ORIGINAL INVESTIGATION

The Effect of Glucosamine-Chondroitin

Supplementation on Glycosylated Hemoglobin
Levels in Patients With Type 2 Diabetes Mellitus
A Placebo-Controlled, Double-blinded, Randomized Clinical Trial
Daren A. Scroggie, MD; Allison Albright, MD; Mark D. Harris, MD

Background: With increasing use of glucosamine-
containing supplements for the treatment of osteoarthri-
tis, there is increasing concern in the medical commu-
nity about possible toxic effects. The present study was
undertaken to determine whether glucosamine supple-
mentation altered hemoglobin A1c concentrations in pa-
tients with well-controlled diabetes mellitus.
Objective: To evaluate possible effects of glucosamine
supplementation on glycemic control in a selected popu-
lation of patients with type 2 diabetes mellitus.
Design: Placebo-controlled, double-blinded, random-
ized clinical trial.
Setting: Outpatient, diabetes monitoring clinic.
Patients: Patients were typically elderly patients, evenly
divided between men and women. Most of the patients
were being treated with 1 or 2 drugs for glycemic con-
trol.
Intervention: In daily doses for 90 days, patients re-
ceived either placebo or a combination of 1500 mg of glu-
cosamine hydrochloride with 1200 mg of chondroitin sul-
fate (Cosamin DS; Nutramax Laboratories Inc, Edgewood,
Md).
Main Outcome Measure: Hemoglobin A1c levels be-
fore and after 90 days of therapy.
Results: There were 4 withdrawals from the glucosamine-
treated group. Three were related to comorbidities (myo-
cardial infarction, congestive heart failure, and atrial fi-
brillation) and 1 to a possible adverse reaction (excessive
flatus). No other patient reported any adverse effects of
glucosamine therapy, and no patient had any change in
their diabetes management. Mean hemoglobin A1c con-
centrations were not significantly different between groups
prior to glucosamine therapy. Posttreatment hemoglo-
bin A1c concentrations were not significantly different be-
tween groups, nor were there any significant differences
within groups before and after treatment.
Conclusion: This study demonstrates that oral glu-
cosamine supplementation does not result in clinically
significant alterations in glucose metabolism in patients
with type 2 diabetes mellitus.
Arch Intern Med. 2003;163:1587-1590

From the Department of
Rheumatology, 59th Medical
Wing, Wilford Hall Medical
Center, Lackland Air Force
Base, Lackland, Tex, and the
Department of Medicine,
Uniformed Services University
of the Health Sciences,
Bethesda, Md. The authors have
no relevant financial interest in
this article.
T
YPE 2 diabetes mellitus is
common in the aging
American population, with
a prevalence of 10% to 15%
for patients older than 50
years.1 Osteoarthritis is also very com-
mon, affecting 40% of Americans older
than 60 years. 2 These 2 diseases fre-
quently overlap. Traditional therapies for
osteoarthritis, such as nonsteroidal anti-
inflammatory drugs (NSAIDs) and acet-
aminophen, have significant potential toxic
effects. Patients with diabetes often have
comorbid illnesses, which increase their
risk of toxic effects from NSAIDs. Many
patients have experimented with nutri-
tional supplements in the belief that these
therapies are safe and “natural.” In a sur-
vey of patients visiting rheumatologists,
94% reported having either used alterna-
tive therapy or visited an alternative medi-
cine provider.3 The use of combination glu-
cosamine and chondroitin sulfate for
treatment of osteoarthritis is becoming
commonplace.4-7 Glucosamine and chon-
droitin are classified as dietary supple-
ments and therefore are not regulated by
the Food and Drug Administration; their
manufacturers and distributors are not re-
quired to report adverse events. In addi-
tion, concerns have been raised about the
content and purity of glucosamine supple-
ments. 8,9 The safety of these types of
supplements is being increasingly ques-
tioned by the medical establishment.10-13
Animal studies have shown that high
levels of glucosamine administered par-
enterally can raise plasma glucose levels,

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©2003 American Medical Association. All rights reserved.
and if this is true, there is a theoretical risk of altering
the glucose metabolism in humans. The Physicians’ Desk
Reference for Nonprescription Drugs and Dietary Supple-
ments carries a precaution about the use of glucosamine
for patients with diabetes.14 Therefore, if it could be shown
that glucosamine, in doses and formulations available to
patients over the counter, did not affect glycemic con-
trol, it might be used as an alternative therapy. This study
was designed as a placebo-controlled, double-blinded, ran-
domized clinical trial to determine the clinical effect of
glucosamine supplementation on serum glucose levels
in patients with type 2 diabetes mellitus.
