bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention of Cyclophosphamide‐induced Accelerated Diabetes in the NOD Mouse by Nicotinamide or a Soy Protein‐based Infant Formula
Authors: Reddy S. , Karanam M. , Robinson E.
Published: March 2007

Spontaneous diabetes in the NOD mouse can be
prevented by nicotinamide or by an infant formula
diet in which the protein source is replaced with
casein hydrolysate (Pregestimil) or soy protein
(Prosobee). NOD mice maintained on the standard
diet (chow and water) and given cyclophosphamide
(Cy) at day 95 develop accelerated and synchronised
diabetes within 14 days. Here, we compared the
ability of oral nicotinamide or Prosobee, either given
alone or concurrently, from weaning, in preventing
diabetes in the Cy model. The resulting insulitis and
the expression of intra‐islet inducible nitric oxide
synthase (iNOS) were examined at days 0, 4, 7, 11
and 14 following Cy administration. Intra‐islet CD4
and CD8 cells and macrophages were also enumerated
at day 11. In mice given the standard diet and
injected with Cy at day 95 (group 5), diabetes
developed in 7/11 mice, 14 days later. Mice exposed
to oral nicotinamide (group 2), Prosobee (group 3) or
both (group 4), did not develop the disease during
this period and until a further 30 days (p = 0.03). In
mice exposed to the standard diet and without Cy
treatment (group 1) the insulitis scores increased
slowly until day 11 and then declined slightly at day
14 whereas mice exposed to the same diet but given
Cy at day 95, showed a sharp decline at day 4
followed by a rapid increase between day 7–14.
However, in mice given either nicotinamide, Prosobee
or both, the insulitis scores at most time‐points
were generally lower than in Cy‐teated animals on
the standard diet. In the latter group, CD4 and CD8
cells and macrophages were also higher at day 11
than all other 4 groups (CD4: p < 0.05; CD8: p < 0.05;
macrophages: p < 0.0001). The number of iNOS
labelled cells increased progressively in mice on
the standard diet and given Cy and were significantly
higher at days 4, 7 and 11 than in the 3 dietary
groups. Thus, oral nicotinamide or Prosobee, either
alone or together, prevents Cy induced diabetes in
the NOD mouse. The protective diets suppress Cyinduced
intra‐islet immune cell influx and iNOS
expression.
Pentoxifylline Effects on Nerve Conduction Velocity and Blood Flow in Diabetic Rats
Authors: Flint Heather , Cotter Mary A. , Cameron Norman E.
Published: March 2007

Pentoxifylline has several actions that improve
blood rheology and tissue perfusion and may therefore
potentially be applicable to diabetic neuropathy.
The aims of this study were to ascertain whether 2
weeks of treatment with pentoxifylline could correct
nerve conduction velocity and blood flow deficits in
6‐week streptozotocin‐diabetic rats and to examine
whether the effects were blocked by co‐treatment
with the cyclooxygenase inhibitor, flurbiprofen, or
the nitric oxide synthase inhibitor, NG‐nitro‐ʟ‐arginine. Diabetic deficits in sciatic motor and saphenous
sensory nerve conduction velocity were 56.5%
and 69.8% corrected, respectively, with pentoxifylline
treatment. Sciatic endoneurial blood flow was
approximately halved by diabetes and this deficit
was 50.4% corrected by pentoxifylline. Flurbiprofen
co‐treatment markedly attenuated these actions of
pentoxifylline on nerve conduction and blood flow
whereas NG‐nitro‐ʟ‐arginine was without effect.
Thus, pentoxifylline treatment confers neurovascular
benefits in experimental diabetic neuropathy,
which are linked at least in part to cyclooxygenasemediated
metabolism.
Prevention of Diabetes in the NOD Mouse by Intra‐muscular Injection of Recombinant Adeno‐associated Virus Containing the Preproinsulin II Gene
Authors: Jindal Rahul M. , Karanam M. , Shah Rita
Published: March 2007

Using the Adeno‐associated virus (AAV) as a gene
delivery vehicle, we have constructed a recombinant
vector containing the full length rat preproinsulin
gene (vLP‐1). Utilizing the well described non‐obese
diabetic (NOD) mouse model, an experimental
group (n=10) of animals were intramuscularly (IM)
injected with 107 rAAV virions containing the
insulin gene and compared to a mock‐injected control
group (n=10). Blood glucose (glc) was then
measured weekly for 16 weeks. Data showed that
the experimental group contained 70% euglycemic
animals (defined as glc <200mg/dL) versus 10% of
the control animals (P<.05) at 14 weeks. Mean
weight in the treated group was greater than the
untreated group. Insulin mRNA was detected at the
injection site of all of the treated animals, but not
controls. Complete destruction of islets was confirmed
by histology ruling out the possibility of
spontaneous reversal of insulinitis. We conclude
that IM delivery of the insulin gene in the NOD
mouse was able to prevent clinical DM up to 14
weeks in a majority of treated animals. Our experimental
data suggests that gene therapy may be an
alternative treatment for IDDM in the future.
Proinsulin C‐peptide ‐ A Consensus Statement
Authors: Sima Anders A. F. , Grunberger George , Jörnvall Hans , Wahren John , The C-Peptide Study Group
Published: March 2007

In recent years the physiological role of the proinsulin
C‐peptide has received increasing attention,
focusing on the potential therapeutic value of
C‐peptide replacement in preventing and ameliorating
type 1 diabetic complications. In order to consolidate
these new data and to identify the immediate
directions of C‐peptide research and its clinical
usefulness, an International Symposium was held
in Detroit, Michigan, on October 20–21, 2000, under
the auspices of the Wayne State University/Morris
Hood Jr. Comprehensive Diabetes Center. In this
communication, we review the cellular, physiological
and clinical effects of C‐peptide replacement in
animal models and in patients with type 1 diabetes.
Finally, recommendations are presented as to the
most urgent studies that should be pursued to further
establish the biological action of C‐peptide and
its therapeutic value.
Substrate‐induced Nuclear Export and Peripheral Compartmentalization of Hepatic Glucokinase Correlates with Glycogen Deposition
Authors: Jetton Thomas L. , Shiota Masa , Knobel Susan M. , Piston David W. , Cherrington Alan D. , Magnuson Mark A.
Published: March 2007

