, while
glimepiride and glyburide caused, respectively, no
change and a right shift of the EC50. These data
demonstrate that despite a common basic mechanism
of action, the insulinotropic effects of different
agents can be influenced differentially by ambient
glucose and can differentially influence the islet
responsiveness to glucose. Further, the present
findings suggest that nateglinide may exert a more
physiologic effect on insulin secretion than comparator
agents and thereby have less propensity to
elicit hypoglycemia in vivo.
Effectiveness of Nateglinide on In Vitro Insulin Secretion from Rat Pancreatic IsletsDesensitized to Sulfonylureas
Authors: Hu Shiling , Wang Shuya , Dunning Beth E.
Published: March 2007

Chronic exposure of pancreatic islets to sulfonylureas
(SUs) is known to impair the ability of islets
to respond to subsequent acute stimulation by
SUs or glucose. Nateglinide (NAT) is a novel
insulinotropic agent with a primarily site of action
at β‐cell KATP channels, which is common to the
structurally diverse drugs like repaglinide (REP)
and the SUs. Earlier studies on the kinetics, glucosedependence
and sensitivity to metabolic inhibitors
of the interaction between NAT and KATP channels
suggested a distinct signaling pathways with NAT
compared to REP, glyburide (GLY) or glimepiride
(GLI). To obtain further evidence for this concept,
the present study compared the insulin secretion in
vitro from rat islets stimulated acutely by NAT, GLY,
GLI or REP at equipotent concentrations during 1‐hr
static incubation following overnight treatment
with GLY or tolbutamide (TOL). The islets fully
retained the responsiveness to NAT stimulation
after prolonged pretreatment with both SUs, while
their acute response to REP, GLY, and GLI was
markedly attenuated, confirming the desensitization
of islets. The insulinotropic efficacy of NAT in islets
desensitized to SUs may result from a distinct
receptor/effector mechanism, which contributes to
the unique pharmacological profile of NAT.
In Vitro Effect of Fenugreek Extracts on Intestinal Sodium‐dependent Glucose Uptake and Hepatic Glycogen Phosphorylase A
Authors: Al-Habori M. , Raman A. , Lawrence M. J. , Skett P.
Published: March 2007

Fenugreek (Trigonella foenum-graecum L. seed) is a food with traditional medicinal use in diabetes. Beneficial effects have been demonstrated in diabetic animals and both insulin‐dependent and non‐insulin‐dependent diabetic subjects. Effects of a lipid extract A, crude ethanolic extract B, further sub‐fractions of B (saponin‐free C, saponin D and sapogenin E) and a gum fibre fraction F on intestinal sodium‐dependent glucose uptake were investigated in vitro using rabbit intestinal brush border membrane vesicles. All fractions except A inhibited glucose‐uptake at 0.33 and/or 3.3mg/mL (p < 0.001). Greatest inhibition was observed with fractions D and E. Diosgenin and trigonelline (compounds reported in fenugreek)also inhibited glucose‐uptake (IC50 values approximately 3mg/ml, equivalent to 8mM and 19mM respectively) but did not account for the activity of the crude extracts. Fenugreek extracts had no effect on basal levels of glycogen phosphorylase a (HGPa) activity in rat hepatocyte suspensions. However fractions C and E caused a marginal but statistically significant inhibition (18.9 and 15.1% respectively, p < 0.05) of glucagon induction of this enzyme suggesting a glucagon‐antagonist effect. Diosgenin (1.65mg/ml; 4mM) inhibited glucagon‐induced HGPa activity by 20% (p < 0.05), and was more effective than trigonelline (non significant inhibition of 9.4% at 1.65mg/ml, 10mM).
Different Diabetogenic Response to Moderate Doses of Streptozotocin in Pregnant Rats, and Its Long‐TermConsequences in the Offspring
Authors: López-Soldado Iliana , Herrera Emilio
Published: March 2007

Diabetes during pregnancy results in congenital malformations
and long‐term postnatal diseases. Experimental
models are still needed to investigate the mechanism
responsible for these alterations. Thus, by the administration
of different doses of streptozotocin (STZ) (0, 25,
30, or 35 mg/kg body weight, intravenous) at the onset
of pregnancy in rats, the present study sought an appropriate
animal model for this pathology. At day 6 of pregnancy,
plasma glucose was progressively higher with an increasing
STZ dose, and in rats receiving the 35‐mg dose,
2 subgroups were detected: some animals had plasma glucose
levels above controls but below 200 mg/dL (mildly diabetic,
MD), whereas others had levels above 400 mg/dL
(severely diabetic, SD). At day 20 of pregnancy, the MD
rats had normal glycemia, but after an oral glucose load
(2 g/kg body weight), plasma glucose increased more and
insulin increased less than in controls. The SD rats maintained
their hyperglycemia and had a greatly impaired
oral glucose tolerance. At day 20, fetuses of SD dams were
fewer, weighed less, and had enhanced plasma glucose and
triglycerides and decreased insulin, whereas those from
MD dams did not differ from controls. At birth, newborns
from MD dams had higher body weight, plasma insulin,
and liver triglycerides as well as total body lipid concentrations
than controls, and on day 21, remained macrosomic and showed higher plasma glucose and liver triglyceride
concentrations. At 70 days of age, offspring of MD dams had
impaired oral glucose tolerance but normal plasma insulin
change in the case of females, whereas plasma insulin increased
less in males. These alterations were manifest more
in those offspring from dams that had > 50% macrosomic
newborns than in those from dams that had < 50% macrosomic
newborns. In conclusion, whereas our MD rats mimic
the changes taking place in gestational diabetic women and
show the long‐term risk of macrosomia, the SD rats are
more similar to uncontrolled diabetics. Thus these two rat
models, obtained with moderate amounts of STZ, could be
used to study the pathophysiological consequences of these
different diabetic conditions.
The Role of the Insulin‐Like Growth Factors and Their Binding Proteins in Glucose Homeostasis
Authors: Murphy Liam J.
Published: March 2007

