Abstract
The metabolic activity of insulin has been studied extensively in vitro and in vivo, based on the initial assessment of insulin receptor affinity, followed by methods to estimate the metabolic activity in vitro. These estimates provide some guidance about the biological activity which will be found in vivo; they need to be confirmed and supplemented by testing the glucose-lowering activity in animals (mice, rats, dogs, pigs). The biological effects (hypoglycemic activity) are related to the direct activation of the insulin receptor and subsequent signaling through intracellular mechanisms. The second group of biological effects is related to cell proliferation (mitogenic activity), which may be mediated by the insulin receptor, by the IGF-I receptor, and by hybrids of the two receptors. The evaluation of the relevance of mitogenicity estimates may be performed in in vitro and in vivo. One approach is cell proliferation in benign and malignant cell lines, for example, on mammary epithelial cell lines MCF-10 and MCF-7 (Milazzo et al. 1997).
References and Further Reading
Introduction and Application to Insulin Analogs
Baehr M, Kolter T, Seipke G, Eckel J (1997) Growth promoting and metabolic activity of the human insulin analog [GlyA21, ArgB31, ArgB32] insulin (HOE 901) in muscle cells. Eur J Pharmacol 320:259–265
Berti L, Kellerer M, Bossenmaier B, Seffer E, Seipke G, Haring H (1998) The long-acting human insulin analog HOE901: characteristics of insulin signalling in comparison to Asp(B10) and regular insulin. Horm Metab Res 30:123–129
Bowsher RR, Lynch RA, Brown-Augsburger P, Santa PF, Legan WE, Woodworth JR, Chance RE (1999) Sensitive RIA for the specific determination of insulin lispro. Clin Chem. 45(1):104–110
EMEA (European Agency for the Evaluation of Medical Products) (2001) Points to consider document on the non-clinical assessment of the carcinogenic potential of insulin analogs. European Agency for the Evaluation of Medicinal Products, London
Hamel FG, Siford GL, Fawcett J, Chance RE, Frank BH, Duckworth WC (1999) Differences in the cellular processing of AspB10 human insulin compared with human insulin and LysB28ProB29 human insulin. Metabolism 48(5):611–617
Hennige AM, Strack V, Metzinger E, Seipke G, Haring HU, Kellerer M (2005) Effects of new insulin analogs HMR1964 (insulin glulisine) and HMR1423 on insulin receptors. Diabetologia 48(9):1891–1897. Epub 2005 July 29
Jorgensen L, Dideriksen L, Drejer K (1992) Carcinogenic effect of the human insulin analog B10Asp in female rats. Diabetologia 35(Suppl 1):A3
Kang S, Brange J, Burch A, Volund A, Owens DR (1991a) Subcutaneous insulin absorption explained by insulin’s physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogs in humans. Diabetes Care 14(11):942–948
Kang S, Brange J, Burch A, Volund A, Owens DR (1991b) Absorption kinetics and action profiles of subcutaneously administered insulin analogs (AspB9GluB27, AspB10, AspB28) in healthy subjects. Diabetes Care 14(11):1057–1065
Kellerer M, Haering HU (2001) Insulin analogs: impact of cell model characteristics on results and conclusions regarding mitogenic properties. Exp Clin Endocrinol Diabetes 109:63–64
Kurtzhals P, Schaffer L, Sorenson A, Kristensen C, Jonassen I, Schmid C, Trub T (2000) Correlations of recepwtor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005
Lin S, Wang SY, Chen EC, Chien YW (1999) Insulin lispro: invivo potency determination by intravenous administration in conscious rabbits. J Pharm Pharmacol 51(3):301–306
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(1): 19–25
Nielsen FS, Jorgensen LN, Ipsen M, Voldsgaard AI, Parving HH (1995) Long-term comparison of human insulin analog B10Asp and soluble human insulin in IDDM patients on a basal/bolus insulin regimen. Diabetologia 38:592–598
Rakatzi I, Stosik M, Gromke T, Siddle K, Eckel J (2006) Differential phosphorylation of IRS-1 and IRS-2 by insulin and IGF-I receptors. Arch Physiol Biochem 112(1):37–47
Slieker LJ, Brooke GS, DiMarchi RD, Flora DB, Green LK, Hoffmann JA, Long HB, Fan L, Shields JE, Sundell KL, Surface PL, Chance RE (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
von Mach MA, Brinkmann C, Hansen T, Weilemann LS, Beyer J (2002) Differences in pharmacokinetics and pharmacodynamics of insulin lispro and aspart in healthy volunteers. Exp Clin Endocrinol Diabetes 110(8):416–419
Zib I, Raskin P (2006a) Novel insulin analogs and its mitogenic potential. Diabetes Obes Metab 8(6):611–620
Insulin Receptor Affinity
De Meyts P, Christoffersen CT, Ursø B et al (1993) Insulin potency as a mitogen is determined by the half-life of the insulin-receptor complex. Exp Clin Endocrinol Leipzig 101:22–23
Drejer K, Kruse V, Larsen UD, Hougaard P, Bjørn S, Gammeltoft S (1991) Receptor binding and tyrosine kinase activation by insulin analogs with extreme affinities studied in human hepatoma HepG2 cells. Diabetes 40:1488–1495
Gammeltoft S (1984) Insulin receptors: binding kinetics and structure-function relationship of insulin. Physiol Rev 64:1321–1378
Hansen BF, Danielsen GM, Drejer K et al (1996) Sustained signalling from the insulin receptor after stimulation with insulin analogs exhibiting increased mitogenic potency. Biochem J 315:271–279
Kohanski RA, Lane MD (1983) Binding of insulin to solubilized insulin receptor from human placenta. Evidence for a single class of noninteracting binding sites. J Biol Chem 258:7460–7468
Kohanski RA, Lane MD (1985) Homogeneous functional insulin receptor from 3T3-L1 adipocytes. Purification using N alpha B1-(biotinyl-epsilon-aminocaproyl)insulin and avidin-sepharose. J Biol Chem 260:5014–5025
Kurtzhals P, Schaffer L, Sorenson A, Kristensen C, Jonassen I, Schmid C, Trub T (2000) Correlations of recepwtor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005
Lee J, Pilch PF (1994) The insulin receptor: structure, function, and signaling. Am J Physiol 266:C319–C334
