胰島素在中樞負責調控血糖恆定及生殖激素的分泌，同時具有保護神經的功能。胰島素對長期血糖恆定主要透過迷走神經降低肝糖輸出。此外，胰島素是否能透過其他機轉，對葡萄糖代謝產生短期調控，目前仍不清楚。本研究發現，中樞給予胰島素能促進周邊胰島素釋放，且在一小時內達到降低血糖的效果。並且，中樞給予胰島素所產生的血中胰島素濃度增加及血糖下降，在迷走神經截斷或腹腔注射第三型蕈毒鹼受體阻斷劑後受到抑制。此說明迷走神經負責將中樞刺激傳至周邊，導致周邊的胰島素釋放和血糖下降的主要機轉。先前文獻指出，鉀離子通道的開啟是胰島素的中樞功能中，必須的訊息傳遞路徑。本研究中所發現的短期調控，在前處理磺醯尿素類降血糖藥物時受到抑制。針對磺醯尿素類降血糖藥物在中樞及周邊的功能性差異，利用動物模式，發現周邊給予磺醯尿素類降血糖藥物(sulphonylurea)能減弱中樞胰島素的食慾抑制效果。若長時間給予磺醯尿素類降血糖藥物能影響其短期血糖調控。綜上所述，經由鉀離子通道的開啟及迷走神經的活化，中樞給予胰島素透過促進周邊胰島素釋放，造成血糖下降。且周邊給予的磺醯尿素類降血糖藥物有可能對胰島素產生抑制作用。

Central administration of insulin has metabolic, reproductive and neurotrophic effects. The metabolic effects of insulin are responsible for controlling the long-term glucose homeostasis via an activation of parasympathetic nerves in peripheral, which results in reduction of hepatic glucose output. However, it is still unclear whether central insulin exerts the regulation of plasma glucose within short term. In this study, we found that central administration of insulin caused an increment of plasma insulin level and a counterpart decrement in plasma glucose level within one hour. These effects were blocked by vagotomy and intraperitoneal administration of 4-DAMP, a specific M3 antagonist, which points out the importance of vagus nerve in insulin release and plasma glucose lowering effect. KATP is a key mediator in central signaling pathway of insulin. We also found that plasma glucose-lowering effect was blocked by central administration of sulphonylurea, a KATP blocker. After investigation the opposing effect of sulphonylurea to central effect of insulin, we found that the anorexic effect of central insulin is abolished after peripheral administration of sulphonylurea. Administration of sulphonylurea for 7 days results in diminished plasma glucose-lowering effect of central insulin. In conclusion, central insulin decreased plasma glucose level by activation of vagus nerve, which resulted in release of insulin, and intraperitoneal administration of sulphonylurea interferes with central effect of insulin.

Ball EG. Regulation of fatty acid synthesis in adipose tissue. Adv Enzyme Regul 4:3-18, 1966.

Bates SH & Myers GM. The role of leptin-STAT3 signaling in neuroendocrine function: an integrative perspective. J Mol Med 82:12-20, 2004.

Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Mller-Wieland D & Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 289:2122-2125, 2000.

Clark JT, Kalra PS & Kalra SP. Neuropeptide Y stimulates feeding but inhibits sexual behavior in rats. Endocrinology 117:2435-2442, 1985

Figlewicz DP. Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Physiol Regul Integr Comp Physiol 284:R882-R892, 2003.

Ford ES, Giles WH & Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287:356-359, 2002.

Gautam D, Han SJ, Duttaroy A, Mears D, Hamdan FF, Li JH, Cui Y, Jeon J & Wess J. Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis. Diabetes Obes Metab 9 Suppl.2:158-169, 2007.

Hallschmid M, Benedict C, Schultes B, Fehm H-L, Born J & Kern W. Intranasal insulin reduces body fat in men but not in women. Diabetes 53:3024-3029, 2004.

Havrankova J, Roth J & Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272:827-829, 1978.

Hermann LS. Metformin: a review of its pharmacological properties and therapeutic use. Diabete Metab 5:233-45, 1979.

van den Hoek AM, Voshol PJ, Karnekamp BN, Buijs RM, Romijn JA, Havekes LM & Pijl H. Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. Diabetes 53:2529-2534, 2004.

Kolta MG, Wallace LJ & Gerald MC. Streptozocin-induced diabetes affects rat urinary bladder response to autonomic agents. Diabetes 34:917-921, 1985.

Margolis RU & Altszuler N. Insulin in the cerebrospinal fluid. Nature 215:1375-1376, 1967.

Mark M & Grell W. Hypoglycaemic effects of the novel antidiabetic agent repaglinide in rats and dogs. Br J Pharmacol 121:1597-1606, 1997.

Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS & Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289:76-79, 2001.

Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, Torisu T, Chien KR, Yasukawa H & Yoshimura A. SOSC3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10:739-743, 2004.

Norgren R & Smith GP. Central distribution of subdiaphragmatic vagal branches in the rat. J Comp Neurol 273:207-223, 1988.

Obici S, Feng Z, Arduini A, Conti R & Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nature Med 9:756-761, 2003.

Obici S, Feng Z, Karkanias G, Baskin DG & Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat Neurosc 5:566-572, 2002.

Obici S, Zhang BB, Karkanias G & Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376-1382, 2002.

Okamoto H, Nakae J, Kitamura T, Park BC, Dragatsis I & Accili D. Transgenic rescue of insulin receptor-deficient mice. J Clin Invest 114:214-223, 2004.

Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I & Barsh GS. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278:135-138, 1997.

Plum L, Belgardt BF & Brning JC. Central insulin action in energy and glucose homeostasis. J Clin Invest 116:1761-1766, 2006.

Pocai A, Lam TK, Gutierrez-Juarez R, Obici S, Schwartz GJ, Bryan J, Aguilar-Bryan L & Rossetti L. Hypothalamic KATP channels control hepatic glucose production. Nature 434:1026-1031, 2005.

Schwartz AV. Diabetes, TZDs, and Bone: A Review of the Clinical Evidence. PPAR Res 2006(24502):1-6, 2006.

Schwartz MW, Woods SC, Porte D Jr., Seeley RJ & Baskin DG. Central nervous system control of food intake. Nature 404:661-671, 2000.

Seaquist ER, Damberg GS, Tkac I & Gruetter R. The effect of insulin on in vivo cerebral glucose concentrations and rates of glucose transport/metabolism in humans. Diabetes 50:2203-2209, 2001.

Seeley RJ & Woods SC. Monitoring of stored and available fuel by the CNS: implications for obesity. Nat Rev Neurosci 4:901-909, 2003.

Steiner DF. Insulin and the regulation of hepatic biosynthetic activity. Vitam Horm 24:1-61, 1966.

Ueki K, Kondo T & Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24:5434-5446, 2004.

Vergoni AV, Poggioli R & Bertolini A. Corticotropin inhibits food intake in rats. Neuropeptides 7:153-138, 1986

Wada A, Yokoo H, Yanagita T & Kobayashi H. New twist on neuronal insulin receptor signaling in health, disease, and therapeutics. J Pharmacol Sci. 99:128-143, 2005.

Watson GS, Peskind ER, Asthana S, Purganan K, Wait C, Chapman D, Schwartz MW, Plymate S & Craft S. Insulin increases CSF Aβ42 levels in normal older adults. Neurology 60:1899-1903, 2003.

White MF. Insulin signaling in health and disease. Science 302:1710-1711, 2003.

Woods SC, Lotter EC, McKay LD & Porte D Jr.. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282:503-505, 1979.

Zhao WQ, Chen H, Quon MJ & Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 490:71-81, 2003.