本實驗的目的為探討血清素對胰島素阻抗的影響，而使用選擇性血清素吸回抑制劑(SSRI)來評估其對胰島素抗阻性的改善效果及可能的機制。由HOMA-IR的實驗發現，在果糖誘發胰島素抗性的大白鼠身上，長期投予fluoxetine及paroxetine，可改善胰島素的抗阻性，同時，可以促進骨骼肌的葡萄糖吸入。在離體骨骼肌直接以5-HT刺激，也能夠以劑量相關性的方式促進葡萄糖的吸入；顯示SSRI能夠藉由5-HT來促進骨骼肌的葡萄糖吸入作用而改善胰島素抗阻性。文獻指出，在大白鼠的骨骼肌具有5-HT2受體的分布，因此，利用5-HT2受體拮抗劑ketanserin 探討5-HT2受體在SSRI改善胰島素抗性的角色。本研究看到，ketanserin 可以阻擋fluoxetine及paroxetine 改善胰島素抗阻的作用，也能夠以劑量相關性的方式阻擋5-HT在離體骨骼肌促進的葡萄糖吸入作用。另外，5-HT2受體作用劑DOI，也能夠改善果糖老鼠的胰島素抗性，促進離體骨骼肌的葡萄糖吸入。由以上可知，SSRI可以經由5-HT2受體促進骨骼肌的葡萄糖吸入作用來改善胰島素抗阻性，顯示5-HT2受體在改善胰島素抗阻性上扮演一個重要的角色。

　In the present study, the effect of selective serotonin reuptake inhibitors (SSRIs) on insulin resistance was investigated. Chronic administration of fluoxetine and paroxetine could improve insulin resistance in fructose-fed rats by homeostasis model assessment-insulin resistance (HOMA-IR), and increase glucose uptake of skeletal muscle. 5-HT could directly stimulate glucose uptake of isolated skeletal muscle in a dose-dependent manner. The results indicate SSRIs could improve insulin resistance through increasing glucose uptake of skeletal muscle. Other study has report that there was the expression of 5-HT2 receptor in rat skeletal muscle. Therefore, the role of 5-HT2 receptor in improvement of insulin resistance by SSRIs was also investigated by using 5-HT2 antagonist, ketanserin. Experiments observed ketanserin could inhibit the effect of fluoxetine and paroxetine on improvement of insulin resistance. Ketanserin dose-dependently suppressed the stimulatory effect of 5-HT on glucose uptake of skeletal muscle. Besides,
5-HT2 agonist, DOI improved insulin resistance in fructose-fed rats, as well as dose-dependently increased glucose uptake of skeletal muscle. The present results indicate that SSRIs can improve insulin resistance by stimulating glucose uptake in skeletal muscle via 5-HT2 receptor. Thus, 5-HT2 receptor had an important role in the improvement of insulin resistance.

Bergman RN, Finegood DT, Kahn SE. The evolution of β-cell dysfunction and insulin resistance in type 2 diabetes. Eur. J. Clin. Invest. 32:35-45, 2002

Borona E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, Monauni T, Muggeo M. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity. Diabetes Care 23:57-63, 2000

Cannon JG. Acute phase response in exercise. II. Associations between vitamin E. cytokines, and muscle proteolysis. Am. J. Physiol. 260:R1235-R1240, 1991

Chang SL, Lin JG, Chi TC, Liu IM, Cheng JT. An insulin-dependent hypoglycaemia induced by electroacupuncture at the Zhongwan (CV12) acupoint in diabetic rats. Diabetologia 42:250-255, 1999

Chaouloff F, Baudrie V, Laude D. Evidence that 5-HT1A receptors are involved in the adrenaline-releasing effects of 8-OH-DPAT in the conscious rat. Naunyn. Schmiedebergs. Arch. Pharmacol. 341:381-384, 1990a

Chaouloff F, Laude D, Baudrie V. Ganglionic transmission is a prerequisite for the adrenaline-releasing and hyperglycemic effects of 8-OH-DPAT. Eur. J. Pharmacol.185:11-18, 1990b

