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The Effect of
Ipomoea batatas
(Caiapo) on Glucose
Metabolism and
Serum Cholesterol in
Patients With Type 2
Diabetes
A randomized study
There is considerable
and growing interest
in neutraceutical
products for
the treatment of
diabetes (1). Recently,
it has been shown that
caiapo, the
extract of white-skinned
sweet potato
(Ipomoea batatas),
improves glycemic
control in rodents by
reducing insulin
resistance
(2). The aim of our
study was to
assess the effect of
caiapo on glucose
metabolism
and its tolerability and
mode of
action in male Caucasian
type 2 diabetic
patients in a
randomized, double-blind
prospective study in
parallel groups
controlled
with placebo.
A total of 18 male type
2 diabetic patients
(age: 58 8 years;
weight: 88 3
kg; BMI: 27.7 2.7 kg/m2;
means
SEM) treated by diet
alone were randomized
to receive placebo or 2
(low dose) or
4 g (high dose) caiapo
(four tablets each
containing 168 or 336 mg
powdered
white-skinned sweet
potato [I. batatas],
respectively) before
breakfast, lunch, and
dinner for 6 weeks. The
study protocol
was approved by the
Ethics Committee of
the University of
Vienna, and informed
consent was obtained
from all patients before
inclusion into the
study. Safety parameters
(hematology and blood
chemistry, including
hepatic enzymes
and urinanalysis) were
controlled before
and at the end of the
study, and patients
were asked to report any
adverse events.
Patients were seen
weekly during the
6-week trial, and
fasting blood glucose
was measured. Each
subject underwent a
frequently sampled
intravenous glucose
tolerance test (FSIGT)
in randomized order
before and after 6 weeks
of caiapo
administration for
measurement of insulin
sensitivity. Plasma
glucose was measured
using glucose oxidase
(Glucose
Analyzer II; Beckman,
Fullerton, CA) and
plasma insulin
(coefficents of
variation:
8%) by radioimmunoassay
(Pharmacia-
Upjohn, Uppsala,
Sweden).
The FSIGT was performed
according
to the protocol used for
the analysis with
the minimal model of
glucose disappearance
(3). FSIGT data were
analyzed by the
minimal model method
(4), and the insulin
sensitivity index (SI;
min 1 U–1
ml–1), which describes
the ability of insulin
to promote glucose
disappearance,
was obtained.
The comparison among the
values of
the biochemical
parameters of the three
groups before and after
treatment was
evaluated by analysis of
variance. In every
group, paired Student’s
t test was used to
assess the statistical
significance of the
differences
of insulin sensitivity.
The statistical
evaluation was performed
using the
computer programs
Statview (Abacus,
Berkley, CA) and S-plus
(Insightful, Seattle,
WA). Data are expressed
as means
SEM.
The biochemical
parameters before
and after treatment
(Table 1) show a
decrease
(P 0.05) of fasting
plasma glucose
as well as of
cholesterol (total and
LDL cholesterol) after 6
weeks of treatment
with high-dose caiapo.
No statistically
significant changes
occurred after
treatment with low-dose
caiapo or placebo.
Body weight and blood
pressure remained
unchanged in all three
groups. In
patients receiving
low-dose caiapo, the
FSIGT demonstrated an
increase of SI by
37% (2.02 0.70 vs. 2.76
0.89 104
min 1 U–1 ml–1, P 0.05);
in those
on high-dose caiapo, the
FSIGT demonstrated
an increase of SI by 42%
(1.21
0.32 vs. 1.73 0.40 104
min 1 U–1
ml–1, P 0.03). No
changes were seen for
SI in patients receiving
placebo (1.52
0.28 vs. 1.35 0.21 104
min 1 U–1
ml–1).
No adverse events have
been reported
by the patients. The
results of the
hematology
and blood chemistry,
including hepatic
enzymes (except for
glucose and
cholesterol [Table 1])
and urinanalysis,
were not altered by 6
weeks of treatment
with caiapo. Body weight
remained stable.
This pilot study
demonstrates that
ingestion
of 4 g caiapo/day for 6
weeks reduces
fasting blood glucose
and total as
well as LDL cholesterol
in male Caucasian
type 2 diabetic patients
previously treated
by diet alone. The
improvement of insulin
sensitivity in the FSIGT
indicates that caiapo
exerts its beneficial
effects via reducing
insulin resistance. The
treatment was
well tolerated, with no
apparent side
effects.
The increase of insulin
sensitivity has
been observed for both
the low- and the
high-dose caiapo group
according to the
FSIGT data. The results
of the dynamic
study (FSIGT) indicate
that an increase of
insulin sensitivity
independent of body
weight seems to be the
mechanism responsible
for the improvement of
metabolic
control with caiapo
administration.
