ArticlePDF Available

French Maritime Pine Bark Extract Pycnogenol Dose-Dependently Lowers Glucose in Type 2 Diabetic Patients

Authors:

Abstract and Figures

Pycnogenol, a standardized extract from the bark of the French maritime pine, consists of phenolic compounds including catechin, taxifolin, procyanidins, and phenolic acids (1). We investigated whether Pycnogenol has a glucose-lowering effect because of personal verbal communication from patients reporting no need for insulin following supplementation with Pycnogenol. The study was designed as an open, controlled, dose-finding study and was approved by the ethical committee of Guangnamen Hospital. Patients gave written informed consent. We recruited 18 men and 12 women among outpatients of the Guangnamen Hospital and Municipal Dental Hospital. Patients were 28–64 years of age and had a BMI 22–34 kg/m2. Patients with type 2 diabetes were included with fasting plasma glucose between 7 and …
Content may be subject to copyright.
OBSERVATIONS
French Maritime
Pine Bark Extract
Pycnogenol Dose-
Dependently Lowers
Glucose in Type 2
Diabetic Patients
P
ycnogenol, a standardized extract
from the bark of the French mari-
time pine, consists of phenolic com-
pounds including catechin, taxifolin,
procyanidins, and phenolic acids (1).
We investigated whether Pycnog-
enol has a glucose-lowering effect because
of personal verbal communication
from patients reporting no need for insu-
lin following supplementation with
Pycnogenol.
The study was designed as an open,
controlled, dose-finding study and was
approved by the ethical committee of
Guangnamen Hospital. Patients gave
written informed consent. We recruited
18 men and 12 women among outpa-
tients of the Guangnamen Hospital and
Municipal Dental Hospital. Patients were
2864 years of age and had a BMI 22–34
kg/m
2
. Patients with type 2 diabetes were
included with fasting plasma glucose be-
tween 7 and 10 mmol/l after participation
in a diet and sports program for 1 month.
Exclusion criteria were type 1 diabetes,
manifest or malignant hypertension and
any diseases requiring continuous treat-
ment with drugs, and pregnant or lactat-
ing women.
During the first and last visit, a phys-
ical examination and assessment of demo-
graphic data, medical history, body
weight, height, vital signs, blood pres-
sure, electrocardiogram, diet, and medi-
cation was carried out. Samples for fasting
blood glucose, HbA
1c
, insulin, and endo-
thelin-1 were taken. Blood samples were
taken to measure postprandial blood glu-
cose 2 h after breakfast.
Glucose was measured enzymatically,
HbA
1c
by high-performance liquid chro-
matography, and insulin and endothe-
lin-1 by immunoassays. Statistical
analysis was done with SPSS 16.0 soft-
ware using one-factorial ANOVA with
Fisher projected least significant differ-
ence test. Patients received in succession
50, 100, 200, and 300 mg Pycnogenol in
intervals of 3 weeks. Every 3 weeks, fast-
ing and postprandial glucose, endothe-
lin-1, HbA
1c
, and insulin were analyzed.
No changes were observed in vital
signs, electroencephalogram, or blood
pressure over the 12-week period.
Fasting blood glucose was lowered
dose dependently until a dose of 200 mg
Pycnogenol was administered. Increasing
the dose from 200 to 300 mg did not fur-
ther decrease blood glucose. Compared
with baseline, 100–300 mg lowered fast-
ing glucose significantly from 8.64
0.93 to 7.54 1.64 mmol/l (P0.05).
Fifty milligrams of Pycnogenol lowered
postprandial glucose significantly from
12.47 1.06 to 11.16 2.11 mmol/l
(P0.05). Maximum decrease of post-
prandial glucose was observed with 200
mg to 10.07 2.69 mmol/l; 300 mg had
no stronger effect.
HbA
1c
levels decreased continuously
from 8.02 1.04 to 7.37 1.09%. Dif-
ference to baseline became significant af-
ter 9 and 12 weeks of treatment with 200
or 300 mg Pycnogenol (P0.05). Endo-
thelin-1 decreased significantly after
100–300 mg Pycnogenol from 104 16
to 91 15 pg/ml (P0.05). There was
no additional decrease with 300 mg. In-
sulin levels were not changed at any dos-
age level of Pycnogenol.
Four patients reported dizziness, two
headache, two gastric discomfort, and
one mouth ulcer. None of the patients dis-
continued the study. All unwanted effects
were minor and transitory.
Stimulation of insulin secretion can
be excluded as a cause for lower glucose
levels because insulin secretion was not
affected. Mechanistic investigations are
underway to elucidate the mechanism of
glucose lowering with Pycnogenol.
The decrease of endothelin-1 follow-
ing supplementation with Pycnogenol
points to an ameliorated function of the
endothelium.
This dose-finding study encourages
further mechanistic and clinical studies
with Pycnogenol to explore its potential
in obtaining metabolic control in patients
with mild type 2 diabetes. A double-blind
placebo-controlled study with 77 patients
confirmed the glucose-lowering effect of
Pycnogenol (2).
XIMING LIU,
MD
1
HA-JUN ZHOU,
MD
2
PETER ROHDEWALD,
PHD
3
From the
1
Guang An Men Hospital of Chinese Med-
ical Science Research Institute, Beijing, China; the
2
Wei-Hai Stomatology Hospital of Shan-Dong Prov-
ince, Wei-Hai, China; and the
3
Institute of Pharma-
ceutical Chemistry, University of Mu¨ nster, Munster,
Germany.
Address correspondence to Prof. Dr. P. Rohde-
wald, Department of Pharmaceutical Chemistry,
University of Muenster, Hittorfstrasse 58-62, 48149
Mu¨nster, Germany. E-mail: rohdewa@uni-
muenster.de.
P.R. is a paid consultant of Horphag Research. X.L.
receives research funds from Horphag Research.
© 2004 by the American Diabetes Association.
Acknowledgments The study was spon-
sored by Horphag Research, Guernsey, Chan-
nel Islands.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Rohdewald P: A review of the French mar-
itime pine bark extract (Pycnogenol), a
herbal medication with a diverse clinical
pharmacology. Int J Clin Pharm Ther 40:
158–168, 2002
2. Liu X, Wei J, Tan F, Zhou S, Wu¨rthwein
G, Rohdewald P: Antidiabetic effect of
French maritime pine bark extract Pyc-
nogenol in patients with type II diabetes.
Life Sci. In press
A Systematic
Quantitative
Analysis of the
Literature of the
High Variability in
Ginseng (Panax
spp.)
Should ginseng be trusted in
diabetes?
H
erbs have experienced an unprece-
dented surge in popularity (1). This
has occurred in the absence of ade-
quate safety and efficacy evidence,
prompting calls for rigorous clinical as-
sessments (2). Complicating these assess-
ments is compositional variability. This is
a concern with one of the most popular
herbs, ginseng (3). The principal refer-
ence components, to which pharmaco-
logical effects have been attributed, are its
ginsenosides (steroidal glycosides). We
undertook a systematic quantitative anal-
ysis of the literature to assess the coeffi-
LETTERS
DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 839
cient of variation (CV) in ginsenosides
across species, assay technique, and gin-
senoside type.
The PubMed (1966present), EM-
BASE (1980present), HealthSTAR
(1975present), Cochrane library (issue
2, 2002), and AGRICOLA (1979
present) databases were searched using
ginsenosides AND (chromatography OR
HPLC OR HPTLC OR TLC OR LC OR
DCC OR GC OR ELISA OR UV OR MS
OR NMR OR ELSD). One-hundred
eleven articles were identied. Two re-
viewers applied three inclusion criteria:
publication quality: peer-reviewed; end
point: quantitative ginsenoside concen-
trations; and ginseng type: dried deriva-
tives of panax species roots. Thirty-two
articles met these criteria, reporting gin-
senoside concentrations for 317 ginseng
batches.
A three-factor analysis was performed
to assess the independent and interactive
effects of species, assay technique, and
ginsenoside type on the CV of ginsenoside
concentrations using ANOVA (NCSS
2000; NCSS, Kaysville, UT). The CVs of
ginsenoside concentrations were calcu-
lated as CV SD/mean 100% in a fac-
torial block design. A blocking principle
was applied to the data such that each
level of each factor was crossed with each
level of the other factors for the calcula-
tion of CV. Species was comprised of 10
levels of panax species, their prepara-
tions, and their varieties: Asian (Panax
ginseng C.A. Meyer), Asian red (Panax gin-
seng C.A. Meyer [red]), Asian wild (Panax
ginseng C.A. Meyer [wild]), Asian extract
(Panax ginseng C.A. Meyer [extract]),
American (Panax quinquefolius L.), Amer-
ican wild (Panax quinquefolius L. [wild]),
American extract (Panax quinquefolius L.
[extract]), Japanese (Panax japonicus C.A.
Meyer), Pseudo (Panax pseudoginseng
WALL), and Sanchi (Panax notoginseng
[Burk] F.H. Chen) ginsengs. Assay tech-
nique was comprised of six levels of
different assay techniques: high-
performance liquid chromatography
(HPLC)-ultraviolet (UV), gas chromatog-
raphy (GC)-mass spectrometry (MS),
HPLC-MS, diode counter current DCC,
HPLCdifferential refractometry DR, and
HPLCelectrospray light-scattering de-
tection (ELSD). Ginsenoside type was
comprised of 21 levels of different ginsen-
oside indexes: protopanaxadiol (PPD)
ginsenosides (Rb
1
,Rb
2
, Rc, Rd, and Rg
3
),
protopanaxatriol (PPT) ginsenosides
(Rg
1
, Rf, Re, and Rg
2
), and their sums
(PPD, PPT, and total) and ratios (PPD:
PPT, Rb
1
:Rg
1
,Rb
2
:Rc, Re:Rb
1
, Rc:Rb
1
,
Rd:Rb
1
,Rb
2
:Rb
1
, Rf:Rb
1
, and Rg
1
:Re).
The CV data calculated for each possible
combination of levels from the three fac-
tors were pooled and then meaned for
each level of each factor. As a result, CV
data are means SD.
This systematic quantitative analysis
of the literature demonstrated high CV in
ginsenosides across species, assay tech-
nique, and ginsenoside type (26103,
3181, and 36112%, respectively).
These large ranges produced signicant
differences in each main effect (P
0.00030, P0.014, and P0.00031,
respectively), with differences in species
sensitive to assay technique (P0.00011
for two-way interaction).
The high variability in ginseng iden-
tied by this analysis might have serious
clinical sequelae. Variable pharmacologi-
cal effects appear secondary to ginsen-
oside variability. We have shown in
healthy humans that while two batches of
American ginseng (cultivated Panax quin-
quefolius L.) (46) demonstrated similar
acute postprandial glycemic-lowering ef-
cacy, a third batch with a depressed gin-
senoside prole was ineffective (4),
whereas Japanese, Asian red, and Sanchi
ginsengs had null effects (6) and Asian
(6,7), American wild, and Siberian gin-
sengs (Eleutherococcus senticosus)(6)
raised glycemia. These data suggest that
the antihyperglycemic efcacy of ginseng
might be as highly variable as its ginsen-
oside composition.
Although this makes a compelling ar-
gument for better standardization, there
are mitigating factors. It is unclear which
of the 30 ginsenosides or myriad of other
principles should be targeted for an antihy-
perglycemic indication. There is also no
universal ginsenoside assay. Until these is-
sues are resolved, the reproducibility of gin-
sengs composition, safety, and efcacy
cannot be trusted. This conclusion likely
holds true for other less well-studied herbal
remedies used to treat diabetes.
JOHN L. SIEVENPIPER,
MSC
1,3
JOHN T. ARNASON,
PHD
2
EDWARD VIDGEN,
BSC
3
LAWRENCE A. LEITER,
MD
1,3
VLADIMIR VUKSAN,
PHD
1,3
From the
1
Clinical Nutrition and Risk Factor Mod-
ication Centre, St. Michaels Hospital, Toronto,
Canada; the
2
Department of Biology, Faculty of Sci-
ence, University of Ottawa, Ottawa, Canada; and the
3
Department of Nutritional Sciences, Faculty of
Medicine, University of Toronto, Toronto, Canada.
Address correspondence to Vladimir Vuksan,
PhD, Clinical Nutrition and Risk Factor Modica-
tion Centre, St. Michaels Hospital, no. 6, 138-61
Queen St. East, Toronto, Ontario M5C 2T2, Canada.
E-mail: v.vuksan@utoronto.ca.
V.V. has received research and travel funding
from The Ontario Ginseng Growers Association and
Natural Factors Nutritional Products.
© 2004 by the American Diabetes Association.
AcknowledgmentsFunding for this sys-
tematic quantitative analysis of the literature
was provided by a Grant for Applied Research
and Education from the Canadian Diabetes
Association. J.L.S. was supported by an On-
tario Graduate Scholarship.
The authors thank Dr. Dennis V.C. Awang
for invaluable intellectual input in the area of
phytochemistry.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Eisenberg DM, Davis RB, Ettner SL, Appel
S, Wilkey S, Van Rompay M, Kessler RC:
Trends in alternative medicine use in the
United States, 19901997: results of a
follow-up national survey. JAMA 280:
15691575, 1998
2. Angell M, Kassirer JP: Alternative medi-
cine: the risks of untested and unregu-
lated remedies. N Engl J Med 339:839
841, 1998
3. Straus SE: Herbal medicines: whatsinthe
bottle? N Engl J Med 347:19971998, 2002
4. Vuksan V, Sieveniper JL, Koo VYY, Fran-
cis T, Beljan-Zdravkovic U, Xu Z, Vidgen
E: American ginseng reduces postpran-
dial glycemia in nondiabetic and diabetic
individuals. Arch Intern Med 160:1009
1013, 2000
5. Sievenpiper JL, Arnason JT, Leiter LA, Vuk-
san V: Differential effects of American gin-
seng (Panax quinquefolius L.): a batch of
American ginseng with depressed ginsen-
oside prole does not affect postprandial
glycemia. Eur J Clin Nur 57:243248, 2003
6. Sievenpiper JL, Arnason JT, Leiter LA,
Vuksan V: Decreasing, null, and increas-
ing effects of eight common types of gin-
seng on postprandial glycemic indices in
healthy humans: the role of ginsenosides.
J Am Coll Nutr. In press
7. Sievenpiper JL, Arnason JT, Leiter LA,
Vuksan V: Null and opposing effects of
Asian ginseng (Panax ginseng C. A. Meyer)
on glycemia: results of two acute dose es-
calation studies. J Am Coll Nutr 22:524
532, 2003
Letters
840 DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004
Is a Long-Term
Aerobic Plus
Resistance Training
Program Feasible for
and Effective on
Metabolic Profiles in
Type 2 Diabetic
Patients?
