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

April 2004
Diabetes Care 27(3):839

DOI:10.2337/diacare.27.3.839

Source
PubMed

Authors:

University of Münster

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 …

The first patient before (A) and after (B) botulinum toxin A application. There is complete resolution of strabismus and associated diplopia.

…

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).

…

The 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 correction (B).

…

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Content uploaded by Peter Rohdewald

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OBSERVATIONS

French Maritime

Pine Bark Extract

Pycnogenol Dose-

Dependently Lowers

Glucose in Type 2

Diabetic Patients

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

28–64 years of age and had a BMI 22–34

kg/m

. 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

, 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

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

, 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 (P⬍0.05).

Fifty milligrams of Pycnogenol lowered

postprandial glucose signiﬁcantly from

12.47 ⫾1.06 to 11.16 ⫾2.11 mmol/l

(P⬍0.05). 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

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 (P⬍0.05). Endo-

thelin-1 decreased signiﬁcantly after

100–300 mg Pycnogenol from 104 ⫾16

to 91 ⫾15 pg/ml (P⬍0.05). 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,

HA-JUN ZHOU,

PETER ROHDEWALD,

PHD

From the

Guang An Men Hospital of Chinese Med-

ical Science Research Institute, Beijing, China; the

Wei-Hai Stomatology Hospital of Shan-Dong Prov-

ince, Wei-Hai, China; and the

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.

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?

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 (1966–present), EM-

BASE (1980–present), HealthSTAR

(1975–present), 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 identiﬁed. 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,

HPLC–differential refractometry DR, and

HPLC–electrospray light-scattering de-

tection (ELSD). Ginsenoside type was

comprised of 21 levels of different ginsen-

oside indexes: protopanaxadiol (PPD)

ginsenosides (Rb

,Rb

, Rc, Rd, and Rg

protopanaxatriol (PPT) ginsenosides

(Rg

, Rf, Re, and Rg

), and their sums

(PPD, PPT, and total) and ratios (PPD:

PPT, Rb

:Rg

,Rb

:Rc, Re:Rb

, Rc:Rb

Rd:Rb

,Rb

:Rb

, Rf:Rb

, and Rg

: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 (26–103,

31–81, and 36–112%, respectively).

These large ranges produced signiﬁcant

differences in each main effect (P⫽

0.00030, P⫽0.014, and P⫽0.00031,

respectively), with differences in species

sensitive to assay technique (P⫽0.00011

for two-way interaction).

The high variability in ginseng iden-

tiﬁed 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.) (4–6) demonstrated similar

acute postprandial glycemic-lowering ef-

ﬁcacy, a third batch with a depressed gin-

senoside proﬁle 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 efﬁcacy 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-

seng’s composition, safety, and efﬁcacy

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

EDWARD VIDGEN,

BSC

LAWRENCE A. LEITER,

1,3

VLADIMIR VUKSAN,

PHD

1,3

From the

Clinical Nutrition and Risk Factor Mod-

iﬁcation Centre, St. Michael’s Hospital, Toronto,

Canada; the

Department of Biology, Faculty of Sci-

ence, University of Ottawa, Ottawa, Canada; and the

Department of Nutritional Sciences, Faculty of

Medicine, University of Toronto, Toronto, Canada.

Address correspondence to Vladimir Vuksan,

PhD, Clinical Nutrition and Risk Factor Modiﬁca-

tion Centre, St. Michael’s 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.