Hepatic glucokinase (GK) is acutely regulated by
binding to its nuclear‐anchored regulatory protein
(GKRP). Although GK release by GKRP is tightly
coupled to the rate of glycogen synthesis, the nature
of this association is obscure. To gain insight into
this coupling mechanism under physiological stimulating
conditions in primary rat hepatocytes, we
analyzed the subcellular distribution of GK and
GKRP with immunofluorescence, and glycogen deposition
with glycogen cytochemical fluorescence,
using confocal microscopyand quantitative image
analysis. Following stimulation, a fraction of the GK
signal translocated from the nucleus to the cytoplasm.
The reduction in the nuclear to cytoplasmic
ratio of GK, an index of nuclear export, correlated
with a >50% increase in glycogen cytochemical
fluorescence over a 60min stimulation period. Furthermore,
glycogen accumulation was initially deposited
in a peripheral pattern in hepatocytes
similar to that of GK. These data suggest that a compartmentalization
exists of both active GK and the
initial sites of glycogen deposition at the hepatocyte
surface.
Human C‐peptide Dose Dependently Prevents Early Neuropathy in the BB/Wor‐rat
Authors: Zhang W. , Yorek M. , Pierson C. R. , Murakawa Y. , Breidenbach A. , Sima A. A. F.
Published: March 2007

In order to explore the neuroprotective and crossspecies
activities of.C‐peptide on type 1 diabetic
neuropathy, spontaneously diabetic BB/W‐rats were
given increasing doses of human recombinant Cpeptide
(hrC‐peptide). Diabetic rats received 10, 100,
500, or 1000 μg of hrC‐peptide/kg body weight/
day from onset of diabetes. After 2 months of hrC‐peptide
administration, 100 μg and greater doses
completely prevented the nerve conduction defect,
which was associated with a significant but incomplete
prevention of neural Na+/K+‐ATPase activity
in diabetic rats with 500 μg or greater C‐peptide replacement.
Increasing doses of hrC‐peptide showed
increasing prevention of early structural abnormalities
such as paranodal swelling and axonal degeneration
and an increasing frequency of regenerating
sural nerve fibers. We conclude that hrC‐peptide exerts
a dose dependent protection on type 1 diabetic
neuropathy in rats and that this effect is probably
mediated by the partially conserved sequence of the
active C‐terminal pentapeptide
The Diabetic Nephropathy and the Development of Hypertension in Rats
Authors: Zuccollo Adriana , Navarro Monica , Catanzaro Orlando
Published: March 2007

The present study was designed to examine the development
of hypertension in diabetic rats treated
with streptozotocin (STZ, 1mg/g bw). The rats were
studied at 3, 6, 9, 12 and 15 weeks. From the third
week the rats were divided in diabetic rats according
their glycemias and controls, along 15 weeks. After
the third week a group, of rats showed increased urinary
protein excretion (93, 134, 155 and 191%) compared
to controls. In this group of rats the urinary
kallikrein excretion was lower than control and the
systolic blood pressure became significantly elevated
between 3 and 6 weeks and persisted up to 15 weeks.
On the other hand a group of diabetic rats were normotensive
with urinary protein excretion similar to
controls and urinary kallikrein lower compared to
control but significantly higher compared diabetic
hypertensive rats. These data suggest that the association
of progressive diabetic nephropathy with abnormal
endothelium‐dependent vasodilation may
produce a high prevalence of hypertensive diabetes.
Characterization of Oxidative Stress in Various Tissues of Diabetic and Galactose‐fed Rats
Authors: Strother Robert M. , Thomas Tonya G. , Otsyula Mary , Sanders Ruth A. , III John B. Watkins
Published: March 2007

Rats fed a galactose‐rich diet have been used for
several years as a model for diabetes to study, particularly
in the eye, the effects of excess blood hexoses.
This study sought to determine the utility of galactosemia
as a model for oxidative stress in extraocular
tissues by examining biomarkers of oxidative
stress in galactose‐fed rats and experimentally‐induced
diabetic rats. Sprague‐Dawley rats were
divided into four groups: experimental control;
streptozotocin‐induced diabetic; insulin‐treated diabetic;
and galactose‐fed. The rats were maintained
on these regimens for 30 days, at which point the
activities of catalase, glutathione peroxidase, glutathione
reductase, and superoxide dismutase, as
well as levels of lipid peroxidation and reduced and
oxidized glutathione were determined in heart,
liver, and kidney. This study indicates that while
there are some similarities between galactosemic
and diabetic rats in these measured indices of oxidative
stress (hepatic catalase activity levels and hepatic
and renal levels of oxidized glutathione in
both diabetic and galactosemic rats were significantly
decreased when compared to normal), overall
the galactosemic rat model is not closely parallel to
the diabetic rat model in extra‐ocular tissues. In addition,
several effects of diabetes (increased hepatic
glutathione peroxidase activity, increased superoxide
dismutase activity in kidney and heart, decreased
renal and increased cardiac catalase activity)
were not mimicked in galactosemic rats, and glutathione
concentration in both liver and heart was
affected in opposite ways in diabetic rats and galactose‐
fed rats. Insulin treatment reversed/prevented
the activity changes in renal and cardiac superoxide
dismutase, renal and cardiac catalase, and hepatic
glutathione peroxidase as well as the hepatic
changes in lipid peroxidation and reduced and oxidized
glutathione, and the increase in cardiac glutathione.
Thus, prudence should be exercised in the
use of experimentally galactosemic rats as a model
for diabetes until the correspondence of the models
has been more fully characterized.
Leptin and Its Relation to Obesity and Insulin in the SHR/N‐corpulent Rat, A Model of Type II Diabetes Mellitus
Authors: Velasquez Manuel T. , Bhathena Sam J. , Hansen Carl T.
Published: March 2007

