Nutrition, Insulin, Insulin-like Growth Factors and Cancer

Abstract

The incidence of colon, pancreatic, and kidney cancers, as well as aggressive prostate cancer in men, and breast and endometrial cancer in women is invariably high in Western countries. Nutritional and related factors have been typically implicated. This review presents a model integrating nutrition, insulin and IGF-1 physiology (”bioactive” IGF-1), and carcinogenesis based on the following: (1) insulin and the IGF-1 axis function in an integrated fashion to promote cell growth and survival; (2) chronic exposure to these growth properties enhances carcinogenesis; (3) factors that influence bioactive IGF-1 will affect cancer risk. The model presented here summarizes the data that chronic exposure to high levels of insulin and IGF-1 may mediate many of the risk factors for some cancers that are high in Western populations. This hypothesis may help explain some of the epidemiologic patterns observed for these cancers, both from a cross-national perspective and within populations. Of particular importance is that some of relevant factors are modifiable through nutritional and lifestyle interventions. Out of a variety of perspectives presented, nutritional manipulation through the insulin pathway may be more feasible than attempting to influence total IGF-1 concentrations, which are determined largely by growth hormone. Further study is required to test these conclusions.

Key words

Obesity - Exercise - Epidemiology - Dietary fat - Protein - Diabetes - Acromegaly

References

• 1 Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today.  J Natl Cancer Inst. 1981;  66 1191-1308
• 2 Giovannucci E. Insulin and colon cancer.  Cancer Causes Control. 1995;  6 164-179
• 3 Gerber M, Corpet D. Energy balance and cancers.  Eur J Cancer Prev. 1999;  8 77-89
• 4 McKeown-Eyssen G. Epidemiology of colorectal cancer revisited: Are serum triglycerides and/or plasma glucose associated with risk?.  Cancer Epidemiol Biomarkers Prev. 1994;  3 687-695
• 5 Kaaks R. Nutrition, hormones, and breast cancer: Is insulin the missing link?.  Cancer Causes Control. 1996;  7 605-625
• 6 Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence.  J Nutr. 2001;  131 3109S-3120S
• 7 Hursting S D, Lavigne J A, Berrigan D, Perkins S N, Barrett J C. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans.  Annu Rev Med. 2003;  54 131-152
• 8 Pollak M. Insulin-like growth factor physiology and cancer risk.  Eur J Cancer. 2000;  36 1224-1228
• 9 Bruce W R, Wolever T M, Giacca A. Mechanisms linking diet and colorectal cancer: the possible role of insulin resistance.  Nutr Cancer. 2000;  37 19-26
• 10 Jones J, Clemmons D. Insulin-like growth factors and their binding proteins: biological actions.  Endocr Rev. 1995;  16 3-34
• 11 Hall K, Hilding A, Thoren M. Determinants of circulating insulin-like growth factor-I.  J Endocrinol Invest. 1999;  22 48-57
• 12 Underwood L E, Thissen J P, Lemozy S, Ketelslegers J M, Clemmons D R. Hormonal and nutritional regulation of IGF-I and its binding proteins.  Horm Res. 1994;  42 145-151
• 13 Smith W J, Underwood L E, Clemmons D R. Effects of caloric or protein restriction on insulin-like growth factor-1 (IGF-1) and IGF-binding proteins in children and adults.  J Clin Endocrinol Metab. 1995;  80 443-449
• 14 Brismar K, Fernqvist-Forbes E, Wahren J, Hall K. Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-1 in insulin-dependent diabetes.  J Clin Endocrinol Metab. 1994;  79 872-878
• 15 Bereket A, Lang C H, Blethen S L, Fan J, Frost R A, Wilson T A. Insulin-like growth factor binding protein-3 proteolysis in children with insulin-dependent diabetes mellitus: a possible role for insulin in the regulation of IGFBP-3 protease activity.  J Clin Endocrinol Metab. 1995;  80 2282-2288
