Horm Metab Res 2011; 43(1): 1-10
DOI: 10.1055/s-0030-1267203
Review

© Georg Thieme Verlag KG Stuttgart · New York

Review on the In Vitro Interaction of Insulin Glargine with the Insulin/Insulin-like Growth Factor System: Potential Implications for Metabolic and Mitogenic Activities

T. P. Ciaraldi1 , T. Sasaoka2
  • 1VA San Diego Healthcare System and University of California, San Diego, La Jolla, CA, USA
  • 2Department of Clinical Pharmacology, University of Toyama, Toyama, Japan
Further Information

Publication History

received 30.06.2010

accepted 14.09.2010

Publication Date:
11 October 2010 (online)

Abstract

Insulin analogues provide clinically important benefits for people with diabetes, including more predictable action profiles and lower risk of hypoglycemia compared with human insulin. However, it has been suggested that certain insulin analogues may lead to greater activation of insulin-like growth factor-1 (IGF-1) signaling, with risk for adverse mitogenic effects. This article aims to critically review studies on the mitogenic effects of the insulin analogue insulin glargine (glargine) and its metabolites. A review of in vitro studies suggests that glargine may stimulate mitogenic activity in some cell lines at supraphysiological concentrations (nanomolar/micromolar concentrations). Mitogenicity appeared to be related to the expression of the IGF-1 receptor, being present in cells expressing high levels of the receptor and absent in cells with limited or no IGF-1 receptor expression. In animal studies, glargine did not promote tumor growth, despite administration at supraphysiological concentrations (nanomolar/micromolar), which are unlikely to be observed in clinical practice because the doses needed to produce these concentrations are liable to lead to hypoglycemia. Furthermore, glargine in vivo is rapidly transformed into its metabolites, the metabolic and mitogenic characteristics of which have been shown to be broadly equal to those of human insulin. Thus, the suggestion of increased relative mitogenic potency of insulin glargine seen in some cell lines does not appear to carry over to the in vivo situation in animals and humans.