A
erobic physical activity is a major
therapeutic modality for type 2 di-
abetes (1,2). It is well known that
regular aerobic exercise produces bene-
cial effects on glycemic control, insulin
sensitivity, lipid abnormalities, and
hypertension (3,4). On the other hand,
several recent studies (5,6) have demon-
strated the benecial effect of resistance
exercise in diabetes, and these results
should encourage its practice because of
the increasing number of sedentary,
older, and obese people in industrialized
countries. In fact, this is particularly im-
portant in the case of individuals who
may be noncompliant with aerobic exer-
cise. To prove the effectiveness of resis-
tance training, a recent study (7) showed
the positive effects of prescribed and su-
pervised high-intensity resistance train-
ing for 16 weeks in high-risk older adults
with type 2 diabetes, resulting in im-
proved glycemic and metabolic control.
Similarly, 16 weeks of resistance plus aer-
obic training is reported to enhance glu-
cose disposal in postmenopausal women
with type 2 diabetes (8). Both of these
studies evaluate the effect of relatively
short-period physical training but neither
investigates prolonged resistance exercise
combined with aerobic training in dia-
betic people.
We therefore investigated the long-
term effects (1 year) of prescribed and su-
pervised combined aerobic and resistance
training on glycemic control, cardiovas-
cular risk factors, and body composition
in type 2 diabetic patients.
Physical examination was performed
to detect the presence and degree of com-
plications as well as to determine any or-
thopedic limitations. After selection, 120
(60 men and 60 women) sedentary type 2
diabetic patients, aged 60.9 8.9 years,
with duration of diabetes 9.8 7.3 years,
were included in the study and randomly
assigned to one of two treatments: 62 sub-
jects (30 men and 32 women) agreed to
perform the aerobic plus resistance train-
ing (ART) program, whereas 58 subjects
(30 men and 28 women) asked to con-
tinue with their current diet and pharma-
cological therapy and formed the control
group. The subjects in both groups
continued to receive their standard med-
ication. Throughout the study, diabe-
tologists were asked to avoid nonessen-
tial changes in drugs and dosages that
might affect the study outcome mea-
sures. Every essential medication change
was implemented and then reported to
the investigators.
The ART group performed 30 min of
aerobic training at 4080% of the heart
rate reserve (based on the initial maximal
graded exercise tolerance test) using
treadmills, stationary bicycles, reclining
bicycles, and elliptical trainers (Techno-
gym), plus another 30-min resistance
training program that included free
weights, such as barbells or dumbbells,
and weight machines at 4060% of a sin-
gle repetition maximal lift (1 RM), which
was retested every 3 weeks. The workload
was 12 repetitions each of six exercises
selected for each major muscle group
(i.e., legs, chest, shoulders, back, arms,
and abdomen) for three sets, three times a
week, for 1 year.
Blood pressure and plasma glucose
levels were assessed in each patient by
means of a One Touch Ultra blood glu-
cose monitoring system (Lifescan) before
and after each training setting. HbA
1c
,
BMI, waist circumference, and glycemic
and lipid proles were evaluated every 3
months. Each participant was provided
with written handouts and with a note-
book in which to take notes and record
food diaries. A 3-day food record was ob-
tained at baseline and every 3 months for
1 year. All nutritional information ob-
tained from food records was analyzed by
a dietitian using Winfood software (Medi-
matica). Body composition was measured
at baseline and after 1 year by means of
dual-energy X-ray absorptiometry (QDR
1000; Hologic).
This study was conducted in accor-
dance with the Declaration of Helsinki
guidelines. Each subject gave his or her
informed consent before the study began.
Each group was compared using the
ANOVA test with multiple comparisons
and 95% CIs. A two-tailed P0.05 indi-
cated statistical signicance. All of the val-
ues are expressed as means SD.
Subjects in the ART group attended
90% of the prescribed program ses-
sions. The subject dropout rates were
17.7% for the ART group and 8.63% for
the control group. We only included pa-
tients who completed the entire year for
statistical analyses.
There were no signicant differences
between the two groups at baseline with
respect to BMI (30 5.6 vs. 30.1 5.6
kg/m
2
), fat mass (33 9.2 vs. 35
10.2%), fat-free mass (48.1 10 vs.
46.8 11 kg), waist circumference
(104 12.8 vs. 103 14 cm), fasting
blood glucose (163 59.6 vs. 165
60.6 mg/dl), total cholesterol (212 31.5
vs. 212 40.2 mg/dl), HDL cholesterol
(45.3 9.8 vs. 43.6 9.1 mg/dl), LDL
cholesterol (134 31.6 vs. 130 34.2
mg/dl), triglycerides (159 80.1 vs.
187 109 mg/dl), HbA
1c
(8.28 1.73
vs. 8.31 1.73%), systolic blood pres-
sure (147 18 vs. 139 17.1 mmHg),
diastolic blood pressure (85.6 7.8 vs.
85.3 8.8 mmHg), and use of lipid-
lowering, hypoglycemic, and antihyper-
tensive medications (32.3 vs. 34.5, 80.8
vs. 86.3, and 48.4 vs. 50%, respectively).
After 1 year, the control group
showed no statistically signicant change
in any measured parameters. The ART
group, conversely, showed a statistically
signicant decrease in BMI (30.1 5.6 to
28.8 4.8 kg/m
2
,P0.0001), fat mass
(35 10.2 to 32.5 10.2%, P
0.0001), waist circumference (103 14
to 98 12.7 cm, P0.0001), fasting
blood glucose (165 60.6 to 129 37
mg/dl, P0.0001), total cholesterol
(212 40.2 to 195 35.4 mg/dl, P
0.0001), LDL cholesterol (130 34.2 to
124 28.7 mg/dl, P0.0001), triglyc-
erides (187 109 to 146 81 mg/dl,
P0.0001), HbA
1c
(8.31 1.73 to
7.1 1.16%, P0.0001), systolic blood
pressure (139 17.1 to 135 15.5
mmHg, P0.04), and diastolic blood
pressure (85.3 8.8 to 81.3 6.7
mmHg, P0.0001) and a signicant in-
crease in fat-free mass (46.8 11 to
47.2 10.8 kg, P0.0001) and HDL
cholesterol (43.6 9.1 to 48.6 12.1
mg/dl, P0.0001).
The frequency of medication changes
was not signicantly different between
the ART and control groups. We observed
a trend toward decreasing amounts of
medications in all three classes of drugs
(hypolipemic, hypoglycemic, and antihy-
pertensive therapies) in the ART group
Letters
DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 841
(7.85, 3.94, and 5.90%, respec-
tively), whereas in the control group, the
opposite trend occurred (5.67, 7.55, and
5.67%, respectively).
Throughout the entire study, no ad-
verse effects occurred in any patient. The
reasonably low dropout rate in the ART
group (17.7%) indicates that subjects
with type 2 diabetes are willing and able
to participate in a demanding interven-
tion program if it is made available to
them.
In conclusion, the combination of
aerobic and resistance training is well tol-
erated, feasible, and safe, and it improves
glycemic control, cardiovascular risk fac-
tors, and body composition in type 2 di-
abetic patients. Given the epidemic of
diabetes and metabolic syndrome in the
recent years, we stress the use of com-
bined exercise as an adjunct to standard
medical care in the management of these
patients.
STEFANO BALDUCCI,
MD
1
FRIDA LEONETTI,
MD
1
UMBERTO DIMARIO,
MD, PHD
1
FRANCESCO FALLUCCA,
MD
2
From the
1
Department of Clinical Sciences, Endo-
crinology, La Sapienza University, Rome, Italy; and
the
2
Department of Clinical Sciences, La Sapienza
University II Faculty (St. Andrea Hospital), Rome,
Italy.
Address correspondence to Dr. Stefano Balducci,
Department of Clinical Sciences, La Sapienza Uni-
versity, Rome, Italy. E-mail: s.balducci@
hctdiabete.it.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. American Diabetes Association: Diabetes
mellitus and exercise (Position State-
ment). Diabetes Care 25 (Suppl. 1):S64
S68, 2002
2. Albright A, Franz M, Hornsby G, Kriska
A, Marrero D, Ullrich I, Verity LS: Amer-
ican College of Sports Medicine position
stand: exercise and type 2 diabetes. Med
Sci Sports Exerc 32:13451360, 2000
3. Boule NG, Haddad E, Kenny GP, Wells
GA, Sigal RJ: Effects of exercise on gly-
cemic control and body mass in type 2
diabetes mellitus: a meta-analysis of
controlled clinical trials. JAMA 286:
12181227, 2001
4. Goldhaber-Fiebert JD, Goldhaber-Fiebert
SN, Tristan ML, Nathan DM: Randomized
controlled community-based nutrition
and exercise intervention improves glyce-
mia and cardiovascular risk factors in type
2 diabetic patients in rural Costa Rica. Di-
abetes Care 26:2429, 2003
5. Dunston DW, Daly RM, Owen N, Jolley
D, De Courten M, Shaw J, Zimmet P:
High-intensity resistance training im-
proves glycemic control in older patients
with type 2 diabetes. Diabetes Care 25:
17291736, 2002
6. Maiorana A, ODriscoll G, Goodman C,
Taylor R, Green D: Combined aerobic and
resistance exercise improves glycemic
control and tness in type 2 diabetes. Di-
abetes Res Clin Pract 56:115123, 2002
7. Castaneda C, Layne JE, Munoz-Orians L,
Gordon PL, Walsmith J, Foldvari M,
Roubenoff R, Tucker KL, Nelson ME: A
randomized controlled trial of resistance
exercise training to improve glycemic
control in older adults with type 2 diabe-
tes. Diabetes Care 25:23352341, 2002
8. Cuff DJ, Meneilly GS, Martin A, Ignasze-
wski A, Tildesley HD, Frohlich JJ: Effec-
tive exercise modality to reduce insulin
resistance in women with type 2 diabetes.
Diabetes Care 26:29772982, 2003
A Filipino Patient
With Fulminant Type
1 Diabetes
F
ulminant type 1 diabetes is charac-
terized by abrupt onset of loss of
pancreas -cell function with low
initial HbA
1c
levels and absence of auto-
antibodies to islet antigens (1). Initial his-
tological examinations revealed the
absence of insulitis, and it was thought
that the autoimmune process did not me-
diate this type of diabetes. However, with
an accumulation of cases, possible in-
volvement of an immune response to islet
antigens has come to light. CD8
lym-
phocytes inltrating the pancreatic islets
were seen in a patient who died of fulmi-
nant type 1 diabetes (2), and peripheral
GAD-reactive interferon-producing
CD4
lymphocytes were detected in an-
other case of fulminant type 1 diabetes
(3). Thus, T-cellmediated autoimmunity
may be involved. HLA analyses also indi-
cate that an autoimmune process similar
to that in autoimmune type 1 diabetes
may be involved in the development of
fulminant type 1 diabetes. In his editorial
comment regarding the rst report of ful-
minant type 1 diabetes, Lernmark (4)
noted that in Japanese patients most had
HLA class II antigens that confer type 1
diabetes. Furthermore, Tanaka et al. (5)
recently reported that fulminant type 1
diabetes is associated with specic HLA
class II haplotypes, which are also associ-
ated with autoimmune type 1 diabetes in
Japanese patients. Most patients reported
to have fulminant type 1 diabetes were
Japanese. Occurrences in other ethnicities
are rare (6,7), reecting possible immu-
nogenetic differences. We report herein a
Filipino patient with fulminant type 1 di-
abetes and the results of HLA analysis.
A 32-year-old Filipino woman mar-
ried to a Japanese man and living in
Gunma, Japan, had a low-grade fever 2
weeks before admission and visited a gen-
eral practitioner, but no specic diagnosis
was made. Thirst, polydipsia, polyuria,
and general malaise had developed. Then
abdominal pain and vomiting occurred,
and she visited a clinic where severe hy-
perglycemia was found. She was referred
to Shiroyama Hospital and was admitted
for diabetic ketoacidosis. On admission
blood glucose was 800 mg/dl and HbA
1c
was 6.0%. Urinary ketone bodies were
positive. Arterial blood pH was 7.11, se-
rum amylase was 57 (IU/l), lipase was 32
(units/l), and elastase I was 344 ng/dl (all
within normal range). Anti-GAD antibod-
ies and islet cell antibodies were negative.
After metabolic derangement was cor-
rected, insulin secretion was evaluated.
The fasting serum C-peptide concentra-
tion was 0.1 ng/ml; it was 0.2 ng/ml after
glucagon injection. Urinary C-peptide
was 1.6 g/day. The severe abrupt-onset
insulin deciency, low HbA
1c
, and lack of
antibodies to islet antigens were compat-
ible with fulminant type 1 diabetes. DNA
typing of HLA antigens showed homozy-
gosity for the DRB1*0405-DQB1*05031
haplotype, which is unique to the Filipino
population (8). She was also HLA A24
positive.
Most Japanese fulminant type 1 dia-
betes patients studied carried at least
one of two haplotypes, DQA1*0303-
DQB1*0401 and DQA1*0302-
DQB1*0303 (5), which are known to
confer susceptibility to autoimmune type
1 diabetes in the Japanese population.
Only 2 of 22 did not have either haplo-
type. Furthermore, one-third of the pa-
tients were homozygous for the
DQA1*0303-DQB1*0401 haplotype.
Our Filipino patient had neither haplo-
type. However, she had two DRB1*0405
alleles. DRB1*0405 is a risk allele for type
1 diabetes in the Japanese population.
The DQA1*0303-DQB1*0401 haplotype
is in close linkage disequilibrium with
DRB1*0405 in Japanese and Chinese in-
Letters
842 DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004
dividuals. These alleles form an extended
haplotype DRB1*0405-DQA1*0303-
DQB1*0401. Thus it is difcult to deter-
mine whether the DQ molecule, the DR
molecule, or the haplotype is responsible
for the susceptibility to fulminant type 1
diabetes. In Filipino autoimmune type 1
diabetes, the risk haplotypes are
DRB1*0405-DQB1*0302 and DRB1*
0405-DQB1*0201, followed by
DRB1*0405-DQB1*0401 and DRB1*
0405-DQB1*0402 (8). The DRB1*0405-
DQB1*05031 haplotype is neutral to
autoimmune type 1 diabetes. Our nding
of a homozygous DRB1*0405 allele with-
out a risk haplotype in a Filipino patient
suggests that this allele rather than a hap-
lotype is associated with fulminant type 1
diabetes. Continued worldwide collec-
tion of data and HLA analysis will further
clarify the involvement of immunogenet-
ics in fulminant type 1 diabetes.
MATSUO TANIYAMA,
MD
1
RYO KATSUMATA,
MD
2,3
KANEMI AOKI,
MD
1
SEIJI SUZUKI,
MD
1
From the
1
Department of Internal Medicine, Divi-
sion of Endocrinology and Metabolism, Showa Uni-
versity Fujigaoka Hospital, Kanagawa, Japan; the
2
Department of Internal Medicine, Shiroyama Hos-
pital, Gunma, Japan; and the
3
Third Department of
Internal Medicine, Showa University School of Med-
icine, Tokyo, Japan.
Address correspondence to Matsuo Taniyama,
MD, Division of Endocrinology and Metabolism,
Department of Internal Medicine, Showa University
Fujigaoka Hospital, 1-30 Fujigaoka, Aoba, Yoko-
hama, Kanagawa 227-8501 Japan. E-mail:
taniyama@showa-university-fujigaoka.gr.jp.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Imagawa A, Hanafusa T, Miyagawa J, Mat-
suzawa Y, the Osaka IDDM Study Group:
A novel subtype of type 1 diabetes melli-
tus characterized by a rapid onset and an
absence of diabetes-related antibodies.
