Abstract
The main objective of the study was to examine whether crocetin, a natural product
from Gardenia jaminoides Ellis, has beneficial effects on the state of insulin resistance induced by dexamethasone
in a rat model. Measured using the oral glucose tolerance tests (OGTT), male Wistar
rats treated with subcutaneous dexamethasone (0.08 mg/kg/d) for 6 weeks exhibited
reduced insulin sensitivity at weeks 2 and 4 and impaired glucose tolerance at week
4. In the dexamethasone-treated group, serum insulin, free fatty acids (FFA), triglyceride
(TG) and tumor necrosis factor (TNF)-α levels were significantly increased at the
end of the study. In addition, the hepatic glycogen content was reduced as indicated
by periodic acid-Schiff (PAS) staining, and pancreatic islet β cells showed compensatory
hyperactivity suggested by immunohistochemical (IHC) staining using an antibody against
insulin. Treatment with crocetin (40 mg/kg/d) significantly attenuated all the described
effects of dexamethasone. These results suggest that crocetin might prevent the development
of dexamethasone-induced insulin resistance and related abnormalities in rats.
Abbreviations
AUC:area under the curve
CON:control
CRO(H):high-dose crocetin
CRO(L):low-dose crocetin
CRO:crocetin
DEX:dexamethasone
FFA:free fatty acids
GAUC:area under the glucose curve
HE:hematoxylin-eosin
IAUC:area under the insulin curve
IHC:immunohistochemical
ISI:insulin sensitivity index
MET:metformin
OGTT:oral glucose tolerance test
PAS:periodic acid-Schiff
TG:triglyceride
TNF:tumor necrosis factor
Key words
Crocetin - glucocorticoids - insulin resistance - impaired glucose tolerance - rats
References
- 1
Andrews R C, Walker B R.
Glucocorticoids and insulin resistance: old hormones, new targets.
Clin Sci.
1999;
96
513-23
- 2
Perley M, Kipnis D M.
Effect of glucocorticoids on plasma insulin.
N Engl J Med.
1965;
274
1237-41
- 3
Willi S M, Kennedy A, Brant B P, Wallace P, Rogers N L, Garvey W T.
Effective use of thiazolidinediones for the treatment of glucocorticoid-induced diabetes.
Diabetes Res Clin Pract.
2002;
58
87-96
- 4
Arner P.
The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones.
Trends Endocrinol Metab.
2003;
14
137-45
- 5
Borden G.
Role of fatty acids in the pathogenesis of insulin resistance and NIDDM.
Diabetes.
1997;
46
3-10
- 6
Tappy L, Randin D, Vollenweider P, Vollenweider L, Paquot N, Scherrer U. et al .
Mechanism of dexamethasone-induced insulin resistance in healthy humans.
J Clin Endocrinol Metab.
1994;
79
1063-9
- 7
Goldstein B J.
Insulin resistance as the core defect in type 2 diabetes mellitus.
Am J Cardiol.
2002;
90
G3-10
- 8
Liu L S, Spelleken M, Rohrig K, Hauner H, Eckel J.
Tumor necrosis factor-α acutely inhibits insulin signaling in human adipocytes: implication
of the p80 tumor necrosis factor receptor.
Diabetes.
1998;
47
515-22
- 9
Sethi J K, Hotamisligil G S.
The role of TNFα in adipocyte metabolism.
Semin Cell Dev Biol.
1999;
10
19-29
- 10
Abdullaev F I.
Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.)
Exp Biol Med.
2002;
227
20-5
- 11
Giaccio M.
Crocetin from saffron: an active component of an ancient spice.
Crit Rev Food Sci Nutr.
2004;
44
155-72
- 12
Uwaifo G I, Ratner R E.
The role of insulin resistance, hyperinsulinemia, and thiazolidinediones in cardiovascular
disease.
Am J Med.
2003;
115
S12-9
- 13
Reaven GM and Chen Y DI.
Insulin resistance, its consequences, and coronary heart disease: must we choose one
culprit?.
Circulation.
1996;
93
1780-3
- 14
Kajita K, Ishizuka T, Miura A, Kanoh Y, Ishizawa M, Kimura M. et al .
Glucocorticoid-induced insulin resistance associates with activation of protein kinase
C isoforms.
Cell Signal.
2001;
13
169-75
- 15
Wang B H, Polya G M.