This mechanism of action
is supported by
beneficial changes in
hyperinsulinemia
(by 50%), free fatty
acids, and glucose
tolerance
in response to 100 mg
kg–1 day–1
caiapo powder in obese
Zucker fatty rats
(2). In this model, this
effect was similar
to the effect of
treatment with 50 mg
kg–1
day–1 troglitazone. The
direct effect on
insulin sensitivity was
demonstrated in
this study by an
enhanced 14C-glucose
uptake in isolated
adipocytes. Parallel
histological
examinations of the
pancreas
showed a remarkable
regranulation of
pancreatic B-cells.
Contrary to
troglitazone,
no weight gain could be
seen after
caiapo treatment in the
animals.
Recently, the
antidiabetic component
of caiapo was isolated
as an acidic
glycoprotein
(5) that is currently
subject to further
characterization.
Unexpectedly, a
simultaneous lowering of
total and LDL
cholesterol was observed
after treatment
with high-dose caiapo in
our study. This
effect could be
independent of improved
insulin sensitivity and
suggests that caiapo
also could contain more
than one
metabolically active
ingredient. In regard
to triglyceride levels,
no significant
changes were observed,
despite an improvement
of insulin resistance.
This
might be due to the
relatively short period
of the study.
Despite careful
randomization, the
subjects in the
high-dose group showed
higher insulin levels,
whereas those in the
low-dose group were
leaner and more insulin-
sensitive compared with
those in
the high-dose and
placebo groups. We
cannot exclude that the
higher baseline
insulin level of
high-dose subjects might
have predisposed these
subjects to a better
treatment effect. In
this regard, however,
it is remarkable that
low-dose caiapo
exerted its effect on
insulin sensitivity,
even in those moderately
insulin-resistant
patients, which further
supports the contention
of caiapo as an
insulin-sensitizing
agent.
In conclusion, this
pilot study shows
beneficial effects of
high-dose caiapo on
plasma glucose and total
as well as LDL
cholesterol levels in
patients with type 2
diabetes. These effects
relate to a decrease
in insulin resistance,
as also described in
rodents (2), and were
observed without
affecting body weight or
causing side effects.
Therefore, the results
of this pilot
study indicate that
caiapo could potentially
play a role in the
treatment of type 2
diabetes.
Tissue Polypeptide–
Specific Antigen
Serum
Concentrations in
Children,
Adolescents, and
Young Adults With
Type 1 Diabetes
Tissue
polypeptide–specific
antigen
(TPS) is a marker of
proliferation activity
(1–3). Because diabetes
is
characterized by
proliferative lesions in
various organs, we
hypothesized that serum
TPS concentrations might
be elevated
in young patients with
type 1
diabetes. Thus, for the
first time, serum
TPS concentrations in
young patients
with type 1 diabetes
were determined and
compared with those of
age-matched
healthy control
subjects. Furthermore,
their relation to age,
sex, BMI, Tanner
stage, insulin
requirements, existence
of
complications, and
duration and metabolic
control of the disease,
as expressed
by HbA1c, were
investigated. This study
was approved by the
institutional ethics
committee, and informed
consent was
obtained.
We investigated 97
subjects, 60 with
type 1 diabetes (29 male
and 31 female
subjects) and 37 healthy
control subjects
(18 male and 19 female
subjects). Those
with type 1 diabetes
were recruited
consecutively
during the study period
(January
2000 to December 2000)
from the
patients attending our
Diabetes Center.
Control subjects were
healthy siblings
and young students. The
subjects’
characteristics
appear in Table 1.
Pubertal status,
assessed through Tanner
staging, was in
accordance with age in
both groups. Five
type 1 diabetes patients
presented complications
(microalbuminuria, overt
proteinuria,
or retinopathy).
Fasting serum TPS
concentrations
were measured by a
sequential
chemiluminescent
enzyme-labeled
immunometric
assay and were found to
be
significantly higher
(means SD) in type
1 diabetes patients
compared with
healthy control subjects
(54.38 33.27
vs. 29.03 13.10 units/l
[95% CI 15.8–
34.9]; P 0.0005), even
when excluding
patients with
complications from the
analysis (53.12 32.80
vs. 29.03 13.10 units/l;
P 0.0005). Serum TPS
concentrations were
significantly correlated
with HbA1c (r 0.26; P
0.042). A
significant correlation
was also found in a
multiple regression
model between serum
TPS concentrations and
HbA1c (P
0.047; adjusted R2 0.05;
B 4.5; SE[B]
2.2; CI 95% 0.06–8.9)
when HbA1c,
age, and BMI were
introduced as
independent
variables. No other
correlation
existed between serum
TPS concentrations
and age, sex, BMI,
Tanner stage, disease
duration, insulin
requirements, or
the presence of
complications with
bivariate
linear regression
analysis. Also, no
significant difference
existed in serum
TPS concentrations at
different categories
of HbA1c, age, disease
duration, and insulin
requirements.
