Nutrition, Insulin, Insulin-like Growth Factors and Cancer

E. Giovannucci

doi:10.1055/s-2004-814147

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2003; 35(11/12): 694-704
DOI: 10.1055/s-2004-814147

Review

Nutrition, Insulin, Insulin-like Growth Factors and Cancer

E. Giovannucci¹

¹Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston MA, and Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston MA, USA

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

Full Text

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

E. Giovannucci

Department of Nutrition · Harvard School of Public Health

665 Huntington Avenue · Boston MA 02115 · USA

Phone: 617-432-4648

Fax: 617-432-2435 ·

Email: edward.giovannucci@channing.harvard.edu