N Engl J Med 342:301307, 2000
2. Tanaka S, Kobayashi T, Momotsu T: A
novel subtype of type 1 diabetes mellitus.
N Engl J Med 342:18351837, 2000
3. Shimada A, Morimoto J, Kodama K,
Oikawa Y, Irie J, Nakagawa Y, Narumi S,
Saruta T: T-cellmediated autoimmunity
may be involved in fulminant type 1 dia-
betes (Letter). Diabetes Care 25:635636,
2002
4. Lernmark A: Rapid-onset type 1 diabetes
with pancreatic exocrine dysfunction (Edi-
torial). N Engl J Med 342:344345, 2000
5. Tanaka S, Kobayashi T, Nakanishi K,
Koyama R, Okubo M, Murase T, Odawara
M, Inoko H: Association of HLA-DQ ge-
notype in autoantibody-negative and rap-
id-onset type 1 diabetes. Diabetes Care 25:
23022307, 2002
6. Pozzilli P, Visalli N, Leslie D: No evidence
of rapid onset (Japanese) type I diabetes in
Caucasian patients: IMDIAB Group (Let-
ter). Diabetologia 43:1332, 2000
7. Foulis AK, Francic ND, Farquharson MA,
Boylston A: Massive synchronous B-cell
necrosis causing type 1 (insulin-depen-
dent) diabetes: a unique histopathological
case report. Diabetologia 31:4650, 1988
8. Bugawan TL, Klitz W, Alejandrino M,
Ching J, Panelo A, Solfelix CM, Petrone A,
Buzzetti R, Pozzilli P, Erlich HA: The as-
sociation of specic HLA class I and II
alleles with type 1 diabetes among Filipi-
nos. Tissue Antigens 59:452469, 2002
Predictive Value of
Circulating Oxidized
LDL for Cardiac
Events in Type 2
Diabetic Patients
With Coronary
Artery Disease
O
xidized LDL (oxLDL) has been
shown to play an important role in
the initiation and development of
atherosclerosis (1). Individuals with type
2 diabetes exhibit enhanced LDL oxidiz-
ability and accelerated atherosclerosis
(2,3). Past studies demonstrated the asso-
ciation between LDL oxidation and ath-
erosclerosis by indirectmethods, such
as lag times and propagation rates for LDL
oxidation, and antibodies against oxLDL.
Recently, some groups have developed
directmethods for measuring circulat-
ing oxLDL (46). Indeed, several lines of
evidence have demonstrated that the level
of circulating oxLDL is signicantly
higher in patients with type 2 diabetes, is
a marker for identifying patients with cor-
onary artery disease (CAD), and has a
positive relationship with acute coronary
syndromes (7,8). However, the predictive
value of circulating oxLDL for cardiac
events in type 2 diabetic patients with
CAD has not been investigated.
Ninety-six consecutive patients,
who had angiographic documentation
of CAD and fullled the classication of
the American Diabetes Association, were
followed for up to 52 months. Patients
with acute coronary syndrome and/or on-
going congestive heart failure were ex-
cluded. Patients with malignant disease
and/or inammatory disease were also ex-
cluded. We dened cardiac death, nonfa-
tal myocardial infarction, and refractory
angina requiring revascularization as ma-
jor cardiac events. The levels of oxLDL
were measured by a sandwich enzyme-
linked immunosorbent assay, as previ-
ously described (9).
Thirty-ve cardiac events were docu-
mented during the follow-up. Age was
signicantly higher in patients with car-
diac events than in those without cardiac
events (P0.02). The other values and
Figure 1—Kaplan-Meier survival curves demonstrated that the prevalence of cardiac events was
significantly higher in the patients with oxLDL 24.7 units/ml (event/total cases 15/24) than
in those with oxLDL 24.7 units/ml (event/total cases 20/72).
Letters
DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 843
frequencies, including coronary risk fac-
tors, lipid proles, fasting plasma glucose,
and HbA
1c
, were not signicantly differ-
ent between the two groups. Choice of
treatment for diabetes, such as insulin,
sulfonylureas, -glucosidase inhibitors,
and thiazolidinediones, was not different.
The levels of oxLDL (means SD) in pa-
tients with cardiac events were signi-
cantly higher than in those without
cardiac events (23.8 14.2 vs. 18.8
6.9 units/ml, P0.02). The patients were
divided into two groups based on the
75th percentile (24.7 units/ml) of the dis-
tribution of oxLDL levels. Kaplan-Meier
analysis demonstrated that the patients
with oxLDL 24.7 units/ml had a signif-
icantly higher prevalence of cardiac
events (P0.0007) (Fig. 1). After adjust-
ment for age, sex, BMI, hypertension,
smoking history, LDL cholesterol, triglyc-
eride, HDL cholesterol, fasting plasma
glucose, HbA
1c
, number of diseased ves-
sels, and left ventricular ejection fraction,
Cox proportional analysis showed that
the hazard ratio for cardiac events was 3.6
(95% CI 1.58.8, P0.005) times
higher in patients with oxLDL 24.7
units/ml than in those with oxLDL 24.7
units/ml.
This study rstly, to the best of our
knowledge, demonstrated that high levels
of circulating oxLDL can serve as an inde-
pendent and signicant predictor for fu-
ture cardiac events in type 2 diabetic
patients with CAD. Therefore, measure-
ment of circulating oxLDL may be helpful
for identifying high-risk patients with
type 2 diabetes and CAD.
KAZUNORI SHIMADA,
MD
HIROSHI MOKUNO,
MD, PHD
ERIKO MATSUNAGA,
MD
TETSURO MIYAZAKI,
MD
KATSUHIKO SUMIYOSHI,
BS
ATSUMI KUME,
MD
KATSUMI MIYAUCHI,
MD
HIROYUKI DAIDA,
MD, PHD
From the Department of Cardiology, Juntendo Uni-
versity School of Medicine, Tokyo, Japan.
Address correspondence to Kazunori Shimada,
MD, Department of Cardiology, Juntendo Univer-
sity School of Medicine, 2-1-1 Hongo, Bunkyo-ku,
Tokyo 113-8421, Japan. E-mail: shimakaz@
med.juntendo.ac.jp.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Steinberg D, Witztum JL: Is the oxidative
modication hypothesis relevant to hu-
man atherosclerosis? Do the antioxidant
trials conducted to date refute the hypoth-
esis? Circulation 105:21072111, 2002
2. Fonseca VA: Management of diabetes
mellitus and insulin resistance in patients
with cardiovascular disease. Am J Cardiol
92:50J60J, 2003
3. Schwenke DC, DAgostino RB Jr, Goff DC
Jr, Karter AJ, Rewers MJ, Wagenknecht
LE: Differences in LDL oxidizability by
glycemic status: the Insulin Resistance
Atherosclerosis Study. Diabetes Care 26:
14491455, 2003
4. Itabe H, Takeshima E, Iwasaki H, Kimura
J, Yoshida Y, Imanaka T, Takano T: A
monoclonal antibody against oxidized
lipoprotein recognizes foam cells in ath-
erosclerotic lesions: complex formation
of oxidized phosphatidylcholines and
polypeptides. J Biol Chem 269:15274
15279, 1994
5. Palinski W, Horkko S, Miller E, Steinbre-
cher UP, Powell HC, Curtiss LK, Witztum
JL: Cloning of monoclonal autoantibodies
to epitopes of oxidized lipoproteins from
apolipoprotein E-decient mice: demon-
stration of epitopes of oxidized low den-
sity lipoprotein in human plasma. J Clin
Invest 98:800814, 1996
6. Holvoet P, Donck J, Landeloos M, Brou-
wers E, Luijtens K, Arnout J, Lesaffre E,
Vanrenterghem Y, Collen D: Correlation
between oxidized low density lipopro-
teins and von Willebrand factor in
chronic renal failure. Thromb Haemost 76:
663669, 1996
7. Toshima S, Hasegawa A, Kurabayashi M,
Itabe H, Takano T, Sugano J, Shimamura
K, Kimura J, Michishita I, Suzuki T, Nagai
R: Circulating oxidized low density li-
poprotein levels: a biochemical risk
marker for coronary heart disease. Arte-
rioscler Thromb Vasc Biol 20:22432247,
2000
8. Ehara S, Ueda M, Naruko T, Haze K,
Itoh A, Otsuka M, Komatsu R, Matsuo
T, Itabe H, Takano T, Tsukamoto Y, Yo-
shiyama M, Takeuchi K, Yoshikawa J,
Becker AE: Elevated levels of oxidized low
density lipoprotein show a positive rela-
tionship with the severity of acute corona-
ry syndromes. Circulation 103:19551960,
2001
9. Kohno H, Sueshige N, Oguri K, Izumi-
date H, Masunari T, Kawamura M, Itabe
H, Takano T, Hasegawa A, Nagai R:
Simple and practical sandwich-type en-
zyme immunoassay for human oxida-
tively modied low density lipoprotein
using antioxidized phosphatidylcholine
monoclonal antibody and antihuman
apolipoprotein-B antibody. Clin Bio-
chem 33:243253, 2000
Tumor Necrosis
Factor-Is
Associated With
Increased Protein C
Activation in
Nonobese Type 2
Diabetic Patients
T
umor necrosis factor-(TNF-)
plays a critical role in the pathogen-
esis of vascular injury in diabetic pa-
tients (1). Increased circulating levels of
TNF-have been reported in diabetic pa-
tients (2,3). Hyperglycemia stimulates
TNF-secreted from monocytes and en-
dothelial cells (4,5). Moreover, TNF-
may cause vascular injury by affecting the
balance between coagulation and brino-
lysis. For example, TNF-stimulates the
expression of tissue factor that is the ini-
tiator of blood coagulation activation and
the secretion of plasminogen activator in-
hibitor-1 that inhibits brinolysis (1).
Activated protein C (APC) is a serine
protease that inhibits activation of the
blood coagulation system by proteolyti-
cally inactivating factors Va and VIIIa and
by stimulating brinolysis (6,7). APC may
indirectly promote brinolysis by inhibit-
ing thrombin generation and by inhibit-
ing the action of plasminogen activator
inhibitor-1 (8). Recently, it was reported
that APC has an anti-inammatory effect
and that it inhibits vascular injury in-
duced by TNF-(9,10). Therefore, APC
may inhibit hypercoagulability and in-
ammatory response induced by TNF-,
which increases during hyperglycemia.
However, the relationship between circu-
lating TNF-and APC levels has not yet
been reported in diabetic patients. In the
present study, we investigated the rela-
tionship between the plasma levels of
TNF-and APC in normotensive type 2
diabetic patients.
Twenty-four normotensive (140/
90 mmHg) nonobese type 2 diabetic pa-
tients (16 men and 8 women, aged 53.0
2.0 years [mean SE], BMI 23.1 0.5
kg/m
2
, diabetes duration 6.7 1.1 years,
systolic blood pressure 131.0 2.1
mmHg, diastolic blood pressure 78.1
1.9 mmHg, fasting blood glucose levels
7.8 0.32 mmol/l, and HbA
1c
8.9
0.3%) enrolled in the present study. All
patients had normoalbuminuria and were
Letters
844 DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004
being treated with diet therapy alone.
Data obtained in 18 age-matched nono-
bese healthy subjects (14 men and 4
women) were used as control. The plasma
levels of TNF-were measured with an
enzyme immunosorbent assay (EIA) kit
(TNF-EIA kit; Biosourse International,
Camarillo, TX). As a marker of APC gen-
eration, APCprotein C inhibitor (PCI)
complex was measured by enzyme-linked
immunoassay as previously described
(11). Protein C (PC) antigen was mea-
sured by solid-phase immunoassay as
previously described (11). Total protein S
(PS), a cofactor for activation of PC, was
measured as previously reported (11). As
a marker of coagulation activation, the
plasma levels of thrombin-antithrombin
complex (TAT) were measured by an EIA
using anti-human monoclonal TAT anti-
body. As a marker of brinolysis, D-dimer
was measured with a commercial EIA kit
(D-dimer test F; Kokusai Shiyaku, Kobe,
Japan). The plasma levels of TNF-were
signicantly higher (1.60 0.13 vs.
0.81 0.32 pg/ml, P0.05) in diabetic
patients than in normal subjects. The
plasma levels of APC-PCI were signi-
cantly higher (4.63 0.38 vs. 2.58
0.60 pmol/l, P0.005) in diabetic pa-
tients than in normal subjects. There was
a signicant and positive correlation be-
tween the plasma levels of TNF-and
TAT in diabetic patients (r0.46, P
0.05). There was a signicant and in-
verted correlation between the plasma
levels of TNF-and D-dimer in diabetic
patients (r⫽⫺0.52, P0.01). The
plasma levels of TNF-were positively
and signicantly correlated with the
plasma levels of APC-PCI (r0.42, P
0.05) in diabetic patients. There was no
signicant correlation between TNF-
and PC antigen (r0.33) and PS levels
(r0.07).
The elevation of TNF-in diabetic
patients observed in our study is in agree-
ment with previous data (2,3). Propor-
tional correlation of TNF-with TAT and
inverse correlation with D-dimer suggests
the occurrence of hypercoagulability and
hypobrinolysis in association with
TNF-in diabetic patients. Interestingly,
the circulating levels of TNF-were sig-
nicantly correlated with APC-PCI com-
plex, a marker of APC generation. These
data suggest that APC may regulate bri-
nolysis and hypercoagulability induced
by TNF-. It was reported that APC re-
duces vascular injury and hypercoagula-
bility by inhibiting TNF-production in
rats treated with lipopolysaccaride (LPS)
(9). APC may also inhibit production of
TNF-in LPS-treated culture cells (10).
Another report (12) demonstrated that
APC activates protease activated recep-
tor-1 and induced gene expression of A20
(TNF-induced protein 3) and tristetra-
prolin. A20 is cytoplasmic zinc nger pro-
tein that inhibits TNF-induced nuclear
factor B activity (13). Tristetraprolin in-
hibits TNF-production by destabilizing
its messenger RNA (14). Therefore, these
mechanisms may be involved in the pro-
tective effect of APC in diabetic patients.
However, the signicant increase of
TNF-in diabetic patients suggests that
APC may not be sufcient for regulating
TNF-expression. In brief, PC activation
may be important for the regulation of
TNF-induced coagulation abnormali-
ties and inammation in diabetes.
YUTAKA YANO,
MD
1
ESTEBAN C. GABAZZA,
MD
1
NAGAKO KITAGAWA,
MD
1
NELSON E. BRUNO,
MD
1
KAZUTAKA MATSUMOTO,
MD
1
KANAME NAKATANI,
MD
2
RIKA ARAKI,
MD
3
AKIRA KATSUKI,
MD
1
YUKIHIKO ADACHI,
MD
1
YASUHIRO SUMIDA,
MD
1
From the
1
Third Department of Internal Medicine,
Mie University School of Medicine, Tsu, Mie, Japan;
the
2
Laboratory Medicine, Mie University School of
Medicine, Tsu, Mie, Japan; and the
3
Department of
Internal Medicine, National Mie Hospital, Tsu, Mie,
Japan.