References

  • 1 Colhoun HM. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group.  Diabetologia. 2009;  52 1755-1765
  • 2 Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes.  Diabetologia. 2009;  52 1766-1777
  • 3 Hemkens LG, Grouven U, Bender R, Gunster C, Gutschmidt S, Selke GW, Sawicki PT. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study.  Diabetologia. 2009;  52 1732-1744
  • 4 Jonasson JM, Ljung R, Talback M, Haglund B, Gudbjornsdottir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden.  Diabetologia. 2009;  52 1745-1754
  • 5 Smith U, Gale EA. Does diabetes therapy influence the risk of cancer?.  Diabetologia. 2009;  52 1699-1708
  • 6 Ebeling P, Tuominen JA, Koivisto VA. Insulin analogues and carcinoma of the breast.  Diabetologia. 1996;  39 124-125
  • 7 Milazzo G, Sciacca L, Papa V, Goldfine ID, Vigneri R. ASPB10 insulin induction of increased mitogenic responses and phenotypic changes in human breast epithelial cells: evidence for enhanced interactions with the insulin-like growth factor-I receptor.  Mol Carcinog. 1997;  18 19-25
  • 8 De Meyts P, Whittaker J. Structural biology of insulin and IGF1 receptors: implications for drug design.  Nat Rev Drug Discov. 2002;  1 769-783
  • 9 Kristensen C, Wiberg FC, Andersen AS. Specificity of insulin and insulin-like growth factor I receptors investigated using chimeric mini-receptors. Role of C-terminal of receptor alpha subunit.  J Biol Chem. 1999;  274 37351-37356
  • 10 Sciacca L, Costantino A, Pandini G, Mineo R, Frasca F, Scalia P, Sbraccia P, Goldfine ID, Vigneri R, Belfiore A. Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism.  Oncogene. 1999;  18 2471-2479
  • 11 Vella V, Pandini G, Sciacca L, Mineo R, Vigneri R, Pezzino V, Belfiore A. A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer.  J Clin Endocrinol Metab. 2002;  87 245-254
  • 12 Sciacca L, Mineo R, Pandini G, Murabito A, Vigneri R, Belfiore A. In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A.  Oncogene. 2002;  21 8240-8250
  • 13 Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R, Costantino A, Goldfine ID, Belfiore A, Vigneri R. Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells.  Mol Cell Biol. 1999;  19 3278-3288
  • 14 Chisalita SI, Arnqvist HJ. Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells.  Am J Physiol Endocrinol Metab. 2004;  286 E896-E901
  • 15 Belfiore A. The role of insulin receptor isoforms and hybrid insulin/IGF-I receptors in human cancer.  Curr Pharm Des. 2007;  13 671-686
  • 16 Ullrich A, Gray A, Tam AW, Yang-Feng T, Tsubokawa M, Collins C, Henzel W, Le Bon T, Kathuria S, Chen E, Jacobs S, Francke U, Ramachandran J, Fujita-Yamaguchi Y. Insulin-like growth factor I receptor primary structure: comparison with insulin receptor suggests structural determinants that define functional specificity.  Embo J. 1986;  5 2503-2512
  • 17 LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1.  Nat Clin Pract Endocrinol Metab. 2007;  3 302-310
  • 18 Chisalita SI, Nitert MD, Arnqvist HJ. Characterisation of receptors for IGF-I and insulin; evidence for hybrid insulin/IGF-I receptor in human coronary artery endothelial cells.  Growth Horm IGF Res. 2006;  16 258-266
  • 19 Slieker LJ, Brooke GS, DiMarchi RD, Flora DB, Green LK, Hoffmann JA, Long HB, Fan L, Shields JE, Sundell KL, Surface PL, Chance RE. Modifications in the B10 and B26–30 regions of the B chain of human insulin alter affinity for the human IGF-I receptor more than for the insulin receptor.  Diabetologia. 1997;  40 S54-S61
  • 20 Guerci B, Sauvanet JP. Subcutaneous insulin: pharmacokinetic variability and glycemic variability.  Diabetes Metab. 2005;  31 4S7-4S24
  • 21 Bell DS. Insulin therapy in diabetes mellitus: how can the currently available injectable insulins be most prudently and efficaciously utilised?.  Drugs. 2007;  67 1813-1827
  • 22 Schwartz GP, Burke GT, Katsoyannis PG. A superactive insulin: B10-aspartic acid]insulin(human).  Proc Natl Acad Sci USA. 1987;  84 6408-6411
  • 23 Ribel U, Hougaard P, Drejer K, Sorensen AR. Equivalent in vivo biological activity of insulin analogues and human insulin despite different in vitro potencies.  Diabetes. 1990;  39 1033-1039
  • 24 Kang S, Brange J, Burch A, Volund A, Owens DR. Absorption kinetics and action profiles of subcutaneously administered insulin analogues (AspB9GluB27, AspB10, AspB28) in healthy subjects.  Diabetes Care. 1991;  14 1057-1065