METHODS
STUDY DESIGN
The study was a 90-day, placebo-controlled, double-blinded,
randomized clinical trial performed at a single medical center
in the southwestern United States. The study followed the 1975
Declaration of Helsinki as revised in 1983, with institutional
review board approval and written and oral informed consent
obtained from all patients. Personnel not otherwise involved
in the study assigned patients to either glucosamine or pla-
cebo at the central pharmacy in a 2:1 block randomization
scheme. Placebo and glucosamine capsules were identical in
appearance. Patients and investigators were blinded to the as-
signed treatment arm.
PATIENTS
Patients were selected from the Wilford Hall Medical Center
Diabetes Care Clinic, Lackland Air Force Base, Lackland, Tex,
a multidisciplinary clinic treating mainly elderly patients with
stable type 2 diabetes mellitus. The patients were identified by
their staff endocrinologists after completing a routine fol-
low-up visit and were asked if they wished to participate in the
study. Those who expressed interest were given an informa-
tion pamphlet on Cosamin DS (Nutramax Laboratories Inc,
Edgewood, Md) and asked about their current medications.
Patients included in the study were required to have a con-
firmed diagnosis of type 2 diabetes mellitus, be undergoing treat-
ment with a stable dose of oral antihyperglycemic medica-
tions or be under strict diet control, and have a stable hemoglobin
Alc (HbA1c) level (varied by less than 0.2%) for at least 2 con-
secutive measurements separated by at least 90 days. Patients
taking insulin or those with unstable blood glucose levels (eg,
recently diagnosed patients or those taking either a new medi-
cine or new dose of current medicine) were excluded. In ad-
dition, patients taking glucocorticoids were excluded.
TREATMENT
For the duration of the trial, patients took 2 capsules in the morn-
ing and 1 in the evening. The treatment capsules were Cosa-
min DS, containing 500 mg of glucosamine hydrochloride
(FCHG49; Nutramax Laboratories Inc), 400 mg of low-
molecular-weight sodium chondroitin sulfate (TRH122; Nu-
tramax Laboratories Inc), 5 mg of manganese, and 66 mg of
ascorbic acid. This formulation has proven to be bioavailable
and to meet all label claims of content in published re-
search.15,16 Placebo capsules contained cellulose and were iden-
tical in size and shape to the treatment capsules. Prior to study
approval, samples were tested for purity using high-
performance liquid chromatography and were found to con-
tain the stated amounts of glucosamine and chondroitin. Pa-
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tients monitored daily finger-stick glucose values and were
instructed to return to the clinic for any persistent elevations
over baseline values. They were instructed to continue base-
line diabetes medications and report any changes to clinic per-
sonnel. Patients returned their daily blood sugar log and com-
pleted an exit questionnaire detailing any changes in
medications, hospitalizations, or illnesses that occurred dur-
ing their trial participation.
ASSESSMENTS
All patients completed an entry questionnaire and had base-
line serum drawn for analysis of HbA1c levels. Hemoglobin A1c
was measured by ion-exchange high-performance liquid chro-
matography (A1c 2.2 Plus Glycohemoglobin Analyzer; Tosoh
Medics, San Francisco, Calif). The machine was calibrated daily
and certified with the National Glycohemoglobin Standardiza-
tion Program.
DATA ANALYSIS
The primary outcome variable was the HbAlc level. Statistical
analysis was performed using SPSS software (SPSS Inc, Chi-
cago, Ill). Patients were seen twice during the course of the study
and were contacted by phone once during the study period.