Address correspondence to Dr. Yutaka Yano,
Third Department of Internal Medicine, Mie Univer-
sity School of Medicine, Edobashi 2-174, Tsu, Mie
514-8507, Japan. E-mail: yanoyuta@clin.medic.
mie-u.ac.jp.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Okajima K: Regulation of inammatory
responses by natural anticoagulants. Im-
munol Rev 184:258274, 2001
2. Esposito K, Nappo F, Marfella R, Giugli-
ano G, Giugliano F, Ciotola M, Quagliaro
L, Ceriello A, Giugliano D: Inammatory
cytokine concentrations are acutely in-
creased by hyperglycemia in humans: role
of oxidative stress. Circulation 106:2067
2072, 2002
3. Diamant M, Nieuwland R, Pablo RF,
Sturk A, Smit JW, Radder JK: Elevated
numbers of tissue-factor exposing micro-
particles correlate with components of the
metabolic syndrome in uncomplicated
type 2 diabetes mellitus. Circulation 106:
24422447, 2002
4. Shanmugam N, Reddy MA, Guha M, Nat-
arajan R: High glucose-induced expres-
sion of proinammatory cytokine and
chemokine genes in monocytic cells. Dia-
betes 52:12561264, 2003
5. Amore A, Cirina P, Mitola S, Peruzzi L,
Gianoglio B, Rabbone I, Sacchetti C,
Cerutti F, Grillo C, Coppo R: Nonenzy-
matically glycated albumin (Amadori ad-
ducts) enhances nitric oxide synthase
activity and gene expression in endothe-
lial cells. Kidney Int 51:2735, 1997
6. Bajzar L: Thrombin activatable brinoly-
sis inhibitor and an antibrinolytic path-
way. Arterioscler Thromb Vasc Biol 20:
25112518, 2000
7. Esmon CT: Protein C anticoagulant path-
way and its role in controlling microvas-
cular thrombosis and inammation. Crit
Care Med 29 (Suppl.):S48S52, 2001
8. Sakata Y, Loskutoff DJ, Gladson CL, Hek-
man CM, Grifn JH: Mechanism of pro-
tein C-dependent clot lysis: role of
plasminogen activator inhibitor. Blood 68:
12181223, 1986
9. Murakami K, Okajima K, Uchiba M,
Johno M, Nakagaki T, Okabe H, Takat-
suki K: Activated protein C prevents LPS-
induced pulmonary vascular injury by
inhibiting cytokine production. Am J
Physiol 272 (Suppl.):L197L202, 1997
10. Yuksel M, Okajima K, Uchiba M, Horiu-
chi S, Okabe H: Activated protein C in-
hibits lipopolysaccharide-induced tumor
necrosis factor-alpha production by in-
hibiting activation of both nuclear factor-
kappa B and activator protein-1 in human
monocytes. Thromb Haemost 88:267
273, 2002
11. Hori Y, Gabazza EC, Yano Y, Katsuki A,
Suzuki K, Adachi Y, Sumida Y: Insulin
resistance is associated with increased cir-
culating level of thrombin-activatable -
brinolysis inhibitor in type 2 diabetic
patients. J Clin Endocrinol Metab 87:660
665, 2002
12. Riewald M, Petrovan RJ, Donner A, Muel-
ler BM, Ruf W: Activation of endothelial
cell protease activated receptor 1 by the
protein C pathway. Science 296:1880
1882, 2002
13. Lee EG, Boone DL, Chai S, Libby SL,
Chien M, Lodolce JP, Ma A: Failure to
regulate TNF-induced NF-kappaB and
cell death responses in A20-decient
mice. Science 289:23502354, 2000
14. Carballo E, Lai WS, Blackshear PJ:
Feedback inhibition of macrophage tu-
mor necrosis factor-alpha production
by tristetraprolin. Science 281:10011005,
1998
Letters
DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 845
Botulinum Toxin A in
the Early Treatment
of Sixth Nerve Palsy
Induced Diplopia in
Type 2 Diabetes
S
ixth (abducent) cranial nerve palsy
is a typical yet infrequent mononeu-
ropathic complication of diabetes. It
usually causes considerable diplopia,
which can be debilitating and signi-
cantly impair the everyday and profes-
sional activity of aficted individuals. In
most cases, nerve function restores itself,
although it usually takes several months
or even over a year for the symptoms to
resolve (1). No specic treatment of nerve
palsyinduced diplopia in diabetic pa-
tients has been established (2,3). We re-
port the successful use of botulinum toxin
A in the early treatment of diplopia caused
by sixth nerve palsy in two type 2 diabetic
patients. In both patients, diplopia made
it impossible for them to continue with
their professional activities.
The rst patient (female, computer
operator, aged 52 years, with a 15-year
history of type 2 diabetes and HbA
1c
8.2%) complained of diplopia, which oc-
curred several days earlier. Sixth nerve
palsy in the left eye was diagnosed, and
her squint angle was found to be 35
(prism dioptries) when measured with an
orism cover test. After prompt injection of
botulinum toxin A (15 units) into the me-
dial rectus muscle in the left eye, her dip-
lopia and squint resolved completely (Fig.
1). The second patient (male, taxi driver,
aged 50 years, with an 8-year history of
type 2 diabetes and HbA
1c
8.7%) was re-
ferred with sixth nerve palsy in the left eye
persisting for 3 months. His squint angle
was 55. The patient complained of se-
vere diplopia, predominantly when look-
ing left. Botulinum toxin A (15 units) was
injected into the medial rectus muscle in
the left eye, which resulted in the reduc-
tion of the squint angle to 15.To
achieve complete resolution of diplopia,
prism correction was used (Fig. 2). Six
months later, the vision of both patients
remains stable, with no diplopia occur-
ring while looking forward.
Injections of botulinum toxin A in the
treatment of sixth nerve palsy have been
used since the early 1980s (4) with a suc-
cess rate of 15100%, depending on the
severity and duration of the nerve palsy
(57). In general, early botulinum toxin
use is recommended, as then the resolu-
tion of diplopia can be complete (8). In
long-standing cases, successful treatment
inadvertently requires ocular muscle sur-
gery, which might be also associated with
botulinum toxin injections (3,9,10).
However, despite a relatively long
history of botulinum toxin treatment in
ocular muscle paralysis (4,6), its use and
investigations of treatment with it in dia-
betic mononeuropathy have been less
than scarce. Concomitantly, no routine
treatment is offered to patients, who are
often left untreated until the nerve palsy
itself subsides, which actually does hap-
pen in the majority of cases. However,
during this period the patient is usually
unable to work and is regarded a disabled
person.
Our report is, to the best of our
knowledge, the rst one describing the
effects of the early use of botulinum toxin
A in type 2 diabetic patients, in whom
diplopia caused by sixth nerve palsy made
them unable to work. In agreement with
the recommendations mentioned above,
in type 2 diabetic patients the use of bot-
ulinum toxin A at the very beginning of
diplopia and nerve lesion also seems to be
more effective than in patients with a long
duration of symptoms. We believe that
botulinum toxin A, especially if used im-
mediately after nerve palsy occurs, offers
an attractive option in the treatment of
cranial nerve palsyinduced diplopia,
thus saving the patient from surgical
treatment and assuring that quality of life
and professional activity will not suffer
due to signicant disturbance of vision.
ANNA BRONIARCZYK-LOBA,
MD
,
PHD
1
LESZEK CZUPRYNIAK,
MD
,
PHD
2
OLIMPIA NOWAKOWSKA,
MD
,
PHD
1
JERZY LOBA,
MD
,
PHD
2
From the From
1
Ophthalmology Department, Med-
ical University of Lodz, Barlicki University Hospital
No. 1, Lodz, Poland; and the
2
Diabetology Depart-
ment, Medical University of Lodz, Barlicki Univer-
sity Hospital No. 1, Lodz, Poland.
Address correspondence to Leszek Czupryniak,
Medical University of Lodz, Diabetology Depart-
ment, Kopcinskiego 22, Lodz 90153, Poland. E-
mail: bigosik@poczta.onet.pl.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Vinik AI, Park TS, Stansberry KB, Pit-
tenger GL: Diabetic neuropathies. Diabe-
tologia 43:957973, 2000
2. Rush JA, Younge BR: Paralysis of cranial
nerves III, IV, and VI: cause and prognosis
in 1,000 cases. Arch Ophthalmol 99:76
79, 1981
3. Kubatko-Zielinska A, Krzystkowa KM,
Madroszkiewicz A, Wojcik E, Filipowicz
E: Principles and results of treatment in
acquired paralysis of III, IV and VI nerves.
Klin Oczna 97:147151, 1995
4. Elston JS, Lee JP: Paralytic strabismus: the
role of botulinum toxin. Br J Ophthalmol
69:891896, 1985
5. Holmes JM, Leske DA, Christiansen SP: Ini-
tial treatment outcomes in chronic sixth
nerve palsy. J AAPOS 5:370376, 2001
6. Lee J, Harris S, Cohen J, Cooper K, Mac-
Ewan C, Jones S: Results of a prospective
randomized trial of botulinum toxin ther-
apy in acute unilateral sixth nerve palsy.
J Pediatr Ophthalmol Strabismus 31:283
Figure 1The rst patient before (A) and after (B) botulinum toxin A application. There is
complete resolution of strabismus and associated diplopia.
Figure 2The second patient before (A) and after (B) botulinum toxin A application. There is
incomplete resolution of strabismus, and his diplopia resolved only upon the use of prism correc-
tion (B).
Letters
846 DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004
286, 1994
7. Murray AD: Early botulinum toxin treat-
ment of acute sixth nerve palsy. Eye 5:45
47, 1991
8. Quah BL, Ling YL, Cheong PY, Balakrish-
nan V: A review of 5 yearsexperience in
the use of botulinum toxin A in the treat-
ment of sixth cranial nerve palsy at the
Singapore National Eye Centre. Singapore
Med J 40:405409, 1999
9. Biglan AW, Burnstine RA, Rogers GL,
Saunders RA: Management of strabismus
with botulinum A toxin. Ophthalmology
96:935943, 1989
10. Broniarczyk-Loba A, Nowakowska O,
Strak M, Loba J, Omulecki W: VI cranial
nerve palsy: treatment of diplopia. Diabe-
tol Pol 10:314317, 2003
Naltrexone Improves
Blood Glucose
Control in Type 1
Diabetic Women
With Severe and
Chronic Eating
Disorders
E
ating disorders are frequent causes of
chronic failure of blood glucose con-
trol in young type 1 diabetic women
(1) that result in a high incidence of dia-
betic complications (2). Moreover, severe
disorders such as bulimia and binge eat-
ing are commonly associated with inap-
propriate compensatory behaviors to
avoid weight gain, including self-induced
vomiting, insulin misuse, laxative or di-
uretic surreptitious intake, and hyperac-
tivity (3). Because these impulsive
attitudes develop as addictions, naltrex-
one, an antagonist of endogenous opiates
that is currently used to help weaning off
alcohol, opiates, or heroin, might be con-
sidered a potentially effective therapy. Of
note, recent data (4) report signicant im-
provements obtained with naltrexone in
bulimic patients, reinforcing the hypoth-
esis of an opioid-mediated dependence.
To assess the effectiveness of naltrex-
one in type 1 diabetic women presenting
bulimia or binge eating, we conducted an
open-label, 1-year pilot trial in 10 patients
affected by these eating disorders who did
not respond to antidepressive drugs, be-
havioral therapy, and interpersonal psy-
chotherapy. All patients volunteered and
gave their informed consent to enter the
trial, which was ethically approved. Mean
age of the patients was 22 years (range
1729), with type 1 diabetes history of 8
years (range 515). Initial BMI was 25
6 kg/m
2
. One patient affected by binge
eating presented morbid obesity (BMI
41.5 kg/m
2
). Blood glucose control at en-
rollment was very poor, as shown by
HbA
1c
levels (mean SD), which were
11.6 1.6% (by high-performance liq-
uid chromatography, normal range
5.6%). Eating disorders included binge
eating in three subjects (with 14, 21, and
26 episodes per week, respectively) and
bulimia in seven subjects (718 episodes
per week) and were also associated with
purgingbehavior (self-vomiting) in six
subjects (721 episodes per week), ac-
cording to the Diagnostic and Statistical
Manual of Mental Disorders IV classica-
tion. No psychiatric comorbidity was di-
agnosed. The mean history of severe
eating disorders was 6 years (range
411). All patients received oral naltrex-
one 200 mg b.i.d. (Bristol Myers Squibb,
Paris, France) for 1 year. Follow-up in-
cluded a monthly evaluation of the
weekly occurrence of impulsive eating
with or without purging episodes as the
main outcome and monthly measure-
ment of body weight and HbA
1c
assay ev-
ery 2 months as secondary outcomes.
Psychological assessment by self-
administered Eating Disorder Inventory 2
questionnaire was performed before and
at the end of the trial.
Results after 2 months and 1 year are
presented here to estimate the rapidity
and maintenance of drug response.
Weekly binge-eating episodes were dra-
matically reduced by 42, 62, and 86%,
respectively, as early as in the rst 2
months and remained reduced by 31, 52,
and 86%, respectively, after 1 year in the
three patients affected by this eating dis-
order. Weekly bulimic crises were re-
duced by 50% (range 1688) after 2
months and by 64% (range 29 94) after 1
year, while associated purging decreased
by 74% (range 5086) and 75% (range
52100) during the same time periods.
The only patient with nonpurging bu-
limia reduced her weekly crises by 71%
after 2 months, which was sustained after
1 year. Meanwhile, body weight de-
creased by 35% after 2 months and by
57% after 1 year in binge eaters, and
HbA
1c
levels moved from 11.3, 12.1, and
14.1% to 10.4, 9.8, and 10.2% after 2
months and to 9.0, 8.7, and 9.8% after 1
year, respectively. Body weight remained
stable over 1 year in bulimic patients, ex-
cept in the nonpurging subject, who lost
5% of her initial weight. However, HbA
1c
levels (mean SD) improved from
11.6 1.2 to 10.1 0.6% after 2 months
and to 9.0 0.9% after 1 year in these
patients. Scores of the Eating Disorder In-
ventory 2 questionnaire dramatically im-
proved concerning attitude toward
impulsiveness(data not shown, P
0.01) and also improved at a lower level
concerning low self-esteem(data not
shown, P0.05), regardless of which
eating disorder. No undesirable clinical or
biological (liver enzymes and creatinine-
mia) side effects were noted during the
trial.
Similar to results obtained with nal-
trexone in nondiabetic subjects, our data
show a dramatic improvement in impul-
sive eating disorders with this drug in our
cohort of type 1 diabetic women. While
average weekly occurrence of food intake
crises was reduced by 5064%, purging
behaviors were improved even more by
70%. Most of the drug response was
obtained after 2 months, but it was main-
tained or slightly improved further after 1
year. Only binge-eating crises slightly re-
bounded between the second and twelfth
months in two patients, but remained
much less frequent than the initial rate.
