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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:889.)
© 2005 American Heart Association, Inc.

Editorials

The Union of Vascular and Metabolic Actions of Insulin in Sickness and in Health

Jeong-a Kim; Kwang Kon Koh; Michael J. Quon

From the Diabetes Unit, NCCAM (J.K., M.J.Q.), National Institutes of Health, Bethesda, Md; and the Vascular Medicine and Atherosclerosis Unit (K.K.K.), Cardiology, Gil Heart Center, Gachon Medical School, Incheon, Korea.

Correspondence to Michael J. Quon, MD, PhD, Chief, Diabetes Unit, NCCAM, NIH, 10 Center Drive, Building 10, Room 6C-205, Bethesda, MD 20892-1632. E-mail quonm{at}nih.gov

	Introduction

Top Introduction Coupling of Hemodynamic and... Insulin Resistance, Endothelial... Coupling of Vascular and... Future Prospects References

 
Disorders of metabolic homeostasis including type 2 diabetes, obesity, and dyslipidemias are characterized by both insulin resistance and endothelial dysfunction.¹ Insulin resistance and endothelial dysfunction are also prominent features of important cardiovascular disorders including hypertension, coronary artery disease, and atherosclerosis.² Indeed, insulin resistance is thought to be the tie that binds metabolic and cardiovascular disorders together in an unhappy union called the metabolic syndrome (aka the insulin resistance syndrome).^3,4 Although these associations are well established, molecular mechanisms explaining the underlying pathophysiology are not completely understood. Interestingly, inflammation mediated by innate immune signaling pathways has been implicated in both metabolic insulin resistance and vascular endothelial dysfunction.^1,5,6 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Kim et al demonstrate that treatment of vascular endothelial cells with the free fatty acid (FFA) palmitate activates IKKß (a proinflammatory signaling molecule), impairs insulin signaling, and decreases insulin-stimulated production of nitric oxide (NO).⁷ Importantly, inhibitory effects of FFA treatment on insulin signaling and NO production are blocked by overexpression of a dominant inhibitory mutant of IKKß. Moreover, deleterious effects of FFA treatment are recapitulated by overexpression of wild-type IKKß. Thus, Kim et al have uncovered an additional link between metabolic and vascular pathophysiology that helps to explain mechanisms underlying the metabolic syndrome and related cardiovascular diseases. To understand the importance of these findings it is useful to review the mechanisms coupling vascular and metabolic physiology, the role of inflammation in insulin resistance, and the role of insulin resistance to couple vascular and metabolic pathophysiology (Figure).

View larger version (41K): [in this window] [in a new window]   The union of vascular and metabolic actions of insulin in sickness and in health. Insulin-stimulated production of NO in vascular endothelium is mediated by the insulin receptor (IR) tyrosine kinase that phosphorylates IRS-1, leading to binding and activation of PI 3-kinase and activation of PDK-1, which in turn phosphorylates and activates Akt and finally phosphorylates and activates eNOS. The resulting increase in production of NO mediates vasodilation and increased blood flow. Insulin-stimulated glucose uptake in skeletal muscle and adipose tissue involves a similar signaling pathway culminating in translocation of GLUT4 glucose transporters to the cell surface. Under healthy conditions, vasodilator actions of insulin augment direct effects of insulin on glucose transport in skeletal muscle and adipose tissue to increase glucose uptake. In metabolic and cardiovascular diseases including diabetes, obesity, dyslipidemias, hypertension, coronary artery disease, and atherosclerosis, inflammatory signaling through IKKß in response to cytokines and elevated FFA levels causes insulin resistance in both vascular endothelium and metabolic targets of insulin. Thus, inflammatory mechanisms of insulin resistance are shared in vascular endothelium and metabolic targets of insulin, and this contributes to both metabolic and cardiovascular diseases.