The results of this
study indicate that
serum TPS concentrations
are elevated in
young patients with type
1 diabetes compared
with healthy control
subjects and
depend significantly on
the metabolic
control of the disease.
Rebhandl et al. (4)
found that serum
TPS concentrations in
healthy subjects
aged 8–18 years do not
differ from those
in adults, and no
significant differences
exist between male and
female subjects,
findings confirmed in
this study also for
type 1 diabetes
patients. Furthermore,
serum
TPS concentrations do
not seem to
depend on the duration
of the disease, but
rather on its metabolic
control, although
the latter accounts for
only 5% of TPS
variance among
individuals in our
study.
In conclusion, the high
serum TPS
concentrations in young
patients with
type 1 diabetes—even
before disease
complications are
evident—and the
significant
correlation with the
metabolic
control of the disease
argue for further
studies that include
greater numbers of
individuals presenting
complications of
type 1 diabetes in order
to elucidate the
underlying mechanisms
and evaluate
whether serum TPS
concentrations could
serve as a reliable
marker for disease
progression.
The Effect of Qi-Gong
Relaxation Exercise
on the Control of
Type 2 Diabetes
Mellitus
A randomized controlled
trial
Qi-gong relaxation
exercise is one of
the traditional Chinese
health care
self-management
technique. It consists
of two aspects,
controlled synchronized
breathing with slow body
movements as an aerobic
exercise, and relaxation
(1). The purpose of this
study
was twofold: to examine
the effects of Qigong
and to identify
biological and
psychological
characteristics
associated with
a positive response to
therapy.
The study used a paired
group design
with age- and
sex-matched participants
randomly assigned to one
of two groups.
Of the 554 eligible
patients, 36 type 2
diabetic
subjects were randomized
to the
study. This study was
ethically approved
by the board of
directors of the Science
Clinic, and informed
consent was obtained
from all 36 patients.
For a variety of
reasons, 10 of these
subjects were excluded
from analysis, resulting
in data reported
on 26 participants.
Group 1 (16
patients, aged 65.3 7.7
years) received
the initial 4-month
intervention, whereas
group 2 (10 patients,
aged 59.1 9.0
years) served as a
control group. Then,
the intervention was
repeated for the second
group. Weekly 2-h
Qi-gong group
sessions were held by a
Chinese Qi-gong
doctor, and subjects
were also requested
to practice Qi-gong at
home. Conventional
diabetes therapies, such
as pharmacotherapy
band dietary and
exercise treatment, were
not modified during the
study period.
HbA1c levels were
measured. It
changed as follows: 8.13
1.73 before
treatment and 7.33 1.09
after treatment
in group 1, and 8.29
1.63 before
the control period, 8.17
1.30 before
treatment, and 7.23 0.90
after treatment
in group 2. Compared
with the control
period of group 2, the
group 1
patients demonstrated
significant improvement
in HbA1c level (P 0.01)
by
analysis of covariance
using pretreatment
HbA1c as a covariate. In
group 2, HbA1c
levels significantly
decreased by the delayed
treatment, indicated by
a one-way
layout analysis of
variance (F 7.26; P
0.005). Using Tukey’s
HSD multiple
comparison test, no
significant change
was found between values
before and after
the control period, but
a significant
improvement was
ascertained between
values before control
and after treatment
(P 0.01) and between
values before and
after treatment (P
0.05). The changes in
other biological and
psychological factors
in the combined data of
groups 1 and 2
were compared using
paired t tests or
Wilcoxon signed-rank
tests. Whereas
there were no
significant changes in
caloric
intake, caloric
consumption, BMI,
and lipid metabolism,
significant improvements
in C-peptide (P 0.05)
were
demonstrated. Some
psychological
improvements
were demonstrated,
including
the anxiety index (P
0.05) and total
scores (P 0.05) of the
Mood Inventory
(2). The improvement in
HbA1c could be
predicted (total 86.3%
variance; F
25.145; P 0.0001) by
higher pretreatment
HbA1c (70.8%; P 0.0001),
younger age (6.6%; P
0.002), trend of
obesity (2.2%; P 0.01),
stronger selfefficacy
(3) (2.5%; P 0.08), and
weaker
personality trait of
alexithymia, which
means difficulty in
identifying and
describing
one’s own emotions (4)
(1.9%;
P 0.04), on multiple
regression analysis.