The effect on body weight was modest
because reduction of previous intentional
insulinopenia and/or vomiting attenuates
the impact on body weight. The highly
signicant improvement of diabetes con-
trol is shown, with an average HbA
1c
de-
crease of 1.5% after 2 months and 2.5%
after 1 year. If maintained for years, such
reductions in HbA
1c
levels could mean an
even more impressive improvement of
the incidence of diabetic complications,
according to estimations from the Diabe-
tes Control and Complications Trial (5).
Beside reduction of carbohydrate intakes,
psychological changes documented by
the Eating Disorder Inventory 2 question-
naire likely played a role in positive be-
havior toward insulin treatment, which
may explain the HbA
1c
improvement. Al-
though we cannot exclude a nonspecic
study effect,the encouraging results of
this pilot trial warrant further assessment
of naltrexone in controlled studies, espe-
cially as severe eating disorders associated
with type 1 diabetes represent an often
hopeless condition.
Letters
DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 847
ISABELLE RAINGEARD,
MD
1
PHILIPPE COURTET,
MD, PHD
2
ERIC RENARD,
MD, PHD
1
JACQUES BRINGER,
MD
1
From the
1
Endocrinology Department, Lapeyronie
Hospital, Montpellier, France; and the
2
Department
of Psychological Medicine and Psychiatry, Lapey-
ronie Hospital, Montpellier, France.
Address correspondence to Eric M. Renard, MD,
PhD, Endocrinology Department, Lapeyronie Hos-
pital, F 34295 Montpellier cedex 5, France. E-mail:
renard.amtim@wanadoo.fr.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Rodin GM, Daneman D: Eating disorders
and IDDM: a problematic association. Di-
abetes Care 15:14021412, 1992
2. Rydall AC, Rodin GM, Olmsted M, Deve-
nyi RG, Daneman D: Disordered eating
behavior and microvascular complica-
tions in young women with insulin-de-
pendent diabetes mellitus. N Engl J Med
336:18491854, 1997
3. Polonsky WH, Anderson BJ, Lohrer PA,
Aponte JE, Jacobson AM, Cole CF: Insulin
omission in women with IDDM. Diabetes
Care 17:11781185, 1994
4. Marrazi MA, Kinzie J, Luby ED: A de-
tailed longitudinal analysis on the use of
naltrexone in the treatment of bulimia.
Int Clin Psychopharmacol 10:173176, 1995
5. The Diabetes Control and Complications
Trial Research Group: The effect of inten-
sive treatment of diabetes on the develop-
ment and progression of long-term com-
plications in insulin-dependent diabetes
mellitus. N Engl J Med 329:977986, 1993
COMMENTS AND
RESPONSES
Utility of B-Type
Natriuretic Peptide
as a Screen for Left
Ventricular
Dysfunction in
Patients With
Diabetes
Response to Epshteyn et al.
I
n their study recently published in Di-
abetes Care, Epshteyn et al. (1) found
that plasma B-type natriuretic peptide
(BNP) was able to discriminate between
diabetic patients with and without left
ventricular (LV) dysfunction, even among
the subset without any clinical suspicion
of heart failure. It is this last observation
that supports the use of BNP as a screen
for LV dysfunction among people with di-
abetes. Detection of LV dysfunction, an
early feature of diabetic heart disease, pre-
sents an important opportunity for pre-
vention of downstream morbidity and
mortality (2). The question that begs to be
answered is when should screening for LV
dysfunction take place?
Epshteyn et al.s (1) sample of 91 pa-
tients without clinical suspicion of heart
failure did, however, contain a signicant
number with vascular disease. A history
of hypertension, coronary artery disease,
and myocardial infarction was present in
81, 23, and 18% of the sample, respec-
tively. The study reinforced the value of
screening with BNP in a high-risk diabetic
population. What remains unknown is
whether the utility of BNP for the detec-
tion of LV dysfunction extends to asymp-
tomatic individuals without overt
vascular disease.
We addressed this by undertaking a
substudy within the large Australian Dia-
betes, Obesity and Lifestyle (AusDiab)
study (3). A random sample of 100 adults
with type 2 diabetes but free of overt car-
diovascular disease and hypertension
were matched 1:1:1 by age and sex to sub-
jects with normal glucose tolerance
(NGT) and impaired glucose tolerance
(IGT), who were also without overt car-
diovascular disease and hypertension. In
contrast to the study by Epshteyn et al. no
differences were found in mean (SE)
levels of plasma N-terminal BNP across
the three groups: type 2 diabetes, 155
33; IGT, 172 40; and NGT, 162 51
pg/ml (P0.96). However, there were
signicant differences in urinary protein:
type 2 diabetes, 102 15; IGT, 64 7;
and NGT, 50 4 mg/day (P0.001).
There are two possible explanations
for the observed ndings with N-terminal
BNP: 1) among diabetic patients without
overt cardiovascular disease and hyper-
tension, LV dysfunction is not more com-
mon compared with that of those with
IGT and NGT, or 2) plasma N-terminal
BNP is not sensitive to its presence. Echo-
cardiographic studies would be needed to
conrm which explanation holds, but ei-
ther way plasma N-terminal BNP appears
to have little utility for early screening of
LV dysfunction in patients with diabetes
(in the absence of cardiovascular disease
and hypertension). This contrasts with
early screening for renal dysfunction by
urinalysis.
DANNY LIEW,
FRACP
1
HANS SCHNEIDER,
FRACP
2
JOE D’AGOSTINO,
BSC
2
JONATHAN SHAW,
MD
3
HENRY KRUM,
PHD
1
From the
1
NHMRC Centre of Clinical Research Ex-
cellence in Therapeutics, Department of Epidemiol-
ogy and Preventive Medicine, Monash University
Medical School, Alfred Hospital, Melbourne, Victo-
ria, Australia; the
2
Alfred Pathology Service, Alfred
Hospital, Melbourne, Victoria, Australia; and the
3
International Diabetes Institute, Cauleld, Victoria,
Australia.
Address correspondence to Dr. Danny Liew, De-
partment of Epidemiology and Preventive Medicine,
Monash University Medical School, Alfred Hospital,
Melbourne, Victoria 3004, Australia. E-mail:
danny.liew@med.monash.edu.au.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Epshteyn V, Morrison K, Krishnaswamy
P, Kazanegra R, Clopton P, Mudaliar S,
Edelman S, Henry R, Maisel A: Utility of
B-type natriuretic peptide (BNP) as a
screen for left ventricular dysfunction in
patients with diabetes. Diabetes Care 26:
20812087, 2003
2. Bell DS: Heart failure: the frequent, for-
gotten, and often fatal complication of di-
abetes. Diabetes Care 26:24332441, 2003
3. Dunstan DW, Zimmet PZ, Welborn TA,
De Courten MP, Cameron AJ, Sicree RA,
Dwyer T, Colagiuri S, Jolley D, Knuiman
M, Atkins R, Shaw JE: The rising preva-
lence of diabetes and impaired glucose
tolerance: the Australian Diabetes, Obe-
sity and Lifestyle Study. Diabetes Care 25:
829834, 2002
Utility of B-Type
Natriuretic Peptide
as a Screen for Left
Ventricular
Dysfunction in
Patients With
Diabetes
Response to Liew et al.
L
iew et al. (1) are correct in their
premise that their study likely repre-
sents a different population of pa-
tients than our study (2). While their
Letters
848 DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004
study looked at a very early, asymptom-
atic population of diabetic subjects who
were free of overt heart disease or hyper-
tension, our patient population was a Vet-
erans Administration population with
many risk factors for heart disease; hence,
they are a very high-risk population.
The positive predictive value of any
test becomes much stronger as the preva-
lence of disease increases. The negative
predictive value is strong in both studies.
The two peptides B-type natriuretic pep-
tide (BNP), and the inactive NH
2
-terminal
pro-BNP, are cleaved from the same pre-
cursor molecule, prepro BNP. Although
NH
2
-terminal pro-BNP has exclusive re-
nal clearance and a longer half-life than
BNP, these factors should not account for
the differences. However, it is possible
that the elevation of NH
2
-terminal pro-
BNP (and not BNP) with even small
amounts of renal dysfunction might ob-
scure the ability to detect cardiac abnor-
malities.
Liew et al. (1) conclude that NH
2
-
terminal pro-BNP has little utility for early
screening of left ventricular dysfunction
in patients with diabetes. This may be true
in a relatively asymptomatic low-risk
group, but is unlikely to be true in the
majority of patients with type 2 diabetes,
who have many other risk factors. It is
likely that their patients had no cardiac
dysfunction, whereas in our study, almost
all of the patients with high BNP levels did
have diastolic or systolic dysfunction,
even when asymptomatic. We found a
particularly high incidence of diastolic
dysfunction in this group of patients.
We now have 34 years of follow-up
data on this group of patients (V. Ep-
shteyn, K. Morrison, P. Krishnaswamy, R.
Kazanegra, P. Clopton, S. Mudaliar, S.
Edelman, R.H., A. Maisel, unpublished
data), and BNP turns out to be an ex-
tremely strong predictor of future cardiac
events. We believe that if Liew et al. con-
tinue to follow peptide levels in these pa-
tients, they will begin to see increases in
levels as the ventricle begins to either
stiffen and/or fail. This may be the oppor-
tune time to maximize cardiac work-up
and treatment in these patients.
ROBERT R. HENRY,
MD
ALAN MAISEL,
MD
From the VA San Diego Healthcare System, San Di-
ego, California.
Address correspondence to Robert R. Henry, MD,
VA San Diego Healthcare System, 3350 La Jolla Vil-
lage Dr., San Diego, CA 92161. E-mail:
rrhenry@vapop.ucsd.edu.
R.H. holds stock in Biosite, which markets BNP.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Liew D, Schneider H, DAgostino J, Shaw
J, Krum H: Utility of B-type natriuretic
peptide as a screen for left ventricular dys-
function in patients with diabetes (Letter).
Diabetes Care 27:848, 2004
2. Epshteyn V, Morrison K, Krishnaswamy
P, Kazanegra R, Clopton P, Mudaliar S,
Edelman S, Henry R, Maisel A: Utility of
B-type natriuretic peptide (BNP) as a
screen for left ventricular dysfunction in
patients with diabetes. Diabetes Care 26:
20812087, 2003
How to Implement
Evidence Into
Practice to Improve
Diabetes Care
Response to Ilag et al.
I
n their article, Ilag et al. (1) used the
Annual Diabetes Assessment Program
(ADAP) as a model to improve the stan-
dard of care for patients with type 2 dia-
betes. Despite established guidelines for
type 2 diabetes, the majority of patients in
the U.S. do not reach these goals (2). Var-
ious approaches have been used, includ-
ing disease management programs,
physician education, nurse case manage-
ment, and use of information systems to
translate evidence-based recommenda-
tions into clinical practice (3).
Diabetes translation research should
be conducted as an effectiveness trial,
rather than an efcacy trial with loose el-
igibility criteria, in order to produce a het-
erogeneous population to enhance
external validity of the intervention. Ilag
et al. used comparatively strict and sub-
jective eligibility criteria, since 284 of 584
patients were considered eligible. The
study population in this trial was mainly
composed of Caucasian Americans. His-
panic Americans have a higher prevalence
rate of diabetes and its complications (4).
The Hispanic population should be over-
sampled in these trials.
There was a high drop-out rate in
their study group, as only 83 of 173
(48%) subjects who were enrolled re-
turned for the year-2 visit compared with
71 of 111 (64%) in the control group.
Because compliance to treatment is the
major challenge faced in diabetes man-
agement, intent-to-treat analysis should
be included along with protocol analysis
in diabetes translation research trials.
The authors did not mention the costs
and resources of implementation of this
model. Certied diabetes educators
(CDEs) were used for implementation of
the ADAP. It was not described how many
CDEs were used in relation to a certain
number of patients. The use of CDEs for
implementation of guidelines questions
the reproducibility of this model on a
mass scale due to the lack of easy avail-
ability of CDEs.
I agree with the authorscomments
that lack of integration of ADAP providers
in the practice and lack of continuous
communication (once-a-year visit only)
with both patients and physicians re-
sulted in lower enthusiasm in providers
and lack of impact on intermediate out-
comes. The combined effects of a pro-
gram like the ADAP, generating
guideline-driven recommendations and
consistent follow-up by nurse case man-
agers, with management algorithms may
prove more effective.
TIPU FAIZ M. SALEEM,
MD
From the Division of Endocrinology, Department of
Medicine, The Reading Hospital and Medical Cen-
ter, Reading, Pennsylvania.
Address correspondence to Tipu Faiz M. Saleem,
MD, Division of Endocrinology, Department of
Medicine, Reading Health Dispensory, 430 North
2nd St., Reading, PA 19601. E-mail: tipufaiz@
aol.com.
T.F.M.S. is also a student in the Masters in Health
Evaluation Science program, which is supported by
a grant from the National Institutes of Health (NIH
K30).
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Ilag LL, Martin CL, Tabaei BP, Isaman
DJM, Burke Ray, Greene DA, Herman
WH: Improving diabetes processes of care
in managed care. Diabetes Care 26:2722
2727, 2003
2. Saaddine JB, Engelgau MM, Beckles GL,
Gregg EW, Thompson TJ, Narayan KM: A
diabetes report card for the United States:
quality of care in the 1990s. Ann Intern
Med 136:565574, 2002
Letters
DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 849
3. Renders CM, Valk GD, Grifn SJ, Wagner
EH, Van JTE, Assendelft WJJ: Interven-
tions to improve the management of dia-
betes in primary care, outpatient, and
community settings: a systematic review.
Diabetes Care 24:18211833, 2001
4. National Institute of Diabetes and Diges-
tive and Kidney Diseases: Diabetes in His-
panic Americans [article online], 2002.
Available from http://diabetes.niddk.nih.
gov/dm/pubs/hispanicamerican/index.
htm. NIH publ. no. 02-3265. Accessed 21
October 2003
How to Implement
Evidence Into
Practice to Improve
Diabetes Care
Response to Saleem
W
e appreciate Dr. Saleems (1) in-
terest and comments and thank
the editor for the opportunity to
clarify the points raised about our study
(2).
Our study was an effectiveness trial.
The target population for the Annual Di-
abetes Assessment Program (ADAP) in-
cluded all managed care members with
diabetes assigned to the participating pro-
vider groups. The enrollment criteria
were pragmatic, excluding those without
diabetes, those who were no longer being
followed by the primary care physician,
and those who were deemed unsuitable
candidates for the studyby their primary
care physicians. We obtained consent
from both participants and their primary
care physicians to comply with good clin-
ical practice (3). The attrition in the inter-
vention group from 173 eligible
individuals to 103 enrolled subjects re-
ected those who did not consent to the
ADAP. The decrease in sample size from
year 1 to year 2 (from 103 to 83 in the
intervention group and from 111 to 71 in
the comparison group) was largely due to
subjectsinability to come for their year 2
appointments (e.g., moved away, too ill,
etc.). The drop-out rate for the interven-
tion group was 20% (20 of 103), not 52%.