• 16 Ooi G T, Tseng L Y, Tran M Q, Rechler M M. Insulin rapidly decreases insulin-like growth factor binding protein-1 gene transcription in streptozotocin-diabetic rats.  Mol Endocrinol. 1992;  6 2219-2228
• 17 Powell D R, Suwanichkul A, Cubbage M L, DePaolis L A, Snuggs M B, Lee P D. Insulin inhibits transcription of the human gene for insulin-like growth factor-binding protein-1.  J Biol Chem. 1991;  266 18 868-18 876
• 18 Katz L EL, Cohen P, Rosenfeld R. Clinical significance of IGF binding proteins.  Endocrinologist. 1995;  5 36-43
• 19 Cohen P, Fielder P J, Hasegawa Y, Frisch H, Giudice L C, Rosenfeld R G. Clinical aspects of insulin-like growth factor binding proteins.  Acta Endocrinologica. 1991;  124 Suppl 2 74-85
• 20 Lee P D, Conover C A, Powell D R. Regulation and function of insulin-like growth factor-binding protein-1.  Proc Soc Exp Biol Med. 1993;  204 4-29
• 21 Cotterill A M, Holly J M, Wass J A. The regulation of insulin-like growth factor binding protein (IGFBP)-1 during prolonged fasting.  Clin Endocrinol. 1993;  39 357-362
• 22 Busby W H, Snyder D K, Clemmons D R. Radioimmunoassay of a 26,000-dalton plasma insulin-like growth factor-binding protein: control by nutritional variables.  J Clin Endocrinol Metab. 1988;  67 1225-1230
• 23 Suikkari A M, Sane T, Seppala M, Yki-Jarvinen H, Karonen S L, Koivisto V A. Prolonged exercise increases serum insulin-like growth factor-binding protein concentrations.  J Clin Endocrinol Metab. 1989;  68 141-144
• 24 Batch J A, Baxter R C, Werther G. Abnormal regulation of insulin-like growth factor binding proteins in adolescents with insulin-dependent diabetes.  J Clin Endocrinol Metab. 1991;  73 964-968
• 25 Brismar K, Gutniak M, Povoa G, Werner S, Hall K. Insulin regulates the 35 kDa IGF binding protein in patients with diabetes mellitus.  J Endocrinol Invest. 1988;  11 599-602
• 26 Suikkari A M, Koivisto V A, Rutamen E M, Yki-Jarvinen H, Karonen S L, Seppala M. Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein.  J Clin Endocrinol Metab. 1988;  66 266-272
• 27 Argente J, Caballo N, Barrios V, Munoz M T, Pozo J, Chowen J A. et al . Disturbances in the growth hormone-insulin-like growth factor axis in children and adolescents with different eating disorders.  Horm Res. 1997;  48 (Suppl 4) 16-18
• 28 Counts D R, Gwirtsman H, Carlsson L M, Lesem M, Cutler G BJ. The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs) and the IGF-binding proteins.  J Clin Endocrinol Metab. 1992;  75 762-767
• 29 Strasser-Vogel B, Blum W F, Past R, Kessler U, Hoeflich A, Meiler B. et al . Insulin-like growth factor (IGF)-I and -II and IGF-binding proteins-1, -2, and -3 in children and adolescents with diabetes mellitus: correlation with metabolic control and height attainment.  J Clin Endocrinol Metab. 1995;  80 1207-1213
• 30 Nam S Y, Lee E J, Kim K R, Cha B S, Song Y D, Lim S K. et al . Effect of obesity on total and free insulin-like growth factor (IGF)-I and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone.  Int J Obes Relat Metab Dis. 1997;  21 355-359
• 31 Flier J S, Usher P, Moses A C. Monoclonal antibody to the type I insulin-like growth factor (IGF-I) receptor blocks IGF-I receptor-mediated DNA synthesis: clarification of the mitogenic mechanisms of IGF-I and insulin in human skin fibroblasts.  Proc Natl Acad Sci USA. 1986;  83 664-668
• 32 Moller D E, Flier J S. Insulin resistance-mechanisms, syndromes, and implications.  N Engl J Med. 1991;  325 938-948
• 33 Macaulay V M. Insulin-like growth factors and cancer.  Br J Cancer. 1992;  65 311-320