The spontaneously hypertensive/NIH‐corpulent
(SHR/N‐cp) rat is a genetic animal model that exhibits
obesity, metabolic features of hyperinsulinemia,
hyperglycemia, and hyperlipidemia, which are
characteristic of type II diabetes and mild hypertension.
To determine the role of leptin, the protein
product of the ob gene, in the development of obesity
and diabetes in this model, we measured
steady‐state circulating levels of leptin in obese and
lean SHR/N‐cp rats and examined the relation
between plasma leptin levels and metabolic variables
at the stage of established obesity in these animals.
Mean fasting plasma leptin concentration was
8‐fold higher in obese than in lean rats (p<0.01).
This was associated with a 6‐fold elevation in
plasma insulin in the obese group. Fasting levels of
plasma glucose, cholesterol, and triglyceride were
all significantly higher in obese rats than in lean
controls. Spearman correlation analysis showed a
significant positive correlation between plasma leptin
concentration and body weight among the animals
(r=0.73, p<0.01). Similarly, plasma insulin
concentration was significantly correlated with BW
in all animals (r=0.54, p<0.05). There was also a
significant positive.correlation between plasma leptin
and plasma insulin in the entire group (r=0.70,
p<0.01). However, this relationship was significant
only for lean rats but not for obese rats (r=0.59,
p<0.05 for lean rats, and r=0.23, p=NS, for obese
rats). Plasma leptin also correlated positively with
fasting plasma glucose (r=0.75, p<0.05), total cholesterol
(r=0.63, p<0.05), and triglyceride (r=0.67,
p <0.05). The marked elevation of plasma leptin in
obese SHR/N‐cp rats suggests that obesity in this
animal model is related to up‐regulation of the ob
gene. Circulating leptin appears to be one of the
best biological markers of obesity and that hyperleptinemia
is closely associated with several metabolic
risk factors related to insulin resistance in the
diabesity syndrome.
Effects of Aminoguanidine on Glomerular Basement Membrane Thickness and Anionic Charge in a Diabetic Rat Model
Authors: Yavuz Dilek Gogas , Ersöz Halil Önder , Tuncel Mürvet , Sargon Mustafa F. , Küçükkaya Belgin , Ahiskali Rengin , Akalin Sema
Published: March 2007

We investigated the effect of aminoguanidine (AG)
administration on GBM thickness, glomerular heparan
sulfate (HS) content, and urinary albumin and
HS excretion in diabetic rats. After induction of
diabetes, female Wistar rats were divided into 2
groups: Group AGDM (n=11) received 1g/L aminoguanidine
bicarbonate in drinking water, group DC
(n=12) was given only tap water. Control rats received
AG (group AGH, n=8) or tap water (group
HC, n=8). At the end of a period of 8 weeks,
urinary albumin and glycosaminoglycan (GAG)
excretion was detected. GBM heparan sulfate distribution
and count was determined under the electron
microscope. The AGDM group had lower
urinary albumin and GAG excretion than diabetic
controls. GBM thickness was increased in diabetic
rats compared to groups of AGDM and HC. In
AGDM group alcian blue stained particle distribution
and count in the GBM was similar to healthy
controls. In conclusion AG prevents the decrease
of anionic charged molecules in the GBM and
GBM thickening. This can be one of the mechanisms
by which AG decreases albuminuria in diabetic
rats.
Functional Enhancement of Electrofusion‐derived BRIN‐BD11 Insulin‐secreting Cells After Implantation into Diabetic Mice
Authors: Davies Emma L. , Abdel-Wahab Yasser H. A. , Flatt Peter R. , Bailey Clifford J.
Published: March 2007

Electrofusion‐derived BRIN‐BD11 cells are glucosesensitive
insulin‐secreting cells which provide an
archetypal bioengineered surrogate β‐cell for
insulin replacement therapy in diabetes mellitus,
5x106 BRIN‐BD11 cells were implanted intraperitoneally
into severely hyperglycaemic (>24mmol/l)
streptozotocin‐induced insulin‐treated diabetic
athymic nude (nu/nu) mice. The implants reduced
hyperglycaemia such that insulin injections were
discontinued by 5–16 days (<17mmol/l) and normoglycaemia
(<9mmol/l) was achieved by 7–20
days. Implanted cells were removed after 28 days
and re‐established in culture. After re‐culture for 20
days, glucose‐stimulated (16.7mmol/l) insulin
release was enhanced by 121% (p<0.001) compared
to non‐implanted cells. Insulin responses to
glucagon‐like peptide‐1 (10−9mol/l), cholecystokinin‐8 (10−8 mol/l) and L‐alanine (10 mmol/l) were
increased by 32%, 31% and 68% respectively
(p<0.05–0.01). Insulin content of the cells was 148%
greater at 20 days after re‐culture than before
implantation (p<0.001), but basal insulin release (at
5.6 mmol/l glucose) was not changed. After re‐culture
for 40 days, insulin content declined to 68% of
the content before implantation (p<0.01), although
basal insulin release was unchanged. However, the
insulin secretory responses to glucose, glucagonlike
peptide‐1, cholecystokinin‐8 and L‐alanine
were decreased after 40 days of re‐culture to 65%,
72%, 73% and 42% respectively of the values before
implantation (p<0.05–0.01). The functional
enhancement of electrofusion‐derived surrogate β‐cells that were re‐cultured for 20 days after implantation
and restoration of normoglycaemia indicates
that the in vivo environment could greatly assist β‐cell engineering approaches to therapy for diabetes.
Approaches to Type 1 Diabetes Prevention by Intervention in Cytokine Immunoregulatory Circuits
Authors: Suarez-Pinzon Wilma L. , Rabinovitch Alex
Published: March 2007