Acknowledgments—Funding 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, 1990–1997: results of a

follow-up national survey. JAMA 280:

1569–1575, 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: what’sinthe

bottle? N Engl J Med 347:1997–1998, 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 proﬁle does not affect postprandial

glycemia. Eur J Clin Nur 57:243–248, 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?

erobic physical activity is a major

therapeutic modality for type 2 di-

abetes (1,2). It is well known that

regular aerobic exercise produces beneﬁ-

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 beneﬁcial 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 40–80% 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 40–60% 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

BMI, waist circumference, and glycemic

and lipid proﬁles 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 P⬍0.05 indi-

cated statistical signiﬁcance. 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 signiﬁcant differences

between the two groups at baseline with

respect to BMI (30 ⫾5.6 vs. 30.1 ⫾5.6

kg/m

), 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

(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 signiﬁcant change

in any measured parameters. The ART

group, conversely, showed a statistically

signiﬁcant decrease in BMI (30.1 ⫾5.6 to

28.8 ⫾4.8 kg/m

,P⬍0.0001), fat mass

(35 ⫾10.2 to 32.5 ⫾10.2%, P⬍

0.0001), waist circumference (103 ⫾14

to 98 ⫾12.7 cm, P⬍0.0001), fasting

blood glucose (165 ⫾60.6 to 129 ⫾37

mg/dl, P⬍0.0001), 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, P⬍0.0001), triglyc-

erides (187 ⫾109 to 146 ⫾81 mg/dl,

P⬍0.0001), HbA

(8.31 ⫾1.73 to

7.1 ⫾1.16%, P⬍0.0001), systolic blood

pressure (139 ⫾17.1 to 135 ⫾15.5

mmHg, P⬍0.04), and diastolic blood

pressure (85.3 ⫾8.8 to 81.3 ⫾6.7

mmHg, P⬍0.0001) and a signiﬁcant in-

crease in fat-free mass (46.8 ⫾11 to

47.2 ⫾10.8 kg, P⬍0.0001) and HDL

cholesterol (43.6 ⫾9.1 to 48.6 ⫾12.1

mg/dl, P⬍0.0001).

The frequency of medication changes

was not signiﬁcantly 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,

FRIDA LEONETTI,

UMBERTO DIMARIO,

MD, PHD

FRANCESCO FALLUCCA,

From the

Department of Clinical Sciences, Endo-

crinology, La Sapienza University, Rome, Italy; and

the

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.

●●●●●●●●●●●●●●●●●●●●●●●

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 32:1345–1360, 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:

1218–1227, 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 26:24–29, 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:

1729–1736, 2002

6. Maiorana A, O’Driscoll G, Goodman C,

Taylor R, Green D: Combined aerobic and

resistance exercise improves glycemic

control and ﬁtness in type 2 diabetes. Di-

abetes Res Clin Pract 56:115–123, 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 25:2335–2341, 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 26:2977–2982, 2003

A Filipino Patient

With Fulminant Type

1 Diabetes

ulminant type 1 diabetes is charac-

terized by abrupt onset of loss of

pancreas ␤-cell function with low

initial HbA

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 inﬁltrating 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-cell–mediated 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 ﬁrst 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 speciﬁc 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), reﬂecting 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 speciﬁc 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

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 deﬁciency, low HbA

, 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 difﬁcult 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 ﬁnding

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,

RYO KATSUMATA,

2,3

KANEMI AOKI,

SEIJI SUZUKI,

From the

Department of Internal Medicine, Divi-

sion of Endocrinology and Metabolism, Showa Uni-

versity Fujigaoka Hospital, Kanagawa, Japan; the

Department of Internal Medicine, Shiroyama Hos-

pital, Gunma, Japan; and the

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.

●●●●●●●●●●●●●●●●●●●●●●●

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 342:301–307, 2000

2. Tanaka S, Kobayashi T, Momotsu T: A

novel subtype of type 1 diabetes mellitus.

