臺灣博碩士論文加值系統

臨床研究顯示非胰島素依賴型糖尿病病人有很高的死亡率且伴隨許多併發症的產生，而胰島素阻抗則是非胰島素依賴型糖尿病的重要構成要素。鎂是細胞內含量豐富的陽離子，在細胞的新陳代謝中扮演關鍵角色。許多臨床及基礎的研究報告皆顯示鎂離子缺乏與胰島素阻抗及非胰島素依賴型糖尿病有很高的相關性，但缺鎂影響胰島素作用的機制至今並不清楚。脂肪細胞是胰島素目標細胞之一，經常作為研究胰島素作用及胰島素阻抗機制的材料。因此，本實驗的目的為將大白鼠脂肪細胞培養在低鎂的緩衝溶液中造成細胞內缺鎂的現象，以觀察胰島素作用是否受到影響，並探討其機制。脂肪細胞從250~350克的雄性Sprague-Dawley大白鼠的脂肪墊分離後，培養在生理鎂 (1.200 mM) 和低鎂 (0.120、0.012 mM) 不同鎂濃度的緩衝溶液中處理1或3小時。胰島素之作用以葡萄糖攝取實驗評斷；胰島素受體的數目及親和性由碘-125胰島素結合測量；而胰島素受體訊號傳遞途徑之傳訊因子的蛋白質表現量則以Western點墨分析，包括胰島素受體b次單元、Insulin Receptor Substrate-1 (IRS-1) 以及Phosphatidylinositol 3-kinase (PI 3-kinase)。實驗結果顯示與正常鎂處理之脂肪細胞比較，可發現低鎂 (0.012 mM) 處理3小時會造成脂肪細胞基礎及胰島素刺激之葡萄糖攝取下降；但處理1小時只會造成胰島素刺激之葡萄糖攝取下降，對基礎葡萄糖攝取則無影響。而較輕微的低鎂 (0.120 mM) 處理3小時則只會影響基礎葡萄糖攝取。低鎂處理之脂肪細胞其胰島素結合下降，且胰島素受體高親和性結合部位之數量減少；而低親和性結合部位之親和性下降，但結合部位之數量卻增加。Western點墨分析的實驗則發現，胰島素受體b次單元、IRS-1及PI 3-kinase的蛋白質表現量皆有減少的現象，分別降低為生理鎂處理組的60.9%、62.9%、56.9%。由以上的結果得知，低鎂處理脂肪細胞會造成基礎及胰島素刺激之葡萄糖攝取下降，產生胰島素阻抗。而其原因可能為胰島素受體數量及親和性下降，以及胰島素受體訊號傳遞途徑之傳訊因子中，胰島素受體b次單元、IRS-1及PI 3-kinase的蛋白質表現量減少。本實驗也更加說明了低鎂在胰島素阻抗中扮演角色的重要性。

Clinical studies have shown that patients with non-insulin-dependent diabetes mellitus (NIDDM) have much higher mortality and many complications. Insulin resistance is a central component of NIDDM. Magnesium (Mg++), an abundant cation in living cells, plays a key role in cellular metabolism. Numerous studies and clinical reports have shown that Mg++ deficiency is associated with insulin resistance and NIDDM, but the mechanisms of Mg++ deficiency underlying insulin action are not clear. Adipocyte, one of the insulin targets, is often used to study insulin actions. The purpose of this study was to investigate the effect of Mg++ deficiency on insulin action in rat adipocytes. Adipocytes were isolated from epidydimal fat pads of male Sprague-Dawley rats weighting 250~350 g and incubated in physiological (1.200 mM) and low (0.120, 0.012 mM) Mg++ buffer for 1 or 3 hours. Insulin actions were evaluated by glucose uptake. The number and affinity of insulin receptor were measured by 125I-insulin binding. The protein expression of signaling components in insulin receptor signal transduction pathway was analyzed by Western Blot. Our results showed that the basal and insulin-stimulate glucose uptake (ISGU) were significantly reduced in adipocytes incubated in low Mg++ (0.012 mM) concentration buffer for 3 hours. Furthermore ISGU, but not basal glucose uptake was reduced in 1-hour incubation. Moderately low Mg++ (0.120 mM) for 3 hours inhibited basal glucose uptake but had no effect on ISGU. Insulin binding to adipocytes was significantly reduced in low Mg++ group. The Scatchard analysis showed that the number and affinity of insulin receptor was decreased in low Mg++ group. Protein expression levels of insulin receptor b subunit, IRS-1, and PI 3-kinase were decreased in adipocytes treated with low Mg++ concentration buffer. These data showed that Mg++ deficiency inhibited basal and insulin-stimulated glucose uptake in rat adipocytes, possibly via decreases in insulin receptors and insulin receptor affinity, and through suppression of expression of insulin receptor signal transduction pathway proteins, including insulin receptor b subunit, IRS-1, and PI 3-kinase. Our study suggests that Mg++ deficiency may play a role in the development of insulin resistance.