Type 1 (insulin‐dependent) diabetes mellitus, like other
organ specific autoimmune diseases, results from a disorder
of immunoregulation. T cells specific for pancreatic
islet ß cell constituents (autoantigens) exist normally but
are restrained by regulatory mechanisms (self‐tolerant
state). When regulation fails, ß cell‐specific autoreactive T
cells become activated and expand clonally. Current evidence
indicates that islet ß cell‐specific autoreactive T cells
belong to a T helper 1 (Th1) subset, and these Th1 cells
and their characteristic cytokine products, IFNγ and IL‐2,
are believed to cause islet inflammation (insulitis) and ß
cell destruction. Immune‐mediated destruction of ß cells
precedes hyperglycemia and clinical symptoms by many
years because these become apparent only when most of
the insulin‐secreting ß cells have been destroyed.
Therefore, several approaches are being tested or are
under consideration for clinical trials to prevent or arrest
complete autoimmune destruction of islet ß cells and
insulin‐dependent diabetes. Approaches that attempt to
correct underlying immunoregulatory defects in autoimmune
diabetes include interventions aimed at i) deleting ß
cell autoreactive Th1 cells and cytokines (IFNγ and IL‐2)
and/or ii) increasing regulatory Th2 cells and/or Th3 cells
and their cytokine products (IL‐4, IL‐10 and TGFßI).
High Insulin Requirements and Poor Metabolic Control do not Modify the Expression, Regulation and PKC Mediated Activation of the p21ras Pathway in PBMC from Type II Diabetic Patients
Authors: Rapoport M. J. , Levi O. , Weiss M. , Buchs A. , Ramot Y. , Aharoni D. , Mor A. , Elberg G. , Katz Y. , Weissgarten J.
Published: March 2007

Aims To asses whether clinically severe insulin
resistance and poor metabolic control in patients with
type II diabetes are associated with aberrant
expression or function of the p21ras pathway.

Methods We examined the expression and function
of the p21ras pathway in resting and activated PBMC
from 10 insulin treated patients with type II diabetes
characterized by high insulin requirements and poor
metabolic control (IR group) and 10 age and sex
matched well controlled patients treated by diet
alone or oral hypoglycemic medications (WC group).

Results Levels of p21ras and its regulatory
elements: p21rasGAP and hSOS1, were comparable
in the two groups. The induced activities of p21ras
and its associated down‐stream regulatory enzyme
MAP‐kinase following TPA stimulation were also
comparable in the IR and WC patients.

Conclusions Taken together, these data indicate that
clinically significant severe insulin resistance does
not modify the expression, regulation and activation
of p21ras pathway in PBMC of patients with type II
diabetes.
Streptozocin Diabetes Elevates all Isoforms of TGF‐β in the Rat Kidney
Authors: Lane Pascale H. , Snelling Dustin M. , Langer William J.
Published: March 2007

Transforming growth factor beta (TGF‐β) is a major
promoter of diabetic nephropathy. While TGF‐β1 is
the most abundaft renal isoform, types 2 and 3 are
present as well and have identical in vitro effects.
Whole kidney extracts were studied 2 weeks after
induction of streptozocin diabetes and in control
rats. Mean glomerular area was 25% greater in the
diabetic animals. TGF‐β1 showed a 2‐fold increase
in message with a 3‐fold increase in protein. TGF‐β2
mRNA increased approximately 6% while its
protein doubled. TGF‐β‐message increased by 25%,
producing a 35% increase in its protein. TGF‐β‐
inducible gene H3 mRNA was increased 35% in the
diabetic animals, consistent with increased activity
of this growth factor. All isoforms of TGF‐β are
increased in the diabetic rat kidney. Future studies
need to address the specific role that each isoform
plays in diabetic nephropathy as well as the impact
of therapies on each isoform.
Experimental Type 2 Diabetes Induces Enzymatic Changes in Isolated Rat Enterocytes
Authors: Martínez Isabel M. , Morales Inmaculada , García-Pino Guadalupe , Campillo José E. , Tormo María A.
Published: March 2007

Diabetes in humans and in experimental animals
produces changes in the function and structure of the
small intestine. The authors determined the activity of
intestinal disaccharidases (maltase and sucrase) and of
6‐phosphofructo‐1‐kinase (PFK‐1) in enterocytes isolated
from the small intestine of male Wistar rats (2.5 to 3 months
old) with experimental nonobese type 2 diabetes, induced by
streptozotocin (STZ) injection on the day of birth (n0‐STZ)
or on the 5th day of life (n5‐STZ), with different degrees
of hyperglycemia and insulinemia (n0‐STZ and n5‐STZ
models). The glycemia (mmol/L) of the diabetic rats
(n0‐STZ: 8.77 ± 0.47; n5‐STZ: 20.83 ± 0.63) was higher
(P < .01) than that of the nondiabetic (ND) rats
(5.99 ± 0.63); on the contrary, the insulinemia (ng/mL) was
significantly lower in both n0‐STZ (1.74 ± 0.53; P < .05)
and n5‐STZ (1.12 ± 0.44; P < .01) diabetic rats than in normal
rats (3.77 ± 0.22). The sucrase and maltase activities
(U/g protein) in diabetic rats (n0‐STZ: 89 ± 9 and 266 ± 12;
n5‐STZ: 142 ± 23 and 451 ± 57) were significantly higher
than those in the ND group (66 ± 5 and 228 ± 22). The
PFK‐1 activities (mU/mg protein) in the diabetic models
(n0‐STZ: 14.89 ± 1.51; n5‐STZ: 13.35 ± 3.12) were significantly
lower (P < .05) than in ND rats (20.54 ± 2.83). The
data demonstrated enzymatic alterations in enterocytes isolated
fromthe small intestine of n0‐STZ rats that are greater
(P < .05) than in the more hyperglycemic and hypoinsulinemic
n5‐STZ animals. The results also show that nonobese type 2–like diabetes in the rat produces modifications that
favor an increase in glucose absorption rates.
Hyperglycemia‐Induced Protein Kinase C Activation Inhibits Phagocytosis of C3b‐ and Immunoglobulin G–Opsonized Yeast Particles in Normal Human Neutrophils
Authors: Saiepour Daniel , Sehlin Janove , Oldenborg Per-Arne
Published: March 2007