The data were compared with a 1-factor repeated-
measures analysis of variance. The Mann-Whitney U test was
used to assess difference in the median number of diabetes medi-
cations between the groups. All the statistical tests were per-
formed at the .05 ␣ level. Only data from patients who com-
pleted the entire 90-day trial were used in the calculations.
RESULTS
A total of 113 patients were eligible for study participa-
tion, 74 of whom elected not to participate. Reasons given
by patients for not participating included aversion to being
“study patient,” desire to take as few medications as pos-
sible, distrust of “herbal medicines,” and desire to con-
tinue current use of glucosamine product. A total of 39
patients elected to participate in the study. One of these
patients gave consent but never picked up study medi-
cation (was not randomized). Of the remaining 38 pa-
tients in the study, 26 were randomized to treatment and
12 to placebo. Four patients withdrew from the study,
all of whom were in the treatment arm. Reasons for with-
drawal were believed to be unrelated to glucosamine or
worsening glycemic control in 3 of the 4 (myocardial in-
farction, congestive heart failure, and worsening of chronic
atrial fibrillation). The remaining patient withdrew early
owing to excessive flatus (a possible adverse effect of
glucosamine). These patients were among the oldest pa-
tients in the study, with a mean age of 79.3 years, and
this may account for their comorbidities. This left 22 pa-
tients in the glucosamine group to compare with 12 pa-
tients in the placebo group.
At baseline, the groups were similar demographi-
cally (Table). Glycemic control, as reflected by HbA1c
levels, was equivalent between the two. Patients in the
placebo group appeared to have somewhat milder dis-
ease, with fewer patients requiring therapy with antihy-
perglycemic medications.
The HbA1c mean values changed very little in both
groups during the study. In the glucosamine arm, the
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mean HbA1c value increased from 6.45% to 6.50%. This
change was not significant. In the placebo arm, the HbA1c
value decreased from 6.25% to 6.09%, a change of 0.16
percentage points which was also not significant. The
analysis of variance also showed that there were no sig-
nificant differences between the groups (P=.20). Post hoc
analysis revealed that the sample sizes of 22 in the treat-
ment arm and 12 in the placebo arm yielded a power of
80% to detect a large difference (⬎0.3%) between the
groups and a power of 80% to detect a change of 0.15
from before to after treatment in the glucosamine-
treated group.
There were no changes in medical therapy in ei-
ther group during the study period. With the exception
of the hospitalized patients, there were no increased phy-
sician visits in either group.
COMMENT
While the pathogenesis of diabetes has not been com-
pletely defined, the current understanding is that most
type 2 diabetes mellitus develops when ␤-cell produc-
tion of insulin can no longer overcome the body’s resis-
tance to the effects of insulin.17 Instability in the main-
tenance of glucose homeostasis is the hallmark of diabetes.
Measurement of HbAlc levels is a well-accepted and widely
used indicator of the hyperglycemic control among pa-
tients with diabetes. In the present study, we report the
first human placebo-controlled, double-blinded, ran-
domized clinical trial that evaluates the potential ad-
verse effect of a specific grade of glucosamine hydro-
chloride on the control of blood glucose among patients
with type 2 diabetes mellitus. Hemoglobin A1c was se-
lected as the indicator of blood glucose because it is the
most common measure of glycemic control in clinical
trials and in the management of diabetes.
There are 2 possible mechanisms through which glu-
cosamine could affect blood glucose: by acting as a source
of glucose or by interfering with the regulation of blood
glucose. It is unlikely that glucosamine would be con-
verted directly to glucose because the enzymatic path-
way is irreversible in humans. If it were possible to con-
vert the entire dose of glucosamine to glucose, the total
amount of glucose would only be 1500 mg/d.
