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The effect of glucosamine on glucose metabolism in humans: a systematic review of the literature
Osteoarthritis and Cartilage 19 (2011) 375e380
Review
The effect of glucosamine on glucose metabolism in humans: a systematic review of the literature N.R. Dostrovsky, T.E. Towheed*, R.W. Hudson, T.P. Anastassiades Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
a r t i c l e i n f o
s u m m a r y
Article history: Received 16 July 2010 Accepted 9 January 2011
Objective: Glucosamine is commonly used for the treatment of osteoarthritis. It is available as an over the counter preparation and also as a prescription pharmaceutical. There is concern from animal experiments that glucosamine may alter glucose metabolism through the hexosamine biosynthetic pathway. The objective of this systematic review is to determine if exogenous glucosamine adversely affects glucose metabolism in humans. This review does not separate out the effects on glucose metabolism of the various glucosamine preparations. Method: An English-language literature search of MEDLINE, EMBASE and EBM Reviews (1950eFebruary 2009) was conducted. The bibliographies of selected papers were manually searched for additional references. Two reviewers independently analyzed studies for quality and content using a standardized data extraction form. Results: Eleven studies were included. Six studies were randomized controlled trials and the remaining five were prospective studies with or without controls. Four of the studies found decreased insulin sensitivity or increased fasting glucose in subjects taking glucosamine. Three of these were clinical studies using oral glucosamine. Studies that included subjects with baseline impaired glucose tolerance or insulin resistance were more likely to detect an effect on glucose metabolism than studies without such subjects. Conclusion: Clinical studies, including three using oral glucosamine, have provided mixed evidence about the effect of exogenous glucosamine on glucose metabolism in humans. Therefore, more studies are needed, particularly including subjects at high risk for impairments in glucose homeostasis, before a definite conclusion can be made. Ó 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Glucosamine Glucose metabolism Insulin resistance Osteoarthritis Systematic review
Introduction Glucosamine is a popular and widely used treatment for osteoarthritis (OA). It is available as an over the counter nutraceutical in several countries and it is also available as a prescription pharmaceutical in Europe1. In the United States, glucosamine is used by over five million people annually, making it the fourth most commonly used herbal/dietary supplement2,3. Glucosamine is considered to be very safe. A recent Cochrane review (last updated in January 2008) found it to be as safe as placebo1 and there have been no fatal or serious adverse effects reported for oral glucosamine4. Additionally, there were no
* Address correspondence and reprint requests to: Tanveer E. Towheed, Room 2066, Etherington Hall, Queens University, Kingston, Ontario, Canada K7L3N6. E-mail address: [email protected] (T.E. Towheed).
significant differences in safety between the two most common preparations, glucosamine sulfate and glucosamine hydrochloride1. However, there is concern that glucosamine adversely affects glucose metabolism and causes insulin resistance through activation of the hexosamine biosynthetic pathway. In-vitro and animal (mainly rat) studies demonstrate that glucosamine induces insulin resistance in a variety of tissues including adipose, muscle and liver5. Furthermore, glucosamine has been shown to decrease pancreatic insulin secretion6e8. However, these studies used glucosamine concentrations 10e500 times higher than would be achieved by usual oral doses of glucosamine4 and so they may not be clinically relevant. A review article from 2006 evaluated the effect of glucosamine on glucose control in humans2. Glucosamine did not consistently affect glucose metabolism but since most of the studies were of short duration and excluded diabetic subjects, an adverse effect could not be excluded. Other review articles reached similar conclusions4,9,10. However, none of these articles were systematic reviews. Furthermore, since these reviews were published, there have been several additional studies evaluating the effect of glucosamine on glucose
1063-4584/$ e see front matter Ó 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.joca.2011.01.007
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metabolism in humans11e13. In order to better assess the effect of exogenous glucosamine on glucose metabolism in humans we have carried out a systematic review of the literature. Our review does not separate out the different formulations of glucosamine with respect to their effects on glucose metabolism. Methods Criteria for inclusion
Search strategy and study identification The following electronic data sources were systemically searched: MEDLINE (1950eFebruary 2009), EMBASE (1980eFebruary 2009), EMBASE Classic (1947e1979) and EBM Reviews (1991eFebruary 2009). Reference lists of all retrieved articles were also manually searched to identify additional trials. All searches were updated in February 2009. The search strategy used in MEDLINE is shown below: (1) (2) (3) (4) (5) (6)
Types of studies All types of studies and trials of any methodological quality were included. Searches were limited to English-language articles. Types of participants Adults receiving glucosamine. There were no restrictions in age, health, gender, body mass index (BMI) or disease comorbidities. Types of intervention All types of glucosamine and administration by any route. Types of outcome measures All measures of glucose metabolism were included with the exception of single measurements of random or fasting glucose. Criteria for exclusion The following exclusion criteria were applied: (1) In-vitro studies, (2) Animal studies, (3) Unpublished data.
Glucosamine Blood glucose Glucose metabolism Insulin resistance 1 and (2 or 3 or 4) Limit 5 to (English language and humans and yr ¼ “1950e2009”).
A total of 11 studies were included in this systematic review6,11e20 (Tables I and II). Ten of the trials were indexed in MEDLINE. No additional studies were indexed in EMBASE, EMBASE Classic or EBM Reviews. One additional trial was identified by searching reference lists of previously published reviews19. Twenty-seven articles were excluded from this review (Fig. 1). Twenty-four of these did not meet one or more of the inclusion criteria2,4,5,9,10,21e37. Most were review articles or did not administer glucosamine or assess glucose metabolism. One article was a non-English publication37, one was an animal study36 and one was an in-vitro study38.