Munson PJ, Rodbard D (1980) LIGAND: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem 107:220–239
Slieker LJ, Brooke GS, DiMarchi RD, Flora DB, Green LK, Hoffman JA, Long HB, Fan L, Shields JE, Sundell KL, Surface PL, Chance RE (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
Woldin CN, Hing FS, Lee J, Pilch PF, Shipley GG (1999) Structural studies of the detergent-solubilized and vesicle-reconstituted insulin receptor. J Biol Chem 274:34981–34992
Signaling Via Insulin Receptor
Chang L, Chiang SH, Saltiel AR (2004) Insulin signaling and the regulation of glucose transport. Mol Med 10(7–12):65–71
De Meyts P, Ursø B, Christoffersen CT, Shymko RM (1995) Mechanism of insulin and IGF-I receptor activation and signal transduction specificity. Receptor dimer crosslinking, bell-shaped curves, and sustained versus transient signalling. Ann New York Acad Sci 766:388–340
Gronborg M, Wulff BS, Rasmussen JS, Kjeldsen T, Gammeltoft S (1993) Structure-function relationship of the insulinlike growth factor-I receptor tyrosine kinase. J Biol Chem 268(31):23435–23440
Hennige AM, Lehmann R, Weigert C, Moeschel K, Schauble M, Metzinger E, Lammers R, Haring HU (2005) Insulin glulisine: insulin receptor signaling characteristics in vivo. Diabetes 54:361–366
Ish-Shalom D, Tzivion G, Christoffersen CT, Ursø B, De Meyts P Naor D (1995) Mitogenic potential of insulin on lymphoma cells lacking IGF-I receptors. Ann N Y Acad Sci 766:409–415
Lamphere L, Lienhard GE (1992) Components of signaling pathways for insulin and insulin-like growth factor-I in muscle myoblasts and myotubes. Endocrinology 131(5):2196–2202
Shymko RM, De Meyts P, Thomas R (1997) Logical analysis of timing-dependent receptor signalling specificity: application to the insulin receptor metabolic and mitogenic signalling pathways. Biochem J 326(Pt 2):463–469
Valentinis B, Baserga R (2001) IGF-I receptor signalling in transformation and differentiation. Mol Pathol 54(3):133–137
IGF-I Receptor Affinity
Blakesley VA, Scrimgeour A, Esposito D, Le Roith D (1996) Signaling via the insulin-like growth factor-I receptor: does it differ from insulin receptor signaling? Cytokine Growth Factor Rev 7(2):153–159
Ciaraldi TP, Carter L, Seipke G, Mudaliar S, Henry RR (2001) 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 86:5838–5847
Ciaraldi TP, Phillips SA, Carter L, Aroda V, Mudaliar S, Henry RR (2005) Effects of the rapid-acting insulin analog glulisine on cultured human skeletal muscle cells: comparisons with insulin and insulin-like growth factor I. J Clin Endocrinol Metab 90(10):5551–5558
De Meyts P (1994) The structural basis of insulin and insulinlike growth factor-I receptor binding and negative cooperativity, and its relevance to mitogenic versus metabolic signalling. Diabetologia 37(Suppl 2):S135–S148
De Meyts P, Wallach B, Christoffersen CT et al (1994) The insulin-like growth factor-I receptor. Structure, ligand binding mechanism and signal transduction. Horm Res 42:152–169
De Meyts P, Christoffersen CT, Urso B, Wallach B, Gronskov K, Yakushiji F, Shymko RM (1995a) Role of the time factor in signaling specificity: application to mitogenic and metabolic signaling by the insulin and insulin-like growth factor-I receptor tyrosine kinases. Metabolism 44(10 Suppl 4):2–11
De Meyts P, Urso B, Christoffersen CT, Shymko RM (1995b) Mechanism of insulin and IGF-I receptor activation and signal transduction specificity. Receptor dimer crosslinking, bell-shaped curves, and sustained versus transient signaling. Ann N Y Acad Sci 766:388–401
Henry RR, Abrams L, Nikoulina S, Ciaraldi TP (1995) Insulin action and glucose metabolism in non-diabetic control and NIDDM subjects: comparison using human skeletal muscle cell cultures. Diabetes 44:935–945
LeRoith D, Sampson PC, Roberts CT Jr (1994) How does the mitogenic insulin-like growth factor I receptor differ from the metabolic insulin receptor? Horm Res 41(Suppl 2):74–78, discussion 79
Li G, Barrett EJ, Hong Wang H, Weidong C, Zhenqi L (2005) 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 146:4690–4696
Prager D, Melmed S (1993) Insulin and insulin-like growth factor I receptors: are there functional distinctions? Endocrinology 132(4):1419–1420
Rosenzweig SA, Oemar BS, Law NM, Shankavaram UT, Miller BS (1993) Insulin like growth factor 1 receptor signal transduction to the nucleus. Adv Exp Med Biol 343:159–168
Rubin R, Baserga R (1995) Insulin-like growth factor-I receptor. Its role in cell proliferation, apoptosis, and tumorigenicity. Lab Invest 73(3):311–331
Sepp-Lorenzino L (1998) Structure and function of the insulinlike growth factor I receptor. Breast Cancer Res Treat 47(3):235–253
Slieker LJ, Brooke GS, DiMarchi RD, Flora DB, Green LK, Hoffman JA, Long HB, Fan L, Shields JE, Sundell KL, Surface PL, Chance RE (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
Soos MA, Nave BT, Siddle K (1993) Immunological studies of type I IGF receptors and insulin receptors: characterisation of hybrid and atypical receptor subtypes. Adv Exp Med Biol 343:145–157
Staiger K, Hennige AM, Schweitzer MA, Staiger H, Haering HU, Monika Kellerer M (2005) Effect of insulin glargine versus regular human insulin on proliferation of human breast epithelial cells. ADA annual symposium San Diego, abstract 451-P
Stammberger I, Bube A, Durchfeld-Meyer B, Donaubauer H, Troschau G (2002) Evaluation of the carcinogenic potential of insulin glargine in rats and mice. Int J Toxicol 21(3):171–179
Stammberger I, Seipke G, Bartels T (2006) Insulin glulisine—a comprehensive preclinical evaluation. Int J Toxicol 25(1):25–33
Strobl JS, Wonderlin WF, Flynn DC (1995) Mitogenic signal transduction in human breast cancer cells. Gen Pharmacol 26(8):1643–1649
Takata Y, Kobayashi M (1994) Insulin-like growth factor I signalling through heterodimers of insulin and insulin-like growth factor I receptors. Diabete Metab 20(1):31–36
Signaling via IGF-1 Receptor