• 34 Soos M A, Whittaker J, Lammers R, Ullrich A, Siddle K. Receptors for insulin and insulin-like growth factor-I can form hybrid dimers. Characterisation of hybrid receptors in transfected cells.  Biochem J. 1990;  270 383-390
• 35 Bach L A, Rechler M M. Insulin-like growth factors and diabetes.  Diabetes Metab Rev. 1992;  8 229-257
• 36 Gutierrez L, Magee A I, Marshall C J, Hancock J F. Post-translational processing of p21ras is two-step and involves carboxyl-methylation and carboxy-terminal proteolysis.  EMBO J. 1989;  8 1093-1098
• 37 Leitner J W, Kline T, Carel K, Goalstone M, Draznin B. Hyperinsulinemia potentiates activation of p21Ras by growth factors.  Endocrinology. 1997;  138 2211-2214
• 38 Goalstone M L, Wall K, Leitner J W, Kurowski T, Ruderman N, Pan S J. et al . Increased amounts of farnesylated p21Ras in tissues of hyperinsulinaemic animals.  Diabetologia. 1999;  42 310-316
• 39 Rajaram S, Baylink D J, Mohan S. Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions.  Endocr Rev. 1997;  18 801-831
• 40 Thissen J P, Ketelslegers J M, Underwood L E. Nutritional regulation of the insulin-like growth factors.  Endocr Rev. 1994;  15 80-101
• 41 Clemmons D R, Klibanski A, Underwood L E, McArthur J W, Ridgway E C, Beitins I Z. et al . Reduction of plasma immunoreactive somatomedin C during fasting in humans.  J Clin Endocrinol Metab. 1981;  53 1247-1250
• 42 Ho K Y, Veldhuis J D, Johnson M L, Furlanetto R, Evans W S, Alberti K G. et al . Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man.  J Clin Invest. 1988;  81 968-975
• 43 Merimee T J, Zapf J, Froesch E R. Insulin-like growth factors in the fed and fasted states.  J Clin Endocrinol Metab. 1982;  55 999-1002
• 44 Clemmons D R, Seek M M, Underwood L E. Supplemental essential amino acids augment the somatomedin-C/insulin-like growth factor I response to refeeding after fasting.  Metabolism. 1985;  34 391-395
• 45 Devine A, Rosen C, Mohan S, Baylink D, Prince R L. Effects of zinc and other nutritional factors on insulin-like growth factor I and insulin-like growth factor binding proteins in postmenopausal women.  Am J Clin Nutr. 1998;  68 200-206
• 46 Estivariz C F, Ziegler T R. Nutrition and the insulin-like growth factor system.  Endocrine. 1997;  7 65-71
• 47 Clausen T, Dorup I. Micronutrients, minerals and growth control. In: Sandstrom B, Walter P (eds) Role of Trace Elements for Health Promotion and Disease Prevention. Basel; Karger 1998: 84-92
• 48 MacDonald R S. The role of zinc in growth and cell proliferation.  J Nutr. 2000;  130 1500S-1508S
• 49 Ninh N X, Thissen J P, Collette L, Gerard G, Khoi H H, Ketelslegers J M. Zinc supplementation increases growth and circulating insulin-like growth factor I (IGF-I) in growth-retarded Vietnamese children.  A J Clin Nutr. 1996;  63 514-519
• 50 Holmes M D, Pollak M N, Willett W C, Hankinson S E. Dietary correlates of plasma insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations.  Cancer Epidemiol Biomarkers Prev. 2002;  11 852-861
• 51 Giovannucci E, Pollak M, Liu Y, Platz E A, Majeed N, Rimm E B. et al . Nutritional predictors of insulin-like growth factor I and their relationships to cancer in men.  Cancer Epidemiol Biomarkers Prev. 2003;  12 84-89
• 52 Allen N E, Appleby P N, Davey G K, Kaaks R, Rinaldi S, Key T J. The association of diet with serum insulin-like growth factor I and its main binding proteins in 292 women meat-eaters, vegetarians, and vegans.  Cancer Epidemiol Biomarkers Prev. 2002;  11 1441-1448
• 53 Gunnell D, Oliver S E, Peters T J, Donovan J L, Persad R, Maynard M. et al . Are diet-prostate cancer associations mediated by the IGF axis? A cross-sectional analysis of diet, IGF-I and IGFBP-3 in healthy middle-aged men.  Br J Cancer. 2003;  88 1682-1686