Table I Multi-dose administration of glucosamine Study
Design (comparator)
Subjects
Glucosamine
Main outcomes
Effect on glucose metabolism
N
DM/IGT/HN
BMI mean (range)
Almada (2001)19
DBRCT (placebo)
15
DM ¼ 0 IGT ¼ 0 HN ¼ 15 (100%)
x ¼ 27.2 (22.8e31.6) kg/m2
Oral GS 1500 mg OD 12 weeks
Fasting glucose Fasting insulin FIRI
Decreased insulin sensitivity (fasting insulin; FIRI)
Scroggie (2003)14
DBRCT (placebo)
34
DMII ¼ 34 (100%) IGT ¼ 0 HN ¼ 0
N/A
Oral GH 1500 mg OD 90 days
HbA1c
e
Yu (2003)15
Pre-post (no comparator)
14
DM ¼ 0 IGT ¼ 5 (36%) HN ¼ 9 (64%)
7/14 BMI >27 kg/m2; 7/14 BMI <27 kg/m2
Oral GS 1500 mg OD 4 weeks
Fasting glucose Fasting insulin “Meal tolerance test” IVGTT
e
Tannis (2004)6
DBRCT (placebo)
19
DM ¼ 0 IGT ¼ 0 HN ¼ 19 (100%)
x ¼ 25.5 (18.6e31.1) kg/m2
Oral GS 1500 mg OD 12 weeks
Fasting glucose Fasting insulin OGTT (3 h) HbA1c
e
Muniyappa (2006)16
DBRCT; cross-over (placebo)
40
DM ¼ 0 IGT ¼ 0 HN ¼ 40 (100%)
Lean (n ¼ 20): x ¼ 24.3 kg/m2 Obese (n ¼ 20): x ¼ 34.2 kg/m2
Oral GH 1500 mg OD 6 weeks
Fasting glucose Fasting insulin HbA1c QUICKI Clamp
e
Albert (2007)12
DBRCT; cross-over (placebo)
12
DMI ¼ 2 (17%) DMII ¼ 10 (83%) IGT ¼ 0 HN ¼ 0
x ¼ 36.7 (26.8e46.6) kg/m2
Oral, type N/A, 1500 mg/day 2 weeks
Fasting glucose Fructosamine
e
Pham (2007)11
Pre-post (no comparator)
38
DM ¼ 0 IGT* ¼ 7 (18%) HN ¼ 31 (82%)
x ¼ 29.1 (19.2e46.3) kg/m2
Oral, type N/A 1500 mg/day 6 weeks
Decreased insulin sensitivity (HOMA/QUICKI)
Fasting glucose Fasting insulin HbA1c HOMA/QUICKI
DBRCT ¼ Double-Blind Randomized Controlled Trial; N/A ¼ Not available; IGT ¼ Impaired Glucose Tolerance; DM ¼ Diabetes Mellitus; DMI ¼ Type 1 Diabetes Mellitus; DMII ¼ Type 2 Diabetes Mellitus; HN ¼ Healthy Normal; GS ¼ Glucosamine sulfate; GH ¼ Glucosamine HCl; OD ¼ Daily; QUICKI ¼ Quantitative Insulin Sensitivity Check Index; FIRI ¼ Fasting Insulin Resistance Index; IVGTT ¼ Intravenous Glucose Tolerance Test; OGTT ¼ Oral Glucose Tolerance Test; Clamp ¼ Hyperinsulinemic-isoglycemic Glucose Clamp; e ¼ No effect on glucose metabolism. * This study documented increased fasting serum insulin levels (not impaired glucose tolerance).
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Table II Single dose administration of glucosamine Study
Design (comparator)
Subjects N
DM/IGT/HN
BMI mean (range)
Monauni (2000)17
RCT; cross-over (placebo)
10
DM ¼ 0 IGT ¼ 0 HN ¼ 10 (100%)
Pouwels (2001)20
Control (placebo)
20
Laferrere (2004)18
Control (no placebo)
Biggee (2007)13
Control; cross-over (placebo)
*
Glucosamine
Main outcomes
Effect
x ¼ 23.5 (22e25) kg/m2
IV, type N/A. 1.6 Umol/min/kg 300 min (all) 5 Umol/min/kg 300 min (n ¼ 5)
Increased fasting glucose; Decreased insulin sensitivity (IVGTT)
DM ¼ 0 IGT ¼ 0 HN ¼ 20 (100%)
x ¼ 22.3 (20.4e24.2) kg/m2
IV GS 4 Mmol/dL 150 min (n ¼ 6) or 300 min (n ¼ 6) Remaining 8 subjects placebo
Fasting glucose Fasting insulin Clamp
e
20
DM ¼ 0 IGT ¼ 0 HN ¼ 20 (100%)
x ¼ N/A (20.8e29.5) kg/m2
Oral GS 3000 mg 1 dose (n ¼ 6) Oral GS 6000 mg 1 dose (n ¼ 5) Remaining nine subjects control (no glucosamine)
Fasting glucose Fasting insulin Leptin
e
16
DM ¼ 0 IGT ¼ 3 (19%)* HN ¼ 13 (81%)
x ¼ 31 (22e40) kg/m2
Oral GS 1500 mg X1 dose
Decreased insulin sensitivity in subjects with IGT/DM (OGTT)
Fasting glucose IVGTT Clamp Fasting insulin
Fasting glucose Fasting insulin Random insulin OGTT (2 and 3 h)
Three subjects reported to have previously undiagnosed DM or IGT.
Data extraction A data extraction form, modified from the form used in a previous review evaluating OA of the hand, was used to extract information pertaining to trial demographics, methodology, quality and outcomes39. For the studies that were randomized controlled trials (RCTs), the Jadad score was calculated to evaluate the study quality40,41. All studies were independently assessed by two authors (ND and TET) and data extraction forms were compared for disagreements. Results Overview of study demographics A total of 11 studies were analyzed6,11e20 (Tables I and II). Seven of the 11 studies administered multiple doses of glucosamine (1500 mg orally per day, usually in three divided doses). These studies ranged between 2 and 12 weeks. One study also administered chondroitin (1200 mg per day)14. The other four studies administered single doses of glucosamine. Two used oral glucosamine (1500e6000 mg)13,18 and two used intravenous glucosamine infusions (7.2e30.5 g total)4,17,20. The average number of subjects was 21.6 with a range of 10e40 subjects. All of the studies were published between 2000 and 2007.
