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Published in: Diabetologia 9/2005

01-09-2005 | Article

Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells

Authors: K. Staiger, H. Staiger, M. A. Schweitzer, E. Metzinger, B. Balletshofer, H.-U. Häring, M. Kellerer

Published in: Diabetologia | Issue 9/2005

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Abstract

Aims/hypothesis

Present guidelines for the treatment of type 2 diabetes recommend HbA1c values of less than 7%. As beta cell function worsens during progress of the disease, insulin therapy is often necessary to achieve this ambitious goal. However, due to peripheral insulin resistance, many patients need rather high insulin dosages. In the light of the extremely high cardiovascular risk of diabetic patients, it is important to determine whether high concentrations of insulin or its frequently used analogues are harmful to the cardiovascular system. We therefore investigated the modulatory effects of regular human insulin and its analogue glargine on proliferation and apoptosis of human coronary artery endothelial cells (HCAECs) and human coronary artery smooth muscle cells (HCASMCs).

Methods

Cells were treated with regular human insulin or insulin glargine. Proliferation was determined by [3H]thymidine incorporation and by flow cytometric analysis of Ki-67 expression. Apoptosis was assessed by flow cytometry (cell cycle analysis and annexin V staining) and determination of caspase-3 activity.

Results

HCAECs and HCASMCs treated with regular human insulin or insulin glargine did not show significant increases in DNA synthesis or Ki-67 expression. Administration of regular human insulin or insulin glargine did not modulate the extent of apoptotic events. No influence of insulin on lipoapoptotic vascular cell death could be detected.