The aim of this study was to investigate the effects of
elevated glucose concentrations on complement receptor–
and Fcγ receptor–mediated phagocytosis in normal human
neutrophils. D‐Glucose at 15 or 25 mM dose‐dependently
inhibited both complement receptor– and Fcγ receptor–
mediated phagocytosis, as compared to that at a normal
physiological glucose concentration. The protein kinase
C (PKC) inhibitors GF109203X and Go6976 both dose dependently
and completely reversed the inhibitory effect of
25 mM D‐glucose on phagocytosis. Complement receptor–
mediated phagocytosis was dose‐dependently inhibited by
the cell permeable diacylglycerol analogue 1,2‐dioctanoylsn‐
glycerol (DAG), an effect that was abolished by PKC
inhibitors. Furthermore, suboptimal inhibitory concentrations
of DAG and glucose showed an additive inhibitory effect
on complement receptor–mediated phagocytosis. The
authors conclude that elevated glucose concentrations can
inhibit complement receptor and Fcγ receptor–mediated
phagocytosis in normal human neutrophils by activating
PKCα and/or PKCβ, an effect possibly mediated by DAG.
Knockout Mice Challenge our Concepts of Glucose Homeostasis and the Pathogenesis of Diabetes
Authors: Kahn C. Ronald
Published: March 2007

A central component of type 2 diabetes and the metabolic
syndrome is insulin resistance. Insulin exerts a multifaceted
and highly integrated series of actions via its intracellular
signaling systems. Generation of mice carrying null mutations
of the genes encoding proteins in the insulin signaling
pathway provides a unique approach to determining the
role of individual proteins in the molecular mechanism of
insulin action and the pathogenesis of insulin resistance and
diabetes. The role of the four major insulin receptor substrates
(IRS1‐4) in insulin and IGF‐1 signaling have been
examined by creating mice with targeted gene knockouts.
Each produces a unique phenotype, indicating the complementary
role of these signaling components. Combined heterozygous
defects often produce synergistic or epistatic effects,
although the final severity of the phenotype depends
on the genetic background of the mice. Conditional knockouts
of the insulin receptor have also been created using the
Cre‐lox system. These tissue specific knockouts have provide
unique insights into the control of glucose homeostasis
and the pathogenesis of type 2 diabetes, and have led to development
of new hypotheses about the nature of the insulin
action and development of diabetes.
Effect of Gymnema montanum Leaves on Serum and Tissue Lipids in Alloxan Diabetic Rats
Authors: Ananthan R. , Latha M. , Ramkumar K. M. , Pari L. , Baskar C. , Bai V. Narmatha
Published: March 2007

The effect of Gymnema montanum leaves on alloxaninduced
hyperlipidemia was studied in male Wistar rats.
Ethanolic extract of G. montanum leaves was administered
orally and different doses of the extract on blood glucose,
serum and tissue lipids, hexokinase, glucose‐6‐phosphatase,
thiobarbituric acid–reactive substances (TBARS), hydroperoxides,
and glutathione in alloxan‐induced diabetic
rats were studied. G. montanum leaf extract (GLEt) at doses
of 50, 100, 200 mg/kg body weight for 3 weeks suppressed
the elevated blood glucose and lipid levels in diabetic rats.
GLEt at 200 mg/kg body weight was found to be comparable
to glibenclamide, a reference drug. These data indicate
that G. montanum represents an effective antihyperglycemic
and antihyperlipidemic adjunct for the treatment
of diabetes and a potential source of discovery of new orally
active agent for future therapy.
The Insulin‐Like Growth Factor System
Authors: Roith Derek Le
Published: March 2007

The insulin‐like growth factor (IGF) system in ubiquitous
and plays a role in every tissue of the body. It is comprised
of ligands, receptors and binding proteins, each with
specific functions. While it plays an essential role in embryonic
and post‐natal development, the IGF system is also
important in normal adult physiology. There are now numerous
examples of diseases such as diabetes, cancer, and
malnutrition in which the IGF system is a major player and,
not surprisingly, there are attempts to affect these disorders
by manipulating the system.
The Insulin‐Like Growth Factor System and Neurological Complications in Diabetes
Authors: Sima Anders A. F. , Li Zhen-guo , Zhang Weixian
Published: March 2007

The IGF system plays vital roles in neuronal development,
metabolism, regeneration and survival. It consists of
IGF‐I, IGF‐II, insulin, IGF‐I‐receptor, and those of IGF‐II
and insulin as well as IGF‐binding proteins. In the last
decades it has become clear that perturbations of the IGF
system play important roles in the pathogenesis of diabetic
neurological complications. In the peripheral nervous system
IGF‐I, insulin, and C‐peptide particularly in type 1 diabetes
participate in the development of axonal degenerative
changes and contributes to impaired regenerative capacities.
These abnormalities of the IGF system appear to be
less pronounced in type 2 diabetes, which may in part account
for the relatively milder neurological complications
in this type of diabetes. The members of the IGF system
also provide anti‐apoptotic effects on both peripheral and
central nervous system neurons. Furthermore, both insulin
and C‐peptide and probably IGF‐I possess gene regulatory
capacities on myelin constituents and axonal cytoskeletal
proteins. Therefore, replenishment of various members of
the IGF system provides a reasonable rational for prevention
and treatment of diabetic neurological complications.
Nerve Growth Factor and Diabetic Neuropathy
Authors: Pittenger Gary , Vinik Aaron
Published: March 2007