Six studies administered glucosamine sulfate, two administered glucosamine hydrochloride and three did not report the type of glucosamine used. Six of the studies were RCTs6,12,14,16,17,19, three were nonrandomized controlled trials13,18,20 and the remaining two used a pre-post design11,15. The six RCTs had a mean Jadad score of 3.7 (range 2e5). Two of the studies used diabetic subjects. All the subjects in the study by Scroggie et al. had type 2 diabetes14 while the study by Albert et al. included both type 1 and 2 diabetes12. Three of the studies included subjects with impaired glucose tolerance or insulin resistance, although they only made up a minority (37%) of subjects within those studies11,13,15. The remaining six studies did not include any subjects with diabetes or impaired glucose tolerance. The majority of the studies included obese subjects. In seven of the studies, the average BMI was >25 kg/m2. Two studies did not have any obese subjects17,20 and two studies did not report BMI14,18. Many different tests of glucose metabolism were used (Table III). The most common were fasting glucose (10 studies) and fasting insulin (nine studies). Other less commonly used tests included fructosamine and vascular elasticity analysis11,16. Effect on glucose metabolism Four out of the 11 studies reported a significant effect on glucose metabolism11,13,17,19. Two of these studies administered multiple
38 potentially relevant articles reviewed
27 articles excluded 16 – review/comment (no new data) 5 – no measurement of glucose metabolism 3 – did not administer glucosamine 1 – in-vitro 1 – animal 1 – article not in English
11 articles included in systematic review Fig. 1. Study selection for systematic review.
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Table III Measurements of glucose metabolism and study outcome
Table IV Type of glucosamine and study outcome
Measurement of glucose metabolism
# studies
# demonstrating adverse effect on glucose metabolism
Type of glucosamine
# studies
# reporting effect on glucose metabolism
Fasting glucose Fasting insulin HbA1c Oral glucose tolerance test Intravenous glucose tolerance test Composites of fasting glucose and insulin* Hyperinsulinemic-isoglycemic glucose clamp
10 9 4 2 3 3
0 1 0 1 2 2
Sulfate Hydrochloride Not reported
6 2 3
2 (33%) 0 2 (66%)
3
0
*
(11%) (50%) (66%) (66%)
Discussion
FIRI, QUICKI and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR).
% studies demonstrating an effect on glucose metabolism
doses of oral glucosamine11,19. The remaining two used single doses e one administered oral glucosamine13 and the other administered an intravenous infusion17. Of these four ‘positive’ studies, two included subjects with baseline impaired glucose tolerance or insulin resistance (Fig. 2)11,13. Neither of the two studies on diabetic subjects detected a statistically significant effect on glucose metabolism12,14. Three of the seven studies that included obese subjects found an effect on glucose metabolism11,13,19. There was no clear relationship between the type of glucosamine used and the detection of an effect on glucose metabolism (Table IV). Of the studies that reported an effect on glucose metabolism, two used glucosamine sulfate13,19 and two did not report the type of glucosamine11,17. Two of the studies that detected an effect on glucose metabolism were RCTs (Table V)17,19. The other two studies that found an effect were non-randomized; Biggee et al. was a placebo-controlled crossover trial13 and Pham et al. employed a pre-post design with no comparator11. Glucose tolerance tests and composites of fasting glucose and insulin were more likely to detect an effect on glucose metabolism than hemoglobin A1C (HbA1c) or single measures of fasting glucose or insulin (Table III).
This systematic review included 11 studies that directly investigated the effect of exogenous glucosamine on glucose metabolism in humans. The studies were small, of short duration and there was considerable heterogeneity in terms of dose, route and duration of glucosamine administration. Only four of the studies detected an effect on glucose metabolism. Thus, additional studies are needed in order to determine if exogenous glucosamine adversely affects glucose metabolism in humans. Our findings are concordant with the conclusions of four recent reviews2,4,9,10. Two of the studies that detected an effect on glucose metabolism administered 1500 mg of glucosamine every day for 611 or 1219 weeks. The other two ‘positive’ studies used single doses of glucosamine. Biggee et al. administered 1500 mg of oral glucosamine sulfate, which is the typical daily therapeutic dose13. The subjects in the study by Monauni et al. received a supratherapeutic dose of glucosamine by infusion17. The effect on glucose metabolism from this very large dose of parenterally administered glucosamine is probably not applicable to patients using oral glucosamine. In this study, we looked for possible relationships between the detection of an effect on glucose metabolism and subject characteristics, type of glucosamine, study design and method of measuring glucose metabolism. These relationships are compared in Fig. 2 and Tables IIIeV. As shown in Fig. 2, studies that included subjects with impaired glucose tolerance or insulin resistance were more likely to detect an effect on glucose metabolism than studies without those subjects. However, in the two studies that detected an effect, such subjects made up a small minority of total subjects e seven subjects (18%) in
80% 2/3 60%
1/2 4/9
3/7
40% 2/8 20% *
0/2 0%
Yes
No Diabetic subjects
Yes
No
Yes
No
Subjects with Impaired Glucose Obese (Mean BMI † Tolerance >25 or obese group)
* Numbers above bars refer to the number of studies showing an effect on glucose metabolism divided by total number of studies in the specified category †2 studies did not report BMI Fig. 2. Association between subject characteristics (diabetes, impaired glucose tolerance and obesity) and studies reporting an effect of glucose metabolism.