• 54 Probst-Hensch N M, Wang H, Goh V H, Seow A, Lee H P, Yu M C. Determinants of circulating insulin-like growth factor I and insulin-like growth factor binding protein 3 concentrations in a cohort of Singapore men and women.  Cancer Epidemiol Biomarkers Prev. 2003;  12 739-746
• 55 Kaklamani V G, Linos A, Kaklamani E, Markaki I, Koumantaki Y, Mantzoros C S. Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults.  J Clin Oncol. 1999;  17 3291-3298
• 56 Heaney R P, McCarron D A, Dawson-Hughes B, Oparil S, Berga S L, Stern J S. et al . Dietary changes favorably affect bone remodeling in older adults.  J Am Diet Assn. 1999;  99 1228-1233
• 57 Hong Y, Pedersen N L, Brismar K, Hall K, De Faire U. Quantitative genetic analyses of insulin-like growth factor-I (IGF-I), IGF-binding protein-1, and insulin levels in middle-aged and elderly twins.  J Clin Endocrinol Metab. 1996;  81 1791-1797
• 58 Kao P C, Matheny A P, Lang C A. Insulin-like growth factor-I comparisons in healthy twin children.  J Clin Endocrinol Metab. 1994;  78 310-312
• 59 Bjorntorp P. Metabolic implications of body fat distribution.  Diabetes Care. 1991;  14 1132-1143
• 60 Kissebah A H, Vydelingum N, Murray R, Evans D J, Hartz A J, Kalkhoff R K. et al . Relation of body fat distribution to metabolic complications of obesity.  J Clin Endocrinol Metab. 1982;  54 254-260
• 61 DeFronzo R A, Jacot E, Jequier E, Maeder E, Wahren J, Felber J P. The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization.  Diabetes. 1981;  30 1000-1007
• 62 Lillioja S, Mott D M, Zawadzki J K, Young A A, Abbott W G, Bogardus C. Glucose storage is a major determinant of in vivo ”insulin resistance” in subjects with normal glucose tolerance.  J Clin Endocrinol Metab. 1986;  62 922-927
• 63 Shulman G I, Rothman D L, Jue T, Stein P, DeFronzo R A, Shulman R G. Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by ¹³C nuclear magnetic resonance spectroscopy.  N Engl J Med. 1990;  322 223-228
• 64 Koivisto V A, Yki-Jarvinen H, DeFronzo R A. Physical training and insulin sensitivity.  Diabetes Metab Rev. 1986;  1 445-481
• 65 Regensteiner J G, Mayer E J, Shetterly S M, Eckel R H, Haskell W L, Marshall J A. et al . Relationship between habitual physical activity and insulin levels among nondiabetic men and women. San Luis Valley Diabetes Study.  Diabetes Care. 1991;  14 1066-1074
• 66 Dowse G K, Zimmet P Z, Gareeboo H, George K, Alberti M M, Tuomilehto J. et al . Abdominal obesity and physical inactivity as risk factors for NIDDM and impaired glucose tolerance in Indian, Creole, and Chinese Mauritians.  Diabetes Care. 1991;  14 271-282
• 67 Lindgarde F, Saltin B. Daily physical activity, work capacity and glucose tolerance in lean and obese normoglycaemic middle-aged men.  Diabetologia. 1981;  20 134-138
• 68 Wang J T, Ho L T, Tang K T, Wang L M, Chen Y D, Reaven G M. Effect of habitual physical activity on age-related glucose intolerance.  J Am Geriatr Soc. 1989;  37 203-209
• 69 Schneider S H, Amorosa L F, Khachadurian A K, Ruderman N B. Studies on the mechanism of improved glucose control during regular exercise in type 2 (non-insulin-dependent) diabetes.  Diabetologia. 1984;  26 355-360
• 70 Burstein R, Polychronakos C, Toews C J, MacDougall J D, Guyda H J, Posner B I. Acute reversal of the enhanced insulin action in trained athletes. Association with insulin receptor changes.  Diabetes. 1985;  34 756-760
• 71 Blair S N, Kohl H W, Gordon N F, Paffenbarger R S Jr. How much physical activity is good for health?.  Annu Rev Public Health. 1992;  13 99-126
• 72 Kriska A M, Bennett P H. An epidemiological perspective of the relationship between physical activity and NIDDM: from activity assessment to intervention.  Diabetes Metab Rev. 1992;  8 355-372