We analyzed outcomes for study compl-
eters to avoid within-group and between-
group bias in interpreting the results. The
composition of the study population re-
ected the racial and ethnic composition
of the health plan. We saw no reason to
oversample Hispanics. Even if we had
done so, we would not be able to generate
a sample size sufcient to draw inferences
about that population.
The intervention was added to usual
care, and as a result, the ADAP was more
expensive than usual care alone. Since the
ADAP resulted in no improvement in out-
comes, usual care dominated the experi-
mental intervention (4). Three registered
nurses/certied diabetes educators imple-
mented the ADAP. Clearly, it was feasible
to implement the ADAP with nonphysi-
cian providers. The question now is how
to structure the ADAP to improve both
processes of care and intermediate out-
comes. Our study was limited in that the
ADAP generated only patient and pro-
vider feedback. As combinations of inter-
ventions have been shown to be more
effective in producing change (5,6), fu-
ture studies should include the ADAP and
additional interventions such as nurse
case management and more effective
tracking and reminder systems to impact
both processes and outcomes of care.
LIZA L. ILAG,
MD, MS
1
WILLIAM H. HERMAN,
MD, MPH
1,2
From the
1
Department of Internal Medicine, Uni-
versity of Michigan Health System, Ann Arbor,
Michigan; and the
2
Department of Epidemiology,
University of Michigan Health System, Ann Arbor,
Michigan.
Address correspondence to Liza L. Ilag, MD, MS,
Division of Endocrinology and Metabolism, Depart-
ment of Internal Medicine, University of Michigan
Health System, 1500 E. Medical Center Dr., 3920
Taubman Center, Box 0354, Ann Arbor, MI 48109-
0354. E-mail: lilag@umich.edu.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Saleem TFM: How to implement evidence
into practice to improve diabetes care
(Letter). Diabetes Care 27:849850, 2004
2. Ilag LL, Martin CL, Tabaei BP, Isaman
DJM, Burke R, Greene DA, Herman WH:
Improving diabetes processes of care in
managed care. Diabetes Care 26:2722
2727, 2003
3. Good clinical practice [article online],
1996. Available from http://pharmacos.
eudra.org/F2/eudralex/vol-3/pdfs-en/
3cc1aen.pdf. Accessed 15 January 2004
4. Garber AM, Weinstein MC, Torrance
GW, Kamlet MS: Theoretical foundations
of cost-effectiveness analysis. In Cost-Ef-
fectiveness in Health and Medicine. Gold
MR, Siegel JE, Russell LB, Weinstein MC,
Eds. New York, Oxford Press, 1996, p. 27
5. Renders CM, Valk GD, Grifn SJ, Wagner
EH, Eijk van JR, Assendelft WJJ: Interven-
tions to improve the management of dia-
betes in primary care, outpatient, and
community settings. Diabetes Care 24:
18211833, 2001
6. Weingarten SR, Henning JM, Badamgarav
E, Knight K, Hasselblad V, Gano A Jr, Of-
man JJ. Interventions used in disease
management programmes for patients
with chronic illness: which ones work?
Meta-analysis of published works. BMJ
325:925932, 2002
Use of
Thiazolidinediones
and Risk of Heart
Failure in People
With Type 2
Diabetes: A
Retrospective Cohort
Study
Response to Delea et al.
T
here is a growing concern that use of
thiazolidinediones (TZDs) is associ-
ated with congestive heart failure
(CHF) (1), though the causality of this
relationship has not been established.
Commentaries and case reports about this
potential side effect have frequently ap-
peared in the press, but peer-reviewed,
large-scale epidemiologic studies have
been absent. A few European nations have
already limited the use of TZDs despite
the absence of empirical evidence. A re-
cently published, longitudinal observa-
tional study by Delea et al. (2) reported
that initiation of TZDs was associated
with an increased risk of incident CHF
(hazard ratio 1.7; P0.001). While we
welcome this rst population-based
study of TZD use and CHF, we have seri-
ous concerns regarding the methodology
employed.
Our primary concern with the study
by Delea et al. (2) is the potential for re-
sidual confounding by indication or se-
verity (3). For example, this study did not
measure or adjust for levels of glycemia, a
Letters
850 DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004
known risk factor for CHF in diabetes (4).
In a time-to-event analysis, the authors
compared patients who newly initiated
TZDs with those who did not newly initi-
ate TZD therapy while adjusting for other
maintained diabetes therapies. Although
patients may switch therapies due to side
effects, most patients initiate intensied
therapy because they have failed to main-
tain adequate glycemic control with pre-
vious regimens (5). Thus patients who
initiate a new diabetes therapy, particu-
larly a therapy not considered to be rst
line, would likely have poorer glycemic
control and more advanced diabetes than
those who maintain previous therapy and
therefore may be at greater risk for CHF.
We are currently conducting a long-
term study, funded by the American Dia-
betes Association, of TZD use and CHF in
the Kaiser Permanente Northern Califor-
nia Diabetes Registry. In preliminary anal-
yses, we found a substantially elevated
prevalence of several markers of disease
severity, including poor glycemic control
(HbA
1c
9.5%), among patients initiat-
ing new diabetes medications relative to
those not starting new therapies. More-
over, compared with those initiating
other therapies, TZD initiators had a
higher prevalence of many CHF risk fac-
tors, including the greatest prevalence of
ischemic heart disease, hypertension, ele-
vated urinary albumin excretion, elevated
serum creatinine, microalbuminuria, and
obesity; the poorest glycemic control; and
the lowest mean HDL cholesterol levels.
TZD initiators were those most likely to
also be prescribed medications for dyslip-
idemia and hypertension and had the
greatest outpatient and inpatient utiliza-
tion. Thus, TZDs were initiated more fre-
quently in diabetic patients with more
advanced disease. Since there currently
are no generic TZDs, these expensive
therapies are likely being reserved for
more severe or advanced cases of diabetes.
Delea et al. (2) compared CHF inci-
dence in TZD initiators with that among
all other patients, a comparison that is
even more biased than the comparison of
TZD initiators to initiators of other diabe-
tes therapies. Their comparison group is
primarily comprised of those maintaining
rather than initiating therapies and is thus
healthier. These authors acknowledge
that TZD initiators were sicker than sub-
jects in their comparison group. Substan-
tial imbalance in disease severity between
exposure groups makes observational
studies particularly vulnerable to bias, es-
pecially in the absence of thorough statis-
tical adjustment. The authors relied on
adjustment for prevalent conditions re-
ported in the previous 12 months, includ-
ing concurrent medication use and
processes of care. While this may seem to
be adequate at rst glance, the impact of
residual confounding remains unclear
since important clinical adjusters, such as
levels of glycemic control and markers of
disease severity, measured over a longer
time frame were not available. Additional
uncertainties remain. If TZDs confer in-
creased risk for CHF, one might expect a
dose-response effect. No such evidence
was reported in the study of Delea et al.
Even the largest well-designed pre-
marketing trials often fail to uncover seri-
ous side effects caused by new therapies
(6). Spontaneous adverse drug reaction
reports from postmarketing surveillance
are subject to overinterpretation given the
often atypical clinical characteristics of
cases (confounding), unawareness of the
population background rate, and exag-
gerating effect of media focus, underscor-
ing the importance of large epidemiologic
studies to estimate the risk of adverse
events associated with drug use (79). Al-
though it is well accepted that TZDs may
cause volume expansion and peripheral
edema (10), the association between
long-term TZD utilization and increased
CHF risk requires further evaluation (11).
Delea et al. should be commended for tak-
ing the rst step in examining the poten-
tial for TZD side effects. It is clear that
these authors have conducted the best
possible analysis with the available data
and fully acknowledge the potential limi-
tations of their study design. However, we
cannot exclude residual confounding as
an explanation for these authors’findings;
any newly initiated diabetes therapy
might be associated with elevated CHF
risk. We therefore caution that the nd-
ings of Delea et al. should not be inter-
preted as causal. Changes in clinical
recommendations for TZDs should be
based on solid evidence; we do not think
this sufces.
ANDREW J. KARTER,
PHD
AMEENA T. AHMED,
MD, MPH
JENNIFER LIU,
MPH
HOWARD H. MOFFET,
MPH
MELISSA M. PARKER,
MS
ASSIAMIRA FERRARA,
MD, PHD
JOE V. SELBY,
MD, MPH
From the Division of Research, Kaiser Permanente,
Oakland, California.
Address correspondence to Andrew J. Karter, Di-
vision of Research, Kaiser Permanente, 3505 Broad-
way, Oakland, CA 94611. E-mail: andy.j.karter@
kp.org.
© 2004 by the American Diabetes Association.
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Nesto RW, Bell D, Bonow RO, Fonseca V,
Grundy SM, Horton ES, Le Winter M,
Porte D, Semenkovich CF, Smith S,
Young LH, Kahn R: Thiazolidinedione
use, uid retention, and congestive heart
failure: a consensus statement from the
American Heart Association and Ameri-
can Diabetes Association. Diabetes Care
27:256263, 2004
2. Delea TE, Edelsberg JS, Hagiwara M,
Oster G, Phillips LS: Use of thiazo-
lidinediones and risk of heart failure in
people with type 2 diabetes: a retrospec-
tive cohort study. Diabetes Care 26:2983
2989, 2003
3. Salas M, Hofman A, Stricker BH: Con-
founding by indication: an example of
variation in the use of epidemiologic ter-
minology. Am J Epidemiol 149:981983,
1999
4. Iribarren C, Karter AJ, Go AS, Ferrara A,
Liu JY, Sidney S, Selby JV: Glycemic con-
trol and heart failure among adult patients
with diabetes. Circulation 103:2668
2673, 2001
5. Inzucchi SE: Oral antihyperglycemic
therapy for type 2 diabetes: scientic re-
view. JAMA 287:360372, 2002
6. Kessler DA: Introducing MEDWatch:
a new approach to reporting medica-
tion and device adverse effects and prod-
uct problems. JAMA 269:27652768,
1993
7. Wood AJ, Stein CM, Woosley R: Making
medicines safer: the need for an indepen-
dent drug safety board. N Engl J Med 339:
18511854, 1998
8. Ray WA, Grifn MR, Avorn J: Evaluating
drugs after their approval for clinical use.
N Engl J Med 329:20292032, 1993
9. Ray WA: Evaluating medication effects
outside of clinical trials: new-user de-
signs. Am J Epidemiol 158:915920, 2003
10 Tang WH, Francis GS, Hoogwerf BJ,
Young JB: Fluid retention after initiation of
thiazolidinedione therapy in diabetic pa-
tients with established chronic heart fail-
ure. J Am Coll Cardiol 41:13941398,
2003
11. Masoudi FA, Wang Y, Inzucchi SE, Setaro
JF, Havranek EP, Foody JM, Krumholz
HM: Metformin and thiazolidinedione
use in Medicare patients with heart fail-
ure. JAMA 290:8185, 2003
Letters
DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 851
Use of
Thiazolidinediones
and Risk of Heart
Failure in People
With Type 2
Diabetes: A
Retrospective Cohort
Study
Response to Karter et al.
W
e thank Karter et al. (1) for their
comments regarding our study
(2). We agree that its principal
weakness is the possibility of residual
confounding, and we acknowledge this
limitation in our article. We also agree
that comparison of patients initiating
thiazolidinediones (TZDs) with all those
receiving other oral antidiabetic agents
(new starters plus those on maintenance
therapy) may have biased our ndings
against TZDs. On the other hand, the al-
ternative of comparing patients initiating
therapy with TZDs with those initiating
other oral antidiabetic agents could have
imparted a potentially more serious bias
to the study because (as Karter et al. note)
the former may be more likely to be initi-
ated later in the course of the disease than
the latter. Lacking data on the duration of
diabetes, we chose an approach that we
hoped would minimize bias and we at-
tempted to control for confounding using
multivariate analysis and propensity
matching.
Karter et al. (1) present a number of
intriguing preliminary results from the
Kaiser Permanente Northern California
Diabetes Registry. Although the Registry
provides a richer clinical picture than the
claims dataset we employed in terms of
patient characteristics such as glycemic
control, it too has its limitations. The Reg-
istry represents a group of patients receiv-
ing treatment in a single, group practice,
integrated delivery system in which pro-
cesses and outcomes of care for diabetes
patients may differ substantially from
those among the more diverse group of
patients represented in our study. In Kai-
ser Permanente Northern California,
TZDs may be more likely to be reserved
for the sickestpatients. Also, the effects
of TZDs on risk of heart failure may be less
pronounced in settings where patients are
monitored more frequently and edema is
therefore less likely to progress to overt
heart failure before arousing clinical sus-
picion and action.
Thus, although we eagerly await the
results of the analysis by Karter et al., we
suspect that it may not provide a deni-
tive answer with respect to the effects of
TZDs on risk of heart failure because their
analysis will suffer from the same funda-
mental weakness (i.e., possibility of resid-
ual confounding) that they correctly
identied in ours, although perhaps to a
lesser degree. Moreover, their study may
suffer from the additional potential limi-
tation of lack of generalizability to the
overall population of patients receiving
TZDs. As we note in our study, denitive
conclusions must await the results of
long-term, randomized, controlled trials
(although these too may suffer from prob-
lems of generalizability).
So where does this leave us? While
awaiting the results of ongoing studies,
clinicians must make use of the best avail-
able data to guide their decisions. We
agree with Karter et al. that the results of
our study do not warrant changes in clin-
ical practice guidelines. Our recommen-
dation that physicians use these drugs
with caution in patients with heart failure
is entirely consistent with warnings set
forth in U.S. Food and Drug Administra-
tionapproved labeling for rosiglitazone
and pioglitazone (3,4). Our recommen-
dation that physicians seek alternatives
for patients with shortness of breath is
only common sense in light of the
strength and consistency of the associa-
tion that we observed, the known physi-
ologic effects of these agents, and
published reports of TZD-induced heart
failure and pulmonary edema resolving
after discontinuation of such therapy
(5).
Unfortunately, even well-established
treatment guidelines are not consistently
followed in typical clinical practice, as
demonstrated by a recent study (6) that
found that patients hospitalized for heart
failure frequently receive TZDs despite
explicit warnings against this practice.
We hope that our study will increase phy-
sician awareness of the potential risk of
heart failure associated with the use TZDs
so that it may be weighed against the po-
tential benets of these agents in improv-
ing clinical outcomes in patients with
diabetes (78).
THOMAS E. DELEA,
MBA
1
JOHN S. EDELSBERG,
MD, MPH
1
MAY HAGIWARA,
PHD
1
GERRY OSTER,
PHD
1
LAWRENCE S. PHILLIPS,
MD
2
From
1
Policy Analysis, Inc. (PAI), Brookline, Mas-
sachusetts; and the
2
Division of Endocrinology,
School of Medicine, Emory University, Atlanta,
Georgia.
Address correspondence to Thomas E. Delea,
MBA, Policy Analysis, Inc. (PAI), 4 Davis Ct., Brook-
line, MA 02445. E-mail: tdelea@pai2.com.
L.S.P. has received research support from Pzer,
Lilly, Novartis, GlaxoSmithKline, Genentech, and
Pharmacia.