N Engl J Med 342:1835–1837, 2000

3. Shimada A, Morimoto J, Kodama K,

Oikawa Y, Irie J, Nakagawa Y, Narumi S,

Saruta T: T-cell–mediated autoimmunity

may be involved in fulminant type 1 dia-

betes (Letter). Diabetes Care 25:635–636,

2002

4. Lernmark A: Rapid-onset type 1 diabetes

with pancreatic exocrine dysfunction (Edi-

torial). N Engl J Med 342:344–345, 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:

2302–2307, 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 31:46–50, 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 speciﬁc HLA class I and II

alleles with type 1 diabetes among Filipi-

nos. Tissue Antigens 59:452–469, 2002

Predictive Value of

Circulating Oxidized

LDL for Cardiac

Events in Type 2

Diabetic Patients

With Coronary

Artery Disease

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 “indirect”methods, such

as lag times and propagation rates for LDL

oxidation, and antibodies against oxLDL.

Recently, some groups have developed

“direct”methods for measuring circulat-

ing oxLDL (4–6). Indeed, several lines of

evidence have demonstrated that the level

of circulating oxLDL is signiﬁcantly

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 fulﬁlled the classiﬁcation 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 inﬂammatory disease were also ex-

cluded. We deﬁned 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-ﬁve cardiac events were docu-

mented during the follow-up. Age was

signiﬁcantly higher in patients with car-

diac events than in those without cardiac

events (P⫽0.02). 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 ⱕ24.7 units/ml (event/total cases ⫽20/72).

Letters

DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 843

frequencies, including coronary risk fac-

tors, lipid proﬁles, fasting plasma glucose,

and HbA

, were not signiﬁcantly 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 signiﬁ-

cantly higher than in those without

cardiac events (23.8 ⫾14.2 vs. 18.8 ⫾

6.9 units/ml, P⫽0.02). 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 (P⫽0.0007) (Fig. 1). After adjust-

ment for age, sex, BMI, hypertension,

smoking history, LDL cholesterol, triglyc-

eride, HDL cholesterol, fasting plasma

glucose, HbA

, 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 1.5–8.8, P⫽0.005) times

higher in patients with oxLDL ⬎24.7

units/ml than in those with oxLDL ⱕ24.7

units/ml.

This study ﬁrstly, to the best of our

knowledge, demonstrated that high levels

of circulating oxLDL can serve as an inde-

pendent and signiﬁcant 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,

HIROSHI MOKUNO,

MD, PHD

ERIKO MATSUNAGA,

TETSURO MIYAZAKI,

KATSUHIKO SUMIYOSHI,

ATSUMI KUME,

KATSUMI MIYAUCHI,

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.

●●●●●●●●●●●●●●●●●●●●●●●

References

1. Steinberg D, Witztum JL: Is the oxidative

modiﬁcation hypothesis relevant to hu-

man atherosclerosis? Do the antioxidant

trials conducted to date refute the hypoth-

esis? Circulation 105:2107–2111, 2002

2. Fonseca VA: Management of diabetes

mellitus and insulin resistance in patients

with cardiovascular disease. Am J Cardiol

92:50J–60J, 2003

3. Schwenke DC, D’Agostino 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:

1449–1455, 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-deﬁcient mice: demon-

stration of epitopes of oxidized low den-

sity lipoprotein in human plasma. J Clin

Invest 98:800–814, 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:

663–669, 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 20:2243–2247,

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 103:1955–1960,

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 modiﬁed low density lipoprotein

using antioxidized phosphatidylcholine

monoclonal antibody and antihuman

apolipoprotein-B antibody. Clin Bio-

chem 33:243–253, 2000

Tumor Necrosis

Factor-␣Is

Associated With

Increased Protein C

Activation in

Nonobese Type 2

Diabetic Patients

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 ﬁbrino-

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 ﬁbrinolysis (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 ﬁbrinolysis (6,7). APC may

indirectly promote ﬁbrinolysis 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-inﬂammatory effect

and that it inhibits vascular injury in-

duced by TNF-␣(9,10). Therefore, APC

may inhibit hypercoagulability and in-

ﬂammatory 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

, 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

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, APC–protein 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 ﬁbrinolysis, D-dimer

was measured with a commercial EIA kit

(D-dimer test F; Kokusai Shiyaku, Kobe,

Japan). The plasma levels of TNF-␣were

signiﬁcantly higher (1.60 ⫾0.13 vs.