Selective inhibition of cyclic AMP-dependent protein kinase by amphiphilic triterpenoids
and related compounds.
Phytochemistry.
1995;
41
55-63
- 16
Herbert V, Lau K S, Gottlieb C W, Bleicher S J.
Coated charcoal immunoassay of insulin.
J Clin Endocrinol Metab.
1965;
25
1375-84
- 17
Matsuda M, DeFronzo R A.
Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison
with the euglycemic insulin clamp.
Diabetes Care.
1999;
22
1462-70
- 18
Ogawa A, Johnson J H, Ohneda M, McAllister C T, Inman L, Alam T ,. et al .
Roles of insulin resistance and beta-cell dysfunction in dexamethasone-induced diabetes.
J Clin Invest.
1992;
90
497-504
- 19
Mokuda O, Sakamoto Y.
Peripheral insulin sensitivity is decreased by elevated nonesterfied fatty acid level
in dexamethasone-treated rats.
Diabetes Nutr Metab.
1999;
12
252-5
- 20
Ebeling P, Koivisto V A.
Non-esterified fatty acids regulate lipid and glucose oxidation and glycogen synthase
activity.
Diabetologia.
1994;
37
202-9
- 21
Boden G, Chen X, Ruiz J, White J, Rossetti L.
Mechanisms of fatty acid-induced inhibition of glucose uptake.
J Clin Invest.
1994;
93
2438-46
- 22
Grundy S M.
Hypertriglyceridemia, insulin resistance, and the metabolic syndrome.
Am J Cardiol.
1999;
83
F25-9
- 23
Steiner G.
Hyperinsulinaemia and hypertriglyceridaemia.
J Intern Med.
1994;
736
23-6
- 24
Hotamisligil G S, Shargil N S, Spiegelman B M.
Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin
resistance.
Science.
1993;
259
87-91
- 25
Peraldi P, Xu M, Spiegelman B M.
Thiazolidinediones block tumor necrosis factor-induced inhibition of insulin signaling.
J Clin Invest.
1997;
100
1863-9
- 26
Katsuki A, Sumida Y, Murashima S, Murata K, Takarada Y, Ito K. et al .
Serum levels of tumor necrosis factor-α are increased in obese patients with noninsulin-dependent
diabetes mellitus.
J Clin Endocrinol Metab.
1998;
83
859-62
- 27
Nobuhiko T, Nobuyuki U, Katsuhiro H, Hideyuki M, Kazuaki S.
Effect of TNF-α-converting enzyme inhibitor on insulin resistance in fructose-fed
rats.
Hypertension.
2002;
39
578-80
- 28
Consoli A, Nurjhan N, Reilly J J, Bier D M, Gerich J E.
Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus.
Role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism.
J Clin Invest.
1990;
86
2038-45
- 29
Severino C, Brizzi P, Solinas A, Secchi G, Maioli M, Tonolo G.
Low-dose dexamethasone in the rat: a model to study insulin resistance.
Am J Physiol Endocrinol Metab.
2002;
283
E367-73
- 30
Pugazhenthi S, Angel F J, Khandelwal I R.
Effects of high sucrose diet on insulin-like effects of vanadate in diabetic rats.
Mol Cell Biochem.
1993;
122
77-84
- 31
Wier G C, Laybutt D R, Kaneto H, Bonner-Wier S, Sharma A.
Beta-cell adaptation and decompensation during the progression of diabetes.
Diabetes.
2001;
50 (suppl)
S154-9
- 32
Delaunay F, Khan A, Cintra A, Davani B, Ling Z C, Andersson A. et al .
Pancreatic β-cells are important targets for the diabetogenic effects of glucocorticoids.
J Clin Invest.
1997;
100
2094-8
- 33
Pick A, Levisetti M, Baldwin A, Bonner-Wier S.
Failure of beta-cell mass compensation for insulin resistance in dexamethasone induced
diabetes in female Zuck diabetic fatty (ZDF) rats.
Diabetes.
1998;
47 (suppl)
A258
Zhiyu Qian
Department of Pharmacology
China Pharmaceutical University
P.O. Box 46
24 Tongjia Xiang
Nanjing 210009
People’s Republic of China
Telefon: +86-25-8327-1322
Fax: +86-25-8327-1355
eMail: trueqianzhiyu@yahoo.com.cn