Belfiore A, Pandini G, Vella V, Squatrito S, Vigneri R (1999) Insulin/IGF-I hybrid receptors play a major role in IGF-I signaling in thyroid cancer. Biochimie 81(4):403–407
Blanquart C, Boute N, Lacasa D, Issad T (2005) Monitoring the activation state of the insulin-like growth factor-1 receptor and its interaction with protein tyrosine phosphatase 1B using bioluminescence resonance energy transfer. Mol Pharmacol 68:885–894
Blanquart C, Gonzalez-Yanes C, Issad T (2006) Monitoring the activation state of insulin/IGF-1 hybrid receptors using bioluminescence resonance energy transfer. Mol Phrmacol 70:1802–1811
Blanquart C, Achi J, Issad T (2008) Characterization of IRA/IRB hybrid insulin receptors using bioluminescence resonance energy transfer. Biochem Pharmacol 76:873–883
Dupont J, LeRoith D (2001) Insulin and insulin-like growth factor I receptors: similarities and differences in signal transduction. Horm Res 55:22–26
Entingh-Pearsall A, Kahn CR (2004) Differential roles of the insulin and insulin-like growth factor-I (IGF-I) receptors in response to insulin and IGF-I. J Biol Chem 279(36):38016–38024. Epub 2004 Jul 7
Federici M, Lauro D, D’Adamo M, Giovannone B, Porzio O, Mellozzi M, Tamburrano G, Sbraccia P, Sesti G (1998a) Expression of insulin/IGF-I hybrid receptors is increased in skeletal muscle of patients with chronic primary hyperinsulinemia. Diabetes 47(1):87–92
Federici M, Porzio O, Lauro D, Borboni P, Giovannone B, Zucaro L, Hribal ML, Sesti G (1998b) Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity. J Clin Endocrinol Metab 83(8):2911–2915
Frasca F, Pandini G, Vigneri R, Goldfine ID (2003) Insulin and hybrid insulin/IGF receptors are major regulators of breast cancer cells. Breast Dis 17:73–89
Issad T, Blanquart C, Gonzalez-Yanes C (2007) The use of bioluminsecence resonance energy transfer for the study of therapeutic targets: application to tyrosine kinase receptors. Expert Opin Ther Targets 11:541–556
Kim J, Accili D (2002) Signalling through IGF-I and insulin receptors: where is the specificity? Growth Horm IGF Res 12:84
Lamphere L, Lienhard GE (1992) Components of signaling pathways for insulin and insulin-like growth factor-I in muscle myoblasts and myotubes. Endocrinology 131(5):2196–2202
Li G, Barrett EJ, Wang H, Chai W, Liu Z (2005) 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 146(11):4690–4696. Epub 2005 Aug 11
Mosthaf L, Vogt B, Haring HU, Ullrich A (1991) Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients. Proc Natl Acad Sci U S A 88:4728–4730
Nitert MD, Chisalita SI, Olsson K, Bornfeldt KE, Arnqvist HJ (2005) IGF-I/insulin hybrid receptors in human endothelial cells. Mol Cell Endocrinol 229(1–2):31–37
Pandini G, Frasca F, Mineo R, Sciacca L, Vigneri R, Belfiore (2002) A 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
Pandini G, Vigneri R, Costantino A, Frasca F, Ippolito A, Fujita-Yamaguchi Y, Siddle K, Goldfine ID, Belfiore A (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(7):1935–1944
Sakai K, Lowman HB, Clemmons DR (2002) Increases in free, unbound insulin-like growth factor I enhance insulin responsiveness in human hepatoma G2 cells in culture. J Biol Chem 277(16):13620–13627. Epub 2002 Feb 7
Salzman A, Wan CF, Rubin CS (1984) Biogenesis, transit, and functional properties of the insulin proreceptor and modified insulin receptors in 3T3-L1 adipocytes. Use of monensin to probe proreceptor cleavage and generate altered receptor subunits. Biochemistry 23:6555–6565
Schumacher R, Mosthaf L, Schlessinger J, Brandenburg D, Ullrich A (1991) Insulin and insulin-like growth factor-1 binding specificity is determined by distinct regions of their cognate receptors. J Biol Chem 266(29):19288–19295
Siddle K, Soos MA, Field CE, Nave BT (1994) Hybrid and atypical insulin/insulin-like growth factor I receptors. Horm Res 41(Suppl 2):56–64
Soos MA, Field CE, Siddle K (1993) Purified hybrid insulin/insulin-like growth factor-I receptors bind insulinlike growth factor-I, but not insulin, with high affinity. Biochem J 290:419–426
Whitehead JP, Clark SF, Urso B, James DE (2000) Signalling through the insulin receptor. Curr Opin Cell Biol 12:222–228
Mitogenic Activity
Baserga R, Peruzzi F, Reiss K (2002) The IGF-1 receptor in cancer biology. Int J Cancer 107:873
Dalle S, Ricketts W, Imamura T, Vollenweider P, Olefsky JM (2001) Insulin and insulin-like growth factor I receptors utilize different G protein signaling components. J Biol Chem 276:15688–15695
De Meyts P, Christoffersen CT, Ursø B et al (1995a) Role of the time factor in signalling specificity. Application to mitogenic and metabolic signalling by the insulin and insulinlike growth factor-I receptor tyrosine kinases. Metabolism 44(Suppl 4):1–11
De Meyts P, Ursø B, Christoffersen CT, Shymko RM (1995b) Mechanism of insulin and IGF-I receptor activation and signal transduction specificity. Receptor dimer crosslinking, bell-shaped curves, and sustained versus transient signalling. Ann New York Acad Sci 766:388–401
DeMeyts P, Whittaker J (2002) Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov 1:769–783
Hankinson SE, Willett WC, Colditz GA et al (1998) Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 351:1393–1396
Ish-Shalom D, Tzivion G, Christoffersen CT, Ursø B, De Meyts P, Naor D (1995) Mitogenic potential of insulin on lymphoma cells lacking IGF-I receptors. Ann N Y Acad Sci 766:409–415
Jones JI, Clemmons DR (1995) Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 16:3–34
Kellerer M, Haering HU (2001) Insulin analogs: impact of cell model characteristics on results and conclusions regarding mitogenic properties. Exp Clin Endocrinol Diabetes 109:63–64
Koontz JW, Iwahashi M (1981) Insulin as a potent, specific growth factor in a rat hepatoma cell line. Science 211:947–949
Kurtzhals P, Schaffer L, Sorenson A, Kristensen C, Jonassen I, Schmid C, Trub T (2000) Correlations of recepwtor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005