0.81 ⫾0.32 pg/ml, P⬍0.05) in diabetic

patients than in normal subjects. The

plasma levels of APC-PCI were signiﬁ-

cantly higher (4.63 ⫾0.38 vs. 2.58 ⫾

0.60 pmol/l, P⬍0.005) in diabetic pa-

tients than in normal subjects. There was

a signiﬁcant and positive correlation be-

tween the plasma levels of TNF-␣and

TAT in diabetic patients (r⫽0.46, P⬍

0.05). There was a signiﬁcant and in-

verted correlation between the plasma

levels of TNF-␣and D-dimer in diabetic

patients (r⫽⫺0.52, P⬍0.01). The

plasma levels of TNF-␣were positively

and signiﬁcantly correlated with the

plasma levels of APC-PCI (r⫽0.42, P⬍

0.05) in diabetic patients. There was no

signiﬁcant correlation between TNF-␣

and PC antigen (r⫽0.33) and PS levels

(r⫽0.07).

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

hypoﬁbrinolysis in association with

TNF-␣in diabetic patients. Interestingly,

the circulating levels of TNF-␣were sig-

niﬁcantly correlated with APC-PCI com-

plex, a marker of APC generation. These

data suggest that APC may regulate ﬁbri-

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 ﬁnger 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 signiﬁcant increase of

TNF-␣in diabetic patients suggests that

APC may not be sufﬁcient for regulating

TNF-␣expression. In brief, PC activation

may be important for the regulation of

TNF-␣–induced coagulation abnormali-

ties and inﬂammation in diabetes.

YUTAKA YANO,

ESTEBAN C. GABAZZA,

NAGAKO KITAGAWA,

NELSON E. BRUNO,

KAZUTAKA MATSUMOTO,

KANAME NAKATANI,

RIKA ARAKI,

AKIRA KATSUKI,

YUKIHIKO ADACHI,

YASUHIRO SUMIDA,

From the

Third Department of Internal Medicine,

Mie University School of Medicine, Tsu, Mie, Japan;

the

Laboratory Medicine, Mie University School of

Medicine, Tsu, Mie, Japan; and the

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.

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References

1. Okajima K: Regulation of inﬂammatory

responses by natural anticoagulants. Im-

munol Rev 184:258–274, 2001

2. Esposito K, Nappo F, Marfella R, Giugli-

ano G, Giugliano F, Ciotola M, Quagliaro

L, Ceriello A, Giugliano D: Inﬂammatory

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:

2442–2447, 2002

4. Shanmugam N, Reddy MA, Guha M, Nat-

arajan R: High glucose-induced expres-

sion of proinﬂammatory cytokine and

chemokine genes in monocytic cells. Dia-

betes 52:1256–1264, 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 51:27–35, 1997

6. Bajzar L: Thrombin activatable ﬁbrinoly-

sis inhibitor and an antiﬁbrinolytic path-

way. Arterioscler Thromb Vasc Biol 20:

2511–2518, 2000

7. Esmon CT: Protein C anticoagulant path-

way and its role in controlling microvas-

cular thrombosis and inﬂammation. Crit

Care Med 29 (Suppl.):S48–S52, 2001

8. Sakata Y, Loskutoff DJ, Gladson CL, Hek-

man CM, Grifﬁn JH: Mechanism of pro-

tein C-dependent clot lysis: role of

plasminogen activator inhibitor. Blood 68:

1218–1223, 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.):L197–L202, 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 ﬁ-

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-deﬁcient

mice. Science 289:2350–2354, 2000

14. Carballo E, Lai WS, Blackshear PJ:

Feedback inhibition of macrophage tu-

mor necrosis factor-alpha production

by tristetraprolin. Science 281:1001–1005,

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

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 signiﬁ-

cantly impair the everyday and profes-

sional activity of afﬂicted 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 speciﬁc treatment of nerve

palsy–induced 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 ﬁrst patient (female, computer

operator, aged 52 years, with a 15-year

history of type 2 diabetes and HbA

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

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 15–100%, depending on the

severity and duration of the nerve palsy

(5–7). 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 ﬁrst 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 palsy–induced diplopia,

thus saving the patient from surgical

treatment and assuring that quality of life

and professional activity will not suffer

due to signiﬁcant disturbance of vision.