The insulin like growth factors (IGF‐I and ‐II) are structurally
and functionally related to insulin. While insulin is
a key regulator of glucose homeostasis over the short term,
emerging evidence suggests that the IGFs are involved in
the longer term glucose homeostasis, possibly by modulating
insulin sensitivity. Unlike insulin, the IGFs are present in
most biological fluids as complexes with high affinity binding
proteins, the insulin‐like growth factor binding proteins
(IGFBPs). The IGFBPs regulate the bioavailability of the
IGFs. Of the six IGFBPs identified there is evidence from
studies in transgenic mice that both IGFBP‐1 and IGFBP‐3
may have a role in glucose regulation.
Growth Factors in Proliferative Diabetic Retinopathy
Authors: Khan Zia Ali , Chakrabarti Subrata
Published: March 2007

Many growth factors are implicated in the pathogenesis
of proliferative diabetic retinopathy. Alteration of growth
factors and their receptors in diabetes has been shown in
both experimental and clinical studies. Sustained hyperglycemia
resulting from long‐standing diabetes leads to several
biochemical abnormalities that consequently result in
retinal hypoxia. Retinal oxygenation state regulates various
growth factors that promote angiogenesis in order to meet
the oxygen demands of the tissue. However, unregulated expression
of these growth factors and induction of complex
cascades leading to augmentation of other proangiogenic
factors, which may not be regulated by tissue oxygenation,
leads to uncontrolled retinal neovascularization and blindness
in diabetic patients.
Valine Pyrrolidide Preserves Intact Glucose‐Dependent Insulinotropic Peptide and Improves Abnormal Glucose Tolerance in Minipigs With Reduced β‐Cell Mass
Authors: Larsen Marianne Olholm , Rolin Bidda , Ribel Ulla , Wilken Michael , Deacon Carolyn F. , Svendsen Ove , Gotfredsen Carsten F. , Carr Richard David
Published: March 2007

The incretin hormones glucagon‐like peptide‐1 (GLP‐1)
and glucose‐dependent insulinotropic polypeptide (GIP)
are important in blood glucose regulation.However, both incretin
hormones are rapidly degraded by the enzyme dipeptidyl
peptidase IV (DPPIV). The concept of DPPIV inhibition
as a treatment for type 2 diabetes was evaluated in a new
large animal model of insulin‐deficient diabetes and reduced
β‐cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin
(STZ) (125 mg/kg)–treated minipig, using the
DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg).VP did
not significantly affect levels of intact GLP‐1 but increased
levels of intact GIP (from 4543 ± 1880 to 9208 ± 3267 pM
× min; P<.01), thus improving glucose tolerance (area under
the curve [AUC] for glucose reduced from 1904 ± 480 to
1582 ± 353 mM × min;P = .05).VP did not increase insulin
levels during the oral glucose tolerance test (OGTT) but increased
the insulinogenic index in normal animals (from 83 ± 42 to 192 ± 108; P < .05), but not after NIA + STZ,
possibly because of less residual insulin secretory capacity
in these animals. GIP seems to contribute to the antihyperglycemic
effect of VP in this model; however, additional
mechanisms for the effect of DPPIV inhibition cannot be
excluded. The authors conclude that DPPIV inhibitors may
be useful to treat type 2 diabetes, even when this is due to
reduced β‐cell mass.
Risk Factors for a Complicated Clinical CourseAmong Women Hospitalized With PelvicInflammatory Disease
Authors: Jamieson Denise J. , Duerr Ann , Macasaet Milagros A. , Peterson Herbert B. , Hillis Susan D.
Published: March 2007

The aim of this study was to identify factors ascertainable at initial presentation that predict a
complicated clinical course in HIV‐negative women hospitalized with pelvic inflammatory disease
(PID). We used data from a cross‐sectional study of women admitted for clinically diagnosed PID
to a public hospital in New York City. A complicated clinical course was defined as undergoing
surgery, being readmitted for PID, or having a prolonged hospital stay (≥ 14 days) but no surgery.
Logistic regression was used to identify independent predictors of complications. In adjusted analyses,
older age (≥35 years) was a risk factor for prolonged hospital stay (adjusted odds ratio [OR] =
3.9; 95% confidence interval [CI] = 1.3–11.6) and surgery (OR = 10.4; CI = 2.5–44.1); self‐reported
drug use was a risk factor for readmission for PID (OR = 7.7; CI = 1.4‐41.1) and surgery (OR =
6.2; CI = 1.8–20.5). Older age and self‐reported drug use appear to be independent risk factors for
a complicated clinical course among women hospitalized with PID. Infect. Dis. Obstet. Gynecol.
8:88–93, 2000.