N.R. Dostrovsky et al. / Osteoarthritis and Cartilage 19 (2011) 375e380 Table V Study design and outcome Type of study
# studies
# reporting effect on glucose metabolism
RCT Non-randomized controlled trials Pre-post
6 3 2
2 (33%) 1 (33%) 1 (50%)
Pham et al. had baseline insulin resistance11 and only three subjects (19%) in Biggee et al. had glucose intolerance13. There were two studies that involved diabetic subjects. Scroggie et al. found that HbA1c increased by 0.05% in subjects taking glucosamine compared to a decrease of 0.16% in the placebo group14. However, this difference was not statistically significant. The other study of diabetic subjects, Albert et al., similarly did not find a significant difference in fasting glucose or fructosamine between the glucosamine and placebo groups12. Figure 2 also shows that there was no significant difference between the percentage of studies that included obese subjects which detected an effect on glucose metabolism (3/7 or 43%)11,13,19 compared to studies that excluded obese subjects (1/2 or 50%)17. There was no clear association between the type of glucosamine used and studies demonstrating an effect on glucose metabolism (Table IV). In addition to the type of glucosamine (sulfate or hydrochloride), the brand may also be important. In the Cochrane review, only glucosamine made by Rottapharm was shown to significantly improve pain and functional limitations in OA patients1. This implies that pharmacological properties, including effect on glucose metabolism, could differ between brands. Unfortunately, six of the studies did not state which brand of glucosamine was used. However, in the two studies that used glucosamine from Rottapharm13,20 one found an effect on glucose metabolism13 and the other did not, suggesting that this particular brand does not appear to be unique in terms of producing an effect on glucose metabolism. As shown in Table V, there was no association between the type of study design and the ability to observe an effect on glucose metabolism. The six RCTs were overall of good methodological quality, with an average Jadad score of 3.7/5. The RCT by Almada et al. is only published in abstract format19. The Jadad score was designed to evaluate full-length manuscripts and so may be of less value in the appraisal of an abstract. When the RCT by Almada et al. is not included, the average Jadad score of the remaining five RCTs is essentially unchanged (3.8/5). Multiple tests of glucose levels were used (Table III). As expected, more sensitive measures such as glucose tolerance tests or composites of fasting insulin and glucose were more likely to detect an effect on glucose levels than less sensitive measures such as single measures of fasting glucose or insulin. However, the gold standard for assessing insulin resistance, the hyperinsulinemicisoglycemic glucose clamp, did not detect an effect on glucose metabolism in any of the three studies in which it was used16,17,20. Over the last decade there have been several large RCTs evaluating the efficacy of oral glucosamine for the treatment of OA42e45. These studies ranged between 6 months and 3 years in duration and included a combined total of over 2000 subjects. Unfortunately, they could not be included in this systemic review since they only measured random glucose43, did not specify if they actually assessed glucose metabolism45 or did not provide values for measures of glucose metabolism42,44,45. Notably, none of these studies reported an adverse effect on glucose metabolism among subjects taking glucosamine. This suggests that glucosamine likely does not have a major effect on glucose metabolism. However, a minor effect cannot be ruled out since they were not designed to appropriately assess glucose metabolism.
379
A number of limitations of this systematic review are recognized. First, we only included English-language publications. Second, non-published data were excluded, and this may have resulted in a biased selection of trials, which were more likely to include positive trials. Third, although conference abstracts were included19, conference proceedings were not manually searched. It is clear from this review that further research is required, particularly involving subjects with impaired glucose tolerance and insulin resistance, before we can determine if glucosamine has an adverse effect on glucose metabolism in humans. Author contributions TET, RWH and TPA conceived the idea for this review. ND and TET designed the review and acquired and critically analyzed the articles. Initial manuscript drafts were written by ND with guidance from TET. All authors reviewed and revised drafts of this manuscript and approved the final copy. Conflict of interest None of the authors has any conflict of interest. Acknowledgment No funding was obtained for this study. References 1. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;(2). 2. Stumpf JL, Lin SW. Effect of glucosamine on glucose control. Ann Pharmacother 2006;40:694e8. 3. Kennedy J. Herb and supplement use in the US adult population. Clin Ther 2005;27:1847e58. 4. Anderson JW, Nicolosi RJ, Borzelleca JF. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem Toxicol 2005;43:187e201. 5. Hussain MA. A case for glucosamine. Eur J Endocrinol 1998; 139:472e5. 6. Tannis AJ, Barban J, Conquer JA. Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals. Osteoarthritis Cartilage 2004;12:506e11. 7. Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, et al. Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress. J Biol Chem 2001;276:31099e104. 8. Cooksey RC, Pusuluri S, Hazel M, McClain DA. Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in beta-cells. Am J Physiol Endocrinol Metab 2006;290: E334e40. 9. Marshall PD, Poddar S, Tweed EM, Brandes L. Clinical inquiries: do glucosamine and chondroitin worsen blood sugar control in diabetes? J Fam Pract 2006;55:1091e3. 10. Hathcock JN, Shao A. Risk assessment for glucosamine and chondroitin sulfate. Regul Toxicol Pharmacol 2007;47:78e83. 11. Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007;333:333e9. 12. Albert SG, Oiknine RF, Parseghian S, Mooradian AD, Haas MJ, McPherson T. The effect of glucosamine on serum HDL cholesterol and apolipoprotein AI levels in people with diabetes. Diabetes Care 2007;30:2800e3.