  • 25 Kang S, Creagh FM, Peters JR, Brange J, Volund A, Owens DR. Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type I diabetic subjects.  Diabetes Care. 1991;  14 571-577
  • 26 Berti L, Kellerer M, Bossenmaier B, Seffer E, Seipke G, Haring HU. The long acting human insulin analog HOE 901: characteristics of insulin signalling in comparison to Asp(B10) and regular insulin.  Horm Metab Res. 1998;  30 123-129
  • 27 Bonnesen C, Nelander GM, Hansen BF, Jensen P, Krabbe JS, Jensen MB, Hegelund AC, Svendsen JE, Oleksiewicz MB. Synchronization in G0/G1 enhances the mitogenic response of cells overexpressing the human insulin receptor A isoform to insulin.  Cell biology and toxicology. 2010;  26 293-307
  • 28 LeRoith D, Roberts Jr CT. The insulin-like growth factor system and cancer.  Cancer letters. 2003;  195 127-137
  • 29 Pollak M. Insulin and insulin-like growth factor signalling in neoplasia.  Nature reviews. 2008;  8 915-928
  • 30 Kuerzel GU, Shukla U, Scholtz HE, Pretorius SG, Wessels DH, Venter C, Potgieter MA, Lang AM, Koose T, Bernhardt E. Biotransformation of insulin glargine after subcutaneous injection in healthy subjects.  Curr Med Res Opin. 2003;  19 34-40
  • 31 Agin A, Jeandidier N, Gasser F, Grucker D, Sapin R. Glargine blood biotransformation: in vitro appraisal with human insulin immunoassay.  Diabetes Metab. 2007;  33 205-212
  • 32 Bahr M, Kolter T, Seipke G, Eckel J. Growth promoting and metabolic activity of the human insulin analogue [GlyA21, ArgB31, ArgB32] insulin (HOE 901) in muscle cells.  Eur J Pharmacol. 1997;  320 259-265
  • 33 Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, Trub T. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use.  Diabetes. 2000;  49 999-1005
  • 34 Sciacca L, Cassarino MF, Genua M, Pandini G, Le Moli R, Squatrito S, Vigneri R. Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling.  Diabetologia. 2010;  53 1743-1753
  • 35 Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells.  Diabetes Metab Res Rev. 2009;  25 41-49
  • 36 Mayer D, Shukla A, Enzmann H. Proliferative effects of insulin analogues on mammary epithelial cells.  Arch Physiol Biochem. 2008;  114 38-44
  • 37 Shukla A, Grisouard J, Ehemann V, Hermani A, Enzmann H, Mayer D. Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines.  Endocr Relat Cancer. 2009;  16 429-441
  • 38 Staiger K, Hennige AM, Staiger H, Haring HU, Kellerer M. Comparison of the mitogenic potency of regular human insulin and its analogue glargine in normal and transformed human breast epithelial cells.  Horm Metab Res. 2007;  39 65-67
  • 39 Liefvendahl E, Arnqvist HJ. Mitogenic effect of the insulin analogue glargine in malignant cells in comparison with insulin and IGF-I.  Horm Metab Res. 2008;  40 369-374
  • 40 Muller K, Weidinger C, Fuhrer D. Insulin glargine and insulin have identical effects on proliferation and phosphatidylinositol 3-kinase/AKT signalling in rat thyrocytes and human follicular thyroid cancer cells.  Diabetologia. 2010;  53 1001-1003
  • 41 Staiger K, Staiger H, Schweitzer MA, Metzinger E, Balletshofer B, Haring HU, Kellerer M. Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells.  Diabetologia. 2005;  48 1898-1905
  • 42 Chisalita SI, Johansson GS, Liefvendahl E, Back K, Arnqvist HJ. Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2.  J Mol Endocrinol. 2009;  43 231-239
  • 43 Rensing K, Houttuijn Bloemendaal F, Weijers E, Richel D, Büller H, Koolwijk P, van der Loos C, Twickler T, von der Thüsen J. Could recombinant insulin compounds contribute to adenocarcinoma progression by stimulating local angiogenesis?.  Diabetologia. 2010;  53 966-970
  • 44 Ciaraldi TP, Carter L, Seipke G, Mudaliar S, Henry RR. Effects of the long-acting insulin analog insulin glargine on cultured human skeletal muscle cells: comparisons to insulin and IGF-I.  J Clin Endocrinol Metab. 2001;  86 5838-5847
  • 45 Eckardt K, May C, Koenen M, Eckel J. IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts.  Diabetologia. 2007;  50 2534-2543
  • 46 Wada T, Azegami M, Sugiyama M, Tsuneki H, Sasaoka T. Characteristics of signalling properties mediated by long-acting insulin analogue glargine and detemir in target cells of insulin.  Diabetes Res Clin Pract. 2008;  81 269-277