Chaouloff F, Baudrie V, Laude D. Pentobarbital anaesthesia prevents the adrenaline-releasing effect of the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin. Eur. J. Pharmacol. 180:175-178, 1990c

Chaouloff F, Gunn SH, Young JB. Central 5-hydroxytryptamine2 receptors are involved in the adrenal catecholamine-releasing and hyperglycemic effects of the 5-hydroxytryptamine indirect agonist d-fenfluramine in the conscious rat. J. Pharmacol. Exp. Ther. 260:1008-1016, 1992

Chen Z, Waimey K, Van de Kar LD, Carrasco GA, Landry M, Battaglia G. Prenatal cocaine exposure potentiates paroxetine-induced desensitization of 5-HT2A receptor function in adult male rat offspring. Neuropharmacology. 46:942-953, 2004

Chen Z, Tetzlaff J, Sripathirathan K, Carrasco GA, Shankaran M, Van De Kar LD, Muma NA, Battaglia G. Paroxetine is effective in desensitizing 5-HT1A receptor function in adult offspring exposed prenatally to cocaine. Psychopharmacology (Berl). 180:316-326, 2005

Espinal J, Challiss RA, Newsholme EA. Effect of adenosine deaminase and an adenosine analoguae on insulin sensitivity in soleus muscle of the rat. FEBS Lett. 158:103-106, 1983

Fry JR, Jones CA, Wiebkin P, Bellemann P, Bridges JW. The enzymic isolation of adult rat hepatocytes in a functional and viable state. Anal. Biochem. 71:741-750, 1975

Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr. Rev. 19:491-503, 1998

Gliemann J, Rees WD, Foley JA. The fate of labeled glucose molecules in the rat adipocytes dependence on glucose concentration. Biochim. Biophys. Acta. 804:68-76, 1984

Goldstein DA, Massry SG. Diabetic nephropathy: Clinical course and effect of hemodialysis. Nephron 20:286-296, 1987

Guillet-Deniau I, Burnol AF, Girard J. Identification and localization of a skeletal muscle secrotonin 5-HT2A receptor coupled to the Jak/STAT pathway. J. Biol. Chem. 272:14825-14829, 1997

Hajduch E, Rencurel F, Balendran A, Batty IH, Downes CP, Hundal HS. Serotonin (5-Hydroxytryptamine), a novel regulator of glucose transport in rat skeletal muscle. J. Biol. Chem. 274:13563-13568, 1999

Hamman RF. Genetic and environmental determinants of non-insulin- dependent diabetes mellitus (NIDDM). Diabetes Metab. Rev. 8:287-338, 1992

Hara H, Osakabe M, Kitajima A, Tamao Y, Kikumoto R . MCI-9042, a new antiplatelet agent is a selective S2-serotonergic receptor antagonist. Thromb. Haemost. 65:415-420, 1991

Hervas I, Vilaro MT, Romero L, Scorza MC, Mengod G, Artigas F. Desensitization of 5-HT(1A) autoreceptors by a low chronic fluoxetine dose effect of the concurrent administration of WAY-100635. Neuropsychopharmacology. 24:11-20, 2001

Hotamisligil GS. The role of TNF alpha and TNF receptors in obesity and insulin resistance. J. Intern. Med. 245:621-625, 1999

Jones BJ, Blackburn TP. The medical benefit of 5-HT research. Pharmacol. Biochem. Behav. 71:555-568, 2002

Josefa NC, Rosaura M, Francisco PV, Victoria C, Lius MP, Juan T, Vicente L. Effects of losartan on blood pressure, metabolic alterations, and vascular reactivity in the fructose-induced hypertension rats. Hypertension 26:1074-1078, 1995

Kantor S, Graf M, Anheuer ZE, Bagdy G. Rapid desensitization of 5-HT(1A) receptors in Fawn-Hooded rats after chronic fluoxetine treatment. Eur. Neuropsychopharmacol. 11:15-24, 2001