ANNA BRONIARCZYK-LOBA,

PHD

LESZEK CZUPRYNIAK,

PHD

OLIMPIA NOWAKOWSKA,

PHD

JERZY LOBA,

PHD

From the From

Ophthalmology Department, Med-

ical University of Lodz, Barlicki University Hospital

No. 1, Lodz, Poland; and the

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 90–153, Poland. E-

mail: bigosik@poczta.onet.pl.

●●●●●●●●●●●●●●●●●●●●●●●

References

1. Vinik AI, Park TS, Stansberry KB, Pit-

tenger GL: Diabetic neuropathies. Diabe-

tologia 43:957–973, 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 97:147–151, 1995

4. Elston JS, Lee JP: Paralytic strabismus: the

role of botulinum toxin. Br J Ophthalmol

69:891–896, 1985

5. Holmes JM, Leske DA, Christiansen SP: Ini-

tial treatment outcomes in chronic sixth

nerve palsy. J AAPOS 5:370–376, 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 1—The ﬁrst patient before (A) and after (B) botulinum toxin A application. There is

complete resolution of strabismus and associated diplopia.

Figure 2—The 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 years’experience 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 40:405–409, 1999

9. Biglan AW, Burnstine RA, Rogers GL,

Saunders RA: Management of strabismus

with botulinum A toxin. Ophthalmology

96:935–943, 1989

10. Broniarczyk-Loba A, Nowakowska O,

Strak M, Loba J, Omulecki W: VI cranial

nerve palsy: treatment of diplopia. Diabe-

tol Pol 10:314–317, 2003

Naltrexone Improves

Blood Glucose

Control in Type 1

Diabetic Women

With Severe and

Chronic Eating

Disorders

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 signiﬁcant 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

17–29), with type 1 diabetes history of 8

years (range 5–15). Initial BMI was 25 ⫾

6 kg/m

. One patient affected by binge

eating presented morbid obesity (BMI

41.5 kg/m

). Blood glucose control at en-

rollment was very poor, as shown by

HbA

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 (7–18 episodes

per week) and were also associated with

“purging”behavior (self-vomiting) in six

subjects (7–21 episodes per week), ac-

cording to the Diagnostic and Statistical

Manual of Mental Disorders IV classiﬁca-

tion. No psychiatric comorbidity was di-

agnosed. The mean history of severe

eating disorders was 6 years (range

4–11). 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

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 ﬁrst 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 16–88) after 2

months and by 64% (range 29 –94) after 1

year, while associated purging decreased

by 74% (range 50–86) and 75% (range

52–100) 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 3–5% after 2 months and by

5–7% after 1 year in binge eaters, and

HbA

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

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, P⬍0.05), 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 50–64%, 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

signiﬁcant improvement of diabetes con-

trol is shown, with an average HbA

de-

crease of 1.5% after 2 months and 2.5%

after 1 year. If maintained for years, such

reductions in HbA

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

improvement. Al-

though we cannot exclude a nonspeciﬁc

“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,

PHILIPPE COURTET,

MD, PHD

ERIC RENARD,

MD, PHD

JACQUES BRINGER,

From the

Endocrinology Department, Lapeyronie

Hospital, Montpellier, France; and the

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.