See page 989

	Coupling of Hemodynamic and Metabolic Physiology Through Insulin Action

Top Introduction Coupling of Hemodynamic and... Insulin Resistance, Endothelial... Coupling of Vascular and... Future Prospects References

 
Regulation of hemodynamic and metabolic homeostasis may be coupled by physiological actions of insulin in the vascular endothelium to stimulate production of NO.⁴ The metabolic action of insulin to promote glucose uptake in skeletal muscle and adipose tissue is initiated by activation of the insulin receptor tyrosine kinase, subsequent phosphorylation of IRS-1, binding and activation of PI 3-kinase, activation of the serine kinase PDK-1, that in turn phosphorylates and activates Akt and PKC-, leading to recruitment of GLUT4 glucose transporters to the cell surface.⁸ A similar pathway exists in vascular endothelium involving the insulin receptor, IRS-1, PI 3-kinase, PDK-1, and Akt that leads to phosphorylation and activation of eNOS by Akt with a resultant increase in production of NO.^9–12 Insulin-stimulated production of NO leads to capillary recruitment, vasodilation, and increased blood flow to skeletal muscle that improves delivery of glucose and insulin to skeletal muscle.⁴ Indeed, insulin-stimulated increases in capillary recruitment and total limb blood flow per se may account for up to 40% of insulin-mediated glucose disposal.^13–15 Thus, insulin signaling pathways that are shared in common in distinct tissues with vascular or metabolic functions may help to tightly couple regulation of vascular function with glucose metabolism.

	Insulin Resistance, Endothelial Dysfunction, and Inflammation

Top Introduction Coupling of Hemodynamic and... Insulin Resistance, Endothelial... Coupling of Vascular and... Future Prospects References

 
Metabolic insulin resistance has both genetic and acquired causes. The causes for acquired insulin resistance related to diabetes and obesity include glucotoxicity and lipotoxicity resulting from hyperglycemica and elevated FFA levels.¹⁶ Elevated levels of glucose and lipids increase oxidative stress, advanced glycation end products, flux through the hexosamine biosynthetic pathway, activation of PKC, and activation of proinflammatory pathways in skeletal muscle and adipose tissue leading to insulin resistance. Of note, these same mechanisms also participate in endothelial dysfunction.^17,18 With respect to inflammation, elevations in FFA associated with obesity and diabetes are linked to activation of IKKß.⁵ This leads to cross-talk between inflammatory signaling and insulin signaling that impairs IRS-1/PI 3-kinase function and causes metabolic insulin resistance.^19,20 It is known that elevations in FFA also lead to endothelial dysfunction.¹ The study by Kim et al suggests that IKKß is mediating insulin resistance in endothelium in response to FFA resulting in endothelial dysfunction using a mechanism similar to that in metabolic targets of insulin. Thus IKKß may play an important role in both metabolic insulin resistance and vascular endothelial dysfunction.

	Coupling of Vascular and Metabolic Pathophysiology Through Insulin Resistance

Top Introduction Coupling of Hemodynamic and... Insulin Resistance, Endothelial... Coupling of Vascular and... Future Prospects References

 
A variety of rodent models support the idea that insulin resistance may couple vascular and metabolic pathophysiology. For example, mice that are homozygous null for the eNOS gene have an expected hemodynamic phenotype of increased basal blood pressure.²¹ Interestingly, these eNOS knockout mice also have metabolic insulin resistance and markedly diminished insulin-stimulated increases in hindlimb muscle blood flow.^22,23 Similarly, IRS-1 knock-out mice that have an expected metabolic phenotype of insulin resistance²⁴ are also hypertensive with impaired endothelium-dependent vasodilation.²⁵ Finally, transgenic mice with endothelial-specific ablation of the insulin receptor have a metabolic phenotype of insulin resistance on either a low salt or high salt diet suggesting that insulin signaling in vascular endothelium contributes to insulin-mediated glucose disposal in certain contexts.²⁶ Interestingly, infusing intra-lipid into rats to raise circulating FFA levels causes a significant 65% impairment in insulin-mediated skeletal muscle capillary recruitment with a concomitant 40% decrease in glucose disposal during a glucose clamp.²⁷ The finding by Kim et al that FFA-mediated activation of IKKß in vascular endothelium leads to impaired insulin signaling and decreased insulin-stimulated production of NO provides further support for the idea that parallel signaling mechanisms in skeletal muscle and vascular endothelium serve to couple metabolic and vascular pathophysiology.