Conclusions/interpretation

Taken together, neither regular human insulin nor insulin glargine influences growth and apoptosis of human coronary artery cells in vitro. Our data do not suggest that regular human insulin or insulin glargine promote atherosclerosis through mechanisms affecting the cellularity of human coronary arteries.
Literature
1.
go back to reference UK Prospective Diabetes Study Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853 UK Prospective Diabetes Study Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853
2.
go back to reference Fritsche A, Schweitzer MA, Haring HU (2003) Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med 138:952–959PubMed Fritsche A, Schweitzer MA, Haring HU (2003) Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med 138:952–959PubMed
3.
go back to reference Yki-Jarvinen H, Dressler A, Ziemen M, HOE 901/3002 study group (2000) Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 23:1130–1136PubMed Yki-Jarvinen H, Dressler A, Ziemen M, HOE 901/3002 study group (2000) Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 23:1130–1136PubMed
4.
go back to reference Riddle MC, Rosenstock J, Gerich J (2003) The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 26:3080–3086PubMed Riddle MC, Rosenstock J, Gerich J (2003) The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 26:3080–3086PubMed
5.
go back to reference Vehkavaara S, Makimattila S, Schlenzka A, Vakkilainen J, Westerbacka J, Yki-Jarvinen H (2000) Insulin therapy improves endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol 20:545–550PubMed Vehkavaara S, Makimattila S, Schlenzka A, Vakkilainen J, Westerbacka J, Yki-Jarvinen H (2000) Insulin therapy improves endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol 20:545–550PubMed
6.
go back to reference Vehkavaara S, Yki-Jarvinen H (2004) 3.5 years of insulin therapy with insulin glargine improves in vivo endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol 24:325–330CrossRefPubMed Vehkavaara S, Yki-Jarvinen H (2004) 3.5 years of insulin therapy with insulin glargine improves in vivo endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol 24:325–330CrossRefPubMed
7.
go back to reference Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, Trub T (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005PubMed Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, Trub T (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005PubMed
8.
go back to reference Diabetologia (2004) Plasma insulin and cardiovascular mortality in non-diabetic European men and women: a meta-analysis of data from eleven prospective studies. Diabetologia 47:1245–1256 Diabetologia (2004) Plasma insulin and cardiovascular mortality in non-diabetic European men and women: a meta-analysis of data from eleven prospective studies. Diabetologia 47:1245–1256
9.
go back to reference Caixas A, Ordonez-Llanos J, de Leiva A, Payes A, Homs R, Perez A (1997) Optimization of glycemic control by insulin therapy decreases the proportion of small dense LDL particles in diabetic patients. Diabetes 46:1207–1213PubMed Caixas A, Ordonez-Llanos J, de Leiva A, Payes A, Homs R, Perez A (1997) Optimization of glycemic control by insulin therapy decreases the proportion of small dense LDL particles in diabetic patients. Diabetes 46:1207–1213PubMed
10.
go back to reference Taskinen MR, Kuusi T, Helve E, Nikkila EA, Yki-Jarvinen H (1988) Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes. Arteriosclerosis 8:168–177PubMed Taskinen MR, Kuusi T, Helve E, Nikkila EA, Yki-Jarvinen H (1988) Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes. Arteriosclerosis 8:168–177PubMed
11.
go back to reference Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE (2004) Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 53:2079–2086PubMed Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE (2004) Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 53:2079–2086PubMed
12.
go back to reference Dandona P, Aljada A, Mohanty P (2002) The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 45:924–930CrossRefPubMed Dandona P, Aljada A, Mohanty P (2002) The anti-inflammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 45:924–930CrossRefPubMed
13.
go back to reference Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G (2003) Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 88:1082–1088CrossRefPubMed Hansen TK, Thiel S, Wouters PJ, Christiansen JS, Van den Berghe G (2003) Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 88:1082–1088CrossRefPubMed
14.
go back to reference Banskota NK, Taub R, Zellner K, Olsen P, King GL (1989) Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I. Diabetes 38:123–129PubMed Banskota NK, Taub R, Zellner K, Olsen P, King GL (1989) Characterization of induction of protooncogene c-myc and cellular growth in human vascular smooth muscle cells by insulin and IGF-I. Diabetes 38:123–129PubMed