© 2004 by the American Diabetes Association.
AcknowledgmentsThe study by Delea et
al. was funded by Novartis Pharmaceuticals.
L.S.P. was supported in part by Policy Analy-
sis, Inc., and an award from the Agency for
Healthcare Research and Quality/National In-
stitute of Diabetes and Digestive and Kidney
Diseases (HS-07922).
●●●●●●●●●●●●●●●●●●●●●●●
References
1. Karter AJ, Ahmed AT, Liu J, Moffet HH,
Parker MM, Ferrara A, Selby JV: Use of
thiazolidinediones and risk of heart fail-
ure in people with type 2 diabetes: a ret-
rospective cohort study (Letter). Diabetes
Care 27:850851, 2004
2. Delea TE, Edelsberg JS, Hagiwara M,
Oster G, Phillips LS: Use of thiazo-
lidinediones and risk of heart failure in
people with type 2 diabetes: a retrospec-
tive cohort study. Diabetes Care 26:2983
2989, 2003
3. SmithKline Beecham Pharmaceuticals:
Avandia (Rosiglitazone Maleate) Tablets:
Prescribing Information [package insert].
Philadelphia, PA, SmithKline Beecham
Pharmaceuticals, 2003
4. Takeda Pharmaceuticals America: Actos
(Pioglitazone Hydrochloride) Tablets [pack-
age insert]. Lincolnshire, IL, Takeda Phar-
maceuticals America, 2003
5. Kermani A, Garg A: Thiazolidinedione-
associated congestive heart failure and
pulmonary edema. Mayo Clin Proc 78:
10881091, 2003
6. Masoudi FA, Wang Y, Inzucchi SE, Setaro
JF, Havranek EP, Foody JM, Krumholz
HM: Metformin and thiazolidinedione
use in Medicare patients with heart fail-
ure. JAMA 290:8185, 2003
Letters
852 DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004
7. Diamant M, Heine RJ: Thiazolidinediones
in type 2 diabetes mellitus: current clini-
cal evidence. Drugs 63:13731405, 2003
8. Parulkar AA, Pendergrass ML, Granda-
Ayala R, Lee TR, Fonseca VA: Nonhypo-
glycemic effects of thiazolidinediones.
Ann Intern Med 134:6171, 2001 [pub-
lished erratum appears in Ann Intern Med
135:307, 2001]
Letters
DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 853
... 19 Previous studies have shown that supplementation with PBE could have several beneficial effects such as antioxidant, antiinflammatory, hypolipidemic, hypoglycemic, and antitrombogenic, as well as antiobesity activities. [20][21][22][23][24][25][26] In vitro studies reported that PBE treatment decreases the expression of CAMs in activated endothelial cells. 27,28 However, limited intervention studies have been carried out previously to investigate the possible effects of PBE supplementation on certain metabolic parameters such as microalbuminuria and VCAM-1 in patients with T2DM. ...
... Jankyova et al.35 reported improved FBS and postprandial glucose concentrations with PBE treatment in streptozotocininduced diabetic rats. Several clinical trials also found improvements in glycemia with PBE supplementation.20,[22][23][24][25][26] In the study by Liu et al.23 PBE consumption decreased HbA1c, FBS, and postprandial glucose in a dose-dependent manner in patients with T2DM during 12 weeks, but it did not affect insulin levels at any dosage of administration. ...
... Several clinical trials also found improvements in glycemia with PBE supplementation.20,[22][23][24][25][26] In the study by Liu et al.23 PBE consumption decreased HbA1c, FBS, and postprandial glucose in a dose-dependent manner in patients with T2DM during 12 weeks, but it did not affect insulin levels at any dosage of administration. Another study showed that supplementation with 100 mg/day PBE for 12 weeks reduced HbA1c and FBS concentrations; ...
Article
Full-text available
Objectives This study investigated the effect of French maritime pine bark extract (PBE) supplementation on metabolic parameters, vascular cell adhesion molecule 1 (VCAM-1), urinary albumin-to-creatinine ratio (UACR), and anthropometric indexes in patients with type 2 diabetes (T2DM) and microalbuminuria. Design This randomized, double-blind, placebo-controlled clinical trial was conducted on 46 patients with T2DM and the evidence of microalbuminuria aged 30 to 65 years. Setting Patients were recruited from the endocrinology clinic of Sina hospital (Tabriz, Iran) from March 2018 to April 2019. Interventions The subjects were randomly assigned to receive two capsules/day each containing 50mg of PBE or placebo for eight weeks. Main outcome measures Glycemic parameters, serum VCAM-1 and lipid profile, UACR, and anthropometric indexes were measured for all patients at baseline and the end of the study. Results PBE supplementation significantly reduced glycosylated hemoglobin, VCAM-1, total cholesterol, UACR, waist circumference, and waist-to-height ratio compared to the placebo group at the end of the study (all P < 0.05). Changes in fasting blood glucose, insulin, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were not significant between the two groups (all P > 0.05). Conclusions The study findings demonstrated some favorable effects of PBE supplementation on glycemic control, serum VCAM-1 and total cholesterol levels, and microalbuminuria, as well as abdominal obesity in patients with T2DM.
... Recently, it has been noted that PYC may interact with the blood vessel wall and generate a capillary 'sealing' effect, resulting in reducing edema and capillary absorbency [17]. PYC has shown to have promising results in improving conditions, including diabetes [16,33]. These effects manifested in our result, which demonstrated notable signs of the highly proliferative activity in the stromal lamellae and conspicuous regression of immature collagen fibers proofing the retraction in proinflammatory cytokine. ...
Article
Full-text available
Aim This study aimed to investigate the efficiency of topically applied pycnogenol (PYC) in healing the standardized alkaline corneal ulcer in diabetic and normal rats. Materials and methods The corneal alkali-burn injury (CA-I) model was unilaterally developed in Wistar rats by filter paper saturated with 0.01 M of NaOH and touching the eyes for 45 s. Rats were divided into four groups: Normal control (NC), normal PYC (NPYC), diabetic control (DC), and diabetic PYC (DPYC). Both NPYC and DPYC groups were daily treated with PY eye drops three times, whereas NC and DC ones were treated with ordinary saline for six successive days. Results The wound healing of corneal epithelial was improved in the NPYC group compared to the NC group. Meanwhile, it was significantly improved ( P < 0.05) in the DPYC group than in the DC group. Histological examination revealed that corneal re-epithelialization was more accomplished in the DPYC group than in the DC group. In addition, the inflammatory cells were augmented in the DC group more than those in the DPYC one. Conclusion The findings obtained revealed the efficiency of PYC for enhancing the corneal re-epithelialization and reducing the inflammatory reaction post alkali burn in rats, and thus it could be beneficially valuable as a treatment for the diabetic keratopathy.
... The research conducted so far has mainly concerned the impact of individual food products enriched with various types of polyphenols or dietary supplements that contain them on the selected parameters of cardiometabolic risk. Such studies were also conducted in a group of patients with T2DM and provided unambiguous data on the beneficial effects of these products on the cardiometabolic profile of diabetics, although they do not always confirm their significant effect on IR, glucose concentration, HbA1c percentage, creatinine, lipid profile and other cardiometabolic risk factors, such as blood pressure, anthropometric parameters (body weight, waist circumference, hips, BMI and WHR) and body fat content [44][45][46][47][48][49][50][51][52][53][54]. When analysing these data, it is necessary to take into account the large discrepancy in the amount of food products used, the duration of the studies, as well as the frequent lack of consideration of the diet used by the participants during the study. ...
Article
Full-text available
Background: The aim of the study was to evaluate the relationship between polyphenol or polyunsaturated fatty acids (PUFAs) consumption and the selected metabolic and inflammatory markers in type 2 diabetes (T2DM) patients. Methods: The study enrolled 129 diabetics (49 men, mean age 64.1 ± 9.8 years) with different amounts of polyphenol and PUFAs consumption. Results: A significant effect of polyphenol or PUFAs omega-3 consumption on fasting glucose concentration (FG) or glycated haemoglobin fraction (HbA1c) was reported. A negative association was observed between FG and total polyphenol, flavonoid, flavan-3-ol and stilbene intake. In the group with high flavonoid intake, the FG was significantly lower compared to the group characterised by low flavonoid intake. Polyphenols, except stilbenes, did not modulate HbA1c. Additionally, higher consumption of PUFAs omega-3 significantly decreased HbA1c, and the intake of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids negatively and significantly correlated with FG and HbA1c. Further analysis confirmed a significant association between EPA + DHA intake and HbA1c, with significant interactions with age and gender or with body mass index and waist-to-hip ratio. The dietary intake of polyphenols or PUFAs was independent of familial diabetes or diabetic diet application. Conclusions: Our study indicates a positive effect of high consumption of flavonoids, omega-3 PUFAs and stilbenes on the markers of carbohydrate metabolism balance and the absence of such an effect on other cardiometabolic markers and inflammatory conditions.
... Also, PACs have approximately similar effect that it has also been shown to help normalize blood glucose (sugar) level. these data were in line with previous data from [18] and delay sugar absorption [19]. That PACs one of the constituents of GT, consist of catechins. ...
... First, the dose of oligopin might have been inadequate. One study involved the use of oligopin in type 2 diabetes, showing that a daily consumption in the amount of 100 mg/d to 200 mg/d was required to achieve a protective effect (36). It is uncertain whether the dose required to achieve androgen reduction is similar, or the response to oligopin may be different in different subjects; we included the PCOS women. ...
Article
Full-text available
Background A double blind clinical trial was performed to evaluate whether the polycystic ovary syndrome (PCOS)-specific serum markers and metabolic parameters would change in the women with PCOS during the three-month administration of oligopin. Methods In this double-blind multicenter trial, we randomly assigned 80 PCOS women, based on a 1:1 ratio, to receive oligopin (n= 40) or maltodextrin as placebo (n = 40) for up to 3 months. As PCOS-specific outcomes, we investigated the changes in testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI), dehydroepiandrosterone (DHEA), follicle-stimulating hormone ( FSH ) and luteinizing hormone ( LH ). Secondary end points were metabolic (fasting glycaemia, hemoglobin A1c (HbA1c), lipids, insulin resistance (HOMA-IR)), anthropometrics parameters and blood pressure from the baseline to the end of treatment. We investigated serum transaminase, alkaline phosphatase (ALP), creatinine (Cr) and blood urea nitrogen (BUN) levels as hepatic and kidney outcomes, respectively. Results The first participant was enrolled on April 18, 2018, and the last study visit took place on May 14, 2019. PCOS-specific serum parameters did not change during the three-month administration of oligopin (p > 0.05), except for a small increase in the FSH levels (p=0.03). Oligopin neither changed the metabolic profile nor the anthropometric parameters or blood pressure. ALP levels was significantly increased in placebo group, as compared with oligopin (p=0.01). Conclusion Oligopin supplementation does not seem to be exerting a beneficial effect on both hormonal and metabolic parameters in the women with PCOS. Clinical Trial Registration www.irct.ir , identifier IRCT20140406017139N3.
... After 1 month trial period, they observed maximum significant improvement in glycemic control at the dosage of 200 mg pycnogenol. Supplementation with pycnogenol also decreased endothelin-1, FPG, and LDL as well as albumin concentration in the urine [123]. 25 mg of pycnogenol was administered to patients with type 2 diabetes (5 times/day) in a trial, which showed a decrease in HbA1c significantly after the second and third month of the trial period compared to that of placebo [124]. ...
... After 1 month trial period, they observed maximum significant improvement in glycemic control at the dosage of 200 mg pycnogenol. Supplementation with pycnogenol also decreased endothelin-1, FPG, and LDL as well as albumin concentration in the urine [123]. 25 mg of pycnogenol was administered to patients with type 2 diabetes (5 times/day) in a trial, which showed a decrease in HbA1c significantly after the second and third month of the trial period compared to that of placebo [124]. ...
Chapter
Full-text available
Olive leaves are used in Mediterranean folk medicine for the treatment of diabetes, hypertension, and hypercholesterolemia since ancient times. In the last decade, different authors have studied their chemical composition and ratified their pharmacological properties both in vitro and in vivo, and, more recently, clinical trials focusing on their effects on diabetes and hypertension have been developed. Oleuropein and hydroxytyrosol seem to emerge as promising bioactive phenolics responsible for these beneficial effects. In this chapter, information about recent studies on the olive leaf is compiled, including its effects on the specific subject of this chapter, but also its other potential pharmacological effects.
... First, the dose of oligopin may be inadequate. One study involving the use of oligopin in type 2 diabetes has shown a daily consumption in an amount of 100 mg/d to 200 mg/d is required to achieve a protective effect (28). It is uncertain whether the dose required to achieve androgen reduction is similar, or the response to oligopin may be different in different subjects, we included PCOS women. ...
Preprint
Full-text available
Background: A double blind clinical trial was performed to evaluate whether polycystic ovary syndrome (PCOS)-specific serum markers and metabolic parameters would change in women with PCOS during three months administration of oligopin. Methods: In this double-blind multicenter trial, we randomly assigned 80 PCOS women, in a 1:1 ratio, to receive oligopin (n= 40) or placebo (n = 40) for up to 3 months. As PCOS- specific outcomes, we investigated changes in testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI), dehydroepiandrosterone (DHEA), follicle-stimulating hormone (FSH) and increase luteinizing hormone (LH). Secondary end points were metabolic (fasting glycaemia, hemoglobin A1c (HbA1c), lipids, insulin resistance (HOMA-IR)), anthropometrics parameters and blood pressure from baseline to end of treatment. We investigate serum transaminase, alkaline phosphatase (ALP), creatinine (Cr) and blood urea nitrogen (BUN) levels as hepatic and kidney outcomes, respectively. Results: PCOS-specific serum parameters did not change during three months administration of oligpin (p > 0.05) except for small increase in FSH levels (p=0.03). Oligopin neither changed the metabolic profile nor the anthropometric parameters or blood pressure. ALP levels significantly increased in placebo group compared with oligopin (p=0.01). Conclusion: Oligopin supplementation does not seem to be exerting a beneficial effect on both hormonal and metabolic parameters in women with PCOS. The study was registered at www.irct.ir with the identifier number of IRCT20140406017139N3. Registered 22 December 2018 - Retrospectively registered.
Article
The prevalence of chronic diseases has increased significantly with the rising trend of sedentary lifestyles, reduced physical activity, and dietary modifications in recent decades. Inflammation and oxidative stress play a key role in the pathophysiology of several chronic diseases, such as type II diabetes, cardiovascular diseases, and hepatic conditions. Therefore, reducing inflammation and oxidative stress may be beneficial in the prevention and treatment of various chronic disorders. Since chronic diseases are not completely curable, various methods have been proposed for their control. Complementary therapies and the use of natural antioxidant and antiinflammatory compounds are among these novel approaches. Pycnogenol (PYC) is a natural compound that could control inflammation and oxidative stress. Furthermore, some previous studies have shown that PYC could effectively reduce inflammation through signaling the downstream of insulin receptors, inhibiting the phosphorylation of the serine residues of insulin receptor substrate‐1, reducing pro‐inflammatory cytokines and oxidative stress indices through the stimulation of antioxidant pathways, increasing free radical scavenging activities, preventing lipid peroxidation, and protecting the erythrocytes in glucose‐6‐phosphate dehydrogenase‐deficient individuals, although these effects have not been fully proved. The present study aimed to comprehensively review the evidence concerning the positive physiological and pharmacological properties of PYC, with an emphasis on the therapeutic potential of this natural component for enhancing human health.