目 錄
目錄 i
圖表目錄 iv
中文摘要 vi
英文摘要 viii
緒論 1
一、胰島素阻抗 1
1. 胰島素 1
2. 胰島素受體 2
3. 胰島素受體之訊號傳遞 3
4. 胰島素阻抗 5
二、鎂 7
1. 鎂離子在生物體之簡介 7
2. 低血鎂症及高血鎂症 8
三、鎂與胰島素阻抗 9
四、實驗設計與目的 11
材料與方法 12
一、實驗材料 12
1. 實驗動物 12
2. 儀器設備及材料 12
3. 化學試劑 13
4. 抗體 15
5. 放射性藥品 15
二、實驗方法 17
1. 脂肪細胞之製備 17
2. 脂肪細胞葡萄糖攝取之定量 18
3. 脂肪細胞胰島素受體競爭結合實驗 19
4. Western點墨分析 20
5. 數值與統計分析 22
結果 23
一、脂肪細胞培養液鎂濃度與滲透度之測定 23
二、脂肪細胞葡萄糖攝取之情形 23
1. 不同時間低鎂處理之影響 23
2. 不同程度低鎂處理之影響 24
三、脂肪細胞胰島素結合之情形 25
四、脂肪細胞胰島素受體訊號傳遞之情形 26
1. 胰島素受體b次單元之表現情形 26
2. IRS-1之表現情形 27
3. PI 3-kinase之表現情形 27
總結 29
討論 29
結論 33
參考文獻 34
圖表 44

1. Anai, M., Funaki, M., Ogihara, T., Terasaki, J., Inukai, K., Katagiri, H., Fukushima, Y., Yazaki, Y., Kikuchi, M., Oka, Y., and Asano, T. Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats. Diabetes 47 (1): 13-23, 1998.
2. Araki, E., Lipes, M. A., Patti, M. E., Bruning, J. C., Haag B. 3rd, Johnson, R. S., and Kahn, R. Alternative pathways of insulin signaling in mice with targeted disruption of the IRS-1 gene. Nature 372: 186-190, 1994.
3. Backer, J. M., Myers Jr, M., Shoelson, S. E., Chin, J., Sun, X. J. Miralpeix, M., Hu, P., Margolis, B., Skolnik, E. Y., Schlessinger, J., and White, M. F. Phosphatidylinositol 3'-kinase is activated by association with IRS-l during insulin stimulation. EMBO J. 11: 3469-3479, 1992.
4. Baldi, S., Natali, A., Buzzigoli, G., Galvan, A. Q., Sironi, A. M., and Ferrannini, E. In vivo effect of insulin on intracellular calcium concentrations relation to insulin resistance. Metabolism 45: 1402-1407, 1996.