  • 47 Erbel S, Reers C, Eckstein V, Kleeff J, Buchler W, Nawroth PP, Ritzel RA. Proliferation of colo-357 pancreatic carcinoma cells and survival of patients with pancreatic carcinoma are not altered by insulin glargine.  Diabetes Care. 2008;  31 1105-1111
  • 48 Sommerfeld MR, Muller G, Tschank G, Seipke G, Habermann P, Kurrle R, Tennagels N. In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites.  PloS one. 2010;  5 e9540
  • 49 Stammberger I, Bube A, Durchfeld-Meyer B, Donaubauer H, Troschau G. Evaluation of the carcinogenic potential of insulin glargine (LANTUS) in rats and mice.  Int J Toxicol. 2002;  21 171-179
  • 50 Hofmann T, Horstmann G, Stammberger I. Evaluation of the reproductive toxicity and embryotoxicity of insulin glargine (LANTUS) in rats and rabbits.  Int J Toxicol. 2002;  21 181-189
  • 51 Stammberger I, Seipke G, Bartels T. Insulin glulisine – a comprehensive preclinical evaluation.  Int J Toxicol. 2006;  25 25-33
  • 52 Riddle M, Rosenstock J, Gerich J. Insulin Glargine 4002 Study Investigators: The Treat-to-Target Trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients.  Diabetes Care. 2003;  26 3080-3086
  • 53 Luzio S, Dunseath G, Peter R, Pauvaday V, Owens DR. Comparison of the pharmacokinetics and pharmacodynamics of biphasic insulin aspart and insulin glargine in people with type 2 diabetes.  Diabetologia. 2006;  49 1163-1168
  • 54 Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, Cordoni C, Costa E, Brunetti P, Bolli GB. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro.  Diabetes. 2000;  49 2142-2148
  • 55 Li G, Barrett EJ, Wang H, Chai W, Liu Z. Insulin at physiological concentrations selectively activates insulin but not insulin-like growth factor I (IGF-I) or insulin/IGF-I hybrid receptors in endothelial cells.  Endocrinology. 2005;  146 4690-4696
  • 56 Mannucci E, Monami M, Balzi D, Cresci B, Pala L, Melani C, Lamanna C, Bracali I, Bigiarini M, Barchielli A, Marchionni N, Rotella CM. Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients.  Diabetes Care. 2010;  33 1997-2003
  • 57 Ruberte J, Ayuso E, Navarro M, Carretero A, Nacher V, Haurigot V, George M, Llombart C, Casellas A, Costa C, Bosch A, Bosch F. Increased ocular levels of IGF-1 in transgenic mice lead to diabetes-like eye disease.  J Clin Invest. 2004;  113 1149-1157
  • 58 Rosenthal R, Wohlleben H, Malek G, Schlichting L, Thieme H, Bowes Rickman C, Strauss O. Insulin-like growth factor-1 contributes to neovascularization in age-related macular degeneration.  Biochem Biophys Res Commun. 2004;  323 1203-1208
  • 59 Poulaki V, Joussen AM, Mitsiades N, Mitsiades CS, Iliaki EF, Adamis AP. Insulin-like growth factor-I plays a pathogenetic role in diabetic retinopathy.  Am J Pathol. 2004;  165 457-469
  • 60 Davis MD, Beck RW, Home PD, Sandow J, Ferris FL. Early retinopathy progression in four randomized trials comparing insulin glargine and Nph insulin.  Exp Clin Endocrinol Diabetes. 2007;  115 240-243
  • 61 Rosenstock J, Fonseca V, McGill JB, Riddle M, Halle JP, Hramiak I, Johnston P, Davis M. Similar progression of diabetic retinopathy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: a long-term, randomised, open-label study.  Diabetologia. 2009;  52 1778-1788
  • 62 de Herder WW. Biochemistry of neuroendocrine tumours.  Best Pract Res Clin Endocrinol Metab. 2007;  21 33-41
  • 63 Rosenstock J, Fonseca V, McGill JB, Riddle M, Halle JP, Hramiak I, Johnston P, Davis M. Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from a 5 year randomised, open-label study.  Diabetologia. 2009;  52 1971-1973
  • 64 Home PD, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine.  Diabetologia. 2009;  52 2499-2506
  • 65 Fawcett J, Tsui BT, Kruer MC, Duckworth WC. Reduced action of insulin glargine on protein and lipid metabolism: possible relationship to cellular hormone metabolism.  Metabolism. 2004;  53 1037-1044
  • 66 Sandow J. Growth effects of insulin and insulin analogues.  Arch Physiol Biochem. 2009;  115 72-85
  • 67 Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action.  Nat Rev Mol Cell Biol. 2006;  7 85-96

Correspondence

T. P. CiaraldiPhD 

Department of Medicine (9111G)

University of California

San Diego

9500 Gillman Drive

La Jolla

CA 92093

USA

Phone: +1/858/552 8585 ext. 6450

Fax: +1/858/642 6242

Email: tciaraldi@ucsd.edu

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