Neuropathy is one of the most debilitating complications
of both type 1 and type 2 diabetes, with estimates of prevalence
between 50–90% depending on the means of detection.
Diabetic neuropathies are heterogeneous and there is
variable involvement of large myelinated fibers and small,
thinly myelinated fibers. Many of the neuronal abnormalities
in diabetes can be duplicated by experimental depletion
of specific neurotrophic factors, their receptors or their
binding proteins. In experimental models of diabetes there
is a reduction in the availability of these growth factors,
which may be a consequence of metabolic abnormalities,
or may be independent of glycemic control. These neurotrophic
factors are required for the maintenance of the
neurons, the ability to resist apoptosis and regenerative capacity.
The best studied of the neurotrophic factors is nerve
growth factor (NGF) and the related members of the neurotrophin
family of peptides. There is increasing evidence
that there is a deficiency of NGF in diabetes, as well as the
dependent neuropeptides substance P (SP) and calcitonin
gene‐related peptide (CGRP) that may also contribute to
the clinical symptoms resulting from small fiber dysfunction.
Similarly, NT3 appears to be important for large fiber
and IGFs for autonomic neuropathy. Whether the observed
growth factor deficiencies are due to decreased synthesis, or
functional, e.g. an inability to bind to their receptor, and/or
abnormalities in nerve transport and processing, remains
to be established. Although early studies in humans on the
role of neurotrophic factors as a therapy for diabetic neuropathy
have been unsuccessful, newer agents and the possibilities
uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate
that neurotrophic factor therapy, specifically targeted
at different nerve fiber populations, might enter the therapeutic
armamentarium.
The Possible Role of Tumor Necrosis Factor‐α in Diabetic Polyneuropathy
Authors: Satoh Jo , Yagihashi Soroku , Toyota Takayoshi
Published: March 2007

In this review, the authors provide evidences that imply
the role of tumor necrosis factor‐α (TNF‐α) in the
pathogenesis of diabetic complications, especially diabetic
polyneuropathy. Under chronic hyperglycemia, endogenous
TNF‐α production is accelerated in microvascular and
neural tissues, which may undergo an increased microvascular
permeability, hypercoagulability, and nerve damage,
thus initiating and promoting the development of characteristic
lesions of diabetic microangiopathy and polyneuropathy.
Enhanced TNF‐α production may also promote
atherosclerosis due to increased insulin resistance and the
expression of adhesion molecules. Clinical application of
specific agents that suppress production and/or activity
of TNF‐α may inhibit the development and exacerbation
of chronic diabetic complications.
Growth Hormone (GH) Hypersecretion and GH Receptor Resistance in Streptozotocin Diabetic Mice in Response to a GH Secretagogue
Authors: Johansen Peter B. , Segev Yael , Landau Daniel , Phillip Moshe , Flyvbjerg Allan
Published: March 2007

The growth hormone (GH) and insulin‐like growth factor I (IGF‐I) axis were studied in streptozotocin (STZ) diabetic
and nondiabetic female mice following intravenous (IV) injection of the GH secretagogue (GHS) ipamorelin or
saline. On day 14, blood samples were obtained before and 10 minutes after the injection. Livers were removed and
frozen for determination of the mRNA expressions of the GH receptor, GH‐binding protein, and IGF‐I, and hepatic
IGF‐I peptide. Serum samples were analyzed for GH and IGF‐I. Following ipamorelin injection, the GH levels were
found to be 150 ± 35 μg/L and 62 ± 11 μg/L in the diabetic
compared to the nondiabetic mice (P < .05). Serum IGF‐I
levels were lower in diabetic than in nondiabetic animals, and rose after stimulation only in the nondiabetic animals.
Furthermore, hepatic GH resistance and IGF‐I mRNA levels and IGF‐I peptide were increased in nondiabetic animals
in response to GH stimulation, whereas the low levels per se of all these parameters in diabetic mice were unaffected. The study shows that STZ diabetic mice demonstrate a substantial
part of the clinical features of type 1 diabetes in humans, including GH hypersecretion and GH resistance. Accordingly,
it is proposed that STZ diabetic mice may be a better model of the perturbations of the GH/IGF‐I axis in diabetes
than STZ diabetic rats.
Circulating Glycated Albumin and Glomerular Anionic Charges
Authors: Londoño I. , Gingras D. , Bendayan M.
Published: March 2007

Aiming to discern the mechanisms by which circulating
glycated albumin alters the glomerular filtration properties
that lead to glomerular dysfunction in diabetes, the authors
studied the distribution and densities of anionic charges
through the rat glomerular wall upon intravascular infusion
of Amadori products, as well as in various conditions of
increased glomerular permselectivity. Polylysine‐gold was
used as the probe to reveal the anionic charges. The study
was carried on renal tissue sections of bovine serum albumin
(BSA)‐ and glycated BSA–injected, normoglycemic
animals. Results were generated through morphometrical
evaluations of the gold labeling. Changes in glomerular anionic
distribution were corroborated on renal tissue sections
of short‐ and long‐term diabetic rats and of normal newborn
rats, situations known for abnormal glomerular filtration.
Altered renal function in these conditions was clearly
associated with changes in glomerular anionic charges. On
the other hand, the infusion of glycated albumin in the circulation
of normal rats, though altering glomerular filtration
properties, did not modify the distribution and density of
the polylysine‐gold labeling through the glomerular basement
membrane. Thus, anionic charges seem not to be the
factor involved in the early changes of glomerular permeability
induced by circulating glycated albumin.
Association of Lower Genital Tract Inflammation With Objective Evidence of Endometritis
Authors: Peipert Jeffrey F. , Ness Roberta B. , Soper David E. , Bass Debra
Published: March 2007