• 73 Ross R. Effects of diet- and exercise-induced weight loss on visceral adipose tissue in men and women.  Sports Med. 1997;  24 55-64
• 74 Manson J E, Nathan D M, Krolewski A S, Stampfer M J, Willett W C, Hennekens C H. A prospective study of exercise and incidence of diabetes among US male physicians.  JAMA. 1992;  268 63-67
• 75 DeFronzo R A, Bonadonna R C, Ferrannini E. Pathogenesis of NIDDM. A balanced overview.  Diabetes Care. 1992;  15 318-368
• 76 Wolever T MS, Jenkins D J, Jenkins A L, Josse R G. The glycemic index: methodology and clinical implications.  Am J Clin Nutr. 1991;  54 846-854
• 77 Trout D L, Behall K M, Osilesi O. Prediction of glycemic index for starchy foods.  Am J Clin Nutr. 1993;  58 873-878
• 78 Daly M E, Vale C, Walker M, Alberti K, Mathers J C. Dietary carbohydrates and insulin sensitivity - a review of the evidence and clinical implications.  Am J Clin Nutr. 1997;  66 1072-1085
• 79 Thresher J S, Podolin D A, Wei Y, Mazzeo R S, Pagliassotti M J. Comparison of the effects of sucrose and fructose on insulin action and glucose tolerance.  Am J Phys. 2000;  279 R1334-1340
• 80 Reiser S, Bohn E, Hallfrisch J, Michaelis O E 4th, Keeney M, Prather E S. Serum insulin and glucose in hyperinsulinemic subjects fed three different levels of sucrose.  Am J Clin Nutr. 1981;  34 2348-2358
• 81 Reiser S, Handler H B, Gardner L B, Hallfrisch J G, Michaelis O E, Prather E S. Isocaloric exchange of dietary starch and sucrose in humans. II. Effect on fasting blood insulin, glucose, and glucagon and on insulin and gluccose response to a sucrose load.  Am J Clin Nutr. 1979;  32 2206-2216
• 82 Daly M E, Vale C, Walker M, Littlefield A, Alberti K G, Mathers J C. Acute effects on insulin sensitivity and diurnal metabolic profiles of a high-sucrose compared with a high-starch diet.  Am J Clin Nutr. 1998;  67 1186-1196
• 83 Hallfrisch J, Ellwood K C, Michaelis O E, Reiser S, O'Dorisio T M, Prather E S. Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men.  J Nutr. 1983;  113 1819-1826
• 84 Manolio T A, Savage P J, Burke G L, Hilner J E, Liu K, Orchard T J. et al . Correlates of fasting insulin levels in young adults: the CARDIA study.  J Clin Epidemiol. 1991;  44 571-578
• 85 Rivellese A A, De Natale C, Lilli S. Type of dietary fat and insulin resistance.  Ann NY Acad Sci. 2002;  967 329-335
• 86 Hu F B, van Dam R M, Liu S. Diet and risk of Type II diabetes: the role of types of fat and carbohydrate.  Diabetologia. 2001;  44 805-817
• 87 Slattery M L, Boucher K M, Caan B J, Potter J D, Ma K N. Eating patterns and risk of colon cancer.  Am J Epidemiol. 1998;  148 4-16
• 88 Fung T T, Rimm E B, Spiegelman D, Rifai N, Tofler G H, Willett W C. et al . The association between dietary patterns and plasma biomarkers of obesity and cardiovascular disease risk.  Am J Clin Nutr. 2001;  73 61-67
• 89 Clausen J O, Borch-Johnsen K, Ibsen H, Bergman R N, Hougaard P, Winther K. et al . Insulin sensitivity index, acute insulin response, and glucose effectiveness in a population-based sample of 380 young healthy Caucasians.  J Clin Invest. 1996;  98 1195-1209
• 90 Pedersen O. Genetics of insulin resistance.  Exp Clin Endocrinol Diabetes. 1999;  107 113-118
• 91 Binoux M, Gourmelen M. Statural development parallels IGF I levels in subjects of constitutionally variant stature.  Acta Endocrinol. 1987;  114 524-530
• 92 Juul A, Bang P, Hertel N T, Main K, Dalgaard P, Jorgensen K. et al . Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index.  J Clin Endocrinol Metab. 1994;  78 744-752
• 93 Proos L A. Anthropometry in adolescence - secular trends, adoption, ethnic and environemental differences.  Horm Res. 1993;  39 (Suppl 3) 18-24
• 94 Hauspie R C, Vercauteren M, Susanne C. Secular changes in growth and maturation: an update.  Acta Paediatr Suppl. 1997;  423 20-27