Because obese patients
benefited
more and the significant
decrease in Cpeptide
was demonstrated in this
study,
Qi-gong may improve
insulin resistance.
On the other hand,
several studies
described
the effects of
relaxation training
for type 2 diabetes
(5–8); thus, Qi-gong
can improve glucose
metabolism by the
benefits of relaxation
response. In conclusion,
these findings suggest
that Qi-gong
relaxation exercise may
be a beneficial
adjunctive
treatment for
individuals with
type 2 diabetes.
Leukocytoclastic
Vasculitis Induced by
Subcutaneous
Injection of Human
Insulin in a Patient
With Type 1
Diabetes and
Essential
Thrombocytemia
Both local (1) and
systemic immediatetype
insulin allergy (2) as
well as delayed-
type cutaneous reactions
(3)
to human insulin have
been reported.
Histologically verified
Arthus reaction to
insulin has only been
reported in exceptional
cases in which the
patient was
treated with
bovine/porcine insulin
(4).
To the best of our
knowledge, no
histologically
verified type 3
hypersensitivity
reaction has been
described in a patient
treated with human
insulin.
We report a case of
leucocytoclastic
vasculitis in a
48-year-old
normal-weight
female patient with
well-controlled
(HbA1c 6.4, upper normal
6.4%) type 1
diabetes since 1984 who
had always been
treated with 0.5 units
kg 1 body wt
day 1 semisynthetic
human insulin and,
beginning in 1998,
recombinant human
insulin. The patient did
not have microvascular
complications (normal
fundoscopy,
urinary albumin, and
vibration
perception threshold).
She presented October
1997 with monophasic
tender indurations
at the injection sites
of both
human regular and NPH
insulins (Novo
Nordisk) in the
abdominal and femoral
regions, respectively,
with occurrence
within 2–6 h of
injection and
persistence
from 1 to 3 days, later
(May 1998) preceded
by intense itching and
redness, but
no wheal-and-flare
immediately after
injection.
A macular skin redness
of between
1 and 2 cm was observed,
and the
indurations in the
subcutaneous tissue
developed into nodules
after 3–4 days.
These lesions were
independent of injection
site, and switching to
other insulin,
insulin analogs, as well
as continuous
subcutaneous insulin
infusion was
ineffective.
After 3 years, the
condition had
become incapacitating,
requiring repeated
injections of Humalog
(Eli Lilly)
5–6 times a day,
including one injection
at 3:00 A.M., as the
best-tolerated insulin
therapy.
Intradermal insulin skin
testing (insulin
allergy kit; Novo
Nordisk, Bagsværd,
Denmark) showed
reactions
toward human, porcine,
and bovine insulin
but no reactions to
protamine or other
additives. IgG but not
IgE insulin antibodies,
with a binding capacity
of 28%,
were demonstrated. In
vitro lymphocyte
proliferation was not
induced with human
insulin. Skin biopsies
from 5-h and
5-day-old lesions showed
perivascular
and interstitial
infiltration with
neutrophilic
and eosinophilic
granulocytes and
with considerable
amounts of nuclear
dust and swollen
endothelial cells,
granulocytic
infiltration, and fibrin
deposition
as well as localized
extravasation of
erythrocytes
in the vascular walls,
indicating
leucocytoclastic
vasculitis. Other tests
included:
thrombocytosis (841 109
l 1)
and leukocytosis (19 109
l 1) with neutrophilia;
hyperplastic bone marrow
with
scattered megakaryocytes
(normal); and
normal ultrasound scan
of the abdominal
region and
retroperitoneum, with
special
attention to the spleen
and lymph nodes.
The following normal lab
test were also
normal: hemoglobin;
sedimentation rate;
C-reactive protein;
serum creatinine; liver
enzymes; 24-h urinary
albumin; IgA, IgG,
and IgE antibodies;
eosinophil counts;
Mcomponent;
cryoglobulins;
antinuclear
antibodies; IgM/IgA
rheumatoid factor;
anti-cardiolipin
antibodies; and
antineutrophil
cytoplasmic antibodies.
Immunosuppressive
therapy was
started February 2000,
with prednisolone
10 mg once daily and,
initially, azathioprine
50 mg daily, which was
later substituted
with methotrexate 7.5–15
mg once
weekly because of antral
gastritis. This
treatment induced
complete regression of
symptoms and lesions
within 8 weeks,
and the patient resumed
work, maintaining
optimal glycemic control
on recombinant
human regular and NPH
insulin
(Novo Nordisk). The
differential count
and IgG insulin
antibodies—but not the
thrombocytemia—normalized
during
immunosuppression.