●●●●●●●●●●●●●●●●●●●●●●●

References

1. Rodin GM, Daneman D: Eating disorders

and IDDM: a problematic association. Di-

abetes Care 15:1402–1412, 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

336:1849–1854, 1997

3. Polonsky WH, Anderson BJ, Lohrer PA,

Aponte JE, Jacobson AM, Cole CF: Insulin

omission in women with IDDM. Diabetes

Care 17:1178–1185, 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 10:173–176, 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 329:977–986, 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.

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 signiﬁcant

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 (P⫽0.96). However, there were

signiﬁcant differences in urinary protein:

type 2 diabetes, 102 ⫾15; IGT, 64 ⫾7;

and NGT, 50 ⫾4 mg/day (P⬍0.001).

There are two possible explanations

for the observed ﬁndings 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

conﬁrm 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

HANS SCHNEIDER,

FRACP

JOE D’AGOSTINO,

BSC

JONATHAN SHAW,

HENRY KRUM,

PHD

From the

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

Alfred Pathology Service, Alfred

Hospital, Melbourne, Victoria, Australia; and the

International Diabetes Institute, Caulﬁeld, 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.

●●●●●●●●●●●●●●●●●●●●●●●

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:

2081–2087, 2003

2. Bell DS: Heart failure: the frequent, for-

gotten, and often fatal complication of di-

abetes. Diabetes Care 26:2433–2441, 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:

829–834, 2002

Utility of B-Type

Natriuretic Peptide

as a Screen for Left

Ventricular

Dysfunction in

Patients With

Diabetes

Response to Liew et al.

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

-terminal

pro-BNP, are cleaved from the same pre-

cursor molecule, prepro BNP. Although

-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

-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

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 3–4 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,

ALAN MAISEL,

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.

●●●●●●●●●●●●●●●●●●●●●●●

References

1. Liew D, Schneider H, D’Agostino 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:

2081–2087, 2003

How to Implement

Evidence Into

Practice to Improve

Diabetes Care

Response to Ilag et al.

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 efﬁcacy 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. Certiﬁed 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 authors’comments

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,

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).

●●●●●●●●●●●●●●●●●●●●●●●

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 136:565–574, 2002

Letters

DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 849

3. Renders CM, Valk GD, Grifﬁn 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 24:1821–1833, 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

e appreciate Dr. Saleem’s (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 study”by 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-

ﬂected 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

subjects’inability 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-

ﬂected 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 sufﬁcient 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/certiﬁed 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

WILLIAM H. HERMAN,

MD, MPH

1,2

From the

Department of Internal Medicine, Uni-

versity of Michigan Health System, Ann Arbor,

Michigan; and the

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.

●●●●●●●●●●●●●●●●●●●●●●●

References

1. Saleem TFM: How to implement evidence

into practice to improve diabetes care

(Letter). Diabetes Care 27:849–850, 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, Grifﬁn 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:

1821–1833, 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

325:925–932, 2002

Use of

Thiazolidinediones

and Risk of Heart

Failure in People

With Type 2

Diabetes: A

Retrospective Cohort

Study

Response to Delea et al.

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; P⬍0.001). While we

welcome this ﬁrst 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 intensiﬁed

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 ﬁrst

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

⬎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 ﬁrst 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 (7–9). 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 ﬁrst 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 ﬁnd-

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 sufﬁces.

ANDREW J. KARTER,

PHD

AMEENA T. AHMED,

MD, MPH

JENNIFER LIU,

MPH

HOWARD H. MOFFET,

MPH

MELISSA M. PARKER,

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.

●●●●●●●●●●●●●●●●●●●●●●●

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, ﬂuid retention, and congestive heart

failure: a consensus statement from the

American Heart Association and Ameri-

can Diabetes Association. Diabetes Care

27:256–263, 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 149:981–983,

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: scientiﬁc re-

view. JAMA 287:360–372, 2002

6. Kessler DA: Introducing MEDWatch:

a new approach to reporting medica-

tion and device adverse effects and prod-

uct problems. JAMA 269:2765–2768,

1993

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dent drug safety board. N Engl J Med 339:

1851–1854, 1998

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9. Ray WA: Evaluating medication effects

outside of clinical trials: new-user de-

signs. Am J Epidemiol 158:915–920, 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 41:1394–1398,

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 290:81–85, 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.