The purpose of this report is to evaluate the association between lower genital tract inflammation and objectively diagnosed endometritis. We analyzed the first 157 patients enrolled in the PEACH
study, a multicenter randomized clinical trial designed to compare the effectiveness of outpatient and inpatient therapy for PID. Women less than 38 years of age, who presented with a history of
pelvic discomfort for 30 days or less and who were found to have pelvic organ tenderness (uterine or adnexal tenderness) on bimanual examination, were initially invited to participate. After recruitment
of the first 58 patients (group 1) we added the presence of leukorrhea, mucopurulent cervicitis, or untreated positive test for N. gonorrhoeae or C. trachomatis to the inclusion criteria (group 2, N = 99). We compared rates of endometritis in the two groups and calculated the sensitivity, specificity, and predicted values of the presence of white blood cells in the vaginal wet preparation. The rate of upper genital tract infection in group 1 was 46.5% (27/58) compared to 49.5% (49/99) in group 2. Microbiologic evidence of either N. gonorrhoeae or C. trachomatis increased from 22.4% in group 1 to 38.3% in group 2. The presence of Vaginal white blood cells or mueopus has a high sensitivity (88.9%), but a low specificity (19.4%) for the diagnosis of upper genital‐tract infection. Assessment of the lower genital tract for evidence of infection or inflammation is a valuable component of the diagnostic evaluation of pelvic inflammatory disease. The presence of either mucopus or vaginal white blood cells is a highly sensitive test for endometritis in patients with pelvic pain and tenderness. Infect. Dis. Obstet. Gynecol. 8:83–87, 2000.
In Vitro Inhibition of Commercial Douche ProductsAgainst Vaginal Microflora
Authors: Pavlova S. I. , Tao L.
Published: March 2007

Recently, vaginal douching has been associated with many health risks in women. The aim of this
study was to analyze the effect of commercial douche products against various vaginal microorganisms,
including lactobacilli. Seven commercial douches were tested against eight Lactobacillus
clinical isolates and three type strains from the American Type Culture Collection. BV‐associated
bacteria included six strains of five genera: Gardnerella, Mobiluncus, Mycoplasma, Peptostreptococcus,
and Ureaplasma. Two isolates of group B Streptococcus, and three species of Candida were also
tested. The minimal inhibition concentrations and minimal contact times for these products against
vaginal microorganisms were determined in broth cultures. Four antiseptic‐containing douche
products showed a strong inhibitory effect against all vaginal microorganisms tested with a short
contact time (less than 1 min). Three vinegar‐containing douche products selectively inhibited vaginal
pathogens associated with bacterial vaginosis, group B streptococcal vaginitis, and candidiasis, but not
lactobacilli. The antimicrobial effects of the commercial douche products varied among different brands
and microbial species tested. Infect. Dis. Obstet. Gynecol. 8:99–104, 2000.
Effect of Imiquimod on Cytokine Induction in FirstTrimester Trophoblasts
Authors: Manlove-Simmons Jerry M. , Zaher Fadi M. , Tomai Mark , Gonik Bernie , Svinarich David M.
Published: March 2007

Objectives: Imiquimod (IQ) is used clinically for the topical treatment of external genital warts. IQ
is an immune response modifier and induces the expression of interferon‐α and other cytokines in
human Peripheral Blood Monocytes (PBMC). Trophoblasts have been previously shown to express
inflammatory cytokines upon lipopolysaccharide (LPS) stimulation. The objective of this
study was to evaluate the ability of IQ to induce transcription of cytokines in trophoblasts.

Methods: A transformed human first trimester trophoblast cell line, HTR‐8/SVneo, was cultured
in DMEM containing IQ at concentrations of 0 to 5.0 μg/ml. 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐
diphenyl tetrazolium bromide (MTT) viability assays were conducted to control for any druginduced
cell death. Total RNA was isolated from trophoblasts at 0,8 and 24 hours of culture and
Reverse Transcription‐Polymerase Chain Reaction (RT‐PCR) was conducted using specific amplimers
for the inflammatory cytokines interleukin (IL)‐1α, IL‐1β, IL‐6 and IL‐8. RT‐PCR of
β‐actin was performed to control for equal RNA loading.

Results: RT‐PCR was unable detect an increase in either IL‐1α, IL‐1β, IL‐6 or IL‐8 mRNA in
first trimester trophoblasts cultured in the presence of 0 to 5.0 μg/mL of IQ for up to 24 hours.
RT‐PCR confirmed equal RNA loading and MTT viability assays did not show loss of cell viability
at concentrations of IQ up to 5.0 μg/ml.

Conclusions: IQ, at the concentrations tested, did not induce the transcriptional expression of
inflammatory cytokines in human first trimester trophoblasts. These data suggest that IQ would not
induce the expression of inflammatory cytokines in placental trophoblasts. Infect. Dis. Obstet.
Gynecol. 8:105–111, 2000.
Antifungal Activity of Local Anesthetics AgainstCandida Species
Authors: Pina-Vaz Cidália , Rodrigues Acácio Gonçalves , Sansonetty Filipe , Martinez-De-Oliveira J. , Fonseca António F. , Mårdh Per-Anders
Published: March 2007

Objective: To evaluate the activity of benzydamine, lidocaine, and bupivacaine, three drugs with
local anesthetic activity, against Candida albicans and non‐albicans strains and to clarify their
mechanism of activity.