	Future Prospects

Top Introduction Coupling of Hemodynamic and... Insulin Resistance, Endothelial... Coupling of Vascular and... Future Prospects References

 
Inflammatory mechanisms appear to be important for mediating both metabolic insulin resistance and impaired insulin action in vascular endothelium that contribute to the relationship between metabolic and cardiovascular disorders. This has implications for novel therapeutic strategies because drugs that reduce inflammation would be predicted to improve both metabolic and endothelial function. Indeed, recent clinical studies have demonstrated additive beneficial endothelial and metabolic effects of combining statins (that have antiinflammatory properties) with angiotensin II type 1 receptor blockers, fenofibrate, or angiotensin converting enzyme inhibitors in the treatment of patients with hypertension, hyperlipidemia, or type 2 diabetes, respectively.^28–30

	References

Top Introduction Coupling of Hemodynamic and... Insulin Resistance, Endothelial... Coupling of Vascular and... Future Prospects References

 
1. Caballero AE. Endothelial dysfunction, inflammation, and insulin resistance: a focus on subjects at risk for type 2 diabetes. Curr Diab Rep. 2004; 4: 237–246.[Medline] [Order article via Infotrieve]

2. Hsueh WA, Lyon CJ, Quinones MJ. Insulin resistance and the endothelium. Am J Med. 2004; 117: 109–117.[CrossRef][Medline] [Order article via Infotrieve]

3. Feener EP, King GL. Endothelial dysfunction in diabetes mellitus: role in cardiovascular disease. Heart Fail Monit. 2001; 1: 74–82.[Medline] [Order article via Infotrieve]

4. Vincent MA, Montagnani M, Quon MJ. Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Curr Diab Rep. 2003; 3: 279–288.[Medline] [Order article via Infotrieve]

5. Shoelson SE, Lee J, Yuan M. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. Int J Obes Relat Metab Disord. 2003; 27 (Suppl 3): S49–S52.

6. Perseghin G, Petersen K, Shulman GI. Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes Relat Metab Disord. 2003; 27 (Suppl 3): S6–S11.

7. Kim F, Tysseling KA, Rice J, Pham M, Haji L, Gallis BM, Baas AS, Paramsothy P, Giachelli CM, Corson MA, Raines EW. Free Fatty Acid Impairment of Nitric Oxide Production in Endothelial Cells Is Mediated by IKK{beta}. Arterioscler Thromb Vasc Biol. 2005; 25: 989–994.[Abstract/Free Full Text]

8. Nystrom FH, Quon MJ. Insulin signalling: metabolic pathways and mechanisms for specificity. Cell Signal. 1999; 11: 563–574.[CrossRef][Medline] [Order article via Infotrieve]

9. Zeng G, Quon MJ. Insulin-stimulated production of nitric oxide is inhibited by wortmannin: direct measurement in vascular endothelial cells. J Clin Invest. 1996; 98: 894–898.[Medline] [Order article via Infotrieve]

10. Zeng G, Nystrom FH, Ravichandran LV, Cong LN, Kirby M, Mostowski H, Quon MJ. Roles for insulin receptor, PI3-kinase, and Akt in insulin-signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation. 2000; 101: 1539–1545.[Abstract/Free Full Text]

11. Montagnani M, Chen H, Barr VA, Quon MJ. Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem. 2001; 276: 30392–30398.[Abstract/Free Full Text]