5. Balon, T. W., Gu, J. L., Tokuyama, Y., Jasman, A. P., and Nadler, J. L. Magnesium supplementation reduces development of diabetes in a rat model of spontaneous NIDDM. Am. J. Physiol. 269 (4 Pt 1): E745-52, 1995.
6. Balon, T. W., Jasman, A., Scott, S., Meehan, W. P., Rude, R. K., and Nadler, J. L. Dietary magnesium prevents fructose-induced insulin insensitivity in rats. Hypertension 23, 1036-1039, 1994.
7. Barrett, E. J. and Liu, Z. Hepatic glucose metabolism and insulin resistance in NIDDM and obesity. Baillieres Clin. Endocrinol. Metab. 7: 875-901, 1993.
8. Bell, G. I., Kayano, T., Buse, J. B., Burant, C. F., Takeda, J., Lin, D., Fukumoto, H., and Seino, S. Molecular biology of mammalian glucose transporter. Diabetes Care 13: 198-243, 1990.
9. Berger, J., Hayes, N., Szalkowski, D. M., and Zhang, B. PI 3-kinase activation is required for insulin stimulation of glucose transport into L6 myotubes. Biochem. Biophy. Res. Comm. 205: 570-576, 1994.
10. Bergman, R. N. Toward physiological understanding of glucose tolerance: minimal model approach. Diabetes 38: 1512-1527, 1989.
11. Bergman, R. N., Steil, G. M., Bradley, D. C., and Watanabe, R. M. Modeling of insulin action in vivo. Ann. Rev. Physiol.. 54: 861-883, 1992.
12. Bergstra, A. E., Lemmens, A. G., and Beynen, A. C. Dietary fructose vs. glucose stimulates nephrocalcinogenesis in femal rats. J. Nutr. 123: 1320-1327, 1993.
13. Cahill, G. F. Jr. Starvation in man. J. Clin. Endocrinol. Metab. 5: 397-415, 1976.
14. Clement, K., Pueyo, M. E., Vaxillaire, M., Rakotoambinina, B., Thuillier, F., Passa, P., Froguel, P., Robert, J. J., and Velho, G. Assessment of insulin sensitivity in glucokinase-deficient subjects. Diabetologia 39: 82-90, 1996.
15. Cooksey, R. C., Hebert, L. F. Jr., Zhu, J. H., Wofford, P., Garvey, W. T., and McClain, D. A. Mechanism of hexosamine-induced insulin resistance in transgenic mice overexpressing glutamine: fructose-6-phosphate amidotransferase: decreased glucose transporter GLUT4 translocation and reversal by treatment with thiazolidinedione. Endocrinology 140 (3): 1151-1157, 1999.
16. DeFronzo, R. A., Bonadonna, R. C., and Ferrannini, E. Pathogenesis of NIDDM: a balanced overview. Diabetes Care 15: 318-368, 1992.
17. de Rouffignac, C. and Quamme, C. Renal magnesium handling and its hormone control. Physiol. Rev. 74: 305-322, 1994
18. DiGirolamo, M., Mendlinger, S., and Fertig, J. W. A simple method to determine fat cell size and number in four mammalian species. Am. J. Physiol. 221: 850-858, 1971.
19. Dresner, A., Laurent, D., Marcucci, M., Griffin, M. E., Dufour, S., Cline, G. W., Slezak, L. A., Andersen, D. K., Hundal, R. S., Rothman, D. L., Petersen, K. F., and Shulman, G. I. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J. Clin. Invest. 103 (2): 253-259, 1999.
20. Ebeling, P., Koistinen, H. A., and Koivisto, V. A. Insulin-independent glucose transport regulates insulin sensitivity. FEBS Letters 436 (3): 301-303, 1998.
21. Friedman, J. E., Ishizuka, T., Liu, S., Farrell, C. J., Bedol, D., Koletsky, R. J., Kaung, H. L., and Ernsberger, P. Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat. Am. J. Physiol. 273 (5 Pt 1): E1014-E1023, 1997.