Article
Background: Pine bark (Pinus spp.) extract is rich in bioflavonoids, predominantly proanthocyanidins, which are antioxidants. Commercially-available extract supplements are marketed for preventing or treating various chronic conditions associated with oxidative stress. This is an update of a previously published review. Objectives: To assess the efficacy and safety of pine bark extract supplements for treating chronic disorders. Search methods: We searched three databases and three trial registries; latest search: 30 September 2019. We contacted the manufacturers of pine bark extracts to identify additional studies and hand-searched bibliographies of included studies. Selection criteria: Randomised controlled trials (RCTs) evaluating pine bark extract supplements in adults or children with any chronic disorder. Data collection and analysis: Two authors independently assessed trial eligibility, extracted data and assessed risk of bias. Where possible, we pooled data in meta-analyses. We used GRADE to evaluate the certainty of evidence. Primary outcomes were participant- and investigator-reported clinical outcomes directly related to each disorder and all-cause mortality. We also assessed adverse events and biomarkers of oxidative stress. Main results: This review included 27 RCTs (22 parallel and five cross-over designs; 1641 participants) evaluating pine bark extract supplements across 10 chronic disorders: asthma (two studies; 86 participants); attention deficit hyperactivity disorder (ADHD) (one study; 61 participants), cardiovascular disease (CVD) and risk factors (seven studies; 338 participants), chronic venous insufficiency (CVI) (two studies; 60 participants), diabetes mellitus (DM) (six studies; 339 participants), erectile dysfunction (three studies; 277 participants), female sexual dysfunction (one study; 83 participants), osteoarthritis (three studies; 293 participants), osteopenia (one study; 44 participants) and traumatic brain injury (one study; 60 participants). Two studies exclusively recruited children; the remainder recruited adults. Trials lasted between four weeks and six months. Placebo was the control in 24 studies. Overall risk of bias was low for four, high for one and unclear for 22 studies. In adults with asthma, we do not know whether pine bark extract increases change in forced expiratory volume in one second (FEV1) % predicted/forced vital capacity (FVC) (mean difference (MD) 7.70, 95% confidence interval (CI) 3.19 to 12.21; one study; 44 participants; very low-certainty evidence), increases change in FEV1 % predicted (MD 7.00, 95% CI 0.10 to 13.90; one study; 44 participants; very low-certainty evidence), improves asthma symptoms (risk ratio (RR) 1.85, 95% CI 1.32 to 2.58; one study; 60 participants; very low-certainty evidence) or increases the number of people able to stop using albuterol inhalers (RR 6.00, 95% CI 1.97 to 18.25; one study; 60 participants; very low-certainty evidence). In children with ADHD, we do not know whether pine bark extract decreases inattention and hyperactivity assessed by parent- and teacher-rating scales (narrative synthesis; one study; 57 participants; very low-certainty evidence) or increases the change in visual-motoric coordination and concentration (MD 3.37, 95% CI 2.41 to 4.33; one study; 57 participants; very low-certainty evidence). In participants with CVD, we do not know whether pine bark extract decreases diastolic blood pressure (MD -3.00 mm Hg, 95% CI -4.51 to -1.49; one study; 61 participants; very low-certainty evidence); increases HDL cholesterol (MD 0.05 mmol/L, 95% CI -0.01 to 0.11; one study; 61 participants; very low-certainty evidence) or decreases LDL cholesterol (MD -0.03 mmol/L, 95% CI -0.05 to 0.00; one study; 61 participants; very low-certainty evidence). In participants with CVI, we do not know whether pine bark extract decreases pain scores (MD -0.59, 95% CI -1.02 to -0.16; one study; 40 participants; very low-certainty evidence), increases the disappearance of pain (RR 25.0, 95% CI 1.58 to 395.48; one study; 40 participants; very low-certainty evidence) or increases physician-judged treatment efficacy (RR 4.75, 95% CI 1.97 to 11.48; 1 study; 40 participants; very low-certainty evidence). In type 2 DM, we do not know whether pine bark extract leads to a greater reduction in fasting blood glucose (MD 1.0 mmol/L, 95% CI 0.91 to 1.09; one study; 48 participants;very low-certainty evidence) or decreases HbA1c (MD -0.90 %, 95% CI -1.78 to -0.02; 1 study; 48 participants; very low-certainty evidence). In a mixed group of participants with type 1 and type 2 DM we do not know whether pine bark extract decreases HbA1c (MD -0.20 %, 95% CI -1.83 to 1.43; one study; 67 participants; very low-certainty evidence). In men with erectile dysfunction, we do not know whether pine bark extract supplements increase International Index of Erectile Function-5 scores (not pooled; two studies; 147 participants; very low-certainty evidence). In women with sexual dysfunction, we do not know whether pine bark extract increases satisfaction as measured by the Female Sexual Function Index (MD 5.10, 95% CI 3.49 to 6.71; one study; 75 participants; very low-certainty evidence) or leads to a greater reduction of pain scores (MD 4.30, 95% CI 2.69 to 5.91; one study; 75 participants; very low-certainty evidence). In adults with osteoarthritis of the knee, we do not know whether pine bark extract decreases composite Western Ontario and McMaster Universities Osteoarthritis Index scores (MD -730.00, 95% CI -1011.95 to -448.05; one study; 37 participants; very low-certainty evidence) or the use of non-steroidal anti-inflammatory medication (MD -18.30, 95% CI -25.14 to -11.46; one study; 35 participants; very low-certainty evidence). We do not know whether pine bark extract increases bone alkaline phosphatase in post-menopausal women with osteopenia (MD 1.16 ug/L, 95% CI -2.37 to 4.69; one study; 40 participants; very low-certainty evidence). In individuals with traumatic brain injury, we do not know whether pine bark extract decreases cognitive failure scores (MD -2.24, 95% CI -11.17 to 6.69; one study; 56 participants; very low-certainty evidence) or post-concussion symptoms (MD -0.76, 95% CI -5.39 to 3.87; one study; 56 participants; very low-certainty evidence). For most comparisons, studies did not report outcomes of hospital admissions or serious adverse events. Authors' conclusions: Small sample sizes, limited numbers of RCTs per condition, variation in outcome measures, and poor reporting of the included RCTs mean no definitive conclusions regarding the efficacy or safety of pine bark extract supplements are possible.
Article
Full-text available
To compare the incidence of heart failure in individuals with type 2 diabetes receiving thiazolidinediones (TZDs) versus other oral antihyperglycemic agents. We conducted a retrospective cohort study using a health insurance claims database. The study sample included patients with type 2 diabetes who received an oral antihyperglycemic agent between January 1995 and March 2001. Those with any claims for TZDs were designated "exposed," and each was compared with five randomly selected unexposed patients. Those with diagnoses of heart failure or who received digoxin or a diuretic in the year before their index date were excluded. The primary measure of interest was incidence of heart failure, which was defined as a hospitalization or outpatient visit with a diagnosis of heart failure. TZD patients (n = 5441) were younger than control subjects (n = 28103) but more likely to have coronary artery disease or diabetes complications, receive ACE inhibitors, beta-blockers, metformin, or insulin, and have undergone HbA(1c) tests or eye exams; they also had more comorbidities and higher costs (all P < 0.05). However, TZD use was predictive of heart failure even after controlling for these variables (hazard ratio = 1.7, P < 0.001). Adjusted incidence of heart failure at 40 months was 8.2% for TZD patients and 5.3% for control subjects. The results of this observational study suggest that TZDs may increase the risk of heart failure. Physicians should use TZDs with caution in patients with heart failure, remain vigilant for manifestations of heart failure in those receiving these drugs (especially patients with cardiovasculopathy), and consider alternate therapies for patients who develop symptoms of heart failure, such as shortness of breath.
Article
Three type 2 diabetic patients suffering from diplopia; in two of them diplopia was of recent origin, and in one - of chronic type. All patients underwent full diagnostic procedures of diplopia, strabismus angle and ocular movements were assessed. In each patient an invidualized treatment was applied, including: prism correction, botulinum toxin injections, ocular muscles exercises, and surgery. Results: All patients were free from diplopia after the treatment applied, and they were able to resume their normal activities: in cases of newly developed diplopia botulinum toxin and prism correction were used and in one case of diplopia of several years' duration - the surgical treatment proved to be successful. Conclusions: Cranial nerve palsy developing in the course of type 2 diabetes, although not a frequent condition, result in double vision, which patients find very disturbing. The treatment should start as early as possible. In newly developed diplopia botulinum toxin can be used as it not only improves vision, but also prevents eye muscle from acquiring permanent contraction. In chronic palsies surgery is recommended.
Article
Background: Glycemic control is associated with microvascular events, but its effect on the risk of heart failure is not well understood. We examined the association between hemoglobin (Hb) A(Ic) and the risk of heart failure hospitalization and/or death in a population-based sample of adult patients with diabetes and assessed whether this association differed by patient sex, heart failure pathogenesis, and hypertension status. Methods and results: A cohort design was used with baseline between January 1, 1995, and June 30, 1996, and follow-up through December 31, 1997 (median 2.2 years). Participants were 25 958 men and 22 900 women with (predominantly type 2) diabetes, >/=19 years old, with no known history of heart failure. There were a total of 935 events (516 among men; 419 among women). After adjustment for age, sex, race/ethnicity, education level, cigarette smoking, alcohol consumption, hypertension, obesity, use of beta-blockers and ACE inhibitors, type and duration of diabetes, and incidence of interim myocardial infarction, each 1% increase in Hb A(Ic) was associated with an 8% increased risk of heart failure (95% CI 5% to 12%). An Hb A(Ic) >/=10, relative to Hb A(Ic) <7, was associated with 1.56-fold (95% CI 1.26 to 1.93) greater risk of heart failure. Although the association was stronger in men than in women, no differences existed by heart failure pathogenesis or hypertension status. Conclusions: These results confirm previous evidence that poor glycemic control may be associated with an increased risk of heart failure among adult patients with diabetes.
Article
OBJECTIVES We sought to define the characteristics of fluid retention after thiazolidinedione (TZD) initiation in patients with established heart failure (HF). BACKGROUND Fluid retention associated with the use of TZD is commonly attributed to exacerbation of HF, which has led to the proscription of these potentially useful agents in patients with chronic HF. METHODS We examined 111 consecutive diabetic patients with chronic systolic HF who were treated with TZD from January 1999 to June 2001. A retrospective chart review was performed to determine the incidence of fluid retention in this cohort. Physical signs of fluid retention were compared between TZD users and an age- and gender-matched control group of diabetic, non-TZD users with chronic HF who had fluid retention. Baseline clinical and echocardiographic data were compared between TZD users with and without fluid retention. RESULTS Nineteen TZD users (17.1%) developed fluid retention, which reversed after drug withdrawal and presented predominantly as peripheral and not central edema. Comparing patients in the upper and lower tertiles of weight gain, more female patients and insulin users developed TZD-related fluid retention. However, there were no differences in the baseline New York Heart Association functional class or echocardiographic severity of cardiac dysfunction. CONCLUSIONS Although fluid retention after treatment with TZD in diabetic patients with chronic systolic HF occurs, the mechanism is undefined. Fluid retention related to TZD tends to be peripheral and is usually reversible after drug withdrawal. No direct association between the risk of fluid retention and the baseline degree of severity of HF was observed. (C) 2003 by the American College of Cardiology Foundation.
Article
Glycemic control is associated with microvascular events, but its effect on the risk of heart failure is not well understood. We examined the association between hemoglobin (Hb) A(Ic) and the risk of heart failure hospitalization and/or death in a population-based sample of adult patients with diabetes and assessed whether this association differed by patient sex, heart failure pathogenesis, and hypertension status. A cohort design was used with baseline between January 1, 1995, and June 30, 1996, and follow-up through December 31, 1997 (median 2.2 years). Participants were 25 958 men and 22 900 women with (predominantly type 2) diabetes, >/=19 years old, with no known history of heart failure. There were a total of 935 events (516 among men; 419 among women). After adjustment for age, sex, race/ethnicity, education level, cigarette smoking, alcohol consumption, hypertension, obesity, use of beta-blockers and ACE inhibitors, type and duration of diabetes, and incidence of interim myocardial infarction, each 1% increase in Hb A(Ic) was associated with an 8% increased risk of heart failure (95% CI 5% to 12%). An Hb A(Ic) >/=10, relative to Hb A(Ic) <7, was associated with 1.56-fold (95% CI 1.26 to 1.93) greater risk of heart failure. Although the association was stronger in men than in women, no differences existed by heart failure pathogenesis or hypertension status. These results confirm previous evidence that poor glycemic control may be associated with an increased risk of heart failure among adult patients with diabetes.
Article
Eight patients with total sixth nerve palsy were treated with botulinum toxin injection to the antagonist non-paretic medical rectus, within eight weeks of the onset of the palsy. Within a few days seven of the eight gained fusion without the necessity of a marked head turn, and none complained of confusing reversal of diplopia. The same seven recovered full function. The mean follow-up period after the last injection was 20 months. Seven palsies were the result of head trauma and one was due to cerebro-vascular disease. This preliminary report suggests that early botulinum toxin injection of patients with recent onset sixth nerve palsy is beneficial. Although all of the patients may possibly have recovered full lateral rectus function without treatment, the aetiologies of their palsies were of the type that frequently do no resolve. A randomised double-blind study is necessary more precisely to determine the effectiveness of this form of therapy.
Article
Three hundred eight patients with strabismus were treated with botulinum A toxin (Oculinum) chemodenervation; 153 were followed by the authors for at least 6 months. In this study group, 97 received botulinum A toxin injections as the primary method of treatment of their ocular deviation. Fifty-six received injections after traditional extraocular muscle surgery. Botulinum A toxin was useful for management of patients with recent surgical overcorrections and for management of some patients with sixth cranial nerve palsy. Chemodenervation of an extraocular muscle was not as successful as traditional strabismus surgery for treatment of infantile esotropia and other comitant deviations. Botulinum A toxin injection was ineffective in patients who had restrictive strabismus. This drug has limited application in the management of patients with strabismus.
Article
The most common therapeutic intervention in medicine is the writing of a prescription1. The proliferation of therapeutic alternatives and the growing recognition of the clinical and economic consequences of suboptimal pharmacotherapy2–4 have stimulated a variety of efforts to improve prescribing. These include physician-education programs,2,3 required drug-utilization review for patients covered by Medicaid,5 restrictive access policies (formularies, service limitations, requirements for prior approval, and substitution requirements),6 and direct federal regulation of the indications for using prescription drugs7. However, physicians, third-party payers, and regulators must face a fundamental but rarely asked question: Are there adequate data to guide . . .