15.
go back to reference Pfeifle B, Ditschuneit HH, Ditschuneit H (1982) Binding and biological actions of insulin-like growth factors on human arterial smooth muscle cells. Horm Metab Res 14:409–414PubMed Pfeifle B, Ditschuneit HH, Ditschuneit H (1982) Binding and biological actions of insulin-like growth factors on human arterial smooth muscle cells. Horm Metab Res 14:409–414PubMed
16.
go back to reference Avena R, Mitchell ME, Carmody B, Arora S, Neville RF, Sidaway AN (1999) Insulin-like growth factor-1 receptors mediate infragenicular vascular smooth muscle cell proliferation in response to glucose and insulin not by insulin receptors. Am J Surg 178:156–161PubMed Avena R, Mitchell ME, Carmody B, Arora S, Neville RF, Sidaway AN (1999) Insulin-like growth factor-1 receptors mediate infragenicular vascular smooth muscle cell proliferation in response to glucose and insulin not by insulin receptors. Am J Surg 178:156–161PubMed
17.
go back to reference Yamada H, Tsushima T, Murakami H, Uchigata Y, Iwamoto Y (2002) Potentiation of mitogenic activity of platelet-derived growth factor by physiological concentrations of insulin via the MAP kinase cascade in rat A10 vascular smooth muscle cells. Int J Exp Diabetes Res 3:131–144CrossRefPubMed Yamada H, Tsushima T, Murakami H, Uchigata Y, Iwamoto Y (2002) Potentiation of mitogenic activity of platelet-derived growth factor by physiological concentrations of insulin via the MAP kinase cascade in rat A10 vascular smooth muscle cells. Int J Exp Diabetes Res 3:131–144CrossRefPubMed
18.
go back to reference Cruzado M, Risler N, Castro C, Ortiz A, Ruttler ME (1998) Proliferative effect of insulin on cultured smooth muscle cells from rat mesenteric resistance vessels. Am J Hypertens 11:54–58CrossRefPubMed Cruzado M, Risler N, Castro C, Ortiz A, Ruttler ME (1998) Proliferative effect of insulin on cultured smooth muscle cells from rat mesenteric resistance vessels. Am J Hypertens 11:54–58CrossRefPubMed
19.
go back to reference Kamide K, Hori MT, Zhu JH et al (2000) Insulin and insulin-like growth factor-I promotes angiotensinogen production and growth in vascular smooth muscle cells. J Hypertens 18:1051–1056CrossRefPubMed Kamide K, Hori MT, Zhu JH et al (2000) Insulin and insulin-like growth factor-I promotes angiotensinogen production and growth in vascular smooth muscle cells. J Hypertens 18:1051–1056CrossRefPubMed
20.
go back to reference Agazie YM, Bagot JC, Trickey E, Halenda SP, Wilden PA (2001) Molecular mechanisms of ATP and insulin synergistic stimulation of coronary artery smooth muscle growth. Am J Physiol Heart Circ Physiol 280:H795–H801PubMed Agazie YM, Bagot JC, Trickey E, Halenda SP, Wilden PA (2001) Molecular mechanisms of ATP and insulin synergistic stimulation of coronary artery smooth muscle growth. Am J Physiol Heart Circ Physiol 280:H795–H801PubMed
21.
go back to reference King GL, Goodman AD, Buzney S, Moses A, Kahn CR (1985) Receptors and growth-promoting effects of insulin and insulin-like growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest 75:1028–1036PubMed King GL, Goodman AD, Buzney S, Moses A, Kahn CR (1985) Receptors and growth-promoting effects of insulin and insulin-like growth factors on cells from bovine retinal capillaries and aorta. J Clin Invest 75:1028–1036PubMed
22.
go back to reference King GL, Buzney SM, Kahn CR et al (1983) Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels. J Clin Invest 71:974–979PubMed King GL, Buzney SM, Kahn CR et al (1983) Differential responsiveness to insulin of endothelial and support cells from micro- and macrovessels. J Clin Invest 71:974–979PubMed
23.
go back to reference Chisalita SI, Arnqvist HJ (2004) Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells. Am J Physiol Endocrinol Metab 286:E896–E901CrossRefPubMed Chisalita SI, Arnqvist HJ (2004) Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells. Am J Physiol Endocrinol Metab 286:E896–E901CrossRefPubMed
24.
go back to reference Nitert MD, Chisalita SI, Olsson K, Bornfeldt KE, Arnqvist HJ (2005) IGF-I/insulin hybrid receptors in human endothelial cells. Mol Cell Endocrinol 229:31–37CrossRefPubMed Nitert MD, Chisalita SI, Olsson K, Bornfeldt KE, Arnqvist HJ (2005) IGF-I/insulin hybrid receptors in human endothelial cells. Mol Cell Endocrinol 229:31–37CrossRefPubMed
25.
go back to reference Zeng G, Quon MJ (1996) Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 98:894–898PubMed Zeng G, Quon MJ (1996) Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 98:894–898PubMed
26.