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13. Biggee BA, Blinn CM, Nuite M, Silbert JE, McAlindon TE. Effects of oral glucosamine sulphate on serum glucose and insulin during an oral glucose tolerance test of subjects with osteoarthritis. Ann Rheum Dis 2007;66:260e2. 14. Scroggie DA, Albright A, Harris MD. The effect of glucosaminee chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Arch Intern Med 2003;163:1587e90. 15. Yu JG, Boies SM, Olefsky JM. The effect of oral glucosamine sulfate on insulin sensitivity in human subjects. Diabetes Care 2003;26:1941e2. 16. Muniyappa R, Karne RJ, Hall G, Crandon SK, Bronstein JA, Ver MR, et al. Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects. Diabetes 2006;55: 3142e50. 17. Monauni T, Zenti MG, Cretti A, Daniels MC, Targher G, Caruso B, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes 2000;49: 926e35. 18. Laferrere B, Garcia-Lorda P, Russell CD, Pi-Sunyer FX. Effect of oral glucosamine sulfate on serum leptin levels in human subjects. Nutrition 2004;20:321e2. 19. Almada AL, Harvey PW, Platt PJ. Effect of chronic oral glucosamine sulfate upon fasting insulin resistance index (FIRI) in nondiabetic individuals (Abstract). FASEB J 2001;14. A750. 20. Pouwels MJ, Jacobs JR, Span PN, Lutterman JA, Smits P, Tack CJ. Short-term glucosamine infusion does not affect insulin sensitivity in humans. J Clin Endocrinol Metab 2001;86:2099e103. 21. Muniyappa R, Quon MJ. Glucosamine and glycemic control. J Fam Pract 2007;56:192. 22. Clayton JJ. Nutraceuticals in the management of osteoarthritis. Orthopedics 2007;30:624e9. 23. Wollheim FA. Prescription of glucosamine for osteoarthritis: does it work and is it safe? Nat Clin Pract Rheumatol 2007;3: 364e5. 24. Linley W. An evaluation of the evidence for glucosamine and chondroitin in osteoarthritis. Pharmacy Practice 2007;17: 144e8. 25. Muniyappa R, Quoti MJ. Is further research needed on glucosamine? J Fam Pract 2007;56:343. 26. Chavez M. Can glucosamine be used in patients with diabetes mellitus? J Herbal Pharmacother 2001;1:101e12. 27. Patti M. Nutrient modulation of cellular insulin action. Ann N Y Acad Sci 1999;892:187e203. 28. Chong CAKY, Diaz-Granados N, Hawker GA, Jamal S, Josse RG, Cheung AM. Complementary and alternative medicine use by osteoporosis clinic patients. Osteoporos Int 2007;18:1547e56. 29. Muniyappa R, Quon MJ. Insulin action and insulin resistance in vascular endothelium. Curr Opin Clin Nutr Metab Care 2007; 10:523e30. 30. Persiani S, Rotini R, Trisolino G, Rovati LC, Locatelli M, Paganini D, et al. Synovial and plasma glucosamine concentrations in
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Review
The effect of glucosamine on glucose metabolism in humans: a systematic review of the literature N.R. Dostrovsky, T.E. Towheed*, R.W. Hudson, T.P. Anastassiades Department of Internal Medicine, Queens University, Kingston, Ontario, Canada
a r t i c l e i n f o
s u m m a r y
Article history: Received 16 July 2010 Accepted 9 January 2011
Objective: Glucosamine is commonly used for the treatment of osteoarthritis. It is available as an over the counter preparation and also as a prescription pharmaceutical. There is concern from animal experiments that glucosamine may alter glucose metabolism through the hexosamine biosynthetic pathway. The objective of this systematic review is to determine if exogenous glucosamine adversely affects glucose metabolism in humans. This review does not separate out the effects on glucose metabolism of the various glucosamine preparations. Method: An English-language literature search of MEDLINE, EMBASE and EBM Reviews (1950eFebruary 2009) was conducted. The bibliographies of selected papers were manually searched for additional references. Two reviewers independently analyzed studies for quality and content using a standardized data extraction form. Results: Eleven studies were included. Six studies were randomized controlled trials and the remaining five were prospective studies with or without controls. Four of the studies found decreased insulin sensitivity or increased fasting glucose in subjects taking glucosamine. Three of these were clinical studies using oral glucosamine. Studies that included subjects with baseline impaired glucose tolerance or insulin resistance were more likely to detect an effect on glucose metabolism than studies without such subjects. Conclusion: Clinical studies, including three using oral glucosamine, have provided mixed evidence about the effect of exogenous glucosamine on glucose metabolism in humans. Therefore, more studies are needed, particularly including subjects at high risk for impairments in glucose homeostasis, before a definite conclusion can be made. Ó 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
Keywords: Glucosamine Glucose metabolism Insulin resistance Osteoarthritis Systematic review
Introduction Glucosamine is a popular and widely used treatment for osteoarthritis (OA). It is available as an over the counter nutraceutical in several countries and it is also available as a prescription pharmaceutical in Europe1. In the United States, glucosamine is used by over five million people annually, making it the fourth most commonly used herbal/dietary supplement2,3. Glucosamine is considered to be very safe. A recent Cochrane review (last updated in January 2008) found it to be as safe as placebo1 and there have been no fatal or serious adverse effects reported for oral glucosamine4. Additionally, there were no
* Address correspondence and reprint requests to: Tanveer E. Towheed, Room 2066, Etherington Hall, Queens University, Kingston, Ontario, Canada K7L3N6. E-mail address: [email protected] (T.E. Towheed).
significant differences in safety between the two most common preparations, glucosamine sulfate and glucosamine hydrochloride1. However, there is concern that glucosamine adversely affects glucose metabolism and causes insulin resistance through activation of the hexosamine biosynthetic pathway. In-vitro and animal (mainly rat) studies demonstrate that glucosamine induces insulin resistance in a variety of tissues including adipose, muscle and liver5. Furthermore, glucosamine has been shown to decrease pancreatic insulin secretion6e8. However, these studies used glucosamine concentrations 10e500 times higher than would be achieved by usual oral doses of glucosamine4 and so they may not be clinically relevant. A review article from 2006 evaluated the effect of glucosamine on glucose control in humans2. Glucosamine did not consistently affect glucose metabolism but since most of the studies were of short duration and excluded diabetic subjects, an adverse effect could not be excluded. Other review articles reached similar conclusions4,9,10. However, none of these articles were systematic reviews. Furthermore, since these reviews were published, there have been several additional studies evaluating the effect of glucosamine on glucose
1063-4584/$ e see front matter Ó 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.joca.2011.01.007
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metabolism in humans11e13. In order to better assess the effect of exogenous glucosamine on glucose metabolism in humans we have carried out a systematic review of the literature. Our review does not separate out the different formulations of glucosamine with respect to their effects on glucose metabolism. Methods Criteria for inclusion
Search strategy and study identification The following electronic data sources were systemically searched: MEDLINE (1950eFebruary 2009), EMBASE (1980eFebruary 2009), EMBASE Classic (1947e1979) and EBM Reviews (1991eFebruary 2009). Reference lists of all retrieved articles were also manually searched to identify additional trials. All searches were updated in February 2009. The search strategy used in MEDLINE is shown below: (1) (2) (3) (4) (5) (6)
Types of studies All types of studies and trials of any methodological quality were included. Searches were limited to English-language articles. Types of participants Adults receiving glucosamine. There were no restrictions in age, health, gender, body mass index (BMI) or disease comorbidities. Types of intervention All types of glucosamine and administration by any route. Types of outcome measures All measures of glucose metabolism were included with the exception of single measurements of random or fasting glucose. Criteria for exclusion The following exclusion criteria were applied: (1) In-vitro studies, (2) Animal studies, (3) Unpublished data.