22. Garvey, W. T. Glucose transport and NIDDM. Diabetes Care 15 (3): 396-417, 1992.
23. Garvey, W. T., Huecksteadt, T. P., Matthaei, S., and Olefsky, J. M. The role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus. J. Clin. Invest. 81: 1528-1536, 1988.
24. Garvey, W. T., Olefsky, J. M., Matthaei, S., and Marshall, S. Glucose and insulin co-regulate the glucose transport system in primary cultured adipocytes. J. Biol. Chem. 262: 189-197, 1987.
25. Gould, G. W. and Holman, G. D. The glucose transporter family: structure, function and tissue-specific expression. Biochem. J. 295: 329-341, 1993.
26. Hansen, B. C. Genetics of insulin action. Baillieres Clin. Endocrinol. Metab. 7: 1033-1061, 1993.
27. Henning, B. N. Clinical disorder of insulin resistance. In: International Textbook of Diabetes Mellitus, edited by Alberti, K. G. M. M., DeFronto, R. A., Keen, H., and Zimmet. Chichester, P. Eng: John Wiley & Sons, 1992, pp: 531-550.
28. Himsworth, H. and Kerr, R. B. Insulin-sensitive and insulin-insensitive types of diabetes mellitus. Clin. Sci. 4: 120, 1942.
29. Hong, Y., Pederson, N. L., Brismar, K., and de Faire, U. Genetic and environmental architecture of the features of the insulin-resistance syndrome. Am. J. Hum. Genet. 60: 143-152, 1997.
30. Hornor, R. C., Dhillon, G. S., and Londos, C. c-AMP- dependent protein kinase and lipolysis in rat adipocytes: II. definition of steady--state relationship with lipolytic modulators. J. Biol. Chem. 260: 15130-15138, 1985.
31. Hunnicutt, J. W., Hardy, R. W., Williford, J., and McDonald, J. M. Saturated fatty acid-induced insulin resistance in rat adipocytes. Diabetes 43 (4): 540-545, 1994.
32. Jain, R. G., Andrews, L. G., McGowan, K. M., Pekala, P. H., and Keene, J. D. Ectopic expression of Hel-N1, an RNA-binding protein, increases glucose transporter (GLUT1) expression in 3T3-L1 adipocytes. Mol. Cell. Biol. 17 (2): 954-962, 1997.
33. Jamerson, K. A., Julius, S., Gudbrandsson, T., Andersson, O., and Brant, D. O. Reflex sympathetic activation induces acute insulin resistance in the human forearm. Hypertension 21: 618-623, 1993.
34. James, D. E., Brown, R., Navarro, J., and Pilch, P. F. Insulin-regulatable tissues express a unique insulin-sensitive glucose transport protein. Nature 333 (6169): 183-185, 1988.
35. Julius, S., Gudbrandsson, T., Jamerson, K., Shahab, S. T., and Andersson, O. The hemodynamic link between insulin resistance and hypertension. J. Hypertens. 9: 983-986, 1991.
36. Julius, S. and Nesbitt, S. Sympathetic overactivity in hypertension. A moving target. Am. J. Hypertens. 9: 113S-120S, 1996.
37. Kahn, C. R. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metabolism 27: 1893-1902, 1978.
38. Kahn, C. R. and White, M. F. The insulin receptor and the molecular mechanism of insulin action. J. Clin. Invest. 82: 1151-1156, 1988.
39. Kandeel, F. R., Balon E., Scott, S., and Nadler, J. L. Magnesium defeciency and glucose metabolism in rat adipocytes. Metab. Clin. Exp. 36: 160-164, 1996.
40. Kasuga, M., Karlsson, F. A., and Kahn, C. R. Insulin stimulates the phosphorylation of the 95,000-Dalton subunit of itrs own receptor. Science 215: 185-187, 1982.