Methods: The minimal inhibitory concentration (MIC) was determined for 20 Candida strains
(18 clinical isolates and two American Type Culture Collection strains). The fungistatic activity
was studied with the fluorescent probe FUN‐1 and observation under epifluorescence microscopy
and flow cytometry. The fungicidal activity of the three drugs was assayed by viability counts.
Membrane alterations induced in the yeast cells were evaluated by staining with propidium iodide,
by quantitation of intracellular k+ leakage and by transmission electron microscopy of intact yeast
cells and prepared spheroplasts.

Results: The MIC ranged from 12.5–50.0 μg/mL, 5.0–40.0 mg/mL, and 2.5–10.0 mg/mL for
benzydamine, lidocaine, and bupivacaine, respectively. The inhibitory activity of these concentrations
could be detected with the fluorescent probe FUN‐1 after incubation for 60 minutes. A very
fast fungicidal activity was shown by 0.2, 50, and 30 mg/mL of benzydamine, lidocaine, and bupivacaine,
respectively.

Conclusions: At lower concentrations, the tested drugs have a fungistatic activity, due to yeast
metabolic impairment, while at higher concentrations they are fungicidal, due to direct damage to
the cytoplasmic membrane. Infect. Dis. Obstet. Gynecol. 8:124–137, 2000.
Is Antenatal Group B Streptococcal Carriage aPredictor of Adverse Obstetric Outcome?
Authors: Garland Suzanne M. , Kelly Nigel , Ugoni Antony M.
Published: March 2007

Objectives: While early‐onset neonatal GBS sepsis is positively associated with premature birth and
prolonged rupture of membranes, there is debate in the literature as to whether maternal GBS
colonization is a predictor of adverse obstetric outcome. This is a critical issue to resolve for
appropriate management (expectant vs. interventional management) of the patient presenting with premature rupture of membranes, who has no overt signs of sepsis, but who is colonized with GBS.

Methods: Since 1981 it has been hospital policy to screen all public patients antenatally for genital
carriage of GBS by collection of a low vaginal swab at 28–32 weeks. All patients colonized with GBS antenatally are given penicillin as intrapartum chemoprophylaxis. Review of all GBScolonized
antenatal patients for a 12‐month period (580 of 4,495 patients) and a randomized (every fourth consecutive antenatal patient) number of noncolonized patients (958) was made. Lower vaginal GBS colonization and other risk factors for preterm delivery were assessed using univariate and multivariate generalized linear modeling.

Results: In the study group, the maternal GBS colonization rate was 12.9%. When cofounding
variables were controlled in a multivariate analysis, the association between antepartum GBS colonization and preterm labor and preterm rupture of membranes was not significant.

Conclusion: Maternal antenatal carriage of GBS does not predict preterm labor. Therefore it is appropriate that expectant management occur for a GBS‐colonized woman who ruptures her membranes, is not in labor, and has no evidence of sepsis. Infect. Dis. Obstet. Gynecol. 8:138–142, 2000.
Use of Methergine for the Prevention ofPostoperative Endometritis in Non‐Elective CesareanSection Patients
Authors: Dweck Murray F. , Lynch Catherine M. , Spellacy William N.
Published: March 2007

Objective: Methergine increases constriction of uterine musculature which may facilitate sloughing
of endometrial debris, close uterine vessels, and prevent post‐cesarean endometritis. The objective
of this study was to evaluate the efficacy of methergine in preventing endometritis in patients
undergoing non‐elective cesarean section delivery.

Methods: Eighty patients undergoing non‐elective cesarean section were enrolled in a prospective
randomized clinical trial of methergine (41) versus no methergine (39) administration during the
postpartum period. The hospital records were abstracted after discharge to compare the postpartum
course.

Results: There were no significant demographic differences between the two groups. The women
receiving methergine had a significant reduction in the rate of postoperative endometritis (10% vs.
36%, P < 0.005). In addition, the mean postoperative hemoglobin was significantly higher in the
methergine treated group (P < 0.001).

Conclusions: The use of methergine postpartum in women undergoing non‐elective cesarean
sections significantly reduces the incidence of postoperative endometritis and blood loss. Infect. Dis.
Obstet. Gynecol. 8:151–154; 2000.
Determinants of Incident Vulvovaginal Candidiasis inHuman Immunodeficiency Virus‐Positive Women
Authors: Shifrin Emma , Matityahu Debra , Feldman Joseph , Minkoff Howard
Published: March 2007

Objective: Mucosal infections including vulvovaginal candidiasis are a common problem for women
with human immunodeficiency virus (HIV) infection. Our objective was to determine which factors
predict the development of symptomatic disease among HIV‐infected women.

Materials and Methods: In a prospective study from 1991 to 1995, 205 HIV‐positive women were
evaluated every 6 months for occurrences of vulvovaginal candidiasis. Included in the study were
all initially asymptomatic women, whether they were fungal‐culture‐positive or ‐negative at baseline.
Excluded from the study were all women with symptomatic vulvovaginal candidiasis at the
initial visit, those who developed trichomonas vaginitis at any visit, and those who used any antifungal
agents.

Results: The risk of the development of vulvovaginal candidiasis did not differ between women
who were asymptomatically colonized at baseline and those who were fungal‐culture‐negative.
However, the risk of developing vulvovaginal candidiasis was increased 6.8 times for women with
CD4 counts less than 200 cells/mm3 at baseline.

Conclusions: Fungal culture is not predictive of the development of symptomatic vulvovaginal
candidiasis. Women infected with HIV who have CD4 counts below 200 cells/mm3 should be
monitored more carefully for vulvovaginal candidiasis. Infect. Dis. Obstet. Gynecol. 8:176–180,
2000.