Li G, Barrett EJ, Hong Wang H, Weidong C, Zhenqi L (2005) 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 146:4690–4696
Mamounas M, Gervin D, Englesberg E (1989) The insulin receptor as a transmitter of a mitogenic signal in Chinesehamster ovary CHO-K1 cells. Proc Natl Acad Sci U S A 86:9294–9298
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
Prisco M, Romano G, Peruzzi F, Valentinis B, Baserga R (1999) Insulin and IGF-I receptors signaling in protection from apoptosis. Horm Metab Res 31:80–89
Renehan AG, Zwahlen M, Minder C, O’Dwyer ST, Shalet SM, Egger M (2004) Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis. Lancet 363:1346–1353
Schmid C, Keller C, Gosteli-Peter M, Zapf J (1999) Mitogenic and antiapoptotic effects of insulin-like growth factor binding protein-6 in the human osteoblastic osteosarcoma cell line Saos-2/B-10. Biochem Biophys Res Commun 263(3):786–789
Slaaby R, Schaffer L, Lautrup-Larsen I, Andersen AS, Shaw AC, Mathiasen IS, Brandt J (2006) Hybrid receptors formed by insulin receptor (IR) and insulin-like growth factor I receptor (IGF-IR) have low insulin and high IGF-1 affinity irrespective of the IR splice variant. J Biol Chem 281(36):25869–25874
Slieker LJ, Brooke GS, DiMarchi RD, Flora DB, Green LK, Hoffman JA, Long HB, Fan L, Shields JE, Sundell KL, Surface PL, Chance RE (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
Ullrich A, Schlessinger J (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61:203–212
Insulin and IGF-1 Assays
Andersen L, Jorgensen PN, Jensen LB, Walsh D (2000) A new insulin immunoassay specific for the rapid-acting insulin analog, insulin aspart, suitable for bioavailability, bioequivalence, and pharmacokinetic studies. Clin Biochem 33(8):627–633
Ashby JP, Frier BM (1981) Circulating C peptide: measurement and clinical application. Ann Clin Biochem 18(Pt 3):125–130
Blum WF, Breier BH (1994) Radioimmunoassays for IGFs and IGFBPs. Growth Regul 4(Suppl 1):11–19
Bonser AM, Garcia-Webb P (1981) C-peptide measurement and its clinical usefulness: a review. Ann Clin Biochem 18(Pt 3):200–206
Bowsher RR, Lynch RA, Brown-Augsburger P, Santa PF, Legan WE, Woodworth JR, Chance RE (1999) Sensitive RIA for the specific determination of insulin lispro. Clin Chem 45(1):104–110
Cao Y, Smith WC, Bowsher RR (2001) A sensitive chemiluminescent enzyme immunoassay for the bioanalysis of carboxyl-terminal B-chain analogs of human insulin. J Pharm Biomed Anal 26(1):53–61
Clark PM, Hales CN (1994) How to measure plasma insulin. Diabetes Metab Rev 10(2):79–90
Elmlinger MW, Kuhnel W, Weber MM, Ranke MB (2004) Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med 42(6):654–664
Elmlinger MW, Zwirner M, Kuhnel W (2005) Stability of insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 measured by the IMMULITE automated chemiluminescence assay system in different blood specimens. Clin Lab 51(3–4):145–152
Froesch ER, Hussain MA, Schmid C, Zapf J (1996) Insulin-like growth factor I: physiology, metabolic effects and clinical uses. Diabetes Metab Rev 12(3):195–215
Frystyk J, Skjaerbaek C, Vestbo E, Fisker S, Orskov H (1999) Circulating levels of free insulin-like growth factors in obese subjects: the impact of type 2 diabetes. Diabetes Metab Res Rev 15(5):314–322
Hill DJ, Milner RD (1985) Insulin as a growth factor. Pediatr Res 19(9):879–886
Johansson GS, Arnqvist HJ (2006) Insulin and IGF-I action on insulin receptors, IGF-I receptors, and hybrid insulin/IGF-I receptors in vascular smooth muscle cells. Am J Physiol 291(5):E1124–E1130. Epub 2006 Jun 27
Juul A (2003) Serum levels of insulin-like growth factor I and its binding proteins in health and disease. Growth Horm IGF Res 13:113
Khosravi J, Anastasia D, Umesh B, Najmuddin K, Radha GK (2005) Pitfalls of immunoassay and sample for IGF-I: comparison of different assay methodologies using various fresh and stored serum samples. Clin Biochem 38(7):659–666
Kuerzel GU, Shukla U, Scholtz HE, Pretorius SG, Wessels DH, Venter C, Potgieter MA, Lang AM, Koose T, Bernhardt E (2003) Biotransformation of insulin glargine after subcutaneous injection in healthy subjects. Curr Med Res Opin 19(1):34–40
Lassarre C, Duron F, Binoux M (2001) Use of the ligand immunofunctional assay for human insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) to analyze IGFBP-3 proteolysis and IGF-I bioavailability in healthy adults, GH-deficient and acromegalic patients, and diabetics. J Clin Endocrinol Metab 86(5):1942–1952
Moses AC, Young SC, Morrow LA et al (1996) Recombinant human insulin-like growth factor I increases insulin sensitivity and improves glycemic control in type II diabetes. Diabetes 45:91
Mudaliar S, Mohideen P, Deutsch R, Ciaraldi TP, Armstrong D, Kim B, Sha X, Henry RR (2002) Intravenous glargine and regular insulin have similar effects on endogenous glucose output and peripheral activation/deactivation kinetic profiles. Diabetes Care 25(9):1597–1602
Pedersen O (1983) Insulin receptor assays used in human studies: merits and limitations. Diabetes Care 6(3):301–319
Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, Frank BH, Galloway JA, Van Cauter E (1988a) Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med 318(19):1231–1239
Polonsky KS, Given BD, Van Cauter E (1988b) Twenty-four hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 81(2):442–448
Quarmby V, Quan C, Ling V, Compton P, Canova-Davis E (1998) How much insulin-like growth factor I (IGF-I) circulates? Impact of standardization on IGF-I assay accuracy. J Clin Endocrinol Metab 83:1211–1216
Rutanen EM, Pekonen F (1991) Assays for IGF binding proteins. Acta Endocrinol (Copenh) 124(Suppl 2):70–73
Taylor R (1984) Insulin receptor assays – clinical application and limitations (2). Diabet Med 1(3):181–188
Tchao A, Wong A, Bondy G (1995) Technical and clinical validation of a serum IGF-1 assay. Clin Biochem 28:331–331