• 95 Cole T J. Secular trends in growth.  Proc Nutr Soc. 2000;  59 317-324
• 96 Gunnell D, Okasha M, Davey Smith G, Oliver S E, Sandhu J, Holly J M. Height, leg length, and cancer risk: a systematic review.  Epidemiol Rev. 2001;  23 313-342
• 97 Wolk A, Gridley G, Svensson M, Nyren O, McLaughlin J K, Fraumeni J F. et al . A prospective study of obesity and cancer risk (Sweden).  Cancer Causes Control. 2001;  12 13-21
• 98 Calle E E, Rodriguez C, Walker-Thurmond K, Thun M J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.  New Engl J Med. 2003;  348 1625-1638
• 99 Vainio H, Kaaks R, Bianchini F. Weight control and physical activity in cancer prevention: international evaluation of the evidence.  E J Cancer Prev. 2002;  11 Suppl 2 S94-S100
• 100 Nomura A M. Body size and prostate cancer.  Epidemiol Rev. 2001;  23 126-131
• 101 Giovannucci E, Rimm E B, Liu Y, Leitzmann M, Wu K, Stampfer M J. et al . Body mass index and risk of prostate cancer in U.S. health professionals.  J Natl Cancer Inst. 2003;  95 1240-1244
• 102 Hsing A W, Chua S Jr, Gao Y T, Gentzschein E, Chang L, Deng J. et al . Prostate cancer risk and serum levels of insulin and leptin: a population-based study.  J Natl Cancer Inst. 2001;  93 783-789
• 103 Pasquali R, Casimirri F, Cantobelli S, Melchionda N, Morselli Labate A M, Fabbri R. et al . Effect of obesity and body fat distribution on sex hormones and insulin in men.  Metabolism. 1991;  40 101-104
• 104 Field A E, Colditz G A, Willett W C, Longcope C, McKinlay J B. The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone-binding globulin in middle-aged men.  J Clin Endocrinol Metab. 1994;  79 1310-1316
• 105 Gann P H, Hennekens C H, Ma J, Longcope C, Stampfer M J. A prospective study of sex hormone levels and risk of prostate cancer.  J Natl Cancer Inst. 1996;  88 1118-1126
• 106 Friedenreich C M. Physical activity and cancer prevention: from observational to intervention research.  Cancer Epidemiol Biomarkers Prev. 2001;  10 287-301
• 107 Martinez M E, Giovannucci E, Spiegelman D, Hunter D J, Willett W C, Colditz G A. Leisure-time physical activity, body size, and colon cancer in women. Nurses" Health Study Research Group.  J Natl Cancer Inst. 1997;  89 948-955
• 108 Michaud D S, Giovannucci E, Willett W C, Colditz G A, Stampfer M J, Fuchs C S. Physical activity, obesity, height, and the risk of pancreatic cancer.  JAMA. 2001;  286 921-929
• 109 Rockhill B, Willett W C, Hunter D J, Manson J E, Hankinson S E, Colditz G A. A prospective study of recreational physical activity and breast cancer risk.  Arch Intern Med. 1999;  159 2290-2296
• 110 Giovannucci E, Leitzmann M, Spiegelman D, Rimm E B, Colditz G A, Stampfer M J. et al . A prospective study of physical activity and prostate cancer in male health professionals.  Cancer Res. 1998;  58 5117-5122
• 111 Fung T T, Hu F B, Yu J, Chu N F, Spiegelman D, Tofler G H. et al . Leisure-time physical activity, television watching, and plasma biomarkers of obesity and cardiovascular disease risk.  Am J Epidemiol. 2000;  152 1171-1178
• 112 Fung T, Hu F B, Fuchs C S, Giovannucci E, Hunter D J, Stampfer M J. et al . Major dietary patterns and the risk of colorectal cancer in women.  Arch Intern Med. 2003;  163 309-314
• 113 Giovannucci E, Rimm E B, Liu Y, Willett W C. Height, predictors of C-peptide and cancer risk in men.  Int J Epidemiol (in press). ; 
• 114 Giovannucci E. Epidemiologic studies of folate and colorectal neoplasia: a review.  J Nutr. 2002;  132 2350S-2355S
• 115 Baron J A, Beach M, Mandel J S, van Stolk R U, Haile R W, Sandler R S. et al . Calcium supplements for the prevention of colorectal adenomas. The Calcium Polyp Prevention Study Group.  N Engl J Med. 1999;  340 101-107