Aspirin therapy
was instituted because
of thrombocytosis.
Leucocytoclastic
vasculitis, which
exclusively
or primarily involves
the skin, is
often seen in other
systemic diseases, such
as subacute bacterial
endocarditis, Epstein-
Barr virus infection,
chronic active
hepatitis, ulcerous
colitis, diseases of the
complement system,
retroperitoneal
fibrosis,
primary biliary
cirrhosis, or
myeloproliferative
diseases. In this case,
essential thrombocytosis
is the most likely
diagnosis because
thrombocytosis but not
neutrophilia persisted
during immunosuppressive
therapy. It is therefore
conceivable
that the
myeloproliferative
disorder predisposed to
a B-lymphocyte
clonal abnormality,
leading to antibody
formation against human
insulin and secondarily
leukocytoclastic
vasculitis.
The bone marrow findings
were not
discriminative as to the
question of
whether thrombocytosis
was primary or
secondary. Platelet
morphology, leukocyte
differentiation markers,
and chromosomal
studies were not carried
out
because these studies
would not have
been definitive.
However, the clinical
course of persistent
thrombocytosis, despite
complete clinical
remission and
elimination of insulin
antibodies, speaks
strongly in favor of
essential thrombocytosis
as the underlying
disorder.
Lymphocyte proliferation
toward human
or analog insulin was
not detected.
This is in accordance
with previous findings
that T-cell reactivity
to human insulin
detected by in vitro
lymphocyte
transformation in
patients with insulin
allergy
is usually much weaker
than lymphocyte
transformation toward
beef or
pork insulin in patients
with immune reactivity
toward these species of
insulin
(5). Furthermore, the
antigen may be the
insulin dimer rather
than the insulin
monomer, also
contributing to explain
the lack of lymphocyte
proliferation to
human insulin in this
patient.
Smoking and
Microalbuminuria
A case-control study in
African-
Americans with type 2
diabetes
African-Americans are at
increased
risk of diabetic
nephropathy (1,2).
Cigarette smoking has
been shown
to increase the risk of
microalbuminuria
in Caucasian populations
with type 1 and
type 2 diabetes (3–6).
In contrast, despite
their high risk of
nephropathy, the
association
between cigarette
smoking and
microalbuminuria in
African-Americans
with diabetes has not
previously been
assessed.
We conducted a
case-control
study to examine the
association between
lifetime cigarette
smoking history and risk
of prevalent
microalbuminuria in
patients
with recently diagnosed
type 2 diabetes.
Our study population was
African-
American patients with
type 2 diabetes
duration 2 years who had
an initial visit
to the Grady Diabetes
Clinic in Atlanta,
Georgia, between January
1994 and December
1996. The present study
is partially
based on secondary data
from a cross-sectional
analysis of this study
population,
which has been
previously described
in detail (7). We
excluded
patients missing urine
albumin and/or
urine creatinine
measurements and
patients
with clinical
nephropathy (urine
albumin-
to-creatine [Alb/Cr]
ratio 250
g/mg). Serum and urine
creatinine were
measured in a random
morning urine
specimen at the first
clinic visit. Patients
were divided into two
groups based on
Alb/Cr ratios:
normoalbuminuria (Alb/Cr
25 g/mg) or
microalbuminuria (Alb/Cr
from 25 to 250 g/mg)
(8). All 246
microalbuminuric
patients were case
subjects;
based on a priori power
calculations,
506 control subjects
were randomly sampled
from the 766
normoalbuminuric
patients.
Lifetime smoking history
was obtained
via telephone interview
by three
trained and blinded
interviewers. Patients
were classified as
smokers if they had
smoked at least 100
cigarettes in their
lifetime
and had ever smoked on a
regular
basis for at least 6
months, and number of
pack-years smoked was
estimated. Before
the interview, informed
consent was obtained
from all participants,
and the
Emory University Human
Investigations
Committee approved the
study. Multiple
logistic regression was
done to assess the
relation between
microalbuminuria status
(yes or no) and
pack-years of cigarettes
smoked before diabetes
diagnosis
while controlling for
other clinical
variables.
The Alb/Cr ratio was
calculated for
1,055 (90.4%) of the
1,167 initially eligible
patients; 43 (4.1%) with
evidence of
clinical nephropathy
(Alb/Cr 250 g/
mg) were excluded. Of
the remaining
1,012 patients, 246
(23.3%) had
microalbuminuria
(case subjects), and 766
(72.6%) had
normoalbuminuria
(control
subjects). We
interviewed 138 (56.1%)
of
the case subjects and
297 (58.7%) of the
control subjects.