Teale JD, Marks V (1986) The measurement of insulin-like growth factor I: clinical applications and significance. Ann Clin Biochem 23(Pt 4):413–424
Temple R, Clark PM, Hales CN (1992) Measurement of insulin secretion in type 2 diabetes: problems and pitfalls. Diabet Med 9(6):503–512
Tillil H, Shapiro ET, Given BD, Rue P, Rubenstein AH, Galloway JA, Polonsky KS (1988) Reevaluation of urine C-peptide as measure of insulin secretion. Diabetes 37(9):1195–1201
Yakar S, LeRoith D, Brodt P (2005) The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: lessons from animal models. Cytokine Growth Factor Rev 16:407–420
Zapf J (1998) Growth promotion by insulin-like growth factor I in hypophysectomized and diabetic rats. Mol Cell Endocrinol 140(1–2):143–149
Assessment of Metabolic-Mitogenic Ratio In vitro
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
Baus D, Heermeier K, De HM, Metz-Weidmann C, Gassenhuber J et al (2008) Identification of a novel AS160 splice variant that regulates GLUT4 translocation and glucose-uptake in rat muscle cells. Cell Signal 20:2237–2246
Berchtold H, Hilgenfeld R (1999) Binding of phenol to R6 insulin hexamers. Biopolymers 51:165–172
Brange J, Owens DR, Kang S, Volund A (1990) Monomeric insulins and their experimental and clinical implications. Diabetes Care 13:923–954
Chantelau E (2009) Insulin-responsiveness of tumor growth. Arch Physiol Biochem 115:47–48
Cook N, Harris A, Hopkins A, Hughes K (2002) Scintillation proximity assay (SPA) technology to study biomolecular interactions. Curr Protoc Protein Sci Chapter 19:Unit. 19.8.1
De MP, Whittaker J (2002) Structural biology of insulin and IGF1 receptors: implications for drug design. Nat Rev Drug Discov 1:769–783
Dideriksen LH, Jorgensen LN, Drejer K (1992) Carcinogenic effect of female rats after 12 months administration of the insulin analog B10Asp. Diabetes 41:143A
Eckardt K, Eckel J (2008) Insulin analogues: action profiles beyond glycaemic control. Arch Physiol Biochem 114:45–53
EMEA (European Agency for the Evaluation of Medical Products) (2001) Points to consider document on the nonclinical assessment of the carcinogenic potential of insulin analogs. European Agency for the Evaluation of Medicinal Products, London
Frasca F, Pandini G, Sciacca L, Pezzino V, Squatrito S et al (2008) The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 114:23–37
Frick W, Bauer A, Bauer J, Wied S, Müller G (1998) Structure-activity relationship of synthetic phosphoinositolglycans mimicking metabolic insulin action. Biochemistry 37:13421–13436
Goykhman S, Drincic A, Desmangles JC, Rendell M (2009) Insulin glargine: a review 8 years after its introduction. Expert Opin Pharmacother 10:705–718
Hilgenfeld R, Dörschug M, Geisen K, Neubauer H, Obermeier R (1992) Controlling insulin bioavailability by crystal contact engineering. Diabetologia 35(Suppl 1):A193
Home PD, Ashwell SG (2002) An overview of insulin glargine. Diabetes Metab Res Rev 18(Suppl 3):S57–S63
Kohn WD, Micanovic R, Myers SL, Vick AM, Kahl SD et al (2007) pI-shifted insulin analogs with extended in vivo time action and favorable receptor selectivity. Peptides 28:935–948
Kristensen C, Wiberg FC, Andersen AS (1999) 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 274:37351–37356
Kuerzel GU, Sandow J, Seipke G, Lang A, Maas J et al (2001) Kinetic and metabolic profile of insulin glargine (LANTUS). Diabetologia 44:798
Kuerzel GU, Shukla U, Scholtz HE, Pretorius SG, Wessels DH et al (2003) Biotransformation of insulin glargine after subcutaneous injection in healthy subjects. Curr Med Res Opin 19: 4–40
Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I et al (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005
Le Roith D (2007) Insulin glargine and receptor-mediated signalling: clinical implications in treating type 2 diabetes. Diabetes Metab Res Rev 23:593–599
Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L et al (2000) 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 49:2142–2148
Levien TL, Baker DE, White JR Jr, Campbell RK (2002) Insulin glargine: a new basal insulin. Ann Pharmacother 36:1019–1027
Müller G, Wied S (1993) The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro. Diabetes 42:1852–1867
Rissler K, Engelmann P (1996) Labeling of insulin with non-radioactive 127I and application to incorporation of radioactive 125I for use in receptor-binding experiments by high-performance liquid chromatography. J Chromatogr B Biomed Appl 679:21–29
Rosskamp RH, Park G (1999) Long-acting insulin analogs. Diabetes Care 22(Suppl 2):B109–B113
Sandow J (2009) Growth effects of insulin and insulin analogues. Arch Physiol Biochem 115:72–85
Sciacca L, Costantino A, Pandini G, Mineo R, Frasca F et al (1999) Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism. Oncogene 18:2471–2479
Sciacca L, Mineo R, Pandini G, Murabito A, Vigneri R et al (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
Serrano R, Villar M, Martinez C, Carrascosa JM, Gallardo N et al (2005) Differential gene expression of insulin receptor isoforms A and B and insulin receptor substrates 1, 2 and 3 in rat tissues: modulation by aging and differentiation in rat adipose tissue. J Mol Endocrinol 34:153–161
Shukla A, Grisouard J, Ehemann V, Hermani A, Enzmann H et al (2009) Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines. Endocr Relat Cancer 16:429–441
Smith U, Gale EA (2009) Does diabetes therapy influence the risk of cancer? Diabetologia 52:1699–1708
Staiger K, Hennige AM, Staiger H, Haring HU, Kellerer M (2007) Comparison of the mitogenic potency of regular human insulin and its analogue glargine in normal and transformed human breast epithelial cells. Horm Metab Res 39:65–67
Vella V, Pandini G, Sciacca L, Mineo R, Vigneri R et al (2002) A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab 87:245–254
Depot Activity of Insulin Analogs in Rabbits
Hollander M, Wolfe DA (1973) Nonparametric statistical methods, Wiley series in probability and mathematical statistics. Wiley, New York