• 116 Layman D K, Shiue H, Sather C, Erickson D J, Baum J. Increased dietary protein modifies glucose and insulin homeostasis in adult women during weight loss.  J Nutr. 2003;  133 405-410
• 117 Hu F B, Manson J E, Liu S, Hunter D, Colditz G A, Michels K B. et al . Prospective study of adult onset diabetes mellitus (Type 2) and risk of colorectal cancer in women.  J Natl Cancer Inst. 1999;  91 542-547
• 118 Nilsen T I, Vatten L J. Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis.  Br J Cancer. 2001;  84 417-422
• 119 Lindblad P, Chow W H, Chan J M, Bergstrom A, Wolk A, Gridley G. et al . The role of diabetes mellitus in the aetiology of renal cell cancer.  Diabetologia. 1999;  42 107-112
• 120 Strickler H D, Wylie-Rosett J, Rohan T, Hoover D R, Smoller S, Burk R D. et al . The relation of type 2 diabetes and cancer.  Diabetes Technol Ther. 2001;  3 263-274
• 121 White M F. The IRS-signalling system: a network of docking proteins that mediate insulin action.  Mol Cell Biochem. 1998;  182 3-11
• 122 Cheatham B, Kahn C R. Insulin action and the insulin signaling network.  Endocr Rev. 1995;  16 117-142
• 123 Sasaoka T, Draznin B, Leitner W J, Langlois W J, Olefsky J M. Shc is the predominant signaling molecule coupling insulin receptors to activation of guanine nucleotide releasing factor and p21ras-GTP formation.  J Biol Chem. 1994;  269 10 734-10 738
• 124 Saydah S H, Loria C M, Eberhardt M S, Brancati F L. Abnormal glucose tolerance and the risk of cancer death in the United States.  Am J Epidemiol. 2003;  157 1092-1100
• 125 Schoen R E, Tangen C M, Kuller L H, Burke G L, Cushman M, Tracy R P. et al . Increased blood glucose and insulin, body size, and incident colorectal cancer.  J Natl Cancer Inst. 1999;  91 1147-1154
• 126 Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H. et al . Serum C-peptide, insulin-like growth factor (IGF)-1, IGF-binding proteins, and colorectal cancer risk in women.  J Natl Cancer Inst. 2000;  92 1592-1600
• 127 Yang G, Lu G, Jin F, Dai Q, Best R, Shu X O. et al . Population-based, case-control study of blood C-peptide level and breast cancer risk.  Cancer Epidemiol Biomarkers Prev. 2001;  10 1207-1211
• 128 Palmqvist R, Stattin P, Rinaldi S, Biessey C, Stenling R, Riboli E. et al . Plasma insulin, IGF-binding proteins-1 and -2 and risk of colorectal cancer: a prospective study in Northern Sweden.  Int J Cancer. 2003;  107 89-93
• 129 Ma J, Pollak M N, Giovannucci E, Chan J M, Tao T, Hennekens C H. et al . Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-1 and IGF-binding protein-3.  J Natl Cancer Inst. 1999;  91 620-625
• 130 Manousos O, Souglakos J, Bosetti C, Tzonou A, Chatzidakis V, Trichopoulos D. et al . IGF-I and IGF-II in relation to colorectal cancer.  Int J Cancer. 1999;  83 15-17
• 131 Giovannucci E, Pollak M N, Platz E A, Willett W C, Stampfer M J, Majeed N. et al . A prospective study of plasma insulin-like growth factor-I and binding protein-3 and risk of colorectal neoplasia in women.  Cancer Epidemiol Biomarkers Prev. 2000;  9 345-349
• 132 Renehan A G, Painter J E, Atkin W S, Potten C S, Shalet S M, O'Dwyer S T. High-risk colorectal adenomas and serum insulin-like growth factors.  Br J Surg. 2001;  88 107-113
• 133 Palmqvist R, Hallmans G, Rinaldi S, Biessey C, Stenling R, Riboli E. et al . Plasma insulin-like growth factor 1, insulin-like growth factor binding protein 3, and risk of colorectal cancer: a prospective study in northern Sweden.  Gut. 2002;  50 642-646
• 134 Probst-Hensch N M, Yuan J M, Stanczyk F Z, Gao Y T, Ross R K, Yu M C. IGF-1, IGF-2 and IGFBP-3 in prediagnostic serum: association with colorectal cancer in a cohort of Chinese men in Shanghai.  Br J Cancer. 2001;  85 1695-1699