41. Keller, S. R. and Lienhard, G. E. Insulin signalling: the role of in insulin receptor substrate 1. Trends Cell Biol. 4: 115-119, 1994.
42. Laakso, M., Edelman, S. V., Brechtel, G., and Baron, A. D. Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man: A novel mechanism for insulin resistance. J. Clin. Invest. 85, 1844-1853, 1990.
43. Lima, M. de L., Cruz, T., Pousada, J. C., Rodrigues, L. E., Barbosa, K., and Cangucu, V. The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. Diabetes Care. 21(5): 682-686, 1998.
44. Lowney, P., Tamara, S., Hannon, and Alain D. B. Magnesium deficiency enhances basal glucose disposal in the rat. Am. J. Physiol. 268: E925-E931, 1995.
45. Maloff, B. L. and Lockwood, D. H. In vitro effects of a sulfonylurea on insulin action in adipocytes. J. Clin. Invest. 68: 85-90, 1981.
46. Massry, S. G. and Selling, M. S. Hypomagnesia and hypermagnesemia. Clin. Nephrol. 7: 147-153, 1977.
47. Mayor, P., Maianu, L., and Garvey, W. T. Glucose and insulin chronically regulate insulin action via different mechanisms in BC3H1 myocytes. Effects on glucose transporter gene expression. Diabetes 41 (3): 274-285, 1992.
48. Meisler, M. H. and Howard, G. Effects of insulin on gene transcription. Annu. Rev. Phyiol. 51: 701-714, 1989.
49. Moles, K. W. and McMullen, J. K. Insulin resistance and hypomagnesaemia: case report. Br. Med. J. 285: 262, 1982.
50. Myers, M. G. Jr and White, M. F. The new element of insulin signaling. Diabetes 42: 643-50, 1993.
51. Myers, M. G. Jr and White, M. F. Insulin signal transduction and the IRS proteins. Annu. Rev. Pharmacol. Toxicol. 36: 615-658, 1996.
52. Oka, Y., Asano, T., Shibasaki, Y., Kasuga, M., Kanazawa, Y., and Takaku, F. Studies with antipeptide antibody suggest the presence of at least two types of glucose transporter in rat brain and adipocyte. J. Biol. Chem. 263: 13432-13439, 1988.
53. Olefsky, J. M. Insulin resistance and insulin action: an in vitro and in vivo perspective. Diabetes 30: 148-161, 1981.
54. Olson, A. L. and Pessin, J. E. Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu. Rev. Nutr. 16: 235-256, 1996.
55. O'Nell, T. J., Craparo, A., and Gustafson, T. A. Characterization of an interaction between insulin receptor substrate 1 and insulin receptor by using the Two-Hybrid system. Mol. Cell. Biol. 14: 6433-6442, 1994.
56. Otsu, M., Hiles, I., Gout, I., Fry, M. J., Ruiz-Larrea, F., Panayotou, G., Thompson, A., Dhand, R., Hsuan, J., Totty, N., Smith, A. D., Morgen, S. J., Courtneidge, S. A., Parker, P. J., and Waterfield, M. D. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp69 c-src complexes, and PI 3-kinase. Cell 65: 91-104, 1991.
57. Pajor, A. M., Hirayama, B. A., and Wright, E. M. Molecular biology approaches to comparative study of Na+-glucose cotransport. Am. J. Physiol. 263: R489-R495, 1992.
58. Paolisso, G. and Barbagallo, M. Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium. Am. J. Hypertens. 10 (3) : 346-355, 1997.
59. Polonsky, K. S., Sturis, J., and Bell, G. I. Non-insulin-dependent diabetes mellitus - a genetically programmed failure of the beta cell to compensate for insulin resistance. N. Engl. J. Med. 334: 777-783, 1996.
60. Pulido, N., Romero, R., Suarez, A. I., Rodriguez, E., Casanova, B., and Rovira, A. Sulfonylureas stimulate glucose uptake through GLUT4 transporter translocation in rat skeletal muscle. Biochem. Biophy. Res. Comm. 228 (2): 499-504, 1996.