Streitberg B, Röhmel J (1987) Exakte Verteilung für Rangund Randomisierungstests im allgemeinen Stichprobenproblem. In: EDV (ed) Medizin und Biologie, vol 18. Verlag Eugen Ulmer GmbH/Gustav Fisher Verlag KG, Stuttgart, pp 12–19
Depot Activity of Insulin Analogs in Fasted Dogs
Holm S (1979) A simple sequentially rejective multiple test procedure. Scand J Stat 6:65–70
Lin FO, Hasemann JK (1975) A modified Jonckeere test against ordered alternatives when ties are present at a single extreme value. National Institute of Environmental Health Sciences, North Carolina Environmental Biometric Branch
Lin S, Wang SY, Chen EC, Chien YW (1999) Insulin lispro: invivo potency determination by intravenous administration in conscious rabbits. J Pharm Pharmacol 51(3):301–306
Seipke G, Sandow J, Geisen K, Stammberger I (2000) Preclinical profile of the new long-acting insulin glargine (HOE 901). Endocrine Society annual meeting 2000, Toronto
Mitogenic Risk and Safety Evaluation In vivo
EPAR EMEA Humalog (2006) Document 060195en6 lispro, scientific discussion in the public assessment report for Humalog (insulin lispro INN) http://www.emea.europa.eu/humandocs/Humans/EPAR/humalog
EPAR EMEA Lantus (2006) Document 061500en6 glargine, scientific discussion in the public assessment report for Lantus (insulin glargine INN) http://www.emea.europa.eu/humandocs/Humans/EPAR/lantus
EPAR EMEA Levemir (2006) Document 093604en6 detemir, scientific discussion in the public assessment report for Levemir (insulin detemir INN) http://www.emea.europa.eu/humandocs/Humans/EPAR/levemir
EPAR EMEA Novorapid (2004) Document 272799en6 aspart, scientific discussion in the public assessment report for Novorapid (insulin aspart NN). http://www.emea.europa.eu/humandocs/Humans/EPAR/novorapid
Hennige AM, Kellerer M, Strack V, Metzinger E, Seipke G, Haring HU (1999) New human insulin analogs: characteristics of insulin signalling in comparison to ASP (B10) and regular insulin. Diabetologia 42:A178 (Abstract 665)
Kellerer M, Haering HU (2001c) Insulin analogs: impact of cell model characteristics on results and conclusions regarding mitogenic properties. Exp Clin Endocrinol Diabetes 109:63–64
Leroith D, Baserga R, Helman L, Roberts CT (1995) Insulin-like growth-factors and cancer. Ann Intern Med 122:54–59
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 insulinlike growth factor-I receptor. Mol Carcinog 18(1):19–25
Staiger K, Hennige AM, Schweitzer MA, Staiger H, Haering HU, Monika Kellerer M (2005) Effect of insulin glargine versus regular human insulin on proliferation of human breast epithelial cells. ADA annual symposium San Diego, abstract 451-P
Stammberger I, Bube A, Durchfeld-Meyer B, Donaubauer H, Troschau G (2002) Evaluation of the carcinogenic potential of insulin glargine in rats and mice. Int J Toxicol 21(3):171–179
Stammberger I, Seipke G, Bartels T (2006) Insulin glulisine—a comprehensive preclinical evaluation. Int J Toxicol 25(1):25–33
Zib I, Raskin P (2006b) Novel insulin analogs and its mitogenic potential. Diabetes Obes Metab 8(6):611–620
Oral Drug Delivery
Aoki N, Jin-no S, Nakagawa Y, Asai N, Arakawa E, Tamura N (2007) Identification and characterization of microvesicles secreted by 3T3-L1 adipocytes: redox- and hormone-dependent induction of milk fat globule-epidermal growth factor 8-associated microvesicles. Endocrinology 148:3850–3862
Billingsley ML (2008) Druggable targets and targeted drugs: enhancing the development of new therapeutics. Pharmacology 82:239–244
Black PN (1980) Shedding from normal and cancer-cell surfaces. N Engl J Med 303:1415–1420
Brewis IA, Ferguson MAJ, Mehlert A, Turner AJ, Hooper NM (1995) Structures of the glycosyl-phosphatidylinositol anchors of porcine and human erythrocyte renal membrane dipeptidase. Comprehensive structural studies on the porcine anchor and interspecies comparison of the glycan core structures. J Biol Chem 270:22946–22956
Brown DA (1992) Interactions between GPI-anchored proteins and membrane lipids. Trends Cell Biol 2:338–343
Brown DA, London L (1998) Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 14:111–136
Bütikofer P, Brodbeck U (1993) Partial purification and characterization of a (glycosyl) inositol phospholipid-specific phospholipase C from peanut. J Biol Chem 268:17794–17799
Choi SW, Lee SH, Mok H, Park TG (2010) Multifunctional siRNA delivery system: polyelectrolyte complex micelles of six-arm PEG conjugate of siRNA and cell penetrating peptide with crosslinked fusogenic peptide. Biotechnol Prog 26:57–63
Civenni G, Test ST, Brodbeck U, Bütikofer P (1998) In vitro incorporation of GPI-anchored proteins into human erythrocytes and their fate in the membrane. Blood 9:11784–11792
Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19:43–51
Danielsen EM, Hansen GH (2006) Lipid raft organization and function in brush borders of epithelial cells. Mol Membr Biol 23:71–79
Danielsen EM, Hansen GH (2008) Lipid raft organization and function in the small intestinal brush border. J Physiol Biochem 64:377–382
Ebbesen M, Jensen TG (2006) Nanomedicine: techniques, potentials, and ethical implications. J Biomed Biotechnol. doi:10.1155/JBB/2006/51516
Fevrier B, Raposo G (2004) Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr Opin Cell Biol 16:415–421
Fivaz M, Vilbois F, Thurnheer S, Pasquali C, Abrami L, Bickel PE, Parton RG, van der Goot FG (2002) Differential sorting and fate of endocytosed GPI-anchored proteins. EMBO J 21:3989–4000
Florez JC (2008) The genetics of type 2 diabetes: a realistic appraisal in 2008. J Clin Endocrinol Metab 93:4633–4642
Gao K, Huang L (2009) Nonviral methods for siRNA delivery. Mol Pharm 6:651–658
Gibson G (2009) Decanalization and the origin of complex disease. Nature 10:134–140
Gullotti E, Yeo Y (2009) Extracellularly activated nanocarriers: a new paradigm of tumor targeted drug delivery. Mol Pharm 6:1041–1051