• 135 Chan J M, Stampfer M J, Giovannucci E, Gann P H, Ma J, Wilkinson P. et al . Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study.  Science. 1998;  279 563-566
• 136 Chan J M, Stampfer M J, Ma J, Gann P, Gaziano J M, Pollak M. et al . Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced stage prostate cancer.  J Natl Cancer Inst. 2002;  94 1099-1106
• 137 Stattin P, Bylund A, Rinaldi S, Biessey C, Dechaud H, Stenman U H. et al . Plasma insulin-like growth factor-I, insulin-like growth factor-binding proteins, and prostate cancer risk: a prospective study.  J Natl Cancer Inst. 2000;  92 1910-1917
• 138 Shi R, Berkel H J, Yu H. Insulin-like growth factor-I and prostate cancer: a meta-analysis.  Br J Cancer. 2001;  85 991-996
• 139 Hankinson S E, Willett W C, Colditz G A, Hunter D J, Michaud D S, Deroo B. et al . Circulating concentrations of insulin-like growth factor-I and risk of breast cancer.  Lancet. 1998;  351 1393-1396
• 140 Toniolo P, Bruning P F, Akhmedkhanov A, Bonfrer J M, Koenig K L, Lukanova A. et al . Serum insulin-like growth factor-I and breast cancer.  Int J Cancer. 2000;  88 828-832
• 141 Krajcik R A, Borofsky N D, Massardo S, Orentreich N. Insulin-like growth factor I (IGF-I), IGF-binding proteins, and breast cancer.  Cancer Epidemiol Biomarkers Prev. 2002;  11 1566-1573
• 142 Kaaks R, Lundin E, Rinaldi S, Manjer J, Biessy C, Soderberg S. et al . Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in northern and southern Sweden.  Cancer Causes Control. 2002;  13 307-316
• 143 Yu H, Jin F, Shu X O, Li B D, Dai Q, Cheng J R. et al . Insulin-like growth factors and breast cancer risk in Chinese women.  Cancer Epidemiol Biomarkers Prev. 2002;  11 705-712
• 144 Byrne C, Colditz G A, Willett W C, Speizer F E, Pollak M, Hankinson S E. Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density.  Cancer Res. 2000;  60 3744-3748
• 145 Orme S M, McNally R J, Cartwrigh R A, Belchetz P E. Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group.  J Clin Endocrinol Metab. 1998;  83 2730-2734
• 146 Baris D, Gridley G, Ron E, Weiderpass E, Mellemkjaer L, Ekbom A. et al . Acromegaly and cancer risk: a cohort study in Sweden and Denmark.  Cancer Causes Control. 2002;  13 395-400
• 147 Bang P, Ahlsen M, Berg U, Carlsson-Skwirut C. Free insulin-like growth factor I: are we hunting a ghost?.  Horm Res. 2001;  55 Suppl 2 84-93
• 148 Rechler M. Growth inhibition by insulin-like growth factor (IGF) binding protein-3 - what's IGF got to do with it?.  Endocrinology. 1997;  138 2645-2647
• 149 Ferry R JJ, Cerri R W, Cohen P. Insulin-like growth factor binding proteins: new proteins, new functions.  Horm Res. 1999;  51 53-67
• 150 Taylor A M, Dunger D B, Preece M A, Holly J M, Smith C P, Wass J A. et al . The growth hormone independent insulin-like growth factor-I binding protein BP-28 is associated with serum insulin-like growth factor-I inhibitory bioactivity in adolescent insulin-dependent diabetics.  Clin Endocrinol. 1990;  32 229-239
• 151 Cox G N, McDermott M J, Merkel E, Stroh C A, Ko S C, Squires C H. et al . Recombinant human insulin-like growth factor (IGF)-binding protein-I inhibits somatic growth stimulated by IGF-I and growth hormone in hypophysectomized rats.  Endocrinology. 1994;  135 1913-1920
• 152 Lindgren B F, Segovia B, Lassarre C, Binoux M, Gourmelen M. Growth retardation in constitutionally short children is related both to low serum levels of insulin-like growth factor-I and to its reduced bioavailability.  Growth Regul. 1996;  6 158-164
• 153 Kaaks R, Lukanova A, Kurzer M S. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review.  Cancer Epidemiol Biomarkers Prev. 2002;  11 1531-1543