61. Quamme, G. A. Magnesium homeostasis and renal magnesium handling. Miner. Electrolyte Metab. 19: 218-225, 1993.
62. Quamme, G. A. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 52 (5): 1180-1195, 1997.
63. Reaven, G. M. Role of insulin resistance in human disease. Diabetes 37: 1595-1607, 1988.
64. Rodbell, M. Metabolism of isolated fat cell. I. Effects of hormones on glucose metabolism and lipolysis. J. Biol. Chem. 239: 375-380, 1964.
65. Rosen, O. M. After insulin binding. Science 237: 1452-14532, 1987.
66. Rosolova, H., Mayer, O. Jr., and Reaven, G. Effect of variation in plasma magnesium concentration on resistance on insulin-mediated glucose disposal in nondiabetic subjects. J. Clin. Endocrinol. Metab. 82 (11): 3783-3785, 1997.
67. Rothenberg, P. L., Lane, W. S., Backer, J. M., White, M. F., and Kahn, C. R. Purification and partial sequence analysis of pp185, the major cellular substrate of the insulin receptor tyrosine kinase. J. Biol. Chem. 266: 8302-8311, 1991.
68. Saltiel A. R. Diverse signaling pathways in the cellular actions of insulin. Am. J. Physiol. 270 (3 Pt 1): E375-E385, 1996.
69. Scatchard, G. The attractions of proteins for small molecules and ions. Ann. N. Y. Acad. Sci. 51: 661-672, 1949.
70. Schultz, T. A., Lewis, S. B., Westbie, D. K., and Wallin, J. D. Glucose delivery: a modulator of glucose uptake in contracting skeletal muscle. Am. J. Physiol. 2: E514-E518, 1977.
71. Sheu, W. H., Swislocki, A. L., Hoffman, B., Chen, Y. D., and Reaven., G. M. Comparison of the effects of atenolol and nifedipine on glucose, insulin and lipid metabolism in patients with hypertension. Am. J. Hypertens. 4: 199-205, 1991.
72. Singer, P., Godicke, W., Voltg, S., Hajdu, I., and Weiss, M. Postprandial hyperinsulinemia in patients with mild essential hypertension. Hypertension 7: 182-186, 1995.
73. Sjogren, A., Fioren, C. H., and Nilsson, A. Magnesium, potassium and zinc deficiency in subjects with type II diabetes mellitus. Acta. Med. Scand. 224: 461-465, 1988.
74. Skolnik, E. Y., Margolis, B., Mohammadi, M., Lowenstein, E., Fischer, R., Drepps, A., Ullrich, A., and Schlessinger, J. Cloning of PI 3-kinase-associated p85 utilizing a novel method for expression/cloning of target protein for receptor tyrosine kinase. Cell 65: 83-90, 1991.
75. Standly, C. A., Irtenkauf, S. M., and Cotton, D. B. Anticonvulsant effects of magnesium sulfate in hippocampal-kindled rats. J. Biomed. Sci. 2: 57-62, 1995.
76. Suarez, A., Pulido, N., Casla, A., Casanova, B., Arrieta, F. J., and Rovira, A. Impaired tyrosine-kinase activity of muscle insulin receptors from hypomagnesaemic rats. Diabetologia 38: 1262-1270, 1995.
77. Sun, G. and Budde, R. J. Requirement for an additional divalent metal cation to activate protein tyrosine kinases. Biochemistry 36 (8): 2139-2146, 1997.
78. Sun, X. J., Rothenberg, P. L., Kahn, C. R., Backer, J. M., Araki, E., Wilden, P. A., Cahill, D. A., Goldstein, B. J., and White, M. F. Structure of the insulin receptor substrae IRS-1 defines a unique signal transduction protein. Nature 352: 73-77, 1991.