Patients interviewed
were older than patients
not interviewed
(mean age 53.5 vs. 48.4
years, P
0.0001), had slightly
shorter diabetes
duration
(mean 0.37 vs. 0.44
years, P
0.04), and had higher
HDL cholesterol
levels (mean 44.7 vs.
42.6 mg/dl, P
0.04). The proportion of
women was statistically
significantly higher in
the interviewed
group (71.5 vs. 60.9%).
There
were no differences in
mean arterial blood
pressure or HbA1c. Among
the 435 case
and control subjects who
completed the
interview, the mean
diabetes duration
was just under 5 months,
the mean age
was 53.5 13 years, the
mean BMI was
33.7 8.9 kg/m2, and the
mean number
of years of school
completed was 10.7
2.9. Case subjects had
significantly higher
mean arterial blood
pressures (P 0.002)
and triglycerides (P
0.03) as well as
trends toward fewer
years of education
(P 0.06) and higher BMI
(P 0.06)
than control subjects.
Pack-years of cigarette
smoking was
higher among case than
control subjects
(mean pack-years 15.1
23.0 for case
subjects vs. 11.1 18.8
for control subjects),
but this difference was
not statistically
significant (P 0.17).
Among
current smokers, mean
pack-years was
significantly higher for
case than for control
subjects (34.3 20.9 vs.
22.7
17.7, P 0.007) and was
also significantly
higher among case than
control
subjects when only
looking at ever smokers
(30.2 24.6 for case
subjects vs.
23.9 21.4 for control
subjects, P
0.03). Forty-eight
percent of our
population
either currently smoked
or were exsmokers.
After excluding patients
with estimated
creatinine clearance 250
ml/min
(n 12) from the multiple
logistic regression
analysis, the number of
reported
pack-years of smoking
was independently
associated with
increased risk of
prevalent
microalbuminuria,
controlling
for HbA1c, mean arterial
blood pressure,
age, self-reported
hypertension, and
diabetes
duration. Estimates from
the final
model showed that each
increase of 10
pack-years of smoking
corresponded to a
14% increase in
microalbuminuria risk
(odds ratio [OR] 1.14,
95% CI 1.03–
1.26). An increase of 40
pack-years of
smoking corresponded to
an OR of 1.69
(95% CI 1.12–2.56).
There was evidence
of a linear
dose-response, with
microalbuminuria
risk increasing as
packyears
increased (Table 1).
This case-control study
is the first to
examine the relation
between lifetime
cigarette
smoking, measured in
pack-years,
and microalbuminuria
prevalence in African-
Americans with
recent-onset type 2
diabetes. Pack-years of
cigarettes smoked
until diabetes diagnosis
was independently
related to prevalence of
microalbuminuria
in these patients while
controlling for
HbA1c, age, mean
arterial blood pressure,
hypertension, and
diabetes duration.
Several limitations
should be noted
when interpreting our
results. First, there
is the potential for
misclassification of
both exposure and
outcome.Werelied on
self-reported lifetime
smoking histories to
calculate the main
exposure, pack-years.
Our use of a single
Alb/Cr ratio may have
misclassified the
microalbuminuria status
of some patients.
Misclassification of
normo- and
microalbuminura in our
study is likely to be
random and independent
of the main exposures,
biasing our
ORs toward the null.
Blood pressure was
only measured once, so
we could not assess
patients’ long-term
blood pressure
patterns. Data on the
use of antihypertensive
medications was
incomplete in the
database, and thus we
relied on selfreported
hypertensive status from
the
telephone interview. In
particular, we did
not have complete data
on ACE inhibitor
use in this population;
ACE inhibitors are
known to reverse the
nephrotoxic effects
of smoking (9).
Selection bias is also a
concern due to low
interview response
rates. It is possible
that nonparticipants
had on average smoked
more than subjects
who completed our
interview.
Although response rates
were low
(56.1% of case subjects
and 58.7% of control
subjects), we feel that
these data offer
preliminary evidence
that smoking is an
independent risk factor
for microalbuminuria
in African-Americans
with type 2
diabetes. Given the high
risk for end-state
renal disease in this
group, clinicians
should increase efforts
to encourage patients
with microalbuminuria to
stop
smoking. Further, in
view of the difficulty
that many smokers have
in quitting, patients
with type 2 diabetes and
microalbuminuria
who continue to smoke
should
be more closely
monitored for
progressive
renal disease, and
renoprotective therapies
should be aggressively
applied in
these patients.
Frequency of Blood
Glucose Monitoring
in Relation to
Glycemic Control in
Patients With Type 2
Diabetes
We were disappointed
with the
conclusions of Harris
(1) and the
accompanying editorial
(2) on
self-monitoring of blood
glucose (SMBG).