12. Montagnani M, Ravichandran LV, Chen H, Esposito DL, Quon MJ. Insulin receptor substrate-1 and phosphoinositide-dependent kinase-1 are required for insulin-stimulated production of nitric oxide in endothelial cells. Mol Endocrinol. 2002; 16: 1931–1942.[Abstract/Free Full Text]

13. Vincent MA, Clerk LH, Lindner JR, Klibanov AL, Clark MG, Rattigan S, Barrett EJ. Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes. 2004; 53: 1418–1423.[Abstract/Free Full Text]

14. Vincent MA, Barrett EJ, Lindner JR, Clark MG, Rattigan S. Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol Endocrinol Metab. 2003; 285: E123–E129.[Abstract/Free Full Text]

15. Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD. Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent: a novel action of insulin to increase nitric oxide release. J Clin Invest. 1994; 94: 1172–1179.

16. Sivitz WI. Lipotoxicity and glucotoxicity in type 2 diabetes. Effects on development and progression. Postgrad Med. 2001; 109: 55–59, 63–54.

17. Basta G, Schmidt AM, De Caterina R. Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. Cardiovasc Res. 2004; 63: 582–592.[Abstract/Free Full Text]

18. Endemann DH, Schiffrin EL. Nitric oxide, oxidative excess, and vascular complications of diabetes mellitus. Curr Hypertens Rep. 2004; 6: 85–89.[Medline] [Order article via Infotrieve]

19. Gao Z, Zhang X, Zuberi A, Hwang D, Quon MJ, Lefevre M, Ye J. Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3–L1 adipocytes. Mol Endocrinol. 2004; 18: 2024–2034.[Abstract/Free Full Text]

20. Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem. 2002; 277: 48115–48121.[Abstract/Free Full Text]

21. Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature. 1995; 377: 239–242.[CrossRef][Medline] [Order article via Infotrieve]

22. Shankar RR, Wu Y, Shen HQ, Zhu JS, Baron AD. Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance. Diabetes. 2000; 49: 684–687.[Abstract]

23. Duplain H, Burcelin R, Sartori C, Cook S, Egli M, Lepori M, Vollenweider P, Pedrazzini T, Nicod P, Thorens B, Scherrer U. Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation. 2001; 104: 342–345.[Abstract/Free Full Text]

24. Araki E, Lipes MA, Patti ME, Bruning JC, Haag B, 3rd, Johnson RS, Kahn CR. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994; 372: 186–190.[CrossRef][Medline] [Order article via Infotrieve]

25. Abe H, Yamada N, Kamata K, Kuwaki T, Shimada M, Osuga J, Shionoiri F, Yahagi N, Kadowaki T, Tamemoto H, Ishibashi S, Yazaki Y, Makuuchi M. Hypertension, hypertriglyceridemia, and impaired endothelium-dependent vascular relaxation in mice lacking insulin receptor substrate-1. J Clin Invest. 1998; 101: 1784–1788.[Medline] [Order article via Infotrieve]

26. Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, Bursell S, Yanagisawa M, King GL, Kahn CR. The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J Clin Invest. 2003; 111: 1373–1380.[CrossRef][Medline] [Order article via Infotrieve]

27. Clerk LH, Rattigan S, Clark MG. Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes. 2002; 51: 1138–1145.[Abstract/Free Full Text]

28. Koh KK, Quon MJ, Han SH, Chung W-J, Ahn JY, Seo Y-H, Kang MH, Ahn TH, Choi IS, Shin EK. Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients. Circulation. 2004; 110: 3687–3692.[Abstract/Free Full Text]

29. Koh KK, Quon MJ, Han SH, Chung WJ, Ahn JY, Seo YH, Kang WC, Shin EK. Additive beneficial effects of fenofibrate combined with atorvastatin in the treatment of patients with combined hyperlipidemia. J Am Coll Cardiol. In press.

30. Koh KK, Quon MJ, Han SH, Ahn JY, Jin DK, Kim HS, Kim DS, Shin EK. Beneficial vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes. Hypertension. In press.

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