Abstract
Insulin analogs are artificially modified insulin molecules that allow better metabolic controls of diabetes through either more rapid or more prolonged activity. The interaction of insulin analogs with the insulin receptor isoforms (IR-A and IR-B) and with the IGF-I receptor (IGF-IR) is similar but not identical to that of insulin, and therefore, their biological effects do not always reproduce insulin actions in terms of quantity, quality and timing. Studies on in vitro models indicate that short-acting analogs elicit molecular and biological effects that are similar, but not identical, to those of insulin via IR-A, IR-B and IGF-IR. In contrast, long-acting analogs behave in a more different way relative to insulin. Although data are not homogeneous and observations on the more recently introduced detemir are scarce, both glargine and detemir often show a decreased binding to IR and increased binding to IGF-IR. Also, intracellular signaling is different with respect to insulin, with a prevalent activation of the ERK rather than the AKT pathway. Finally, an increased mitogenic response has often been observed with these analogs in a variety of cell models. Of course, in vitro studies do not necessarily reflect what occurs in patients, due to the different metabolism of analogs in vivo and their interaction with components of the extracellular environment. After many years of analog’s use, observations in patients indicate that insulin analogs are both effective and safe. Prospective clinical studies, however, may add further useful information on the issue of the insulin analogs’ possible differences with respect to native insulin.
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References
Belfiore A, Frasca F, Pandini G, Sciacca L, Vigneri R (2009) Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 30:586–623
Frasca F, Pandini G, Scalia P et al (1999) Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 19:3278–3288
Blanquart C, Achi J, Issad T (2008) Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer. Biochem Pharmacol 76:873–883
Pandini G, Vigneri R, Costantino A et al (1999) Insulin and insulin-like growth factor-I (IGF-I) receptor overexpression in breast cancers leads to insulin/IGF-I hybrid receptor overexpression: evidence for a second mechanism of IGF-I signaling. Clin Cancer Res 5:1935–1944
Bailyes EM, Nave BT, Soos MA, Orr SR, Hayward AC, Siddle K (1997) Insulin receptor/IGF-I receptor hybrids are widely distributed in mammalian tissues: quantification of individual receptor species by selective immunoprecipitation and immunoblotting. Biochem J 327(Pt 1):209–215
Holleman F, Hoekstra JB (1997) Insulin lispro. N Engl J Med 337:176–183
Brems DN, Alter LA, Beckage MJ et al (1992) Altering the association properties of insulin by amino acid replacement. Protein Eng 5:527–533
Slieker LJ, Sundell K (1991) Modifications in the 28–29 position of the insulin B-chain alter binding to the IGF-I receptor with minimal effect on insulin receptor binding. Diabetes 40(Suppl 1):168A
Howey DC, Bowsher RR, Brunelle RL, Woodworth JR (1994) [Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed analogue of human insulin. Diabetes 43:396–402
Simpson KL, Spencer CM (1999) Insulin aspart. Drugs 57:759–765 (discussion 766–757)
Kurtzhals P, Schaffer L, Sorensen A et al (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005
Plank J, Wutte A, Brunner G et al (2002) A direct comparison of insulin aspart and insulin lispro in patients with type 1 diabetes. Diabetes Care 25:2053–2057
Becker RH (2007) Insulin glulisine complementing basal insulins: a review of structure and activity. Diabetes Technol Ther 9:109–121
Becker RH, Frick AD (2008) Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet 47:7–20
Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA (1999) Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia 42:1151–1167
Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R (2000) Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care 23:813–819
Markussen J, Havelund S, Kurtzhals P et al (1996) Soluble, fatty acid acylated insulins bind to albumin and show protracted action in pigs. Diabetologia 39:281–288
Wada T, Azegami M, Sugiyama M, Tsuneki H, Sasaoka T (2008) Characteristics of signalling properties mediated by long-acting insulin analogue glargine and detemir in target cells of insulin. Diabetes Res Clin Pract 81:269–277
Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96
Morrione A, Valentinis B, Xu SQ et al (1997) Insulin-like growth factor II stimulates cell proliferation through the insulin receptor. Proc Natl Acad Sci USA 94:3777–3782
Sciacca L, Mineo R, Pandini G, Murabito A, Vigneri R, Belfiore A (2002) In IGF-I receptor-deficient leiomyosarcoma cells autocrine IGF-II induces cell invasion and protection from apoptosis via the insulin receptor isoform A. Oncogene 21:8240–8250
Pandini G, Medico E, Conte E, Sciacca L, Vigneri R, Belfiore A (2003) Differential gene expression induced by insulin and insulin-like growth factor-II through the insulin receptor isoform A. J Biol Chem 278:42178–42189
Sciacca L, Cassarino MF, Genua M et al (2010) Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia 53:1743–1753
Dideriksen LH, Jorgensen JLN, Drejer K (1992) Carcinogenic effect on female rats after 12 months administration of the insulin analog B10 Asp. Diabetes 41:143A
Milazzo G, Sciacca L, Papa V, Goldfine ID, Vigneri R (1997) 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 18:19–25
Drejer K (1992) The bioactivity of insulin analogues from in vitro receptor binding to in vivo glucose uptake. Diabetes Metab Rev 8:259–285
Sommerfeld MR, Muller G, Tschank G et al (2010) In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites. PLoS One 5:e9540
Moxham CP, Duronio V, Jacobs S (1989) Insulin-like growth factor I receptor beta-subunit heterogeneity. Evidence for hybrid tetramers composed of insulin-like growth factor I and insulin receptor heterodimers. J Biol Chem 264:13238–13244
Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore A (2002) Insulin/insulin-like growth factor I hybrid receptors have different biological characteristics depending on the insulin receptor isoform involved. J Biol Chem 277:39684–39695
Agin A, Jeandidier N, Gasser F, Grucker D, Sapin R (2007) Glargine blood biotransformation: in vitro appraisal with human insulin immunoassay. Diabetes Metab 33:205–212
Havelund S, Plum A, Ribel U et al (2004) The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin. Pharm Res 21:1498–1504
Hennige AM, Strack V, Metzinger E, Seipke G, Haring HU, Kellerer M (2005) Effects of new insulin analogues HMR1964 (insulin glulisine) and HMR1423 on insulin receptors. Diabetologia 48:1891–1897
Berti L, Kellerer M, Bossenmaier B, Seffer E, Seipke G, Haring HU (1998) The long acting human insulin analog HOE 901: characteristics of insulin signalling in comparison to Asp(B10) and regular insulin. Horm Metab Res 30:123–129
Bahr M, Kolter T, Seipke G, Eckel J (1997) Growth promoting and metabolic activity of the human insulin analogue [GlyA21, ArgB31, ArgB32]insulin (HOE 901) in muscle cells. Eur J Pharmacol 320:259–265
Slieker LJ, Brooke GS, DiMarchi RD et al (1997) 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 40(Suppl 2):S54–S61
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Vigneri, R., Squatrito, S. & Sciacca, L. Insulin and its analogs: actions via insulin and IGF receptors. Acta Diabetol 47, 271–278 (2010). https://doi.org/10.1007/s00592-010-0215-3
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DOI: https://doi.org/10.1007/s00592-010-0215-3