The Growth Hormone/Insulin-Like Growth Factor-1 Axis in Health and Disease Derek LeRoith MD PhD Division of Endocrinology, Diabetes and Bone Diseases Mt Sinai School of Medicine, NY 1 GH/IGF-1 axis Agenda: 1. Normal physiology of the axis 2. Disorders of the axis - acromegaly, growth retardation and aging 3. The axis in diabetes, tumor hypoglycemia and in general, forms of cancer 2 Normal physiology of the GH/IGF-1 axis 3
4 - - - 5 B30 Insulin A1 Pro-insulin B1 A21 IGF-I IGF-II 6
Insulin-like growth factors, their receptors and their binding proteins 150 K complex IGF-I Insulin IGFBP-1 IGFBP-2 IGFBP-3 IGFBP-4 IGFBP-5 IGFBP-6 IGF-II Insulin receptor Type I IGF receptor Type II IGF receptor 7 Acromegaly Excessive production of GH and elev ated GH lev els in the serum, non-suppressible on a glucose tolerance test IGF-1 levels are elevated, and are the best measurement for monitoring GH s biological effects since they are stable, whereas GH levels classically fluctuate 8 Primary GH excess Extrapituitary GH excess GHRH excess 9
Gadolinium-enhanced, T1-weighted coronal MRI scans showing a microadenoma and a macroadenoma Schlechte, J. A. N Engl J Med 2003; 349: 2035-2041 10 Treatment of acromegaly Surgery Radiotherapy Drugs Somatostatin analogues Pegv isomant (GH anta gonist) 11 GH-deficiency Childhood Idiopathic GH deficiency Pituitary de ficiency Adult Childhood GH de ficiency Aging 12
Growth failure/short stature Disproportionate Proportionate Skeletal dysplasias Achondroplasia Hypochondroplasia Rickets Psychosocial assessment Karyot ype (girls) Tests for systemic disorders Tests for endocrine disorders Psychosocial growth retardation Turner syndrome Chronic renal insufficiency Gastrointestinal disease Nutritional deficiency Hypothyroidism Hypercortisolism IGF-I/IGFBP-3 GH stimulation test MRI scan GH insensitiv ity/resistance GH deficiency Idiopathic short stature 13 14 15
GH-deficiency in aging GH and IGF-1 serum lev els decline with aging GH replacement therapy has been considered to help prev ent bone loss, muscle wasting and cardiov ascular disease The side-effects including diabe tes and arthritis probably out-way the benefits! 16 The metabolic effects of the GH/IGF-1 axis: glucose GH IGF-1 has has anti-insulin insulin-like effects on on peripheral muscle, tissues such thereby as reducing muscle, thereby insulin reducing resistance, insulin-induced and resulting glucose in lower uptake blood glucose lev els in diabetics The This resultant effect has insulin been resistance demonstrate leads d in type to appearance 1 or diabetics, worsening type of 2 diabetes diabetics in and cases patients of acromegaly with sev ere insulin resistance, following the administration Treatme of therapeutic nt of acromegaly doses of rhigf-1 rev erses this effect 17 IGF-1 treatment 18
19 Type 1 diabetes 20 Dual hormonal replacement with insulin and rhigf-i in type 1 diabetes 43 patients received rhigf-i (or placebo) subcut. daily for 4 weeks rhigf-i reduced the HbA1c by 0.5% and the insulin dosage in this group was also reduced by 0.8 U/kg in the group receiving rhigf-i (Similar studies have shown these results after 12 months) Diabetes Care 20: 374 21
Metabolic defects in type 2 diabetes Insulin secretion Hyperglycemia HGP* Glucose uptake *Hepatic glucose production 22 Type 2 diabetes mellitus rhigf-i administration results in: 1. Lowering of the blood glucose 2. Lower insulin and C-peptide levels 3. Lower GH and glucagon levels 4. Lower triglycerides 23 Effects of rhigf-i on glycemic control in type II diabetes Si determined by FSIVGTT according to Bergman 24
Potential mechanisms of rhigf-i action on insulin resistance Sup pressed glu cagon IGF- I Reduced GH Bet a cell Mus cle Insulin secret ion Insulin toxicit y Directly increases glucose upt ake Upregulat es insulin receptors Induces intracellular mediators Reduces glucose toxicit y 25 The metabolic effects of the GH/IGF-1 axis: lipids GH is lipolytic, and the release of free fatty acids from adipose tissue may explain its anti-insulin effect at peripheral tissues such as muscle, since FFAs inhibit insulin action at the cellular lev el GH treatment results in loss of adipose tissue in GH-deficient indiv iduals and obese indiv iduals 26 The metabolic effects of the GH/IGF-1 axis: proteins GH and IGF-1 are both anabolic in their own right GH s effect is partially mediated by IGF-1 and is partially independent of IGF-1 Therefore when used in combination, an additiv e effect was seen on nitrogen balance in seriously ill patients 27
Non-islet cell tumor hypoglycemia These mesenchymal tumors found in the thorax, abdomen or pelv is, release IGF-2 into the circulation The IGF-2 molecule is big-igf-2, i.e., unprocessed and fails to be completely neutralized by the serum IGF-binding proteins; It therefore is more available to interact with tissue insulin and IGF-1 receptors 28 29 30
Processing of insulin-like growth factor-ii 31 Insulin-like growth factors, their receptors and their binding proteins 150 K complex IGFBP-1 IGFBP-2 IGFBP-3 IGFBP-4 IGFBP-5 IGFBP-6 IGF-I Insulin IGF-II Insulin receptor Type I IGF receptor Type II IGF receptor 32 33
34 Non-islet cell tumor hypoglycemia Diagnostic criteria: During s ymptomatic hypoglycemia measurements of serum GH, insulin, IGF-1 and IGFBP-3 will be reduced, whereas lev els of IGF-2 will be normal or slightly elev ated 35 Plasma insulin-like growth factor-i and prostate cancer risk: a prospective study June M. Chan, *Meir J. Stampfer, Edward Giovannucci, Peter H. Gann, Jing Ma, Peter Wilkinson, Charles H. Henneken s, Michael Pollak Science 279: 563, 1998 36
Involvement of the IGF-IR in cancer The presence of the IGF-IR is important for transformation (Baserga) IGF-IRs are expre ssed at very high levels in most cancers (Macaulay) Overexpression of the IGF-IR results in a transformed phenotype and tumor formation in nude mice (Rutter) Migration of cancer cells is dependent on the IGF-IR Anti-receptor antibodies, as well as antisense oligomers against IGF-IR mrna, inhibit cancer cell growth (LeRoith) etc., etc. 37 38 39
GH/IGF-1 axis Agenda: 1. Normal physiology of the axis 2. Disorders of the axis - acromegaly, growth retardation and aging 3. The axis in diabetes, tumor hypoglycemia and in general, forms of cancer 40 Acknowledgements Intramural NIDDK 41 42