The article is based on
outdated data and
reflects an era with
much less SMBG
capability
and convenience,
reimbursement,
therapeutic modalities,
and
evidence for the
benefits of improved
glycemic
control. Moreover, the
study itself
was uncontrolled,
self-reported, and did
not indicate whether the
patients were
taught about data usage.
It would be unfortunate
if this article and
editorial were
used to justify denial
of appropriate
reimbursement
for SMBG in type 2
diabetes.
Optimal modern therapy
of type 2 diabetes
uses a “treat-to-target”
approach,
expeditiously moving
patients along a
sequence
of therapies to achieve
better diabetes
control (3,4). However,
to make
effective and efficient
decisions about
therapy, patients and
health care
professionals
should rely on
appropriate data, of
which SMBG is a key
component (4).
The ISIS group recently
(October
1996 to September 1999)
assessed data
from 3,000 clinic visits
of 228 patients
with type 2 diabetes
(aged 35–65 years)
who were seen by 65
doctors (assorted
specialties) in four
Adventist Health
clinics.
During this period, the
average HbA1c
decreased by 0.8.
Patients were placed
into two groups based on
diabetes control
(HbA1c 8 for 95% of
measurements
during the 3-year period
or HbA1c 8)
(5). We then examined
the consistency
with which a health care
professional documented
discussing glucose
monitoring
and recorded the
frequency of SMBG. We
created “diabetes care
intervals,” or periods
from one visit in which
the primary
focus was diabetes care
to the next visit
with the same focus.
Patients were
categorized
as “regular SMBG
performer” if,
throughout the 3-year
period, almost all
visits documented
frequency of SMBG
and results. A patient
was labeled “irregular
SMBG performer” if there
were few
mentions of SMBG
documented and/or if
documentation did not
contain the frequency
of SMBG. Finally,
patients were
labeled “not monitored”
if there was no
mention of SMBG or if
documentation
noted that that patient
was not monitoring.
Almost 21% of patients
were regular
SMBG performers, and 70%
of these patients
had HbA1c 8. For the 42%
of patients
who were irregular SMBG
performers and the 37%
of patients not
monitoring, only 18 and
22%, respectively,
had HbA1c 8 (P 0.0001).
Regularly
monitoring and
consistently
discussing blood glucose
appeared to be
positively associated
with a better glycemic
control.
In summary, we should
recognize the
limitations of the
Harris (1) study, not
give it undo prominence
or extend the
data beyond its limited
historical value,
and consider the
important and growing
case for studies
utilizing a
treat-to-target
approach. We believe
that it is not the
collection of blood
glucose data but rather
the effective use of
blood glucose
information
for making clinical
decisions that
leads to improvements in
diabetes control.
Finally, we agree with
Kennedy (2)
that better studies are
needed, but we believe
that the studies should
be large-scale
observational studies of
the usage of
blood glucose data in
normal clinical settings
and stratified by
therapy.
Hormone
Replacement Therapy
and Glycemic Control:
Evidence from
Observational
Studies and
Randomized Clinical
Trials
Response to Dr.
Aquilar-Salinas et al.
We thank Aguilar-Salinas
et al. (1)
for their interest in
our paper (2),
and we agree that the
crosssectional
associations between
hormone replacement
therapy (HRT) and lower
HbA1c levels we reported
do not establish
causality. We concur
with the need of
long-term clinical
trials among women
with diabetes in order
to understand
whether and to what
extent HRT may improve
glycemic control.
However, our
findings are consistent
with small and
short-term randomized
trials in women
with diabetes (3–5). We
demonstrated a
number of differences
between HRT users
and nonusers in our
report and went to
great lengths to balance
these covariates,
including the use of the
propensity score
approach (6). As we
mentioned in our
discussion, HRT remained
significantly
associated with lower
HbA1c levels (P
0.001) in the propensity
score–adjusted
Generalized Estimating
Equation models.
Aguilar-Salinas et al.
(1) found, in
contrast with the
previous randomized
trial of unopposed
estrogen in women
with diabetes, that
conjugated estrogens
at 0.625 mg/day plus the
cyclical medrogestone
at 5 mg/day (for 10
days) may
have slightly worsened
HbA1c levels in
women with good glycemic
control at
baseline.
