Mark Creager, M.D.

Atherosclerosis is a major cause of death and disability in patients with diabetes mellitus. Endothelial dysfunction is an important factor in atherogenesis. Among the substances normally synthesized and released by the endothelium is nitric oxide, which has been shown to regulate vascular tone, inhibit leukocyte adhesion to the vascular wall, inhibit platelet aggregation, and reduce proliferation of vascular smooth muscle. Studies conducted in experimental models of diabetes indicate that endothelium-dependent vasodilation is impaired, implicating decreased bioavailability of nitric oxide. Dr. Creager and his colleagues have extended these findings to humans. Using techniques such as venous occlusion plethysmography and vascular ultrasonography, his laboratory has shown that endothelium-dependent vasodilation is abnormal both in patients with type I diabetes mellitus and in patients with type II diabetes mellitus. Moreover, his laboratory has found that hyperglycemia, per se, a common finding in patients with both type I and type II diabetes mellitus, induces abnormal endothelium-dependent vasodilation. Reactive oxygen species, such as superoxide anion, inactivate nitric oxide and may contribute to alterations in vasomotor reactivity. Dr. Creager's laboratory has shown that the antioxidant, vitamin C, improves endothelium-dependent vasodilation in patients with type I and type II diabetes mellitus, and in healthy subjects exposed to a six hour hyperglycemic clamp. In addition, his laboratory has found that PKC_β, an important intracellular signaling molecule, contributes to hyperglycemia-induced endothelial dysfunction. These findings have implications regarding the pathogenesis of vascular disease in diabetes and treatment strategies that may be considered to reduce vascular complications in this population. Co-investigators and collaborators who have participated in these studies include Dr. Joshua Beckman and Dr. Allison Goldfine.

References:

1. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996;97:22-28.

2. Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567-574.

3. Ting HH, Timimi FK, Haley EA, Roddy M-A, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation. 1997;95:2617-2622.

4. Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy M-A, Simonson DC, Creager MA. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation. 1998;97: 1695-1701.

5. Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation. 2001;103:1618-1623.

6. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA. Inhibition of protein kinase C_ß prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res. 2002;90:107-111.

7. Nohria A, Garrett L, Johnson W, Kinlay S, Ganz P, Creager MA.Endothelin-1 and vascular tone in subjects with atherogenic risk factors. Hypertension. 2003;42:43-8.

8. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Keaney JF Jr, Creager MA. Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol. 2003 ;285:H2392-8.


	Mark Creager, M.D. Atherosclerosis in Diabetes Atherosclerosis is a major cause of death and disability in patients with diabetes mellitus. Endothelial dysfunction is an important factor in atherogenesis. Among the substances normally synthesized and released by the endothelium is nitric oxide, which has been shown to regulate vascular tone, inhibit leukocyte adhesion to the vascular wall, inhibit platelet aggregation, and reduce proliferation of vascular smooth muscle. Studies conducted in experimental models of diabetes indicate that endothelium-dependent vasodilation is impaired, implicating decreased bioavailability of nitric oxide. Dr. Creager and his colleagues have extended these findings to humans. Using techniques such as venous occlusion plethysmography and vascular ultrasonography, his laboratory has shown that endothelium-dependent vasodilation is abnormal both in patients with type I diabetes mellitus and in patients with type II diabetes mellitus. Moreover, his laboratory has found that hyperglycemia, per se, a common finding in patients with both type I and type II diabetes mellitus, induces abnormal endothelium-dependent vasodilation. Reactive oxygen species, such as superoxide anion, inactivate nitric oxide and may contribute to alterations in vasomotor reactivity. Dr. Creager's laboratory has shown that the antioxidant, vitamin C, improves endothelium-dependent vasodilation in patients with type I and type II diabetes mellitus, and in healthy subjects exposed to a six hour hyperglycemic clamp. In addition, his laboratory has found that PKC_β, an important intracellular signaling molecule, contributes to hyperglycemia-induced endothelial dysfunction. These findings have implications regarding the pathogenesis of vascular disease in diabetes and treatment strategies that may be considered to reduce vascular complications in this population. Co-investigators and collaborators who have participated in these studies include Dr. Joshua Beckman and Dr. Allison Goldfine. References: 1. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 1996;97:22-28. 2. Williams SB, Cusco JA, Roddy MA, Johnstone MT, Creager MA. Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1996;27:567-574. 3. Ting HH, Timimi FK, Haley EA, Roddy M-A, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation. 1997;95:2617-2622. 4. Williams SB, Goldfine AB, Timimi FK, Ting HH, Roddy M-A, Simonson DC, Creager MA. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation. 1998;97: 1695-1701. 5. Beckman JA, Goldfine AB, Gordon MB, Creager MA. Ascorbate restores endothelium-dependent vasodilation impaired by acute hyperglycemia in humans. Circulation. 2001;103:1618-1623. 6. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Creager MA. Inhibition of protein kinase C_ß prevents impaired endothelium-dependent vasodilation caused by hyperglycemia in humans. Circ Res. 2002;90:107-111. 7. Nohria A, Garrett L, Johnson W, Kinlay S, Ganz P, Creager MA.Endothelin-1 and vascular tone in subjects with atherogenic risk factors. Hypertension. 2003;42:43-8. 8. Beckman JA, Goldfine AB, Gordon MB, Garrett LA, Keaney JF Jr, Creager MA. Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol. 2003 ;285:H2392-8.