Glucosamine Blood glucose Glucose metabolism Insulin resistance 1 and (2 or 3 or 4) Limit 5 to (English language and humans and yr ¼ “1950e2009”).
A total of 11 studies were included in this systematic review6,11e20 (Tables I and II). Ten of the trials were indexed in MEDLINE. No additional studies were indexed in EMBASE, EMBASE Classic or EBM Reviews. One additional trial was identified by searching reference lists of previously published reviews19. Twenty-seven articles were excluded from this review (Fig. 1). Twenty-four of these did not meet one or more of the inclusion criteria2,4,5,9,10,21e37. Most were review articles or did not administer glucosamine or assess glucose metabolism. One article was a non-English publication37, one was an animal study36 and one was an in-vitro study38.
Table I Multi-dose administration of glucosamine Study
Design (comparator)
Subjects
Glucosamine
Main outcomes
Effect on glucose metabolism
N
DM/IGT/HN
BMI mean (range)
Almada (2001)19
DBRCT (placebo)
15
DM ¼ 0 IGT ¼ 0 HN ¼ 15 (100%)
x ¼ 27.2 (22.8e31.6) kg/m2
Oral GS 1500 mg OD 12 weeks
Fasting glucose Fasting insulin FIRI
Decreased insulin sensitivity (fasting insulin; FIRI)
Scroggie (2003)14
DBRCT (placebo)
34
DMII ¼ 34 (100%) IGT ¼ 0 HN ¼ 0
N/A
Oral GH 1500 mg OD 90 days
HbA1c
e
Yu (2003)15
Pre-post (no comparator)
14
DM ¼ 0 IGT ¼ 5 (36%) HN ¼ 9 (64%)
7/14 BMI >27 kg/m2; 7/14 BMI <27 kg/m2
Oral GS 1500 mg OD 4 weeks
Fasting glucose Fasting insulin “Meal tolerance test” IVGTT
e
Tannis (2004)6
DBRCT (placebo)
19
DM ¼ 0 IGT ¼ 0 HN ¼ 19 (100%)
x ¼ 25.5 (18.6e31.1) kg/m2
Oral GS 1500 mg OD 12 weeks
Fasting glucose Fasting insulin OGTT (3 h) HbA1c
e
Muniyappa (2006)16
DBRCT; cross-over (placebo)
40
DM ¼ 0 IGT ¼ 0 HN ¼ 40 (100%)
Lean (n ¼ 20): x ¼ 24.3 kg/m2 Obese (n ¼ 20): x ¼ 34.2 kg/m2
Oral GH 1500 mg OD 6 weeks
Fasting glucose Fasting insulin HbA1c QUICKI Clamp
e
Albert (2007)12
DBRCT; cross-over (placebo)
12
DMI ¼ 2 (17%) DMII ¼ 10 (83%) IGT ¼ 0 HN ¼ 0
x ¼ 36.7 (26.8e46.6) kg/m2
Oral, type N/A, 1500 mg/day 2 weeks
Fasting glucose Fructosamine
e
Pham (2007)11
Pre-post (no comparator)
38
DM ¼ 0 IGT* ¼ 7 (18%) HN ¼ 31 (82%)
x ¼ 29.1 (19.2e46.3) kg/m2
Oral, type N/A 1500 mg/day 6 weeks
Decreased insulin sensitivity (HOMA/QUICKI)
Fasting glucose Fasting insulin HbA1c HOMA/QUICKI
DBRCT ¼ Double-Blind Randomized Controlled Trial; N/A ¼ Not available; IGT ¼ Impaired Glucose Tolerance; DM ¼ Diabetes Mellitus; DMI ¼ Type 1 Diabetes Mellitus; DMII ¼ Type 2 Diabetes Mellitus; HN ¼ Healthy Normal; GS ¼ Glucosamine sulfate; GH ¼ Glucosamine HCl; OD ¼ Daily; QUICKI ¼ Quantitative Insulin Sensitivity Check Index; FIRI ¼ Fasting Insulin Resistance Index; IVGTT ¼ Intravenous Glucose Tolerance Test; OGTT ¼ Oral Glucose Tolerance Test; Clamp ¼ Hyperinsulinemic-isoglycemic Glucose Clamp; e ¼ No effect on glucose metabolism. * This study documented increased fasting serum insulin levels (not impaired glucose tolerance).
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377
Table II Single dose administration of glucosamine Study
Design (comparator)
Subjects N
DM/IGT/HN
BMI mean (range)
Monauni (2000)17
RCT; cross-over (placebo)
10
DM ¼ 0 IGT ¼ 0 HN ¼ 10 (100%)
Pouwels (2001)20
Control (placebo)
20
Laferrere (2004)18
Control (no placebo)
Biggee (2007)13
Control; cross-over (placebo)
*
Glucosamine
Main outcomes
Effect
x ¼ 23.5 (22e25) kg/m2
IV, type N/A. 1.6 Umol/min/kg 300 min (all) 5 Umol/min/kg 300 min (n ¼ 5)
Increased fasting glucose; Decreased insulin sensitivity (IVGTT)
DM ¼ 0 IGT ¼ 0 HN ¼ 20 (100%)
x ¼ 22.3 (20.4e24.2) kg/m2
IV GS 4 Mmol/dL 150 min (n ¼ 6) or 300 min (n ¼ 6) Remaining 8 subjects placebo
Fasting glucose Fasting insulin Clamp
e
20
DM ¼ 0 IGT ¼ 0 HN ¼ 20 (100%)
x ¼ N/A (20.8e29.5) kg/m2
Oral GS 3000 mg 1 dose (n ¼ 6) Oral GS 6000 mg 1 dose (n ¼ 5) Remaining nine subjects control (no glucosamine)
Fasting glucose Fasting insulin Leptin
e
16
DM ¼ 0 IGT ¼ 3 (19%)* HN ¼ 13 (81%)
x ¼ 31 (22e40) kg/m2
Oral GS 1500 mg X1 dose
Decreased insulin sensitivity in subjects with IGT/DM (OGTT)
Fasting glucose IVGTT Clamp Fasting insulin
Fasting glucose Fasting insulin Random insulin OGTT (2 and 3 h)
Three subjects reported to have previously undiagnosed DM or IGT.