In our study (2), women
using unopposed
estrogen as well as
women using
opposed estrogen had
lower HbA1c levels
then women not using
HRT. A recent
publication (7) of the
results from a shortterm
randomized controlled
cross-over
study of 61 women with
type 2 diabetes
with acceptable glycemic
control (mean
HbA1c 7.1%) receiving
daily 0.625 mg of
conjugated equine
estrogen plus 2.5 mg
of medroxyprogesterone
or placebo
showed that although
HbA1c levels were
not significantly
different between
treatment
periods, fructosamine
levels were
significantly lower
during treatment with
this HRT regime. Another
recent publication
(8) of a randomized
placebocontrolled
trial among 43 women
with
type 2 diabetes showed
no difference in
glycemic control among
women assigned
to continuous
transdermal estradiol in
combination with oral
norethisterone (1
mg daily) or in women
assigned to identical
placebos.
Along with the data of
Aguilar-Salinas
et al. (1), these recent
studies suggest that
the type of progestin
and whether treatment
is continuous or cyclic
may influence
the effect of HRT on
glycemic
control in women with
diabetes. It is also
interesting to note that
clinical trials
(9,10) in women without
diabetes have
shown that although
fasting glucose and
insulin levels decrease
after estrogen therapy
(with or without
progestins), the
addition of progestins
worsens postchallenge
glucose levels.
In conclusion, we
strongly agree with
Aguilar-Salinas et al.
(1) on the need for
long-term randomized
trials of various
HRT regimes among
diabetic women
with a broad spectrum of
glycemic control.
Results from large
observational
studies such as ours can
provide data on
the potential expected
magnitude of the
effect of HRT on HbA1c
and therefore facilitate
calculations of the
minimum required
sample size.
Potential
Pharmacokinetics
Interference
Between
-Glucosidase
Inhibitors and Other
Oral Antidiabetic
Agents
In the study recently
reported by Chiasson
et al. (1), it was
concluded that
miglitol, a
pseudomonosaccharide
-glucosidase inhibitor,
can be combined
effectively with
metformin therapy to
give
significantly greater
reductions in HbA1c
and postprandial plasma
glucose levels
than metformin alone in
middle-aged patients
in whom type 2 diabetes
is insufficiently
controlled by diet
alone. The
combined therapy had a
good safety profile,
with only a trend toward
an increase
in the number of
gastrointestinal
sideeffects
due to miglitol acting
at the small intestine
by delaying the
digestion of
complex carbohydrates
(2).
The absorption of
metformin occurs
mainly in the small
intestine, and it has
been shown that high
concentrations of
the compound (10 –100
times plasma
levels) accumulate in
the walls of the
gastrointestinal
tract (rev. in 3).
Therefore,
possible pharmacokinetic
interference
with drugs acting on the
intestinal wall
are not excluded. We
previously demonstrated
in six healthy subjects
that acarbose
(100 mg), a
pseudotetrasaccharide
that is currently the
leading -glucosidase
inhibitor on the market,
induces significant
reductions in early
(90-, 120-, and
180-min) serum levels,
peak concentrations
(Cmax 1.22 0.14 vs. 1.87
0.60
mg/l; P 0.05), and area
under the curve
for 0–540 min (AUC0 –540
min; 423
55 vs. 652 55 mg min l
1; P 0.05)
of metformin ingested as
two tablets of
500 mg with a
standardized breakfast
(4).
To our knowledge, such
interference
of miglitol on the
pharmacokinetics
of metformin has not yet
been studied.
However, although our
group did not observe
any significant
alteration of the
glibenclamide
pharmacokinetics in
acarbosetreated
type 2 diabetic patients
(5), we
observed slight
modifications of the
pharmacokinetic
parameters of
glibenclamide
after ingestion of
miglitol in six
healthy volunteers
(unpublished data). In
a double-blind crossover
trial, each subject
was randomly allocated
during two
consecutive 7-day
periods to either
miglitol
(3 50 mg during the
first 3 days and
3 100 mg/day during the
last 4 days) or
placebo. At the 7th and
14th day of the
study, the
overnight-fasted
subjects ingested
5 mg glibenclamide with
the first
bite of a standardized
breakfast together
with either 100 mg
miglitol or placebo.
Venous blood samples
were taken from 0
to 540 min to measure
serum glibenclamide
concentrations by
radioimmunoassay.
Time-to-peak (Tmax; 215
40 vs.
230 24 min; NS) and peak
serum glibenclamide
levels (Cmax; 190 33 vs.
225 31 g/l; NS) were
similar after
miglitol and placebo,
respectively. However,
the glibenclamide
AUC0–540 min was
significantly lower
after miglitol than
after
placebo (40,358 3,203
vs. 59,950
9,193 g min l 1; P
0.05).
These observations in
normal subjects
suggest that a potential
interference
of miglitol on the
pharmacokinetics of
metformin cannot be
excluded during
combined therapy in type
2 diabetic patients.
Whether this
interference exists
and to what extent it
may influence the
efficacy and/or safety
of such a combined
therapy remains to be
investigated.
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