Klip A, Logan WJ, Li G. Hexose transport in L6 muscle cells. Kinetic properties and the number of [3H]cytochalasin B binding sites. Biochem. Biophys. Acta. 687:265-280, 1982

Koenig JI, Meltzer HY, Devane GD, Gudelsky GA. The concentration of arginine vasopressin in pituitary stalk plasma of the rat after adrenalectomy or morphine. Endocrinology 118:2534-2539, 1986

Le Poul E, Boni C, Hanoun N, Laporte AM, Laaris N, Chauveau J, Hamon M, Lanfumey L. Differential adaptation of brain 5-HT1A and 5-HT1B receptors and 5-HT transporter in rats treated chronically with fluoxetine. Neuropharmacology. 39:110-122, 2000

Liu IM, Hsu FL, Chen CF, Cheng JT. Antihyperglycemic action of isoferulic acid in streptozotocin-induced diabetic rats. Br. J. Pharmacol. 129:631-636, 2000

Maheux P, Ducros F, Bourque J, Garon J, Chiasson JL. Fluoxetine improves insulin sensitivity in obese patients with non-insulin-dependent diabetes mellitus independently of weight loss. Int. J. Obes. 21:97-102, 1997

Park S, Choi SB. Dose fluoxetine administration influence insulin resistance in 90% pancreatectomized rats? Metabolism 51:38-43, 2002

Scheen AJ, Paolisso G, Salvatore T, Lefebvre PJ. Improvement of insulin-induced glucose disposal in obese patients with NIDDM after 1-wk treatment with d-fenfluramine. Diabetes Care. 14:325-332, 1991

Serres F, Muma NA, Raap DK, Garcia F, Battaglia G, Van de Kar LD. Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 prevents fluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A) receptors in hypothalamus. J. Pharmacol. Exp. Ther. 294:296-301, 2000

Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM. The hormone resistin links obesity to diabetes. Nature 409:307-312, 2001

Sugimoto Y, Yamada J, Kimura I, Watanabe Y, Horisaka K. The effects of the serotonin1A receptor agonist buspirone on the blood glucose and pancreatic hormones in rats. Jpn. J. Pharmacol. 60:145-148, 1992

Sugimoto Y, Yamada J, Yoshikawa T, Horisaka K. Effects of the 5-HT2C/2B receptor agonist 1-(3-chlorophenyl) piperazine on plasma glucose levels of rats. Eur. J. Pharmacol. 307:75-80, 1996a

Sugimoto Y, Yamada J, Yoshikawa T, Horisaka K. The effects of peripheral serotonin2 (5-HT2) and serotonin3 (5-HT3) receptor agonists on blood glucose levels in rats. Biol. Pharm. Bull. 19:1384-1386, 1996b

Takishita E, Takahashi A, Harada N, Yamato M, Yoshizumi M, Nakaya Y. Effect of sarpogrelate hydrochloride, a 5-HT2 blocker, on insulin resistance in Otsuka Long-Evans Tokushima fatty rats (OLETF rats), a type 2 diabetic rat model. J. Cardiovasc. Pharmacol. 43:266-270, 2004

Weidmann P, Boehlen LM, Courten M. Pathogenesis and treatment of hypertension associated with diabetes mellitus. Am. Heart. J. 125:1498-1513, 1993

Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J. Clin. Endocrinol. Metab.86:1930-1935, 2001

Yamada J, Sugimoto Y, Yoshikawa T, Kimura I, Horisaka K. The involvement of the peripheral 5-HT2A receptor in peripheral administered serotonin-induced hyperglycemia in rats. Life Sci. 57:819-825, 1995

Yamamura M, Wang XH, Ohmen JD, Uyemura K, Rea TH, Bloom BR, Modlin RL. Cytokine patterns of immunologically mediated tissue damage. J. Immunol. 149:1470-1475, 1992

Yamauchi M, Tatebayashi T, Nagase K, Kojima M, Imanishi T. Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats. Pharmacol. Biochem. Behav. 78:683-689, 2004