Data extraction A data extraction form, modified from the form used in a previous review evaluating OA of the hand, was used to extract information pertaining to trial demographics, methodology, quality and outcomes39. For the studies that were randomized controlled trials (RCTs), the Jadad score was calculated to evaluate the study quality40,41. All studies were independently assessed by two authors (ND and TET) and data extraction forms were compared for disagreements. Results Overview of study demographics A total of 11 studies were analyzed6,11e20 (Tables I and II). Seven of the 11 studies administered multiple doses of glucosamine (1500 mg orally per day, usually in three divided doses). These studies ranged between 2 and 12 weeks. One study also administered chondroitin (1200 mg per day)14. The other four studies administered single doses of glucosamine. Two used oral glucosamine (1500e6000 mg)13,18 and two used intravenous glucosamine infusions (7.2e30.5 g total)4,17,20. The average number of subjects was 21.6 with a range of 10e40 subjects. All of the studies were published between 2000 and 2007.
Six studies administered glucosamine sulfate, two administered glucosamine hydrochloride and three did not report the type of glucosamine used. Six of the studies were RCTs6,12,14,16,17,19, three were nonrandomized controlled trials13,18,20 and the remaining two used a pre-post design11,15. The six RCTs had a mean Jadad score of 3.7 (range 2e5). Two of the studies used diabetic subjects. All the subjects in the study by Scroggie et al. had type 2 diabetes14 while the study by Albert et al. included both type 1 and 2 diabetes12. Three of the studies included subjects with impaired glucose tolerance or insulin resistance, although they only made up a minority (37%) of subjects within those studies11,13,15. The remaining six studies did not include any subjects with diabetes or impaired glucose tolerance. The majority of the studies included obese subjects. In seven of the studies, the average BMI was >25 kg/m2. Two studies did not have any obese subjects17,20 and two studies did not report BMI14,18. Many different tests of glucose metabolism were used (Table III). The most common were fasting glucose (10 studies) and fasting insulin (nine studies). Other less commonly used tests included fructosamine and vascular elasticity analysis11,16. Effect on glucose metabolism Four out of the 11 studies reported a significant effect on glucose metabolism11,13,17,19. Two of these studies administered multiple
38 potentially relevant articles reviewed
27 articles excluded 16 – review/comment (no new data) 5 – no measurement of glucose metabolism 3 – did not administer glucosamine 1 – in-vitro 1 – animal 1 – article not in English
11 articles included in systematic review Fig. 1. Study selection for systematic review.
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Table III Measurements of glucose metabolism and study outcome
Table IV Type of glucosamine and study outcome
Measurement of glucose metabolism
# studies
# demonstrating adverse effect on glucose metabolism
Type of glucosamine
# studies
# reporting effect on glucose metabolism
Fasting glucose Fasting insulin HbA1c Oral glucose tolerance test Intravenous glucose tolerance test Composites of fasting glucose and insulin* Hyperinsulinemic-isoglycemic glucose clamp
10 9 4 2 3 3
0 1 0 1 2 2
Sulfate Hydrochloride Not reported
6 2 3
2 (33%) 0 2 (66%)
3
0
*
(11%) (50%) (66%) (66%)
Discussion
FIRI, QUICKI and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR).
% studies demonstrating an effect on glucose metabolism
doses of oral glucosamine11,19. The remaining two used single doses e one administered oral glucosamine13 and the other administered an intravenous infusion17. Of these four ‘positive’ studies, two included subjects with baseline impaired glucose tolerance or insulin resistance (Fig. 2)11,13. Neither of the two studies on diabetic subjects detected a statistically significant effect on glucose metabolism12,14. Three of the seven studies that included obese subjects found an effect on glucose metabolism11,13,19. There was no clear relationship between the type of glucosamine used and the detection of an effect on glucose metabolism (Table IV). Of the studies that reported an effect on glucose metabolism, two used glucosamine sulfate13,19 and two did not report the type of glucosamine11,17. Two of the studies that detected an effect on glucose metabolism were RCTs (Table V)17,19. The other two studies that found an effect were non-randomized; Biggee et al. was a placebo-controlled crossover trial13 and Pham et al. employed a pre-post design with no comparator11. Glucose tolerance tests and composites of fasting glucose and insulin were more likely to detect an effect on glucose metabolism than hemoglobin A1C (HbA1c) or single measures of fasting glucose or insulin (Table III).
This systematic review included 11 studies that directly investigated the effect of exogenous glucosamine on glucose metabolism in humans. The studies were small, of short duration and there was considerable heterogeneity in terms of dose, route and duration of glucosamine administration. Only four of the studies detected an effect on glucose metabolism. Thus, additional studies are needed in order to determine if exogenous glucosamine adversely affects glucose metabolism in humans. Our findings are concordant with the conclusions of four recent reviews2,4,9,10. Two of the studies that detected an effect on glucose metabolism administered 1500 mg of glucosamine every day for 611 or 1219 weeks. The other two ‘positive’ studies used single doses of glucosamine. Biggee et al. administered 1500 mg of oral glucosamine sulfate, which is the typical daily therapeutic dose13. The subjects in the study by Monauni et al. received a supratherapeutic dose of glucosamine by infusion17. The effect on glucose metabolism from this very large dose of parenterally administered glucosamine is probably not applicable to patients using oral glucosamine. In this study, we looked for possible relationships between the detection of an effect on glucose metabolism and subject characteristics, type of glucosamine, study design and method of measuring glucose metabolism. These relationships are compared in Fig. 2 and Tables IIIeV. As shown in Fig. 2, studies that included subjects with impaired glucose tolerance or insulin resistance were more likely to detect an effect on glucose metabolism than studies without those subjects. However, in the two studies that detected an effect, such subjects made up a small minority of total subjects e seven subjects (18%) in
80% 2/3 60%
1/2 4/9
3/7
40% 2/8 20% *
0/2 0%
Yes
No Diabetic subjects
Yes
No
Yes
No
Subjects with Impaired Glucose Obese (Mean BMI † Tolerance >25 or obese group)
* Numbers above bars refer to the number of studies showing an effect on glucose metabolism divided by total number of studies in the specified category †2 studies did not report BMI Fig. 2. Association between subject characteristics (diabetes, impaired glucose tolerance and obesity) and studies reporting an effect of glucose metabolism.