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 ﬁndings

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 “sickest”patients. 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 deﬁni-

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

identiﬁed 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, deﬁnitive

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-

tion–approved 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 beneﬁts of these agents in improv-

ing clinical outcomes in patients with

diabetes (7–8).

THOMAS E. DELEA,

MBA

JOHN S. EDELSBERG,

MD, MPH

MAY HAGIWARA,

PHD

GERRY OSTER,

PHD

LAWRENCE S. PHILLIPS,

From

Policy Analysis, Inc. (PAI), Brookline, Mas-

sachusetts; and the

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 Pﬁzer,

Lilly, Novartis, GlaxoSmithKline, Genentech, and

Pharmacia.

Acknowledgments—The 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 27:850–851, 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:

1088–1091, 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 290:81–85, 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 63:1373–1405, 2003

8. Parulkar AA, Pendergrass ML, Granda-

Ayala R, Lee TR, Fonseca VA: Nonhypo-

glycemic effects of thiazolidinediones.

Ann Intern Med 134:61–71, 2001 [pub-

lished erratum appears in Ann Intern Med

135:307, 2001]

Letters

DIABETES CARE,VOLUME 27, NUMBER 3, MARCH 2004 853

Effect of French maritime pine bark extract supplementation on metabolic status and serum vascular cell adhesion molecule-1 levels in patients with type 2 diabetes and microalbuminuria

Article

Full-text available

Feb 2021
COMPLEMENT THER MED

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.

Evidence for Natural Products as Alternative Wound-Healing Therapies

Article

Full-text available

Feb 2023

Chronic, non-healing wounds represent a significant area of unmet medical need and are a growing problem for healthcare systems around the world. They affect the quality of life for patients and are an economic burden, being difficult and time consuming to treat. They are an escalating problem across the developed world due to the increasing incidence of diabetes and the higher prevalence of ageing populations. Effective treatment options are currently lacking, and in some cases chronic wounds can persist for years. Some traditional medicines are believed to contain bioactive small molecules that induce the healing of chronic wounds by reducing excessive inflammation, thereby allowing re-epithelisation to occur. Furthermore, many small molecules found in plants are known to have antibacterial properties and, although they lack the therapeutic selectivity of antibiotics, they are certainly capable of acting as topical antiseptics when applied to infected wounds. As these molecules act through mechanisms of action distinct from those of clinically used antibiotics, they are often active against antibiotic resistant bacteria. Although there are numerous studies highlighting the effects of naturally occurring small molecules in wound-healing assays in vitro, only evidence from well conducted clinical trials can allow these molecules or the remedies that contain them to progress to the clinic. With this in mind, we review wound-healing natural remedies that have entered clinical trials over a twenty-year period to the present. We examine the bioactive small molecules likely to be in involved and, where possible, their mechanisms of action.

Pycnogenol a promising remedy for diabetic keratopathy in experimentally induced corneal alkali burns in diabetic rats

Article

Full-text available

May 2022
BMC Vet Res

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.

Dietary Intake of Polyphenols or Polyunsaturated Fatty Acids and Its Relationship with Metabolic and Inflammatory State in Patients with Type 2 Diabetes Mellitus

Article

Full-text available

Mar 2022

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.

Biochemical Studies on The Effect of Some Biologically Active Compounds on The Complication of Diabetes

Article

Full-text available

Apr 2021

Shaaban Kamel Mohamed

The Effect of Oligopin Supplementation on Hormonal and Metabolic Profiles in the Polycystic Ovary Syndrome: A Randomized Controlled Trial

Article

Full-text available

Dec 2020

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.