Hoener MC, Stieger S, Brodbeck U (1990) Isolation and characterization of a phosphatidylinositol-glycan-anchor-specific phospholipase D from bovine brain. Eur J Biochem 190:593–600
Ikezawa H (2002) Glycosylphosphatidylinositol (GPI)-anchored proteins. Biol Pharm Bull 25:409–417
Ilangumaran S, Robinson PJ, Hoessli DC (1996) Transfer of exogenous glycosylinositol (GPI)-linked molecules to plasma membranes. Trends Cell Biol 6:163–169
Janssens ACJW, Pardo MC, Steyerberg EW, van Dujin CM (2004) Revisiting the clinical validity of multiplex genetic testing in complex diseases. Am J Hum Genet 74:585–588
Keller S, Sanderson MP, Stoeck A, Altevogt P (2006) Exosomes: from biogenesis and secretion to biological function. Immunol Lett 107:102–108
Kim DH, Rossi JJ (2007) Strategies for silencing human disease using RNA interference. Nat Rev Genet 8:173–184
Kirpotin DB, Drummond DC, Shao Y, Shalaby MR, Hong KL, Nielsen UB, Marks JD, Benz CC, Park JW (2006) Antibody targeting of long-circulating lipidic nanoparticles does not increase tumor localization but does increase internalization in animal models. Cancer Res 66:6732–6740
Kooyman DL, Byrne GW, Logan JS (1998) Glycosyl phosphatidylinositol anchor. Exp Nephrol 6:148–151
Küng M, Bütikofer P, Brodbeck U, Stadelmann B (1997) Expression of intracellular and GPI-anchored forms of GPI-specific phospholipase D in COS-1 cells. Biochem Biophys Acta 1357:329–338
Li SD, Huang L (2007) Non-viral is superior to viral gene delivery. J Control Release 123:181–183
Lin YH, Mi FL, Chen CT, Chang WC, Peng SF, Liang HF, Sung HW (2007) Preparation and characterization of nanoparticles shelled with chitosan for oral insulin delivery. Biomacromolecules 8:146–152
Lindgren CM (2007) Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity. Nat Clin Pract 4:156–163
Lisanti MP, Scherer PE, Tang ZL, Sargiacomo M (1994) Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis. Trends Cell Biol 4:231–238
Lusis AJ, Attie AD, Reue K (2008) Metabolic syndrome: from epidemiology to systems biology. Nat Genet 9:819–830
Martin SE, Caplen NJ (2007) Development of new RNAi therapeutics. Histol Histopathol 22:211–217
Mathiowitz E (2008) Drug delivery system. Toxicol Pathol 36:16–22
Mathiowitz E, Jacob JS, Jong YS, Carino GP, Chickering DE, Chaturvedi P, Santos CA, Vijayaraghavan K, Montgomery S, Bassett M, Morrell C (1997) Biologically erodable microspheres as potential oral drug delivery systems. Nature 386:410–414
Matsumara Y (2008) Polymeric micellar delivery systems in oncology. Jpn J Clin Oncol 38:793–802
Mayor S, Rothberg KG, Maxfield FR (1994) Sequestration of GPI-anchor proteins in caveolae triggered by cross-linking. Science 264:1948–1951
McHugh RS, Ahmed SN, Wang Y, Sell KW, Selvavaj P (1995) Construction, purification, and functional incorporation on tumor cells of glycolipid-anchored human B7-1 (CD80). Proc Natl Acad Sci U S A 92:8059–8063
McLendon PM, Fichter KM, Reineke TM (2010) Poly(glycoamidoamine) vehicles promote pDNA uptake through multiple routes and efficient gene expression via caveolae-mediated endocytosis. Mol Pharm 7:738–750
Medof ME, Nagarajan S, Tykocinski ML (1996) Cell-surface engineering with GPI-anchored proteins. FASEB J 10:574–586
Milhiet P-E, Giocondi M-C, Baghdadi O, Ronzon F, Roux B, Le Grimellec C (2002) Spontaneous insertion and partitioning of alkaline phosphatase into model lipid rafts. EMBO Rep 3:485–490
Mok H, Bae KH, Ahn C-H, Park TG (2009) PEGylated and MMP-2 specifically dePEGylated quantum dots: comparative evaluation of cellular uptake. Langmuir 25:1645–1650
Morandat S, Bortolato M, Roux B (2002) Cholesterol-dependent insertion of glycosylphosphatidylinositol-anchored enzyme. Biochim Biophys Acta 1564:473–478
Müller G (2005) The mode of action of glimepiride – beyond insulin secretion. Curr Med Chem 5:499–518
Müller G (2010) Personalized prognosis and diagnosis of type II diabetes – vision or fiction? Pharmacology 85:168–187
Müller G, Frick W (1999) Signalling via caveolin: involvement in the cross-talk between phosphoinositolglycans and insulin. Cell Mol Life Sci 56:945–970
Müller G, Dearey E-A, Korndörfer A, Bandlow W (1994a) Stimulation of a glycosyl-phosphatidylinositol-specific phospholipase by insulin and the sulfonylurea, glimepiride, in rat adipocytes depends on increased glucose transport. J Cell Biol 126:1267–1276
Müller G, Wetekam E-M, Jung C, Bandlow W (1994b) Membrane association of lipoprotein lipase and a cAMP-binding ectoprotein in rat adipocytes. Biochemistry 33:12149–12159
Müller G, Jung C, Wied S, Welte S, Frick W (2001a) Insulin-mimetic signaling by the sulfonylurea glimepiride and phosphoinositolglycans involves distinct mechanisms for redistribution of lipid raft components. Biochemistry 40:14603–14620
Müller G, Jung C, Wied S, Welte S, Jordan H, Frick W (2001b) Redistribution of glycolipid raft domain components induces insulin-mimetic signaling in rat adipocytes. Mol Cell Biol 21:4553–4567
Müller G, Hanekop N, Kramer W, Bandlow W, Frick W (2002a) Interaction of phosphoinositolglycan(-peptides) with plasma membrane lipid rafts of rat adipocytes. Arch Biochem Biophys 408:17–32
Müller G, Jung C, Frick W, Bandlow W, Kramer W (2002b) Interaction of phosphoinositolglycan(-peptides) with plasma membrane lipid rafts triggers insulin-mimetic signaling in rat adipocytes. Arch Biochem Biophys 408:7–16
Müller G, Schulz A, Wied S, Frick W (2005) Regulation of lipid raft proteins by glimepiride- and insulin-induced glycosylphosphatidylinositol-specific phospholipase C in rat adipocytes. Biochem Pharmacol 69:761–780
Müller G, Jung C, Wied S (2008a) Translocation of glycosylphosphatidylinositol-anchored proteins from plasma membrane microdomains to lipid droplets in rat adipocytes is induced by palmitate, H2O2 and the sulfonylurea drug, glimepiride. Mol Pharmacol 73:1513–1529