N.R. Dostrovsky et al. / Osteoarthritis and Cartilage 19 (2011) 375e380 Table V Study design and outcome Type of study
# studies
# reporting effect on glucose metabolism
RCT Non-randomized controlled trials Pre-post
6 3 2
2 (33%) 1 (33%) 1 (50%)
Pham et al. had baseline insulin resistance11 and only three subjects (19%) in Biggee et al. had glucose intolerance13. There were two studies that involved diabetic subjects. Scroggie et al. found that HbA1c increased by 0.05% in subjects taking glucosamine compared to a decrease of 0.16% in the placebo group14. However, this difference was not statistically significant. The other study of diabetic subjects, Albert et al., similarly did not find a significant difference in fasting glucose or fructosamine between the glucosamine and placebo groups12. Figure 2 also shows that there was no significant difference between the percentage of studies that included obese subjects which detected an effect on glucose metabolism (3/7 or 43%)11,13,19 compared to studies that excluded obese subjects (1/2 or 50%)17. There was no clear association between the type of glucosamine used and studies demonstrating an effect on glucose metabolism (Table IV). In addition to the type of glucosamine (sulfate or hydrochloride), the brand may also be important. In the Cochrane review, only glucosamine made by Rottapharm was shown to significantly improve pain and functional limitations in OA patients1. This implies that pharmacological properties, including effect on glucose metabolism, could differ between brands. Unfortunately, six of the studies did not state which brand of glucosamine was used. However, in the two studies that used glucosamine from Rottapharm13,20 one found an effect on glucose metabolism13 and the other did not, suggesting that this particular brand does not appear to be unique in terms of producing an effect on glucose metabolism. As shown in Table V, there was no association between the type of study design and the ability to observe an effect on glucose metabolism. The six RCTs were overall of good methodological quality, with an average Jadad score of 3.7/5. The RCT by Almada et al. is only published in abstract format19. The Jadad score was designed to evaluate full-length manuscripts and so may be of less value in the appraisal of an abstract. When the RCT by Almada et al. is not included, the average Jadad score of the remaining five RCTs is essentially unchanged (3.8/5). Multiple tests of glucose levels were used (Table III). As expected, more sensitive measures such as glucose tolerance tests or composites of fasting insulin and glucose were more likely to detect an effect on glucose levels than less sensitive measures such as single measures of fasting glucose or insulin. However, the gold standard for assessing insulin resistance, the hyperinsulinemicisoglycemic glucose clamp, did not detect an effect on glucose metabolism in any of the three studies in which it was used16,17,20. Over the last decade there have been several large RCTs evaluating the efficacy of oral glucosamine for the treatment of OA42e45. These studies ranged between 6 months and 3 years in duration and included a combined total of over 2000 subjects. Unfortunately, they could not be included in this systemic review since they only measured random glucose43, did not specify if they actually assessed glucose metabolism45 or did not provide values for measures of glucose metabolism42,44,45. Notably, none of these studies reported an adverse effect on glucose metabolism among subjects taking glucosamine. This suggests that glucosamine likely does not have a major effect on glucose metabolism. However, a minor effect cannot be ruled out since they were not designed to appropriately assess glucose metabolism.
379
A number of limitations of this systematic review are recognized. First, we only included English-language publications. Second, non-published data were excluded, and this may have resulted in a biased selection of trials, which were more likely to include positive trials. Third, although conference abstracts were included19, conference proceedings were not manually searched. It is clear from this review that further research is required, particularly involving subjects with impaired glucose tolerance and insulin resistance, before we can determine if glucosamine has an adverse effect on glucose metabolism in humans. Author contributions TET, RWH and TPA conceived the idea for this review. ND and TET designed the review and acquired and critically analyzed the articles. Initial manuscript drafts were written by ND with guidance from TET. All authors reviewed and revised drafts of this manuscript and approved the final copy. Conflict of interest None of the authors has any conflict of interest. Acknowledgment No funding was obtained for this study. References 1. Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005;(2). 2. Stumpf JL, Lin SW. Effect of glucosamine on glucose control. Ann Pharmacother 2006;40:694e8. 3. Kennedy J. Herb and supplement use in the US adult population. Clin Ther 2005;27:1847e58. 4. Anderson JW, Nicolosi RJ, Borzelleca JF. Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy. Food Chem Toxicol 2005;43:187e201. 5. Hussain MA. A case for glucosamine. Eur J Endocrinol 1998; 139:472e5. 6. Tannis AJ, Barban J, Conquer JA. Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals. Osteoarthritis Cartilage 2004;12:506e11. 7. Kaneto H, Xu G, Song KH, Suzuma K, Bonner-Weir S, Sharma A, et al. Activation of the hexosamine pathway leads to deterioration of pancreatic beta-cell function through the induction of oxidative stress. J Biol Chem 2001;276:31099e104. 8. Cooksey RC, Pusuluri S, Hazel M, McClain DA. Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in beta-cells. Am J Physiol Endocrinol Metab 2006;290: E334e40. 9. Marshall PD, Poddar S, Tweed EM, Brandes L. Clinical inquiries: do glucosamine and chondroitin worsen blood sugar control in diabetes? J Fam Pract 2006;55:1091e3. 10. Hathcock JN, Shao A. Risk assessment for glucosamine and chondroitin sulfate. Regul Toxicol Pharmacol 2007;47:78e83. 11. Pham T, Cornea A, Blick KE, Jenkins A, Scofield RH. Oral glucosamine in doses used to treat osteoarthritis worsens insulin resistance. Am J Med Sci 2007;333:333e9. 12. Albert SG, Oiknine RF, Parseghian S, Mooradian AD, Haas MJ, McPherson T. The effect of glucosamine on serum HDL cholesterol and apolipoprotein AI levels in people with diabetes. Diabetes Care 2007;30:2800e3.
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