The second possible mechanism involves the role of
glucosamine and the hexosamine biosynthesis pathway in
the regulation of glucose transport. Endogenous glu-
cosamine is synthesized from fructose-6-phosphate and glu-
tamine by the enzyme glutamine:fructose-6-phosphate ami-
dotransferase (GFAT) in the hexosamine pathway. This
pathway represents an alternative metabolic destiny for glu-
cose. Overexpression of GFAT results in high levels of glu-
cosamine and insulin resistance in animal models.18,19 In
normal cellular situations, the glucose is shunted into the
hexosamine pathway when intracellular energy require-
ments have been met. Experimental models suggest that
the shift to hexosamine production acts as a signal that in-
tracellular glucose levels are sufficient and that further in-
flux of glucose is not needed. This results in decreased up-
take of extracellular glucose via down-regulation of glucose
transport receptors. This insulin resistance can occur even
in the face of hyperglycemia and insulin stimulation.20-22
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Clinical and Demographic Patient Data
Glucosamine Placebo
Group Group
Characteristic (n = 22) (n = 12)
Male-female ratio 12:10 6:6
Mean age, y 68.6 70.7
Median No. of drugs 1 1
Diet controlled, No. (%) 4 (18) 3 (25)
Baseline hemoglobin A1c, % 6.45 6.25
Final hemoglobin A1c, % 6.50 6.09
In theory, exogenous glucosamine could bypass the nor-
mal metabolic regulations of GFAT and signal that the cell
has adequate glucose stores. Glucose transport would be
curtailed, which could then lead to hyperglycemia and in-
sulin resistance.18
Several experimental studies have been under-
taken to evaluate the effects of exogenous glucosamine
on regulation of glucose. In these studies, large amounts
of glucosamine were intravenously infused into ani-
mals.21-29 Under these conditions, glucosamine tended to
decrease insulin secretion and/or induce insulin resis-
tance in peripheral tissues, thus causing a rise in blood
glucose levels. However, the intravenous doses used in
these experimental studies were very high, ranging from
3283.2 mg/kg per day to 436363 mg/kg per day. The typi-
cal dose of oral glucosamine supplements for treatment
of arthritis is about 20 mg/kg per day. Oral dosing of glu-
cosamine at the recommended doses will not achieve the
plasma levels observed in these studies.30 Other authors
investigating the clinical use of glucosamine supple-
ments in animals did not find any adverse effect on blood
glucose.31-33 Another recent study examined the effects
of oral glucosamine in rat models sensitive to sugar-
induced insulin resistance and found that oral glu-
cosamine did not induce insulin resistance.34
Two studies have investigated the effects of intra-
venous glucosamine infusion in healthy human volun-
teers. Neither study showed any effect on insulin sensi-
tivity or plasma glucose.35,36 The findings of the present
study seem to parallel those of the 2 human studies in
that no effect on glucose control (HbA1c levels) was ob-
served. The present study observed patients for 90 days;
if a very mild effect developed after 90 days, it would not
have been detected. However, a recent long-term (3-
year) clinical trial found that glucosamine supplemen-
tation actually tended to lower plasma glucose levels in
patients with knee osteoarthritis.37
Since patients with diabetes are at risk for toxic ef-
fects from some of the current treatments for osteoar-
thritis (NSAIDs in particular), glucosamine may pro-
vide a safe alternative treatment for these patients. The
present study has demonstrated that oral glucosamine
supplementation does not adversely affect glycemic con-
trol when administered to patients with type 2 diabetes
mellitus at doses recommended by the manufacturer.
Accepted for publication September 19, 2002.
Nutramax Laboratories Inc (Edgewood, Md) donated
the Cosamin DS and placebo capsules for this study. The
WWW.ARCHINTERNMED.COM
work contained herein was supported by the Surgeon Gen-
eral’s Office of the US Air Force, protocol SG0-
FWH20000097. The authors have no other corporate af-
filiations.
The opinions and assertions contained herein are the
private views of the authors and are not to be considered as
official doctrine or as reflecting the views of the Depart-
ment of Defense or other departments of the US govern-
ment.
Corresponding author and reprints: Daren A. Scrog-
gie, MD, 759 MDOS MMIR, 2200 Bergquist Dr, Suite 1,
Lackland AFB, Lackland, TX 78236 (e-mail:
Daren.Scroggie@lackland.af.mil).
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