Updates on Clinical Study Reports of Phytotherapy in the Management of Type 2 Diabetes Mellitus

Chapter

Nov 2020

Olive Leaf: A Traditional Phytomedicine for Diabetes and Hypertension

Chapter

Full-text available

Nov 2020

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.

Effect of a polyphenol-rich dietary supplement containing Pinus Massoniana bark extract on blood pressure in healthy adults: a parallel, randomized placebo-controlled trial

Article

Oct 2022
COMPLEMENT THER MED

Objectives High blood pressure (BP) is a major risk factor for cardiovascular disease and prevalence rates continue to rise with ageing populations. Polypharmacy remains a burden among the ageing, thus alternative effective strategies are warranted. This study investigated the effects of a polyphenols rich dietary supplement containing Pinus Massoniana bark extract (PMBE) for modulating BP in healthy Australian adults. Design This study is a secondary analysis of data from a double-blinded, placebo-controlled clinical trial. Methods Sixty-two healthy adults aged 55-75 years were randomized to receive 50 mL dietary supplement containing placebo (0 mg PMBE) or PMBE (1322 mg PMBE) daily for 12 weeks. Seated systolic BP (SBP) and diastolic (DBP) were measured at baseline, 6 weeks and 12 weeks. Effects of PMBE on modulating BP was also explored in this study stratified for SBP status (optimal v high) as well as by SBP medication status. Mixed effect regression modelling was employed involving fixed categorical effects for elapsed time, treatment assignment and their interaction as well as random subject-level intercept to account for within-subject correlations resulting from repeated measurements. Significant models were further examined by addition of covariates and power calculations were performed since this study was a secondary analysis. Results SBP significantly reduced (-3.29 mmHg, p=0.028) after PMBE at 12 weeks compared to baseline. SBP in individuals with normal-high SBP (>120 mmHg) in the PMBE group reduced by -6.46 mmHg (p=0.001) at 12 weeks compared to baseline. No significant changes were reported for individuals with optimal (≤120 mmHg) SBP nor did DBP significantly change in either study groups. In individuals with non-medicated normal-high SBP, SBP significantly reduced by -7.49 mmHg (p=0.001) and DBP by -3.06 mmHg (p=0.011) at 12 weeks compared to baseline after PMBE. Cross-group comparisons were not statistically different. Conclusions A polyphenol-rich dietary supplement derived from PMBE led to a clinically and statistically significant reduction in SBP in adults. Future studies to investigate the effects of PMBE-polyphenol supplementation on BP are warranted to confirm and explore optimal dose and impact on hypertension.

The role of Pycnogenol in the control of inflammation and oxidative stress in chronic diseases: Molecular aspects

Article

May 2022

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.

Use of Thiazolidinediones and Risk of Heart Failure in People With Type 2 Diabetes: A Retrospective Cohort Study

Article

Full-text available

Nov 2003
DIABETES CARE

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.

VI cranial nerve palsy - Treatment of diplopia

Article

Jan 2003

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.

Glycemic Control and Heart Failure Among Adult Patients With Diabetes

Article

Jun 2001

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.

Fluid retention after initiation of Thiazolidinedione therapy in diabetic patients with established chronic heart failure

Article

Apr 2003
J AM COLL CARDIOL

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.

Glycemic control and heart failure among adult patients with diabetes

Article

Jun 2001

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.

Metformin and thiazolidinedione use in Medicare patients with heart failure

Article

Sep 2003

Thiazolidinedione Use, Fluid Retention, and Congestive Heart Failure: A Consensus Statement From the American Heart Association and American Diabetes Association

Article

Jul 2004
DIABETES CARE

Richard W Nesto

Early botulinum toxin treatment of acute sixth nerve palsy

Article

Feb 1991

Anthony Murray

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.

Management of Strabismus with Botulinum A Toxin

Article

Aug 1989
OPHTHALMOLOGY

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.

Evaluating Drugs after Their Approval for Clinical Use

Article

Jan 1994

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 . . .

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

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