go back to reference Hermann C, Assmus B, Urbich C, Zeiher AM, Dimmeler S (2000) Insulin-mediated stimulation of protein kinase Akt: a potent survival signaling cascade for endothelial cells. Arterioscler Thromb Vasc Biol 20:402–409PubMed Hermann C, Assmus B, Urbich C, Zeiher AM, Dimmeler S (2000) Insulin-mediated stimulation of protein kinase Akt: a potent survival signaling cascade for endothelial cells. Arterioscler Thromb Vasc Biol 20:402–409PubMed
27.
go back to reference Eitel K, Staiger H, Rieger J et al (2003) Protein kinase C delta activation and translocation to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells. Diabetes 52:991–997PubMed Eitel K, Staiger H, Rieger J et al (2003) Protein kinase C delta activation and translocation to the nucleus are required for fatty acid-induced apoptosis of insulin-secreting cells. Diabetes 52:991–997PubMed
28.
go back to reference Geng YJ, Libby P (2002) Progression of atheroma: a struggle between death and procreation. Arterioscler Thromb Vasc Biol 22:1370–1380CrossRefPubMed Geng YJ, Libby P (2002) Progression of atheroma: a struggle between death and procreation. Arterioscler Thromb Vasc Biol 22:1370–1380CrossRefPubMed
29.
go back to reference Dzau VJ, Braun-Dullaeus RC, Sedding DG (2002) Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med 8:1249–1256CrossRefPubMed Dzau VJ, Braun-Dullaeus RC, Sedding DG (2002) Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med 8:1249–1256CrossRefPubMed
30.
go back to reference Bombeli T, Karsan A, Tait JF, Harlan JM (1997) Apoptotic vascular endothelial cells become procoagulant. Blood 89:2429–2442PubMed Bombeli T, Karsan A, Tait JF, Harlan JM (1997) Apoptotic vascular endothelial cells become procoagulant. Blood 89:2429–2442PubMed
31.
go back to reference Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A (1999) Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99:348–353PubMed Mallat Z, Hugel B, Ohan J, Leseche G, Freyssinet JM, Tedgui A (1999) Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 99:348–353PubMed
32.
go back to reference Libby P (1995) Molecular bases of the acute coronary syndromes. Circulation 91:2844–2850PubMed Libby P (1995) Molecular bases of the acute coronary syndromes. Circulation 91:2844–2850PubMed
33.
go back to reference Jamali R, Bao M, Arnqvist HJ (2003) IGF-I but not insulin inhibits apoptosis at a low concentration in vascular smooth muscle cells. J Endocrinol 179:267–274CrossRefPubMed Jamali R, Bao M, Arnqvist HJ (2003) IGF-I but not insulin inhibits apoptosis at a low concentration in vascular smooth muscle cells. J Endocrinol 179:267–274CrossRefPubMed
34.
go back to reference Goetze S, Blaschke F, Stawowy P et al (2001) TNFalpha inhibits insulin’s antiapoptotic signaling in vascular smooth muscle cells. Biochem Biophys Res Commun 287:662–670CrossRefPubMed Goetze S, Blaschke F, Stawowy P et al (2001) TNFalpha inhibits insulin’s antiapoptotic signaling in vascular smooth muscle cells. Biochem Biophys Res Commun 287:662–670CrossRefPubMed
35.
go back to reference Bennett MR, Evan GI, Schwartz SM (1995) Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 95:2266–2274PubMed Bennett MR, Evan GI, Schwartz SM (1995) Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J Clin Invest 95:2266–2274PubMed
36.
go back to reference Patel VA, Zhang QJ, Siddle K et al (2001) Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling. Circ Res 88:895–902PubMed Patel VA, Zhang QJ, Siddle K et al (2001) Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling. Circ Res 88:895–902PubMed
37.
go back to reference Okura Y, Brink M, Zahid AA, Anwar A, Delafontaine P (2001) Decreased expression of insulin-like growth factor-1 and apoptosis of vascular smooth muscle cells in human atherosclerotic plaque. J Mol Cell Cardiol 33:1777–1789CrossRefPubMed Okura Y, Brink M, Zahid AA, Anwar A, Delafontaine P (2001) Decreased expression of insulin-like growth factor-1 and apoptosis of vascular smooth muscle cells in human atherosclerotic plaque. J Mol Cell Cardiol 33:1777–1789CrossRefPubMed
38.
go back to reference Artwohl M, Roden M, Waldhausl W, Freudenthaler A, Baumgartner-Parzer SM (2004) Free fatty acids trigger apoptosis and inhibit cell cycle progression in human vascular endothelial cells. FASEB J 18:146–148PubMed Artwohl M, Roden M, Waldhausl W, Freudenthaler A, Baumgartner-Parzer SM (2004) Free fatty acids trigger apoptosis and inhibit cell cycle progression in human vascular endothelial cells. FASEB J 18:146–148PubMed
Metadata
Title
Insulin and its analogue glargine do not affect viability and proliferation of human coronary artery endothelial and smooth muscle cells
Authors
K. Staiger
H. Staiger
M. A. Schweitzer
E. Metzinger
B. Balletshofer
H.-U. Häring
M. Kellerer
Publication date
01-09-2005
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2005
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-005-1874-4

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