79. Tafuri, S. R. Troglitazone enhances differentiation, basal glucose uptake, and Glut1 protein levels in 3T3-L1 adipocytes. Endocrinology 137 (11): 4706-4712, 1996.
80. Tamemoto. H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Ueki, K., Kaburagi, Y., Satoh, S., Sekihara, H., Yoshioka, S., Horikoshi, H., FuIuta, Y., Ikawa, Y., Kasuga, M., Yazaki, Y., and Aizawa, S. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372: 182-185, 1994.
81. Terasaki, J. Anai, M., Funaki, M., Shibata, T., Inukai, K., Ogihara, T., Ishihara, H., Katagiri, H., Onishi, Y., Sakoda, H., Fukushima, Y., Yazaki, Y., Kikuchi, M., Oka, Y., and Asano, T. Role of JTT-501, a new insulin sensitiser, in restoring impaired GLUT4 translocation in adipocytes of rats fed a high fat diet. Diabetologia 41 (4): 400-409, 1998.
82. Thirone, A. C., Carvalho, C. R., Brenelli, S. L., Velloso, L. A., and Saad, M. J. Effect of chronic growth hormone treatment on insulin signal transduction in rat tissues. Mol. Cell. Endocrinol. 130 (1-2): 33-42, 1997.
83. Wacker, W. E. C. and Parisi, A. F. Magnesium metabolism. New Engl. J. Med. 278: 658-772, 1968.
84. White, M. F. and Kahn, C. R. The insulin signaling system. J. Biol. Chem. 269: 1-4, 1994.
85. White, M. F., Maron, R., and Kahn, C. R. Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells. Nature 318: 183-186, 1985.
86. White, M. F., Shoelson, S. E., Keutmann, H., and Kahn, C. R. A cascade of tyrosine autophosphorylation in the b-subunit activates insulin receptor. J. Biol. Chem. 263: 2969-2980, 1988.
87. Whitman, M., Downs, C. P. Keeler, M, Keller, T., and Cantley, L. Type I phosphatidylinositol kinase makes a novel inositol phospholipids, phosphatidylinositol-3-phosphate. Nature 332: 644-646, 1984.
88. Whitman, M., Kaplan, D., Roberts, T., and Cantley, L. Evidence for two distinct phosphatidylinositol kinases in fibroblasts. Biochem. J. 247: 165-174, 1987.
89. Yajnik, C. S., Smith, R. F., Hockaday, T. D. K., and Ward, N. I. Fast plasma magnesiumn concentrations and glucose disposal in diabetics. Br. Med. J. 288: 1032-1034, 1984.
90. Yamauchi, T., Tobe, K., Tamemoto, H., Ueki, K., Kaburagi, Y., Yamamoto-Honda, R., Takahashi, Y., Yoshizawa, F., Aizawa, S., Akanuma, Y., Sonenberg, N., Yazaki, Y., Kadowaki, T. Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol. Cell. Biol. 16 (6): 3074-84, 1996.
91. Zavaroni I., Sanders, S., Scott, S., and Reaven, G. M. Effect of fructose feeding on insulin secretion and insulin action in the rat. Metabolism 29: 970-973, 1980.
92. Zierath, J. R., Krook, A. Wallberg-Henriksson, H. Insulin action in skeletal muscle from patients with NIDDM. Mol. Cell. Biochem. 182 (1-2): 153-160, 1998.
93. Zorzano, A., Santalucia, T., Palacin, M., Guma, A., and Camps, M. Searching for ways to upregulate GLUT4 glucose transporter expression in muscle. Gen. Pharmacol. 31 (5): 705-713, 1998.
94. Zorzano, A., Wilkinson, W., Kotliar, N., Thoidis, G., Wadzinksis, B. E., Ruoho, A. E., and Pilch, P. F. Insulin-regulated glucose uptake in rat adipocyte is mediated by two transporter isoforms present in at least two vesicle populations. J. Biol. Chem. 264: 12358-12363, 1989.