Müller G, Over S, Wied S, Frick W (2008b) Association of (c)AMP-degrading glycosylphosphatidylinositol-anchored proteins with lipid droplets is induced by palmitate, H2O2 and the sulfonylurea drug, glimepiride, in rat adipocytes. Biochemistry 47:1274–1287
Müller G, Wied S, Jung C, Over S (2008c) Translocation of glycosylphosphatidylinositol-anchored proteins to lipid droplets and inhibition of lipolysis in rat adipocytes is mediated by reactive oxygen species. Br J Pharmacol 154:901–913
Müller G, Wied S, Jung C, Straub J (2008d) Coordinated regulation of esterification and lipolysis by palmitate, H2O2 and the anti-diabetic sulfonylurea drug, glimepiride, in rat adipocytes. Eur J Pharmacol 597:6–18
Müller G, Wied S, Over S, Frick W (2008e) Inhibition of lipolysis by palmitate, H2O2 and the sulfonylurea drug, glimepiride, in rat adipocytes depends on cAMP degradation by lipid droplets. Biochemistry 47:1259–1273
Müller G, Jung C, Straub J, Wied S, Kramer W (2009a) Induced release of membrane vesicles from rat adipocytes containing glycosylphosphatidylinositol-anchored microdomain and lipid droplet signalling proteins. Cell Signal 21:324–338
Müller G, Jung C, Wied S, Biemer-Daub G (2009b) Induced translocation of glycosylphosphatidylinositol-anchored proteins from lipid droplets to adiposomes in rat adipocytes. Br J Pharmacol 158:749–770
Müller G, Schulz A, Dearey E-A, Wetekam E-M, Wied S, Frick W (2010a) Synthetic phosphoinositolglycans regulate lipid metabolism between rat adipocytes via release of GPI-protein-harbouring adiposomes. Arch Physiol Biochem 116:97–115
Müller G, Schulz A, Hartz D, Dearey E-A, Wetekam E-M, Ökonomopulos R, Crecelius A, Wied S, Frick W (2010b) Novel glimepiride derivatives with potential as double-edged swords against type II diabetes? Arch Physiol Biochem 116:3–20
Müller G, Wied S, Jung C, Biemer-Daub G, Frick W (2010c) Transfer of glycosylphosphatidylinositol-anchored 5′-nucleotidase CD73 from adiposomes into rat adipocytes stimulates lipid synthesis. Br J Pharmacol 160:878–891
Müller G, Wied S, Jung C, Frick W, Biemer-Daub G (2010d) Inhibition of lipolysis by adiposomes containing glycosylphosphatidylinositol-anchored Gce1 protein in rat adipocytes. Arch Physiol Biochem 116:28–41
Nelson KE (2010) The human microbiome jumpstart reference strains consortium (2010) a catalog of reference genomes from the human microbiome. Science 328:994–999
Nosjean O, Roux B (1999) Ectoplasmic insertion of a glycosylphosphatidylinositol-anchored protein in glycosphingolipid- and cholesterol-containing phosphatidylcholine vesicles. Eur J Biochem 263:865–870
Nosjean O, Briolay A, Roux B (1997) Mammalian GPI proteins: sorting, membrane residence and functions. Biochim Biophys Acta 1331:153–186
Orlean P, Menon AK (2007) Thematic review series: lipid posttranslational modifications. GPI anchoring of protein in yeast and mammalian cells, or: how we learned to stop worrying and love glycophospholipids. J Lipid Res 48:993–1011
Parton RG, Joggerst B, Simons K (1994) Regulated internalization of caveolae. J Cell Biol 127:1199–1215
Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21:157–171
Poste G, Nicolson GL (1980) Arrest and metastasis of blood-born tumor cells are modified by fusion of plasma membrane vesicles from highly metastatic cells. Proc Natl Acad Sci U S A 77:399–403
Premkumar DR, Fukuoka Y, Sevlever D, Brunschwig E, Rosenberry TL, Tykocinski ML (2001) Properties of exogenously added GPI-anchored proteins following their incorporation into cells. J Cell Biochem 82:234–245
Prokopenko I, McCarthy MJ, Lindgren CM (2008) Type 2 diabetes: new genes, new understanding. Trends Genet 24:613–621
Rajendran L, Knölker H-J, Simons K (2010) Subcellular targeting strategies for drug design and delivery. Nat Rev Drug Discov 9:29–42
Ridderstrale M, Groop L (2009) Genetic dissection of type 2 diabetes. Mol Cell Endocrinol 297:10–17
Ronzon F, Morandat S, Roux B, Bortolato M (2004) Insertion of a glycosylphosphatidylinositol-anchored enzyme into liposomes. J Membr Biol 197:169–177
Soussan E, Cassel S, Blanzat M, Rico-Lattes I (2009) Drug delivery by soft matter: matrix and vesicular carriers. Angew Chem Int Ed 48:274–288
Stoorvogel W, Kleijmeer MJ, Geuze H, Raposo G (2002) The biogenesis and functions of exosomes. Traffic 3:321–330
Suzuki K, Okumura Y (2000) GPI-linked proteins do not transfer spontaneously from erythrocytes to liposomes. New aspects of reorganization of the cell membrane. Biochemistry 39:9477–9485
Thery C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 3:569–579
Uhrich KE, Cannizzaro SM, Langer RS, Shakesheff KM (1999) Polymeric systems for controlled drug release. Chem Rev 99:3181–3198
Varma R, Mayor S (1998) GPI-anchored proteins are organized in submicron domains at the cell surface. Nature 394:798–801
Xie FY, Woodle MC, Lu PY (2006) Harnessing in vivo siRNA delivery for drug discovery and therapeutic development. Drug Discov Today 11:67–73
Yang T, Choi MK, Cui FD, Kim JS, Chung SJ, Shim CK, Kim DD (2007) Preparation and evaluation of paclitaxel-loaded PEGylated immunoliposome. J Control Release 120:169–177
Yokoyama M (2005) Drug targeting with nano-sized carrier systems. J Artif Organs 8:77–84
Zhang F, Schmidt WG, Hou Y, Williams AF, Jacobson K (1992) Spontaneous incorporation of the glycosyl-phosphatidylinositol-linked protein Thy-1 into cell membranes. Proc Natl Acad Sci U S A 89:5231–5235
Zhao L (2010) The tale of our other genome. Science 465:879–880
Zhu J, Lee B, Buhman KK, Cheng JX (2009) A dynamic, cytoplasmic triacylglycerol pool in enterocytes revealed by ex vivo and in vivo coherent anti-Stokes Raman scattering imaging. J Lipid Res 59:1080–1089
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Müller, G. (2015). Insulin Analogs: Assessment of Insulin Mitogenicity and IGF-I Activity. In: Hock, F. (eds) Drug Discovery and Evaluation: Pharmacological Assays. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27728-3_71-1
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