From much of the media, public-service broadcasts, and, dare I say, most of the medical profession, we hear that controlling blood sugar (glucose) better will prolong life and improve its quality for most patients who have type-1 or type-2 diabetes.
Contrary to popular belief, though, we have little evidence suggesting that lowering or normalizing blood sugar will correct atherosclerosis and heart disease, increase longevity, or improve quality of life. 5, 7-9 We have no clinical intervention trial data showing improvement in cardiovascular complication outcomes with glucose control. 6 Like the man searching for his key under the street lamp, for many years physicians have focused their light on tightly controlling their diabetic patients’ blood glucose. Too often results from large studies are interpreted to justify this approach. Clinical trials suggest treatments that raise insulin levels increase weight and worsen cardiovascular risk factors despite improving glycemia. For example, despite improving glycemia, patients treated intensively in the Veterans Affairs Diabetes Feasibility Trial had a trend toward more cardiovascular events. 3, 4
Syndrome X or insulin resistance syndrome (IRS) or metabolic syndrome includes insulin resistance, hyperinsulinemia, glucose intolerance, dyslipidemia, hypertension, and obesity. 10 These often play a role in the development of CHD even before hyperglycemia occurs or reaches the levels seen in diabetes. 11-13 Insulin-resistant humans demonstrate a delay in the delivery of insulin across the endothelium to the interstitial fluid leading to compensatory hyperinsulinemia until the beta cells are unable to continue to offset the demand 14-17 Hyperglycemia ensues leading to overt type 2 diabetes. 10
Don’t get me wrong — lowering blood glucose is a desirable goal for treatment. The endothelial cell is vulnerable to the metabolic byproducts of hyperinsulinemia and to high glucose levels. Elevated glucose can increase oxidation, 18, 19 and chronic exposure to high glucose concentration impairs beta cells and worsens insulin resistance. 10, 20-22 Excess glucose has been shown to activate the enzyme protein kinase C (PKC) in endothelial cells, making them more permeable or leaky. 23 Moreover, prolonged hyperglycemia can alter proteins forming advanced glycosylated end products — AGEs, which especially injure the endothelial cells in small blood vessels, damaging the eyes, kidneys, and other organs. Cross-linking of AGEs with other proteins probably contributes to the basement membrane thickening associated with diabetes. 24
The endothelium is much more than a semi-permeable membrane. This single cell layer, which could cover 5,000 square meters, lines every blood vessel and is an active organ in its own right. In addition to transporting hormones such as insulin, the endothelial system also plays an important role in the regulation of blood flow, maintenance of vascular architecture, mononuclear cell (e.g., platelets and other leukocytes) migration, and hemostasis. 2, 25 Endothelial cells are constantly exposed to blood circulating toxins, inflammatory mediators, and lipoproteins, which appear to be irritating to the endothelium only when they are oxidized, e.g., OxLDL, OxChol are the main offenders. Acting as mechanosensors, endothelial cells sense changes in the shear stress of turbulent blood flow and responds by secreting factors that affect vessel tone and structure. 26 Endothelial cells regulate hemostasis by synthesizing a variety of pro-coagulant and anticoagulant factors, and they also regulate the inhibition of fibrinolysis. 25, 27, 28 In patients with type 2 diabetes and the insulin resistance syndrome or Syndrome X, several inhibiting and pro-coagulant factors are elevated. 28-31 Increased levels of the endothelial-derived pro-coagulant von Willebrand factor antedate microalbuminuria in type 2 diabetes which is consistent with generalized endothelial cell dysfunction. 32
Endothelial cells, vascular tone, and eicosanoids
The endothelial cells regulate vessel tone by releasing relaxing and contractile eicosanoids such as prostacyclin (PGI2) and thromboxane A2 (TXA2) which tend to have opposing biological functions. 27 Insulin stimulates the production of these arachidonic acid-derived eicosanoids. 33 In diabetes the equilibrium is pushed towards increased TXA2/PGI2 favoring vasoconstriction and hypertension. 27, 33, 34 A proposed mechanism for diabetic neuropathy involves the unopposed vasoconstriction action of TXA2 with ensuing ischemia. 35 Insulin inhibits PGI2 production in adipose tissue, therefore hyperinsulinemia associated with obesity could decrease PGI2 production and contribute to vasoconstriction and hypertension 33, 34 . Insulin also stimulates the endothelium to produce endothelin, a potent vasoconstrictor that is elevated in diabetes and directly stimulates smooth muscle proliferation of arterial walls 36-38 . Nitric oxide (NO), previously referred to as endothelium-dependent relaxing factor (EDRF), is synthesized in the endothelial cell from L-arginine and is the most potent endogenous vasodilator known. 25, 27 NO’s role in diabetes has been well-described.
Lipoxygenase (LO) metabolizes AA to produce leukotrienes and products that play an important role in atherosclerosis by inducing oxidation of LDL and stimulating growth and migration of vascular smooth muscle cells. 39 40 LO products, e.g., the HPETEs and HETEs, also activate many of the pathways linked to increased vascular and renal disease. Elevated glucose has been shown to increase the activity of the LO enzymes and production of LO products 41 . Type 2 diabetes is characterized by the loss of first-phase insulin release in response to glucose and increased and sustained insulin secretion during the second phase. The AA metabolite PGE2 is a potent inhibitor of first-phase insulin release, whereas the AA lipoxygenase product (possibly 12-HETE) sustains increased second-phase insulin release. 42
Next time we will address Measuring endothelial function and more
Eric S. Freedland, MD graduated from University of Rochester School of Medicine in 1982, trained in internal medicine at Mt. Auburn Hospital in Cambridge, MA, and emergency medicine at Harbor-UCLA Medical Center in Torrance, CA, and has held faculty positions at Harvard Medical School (1990-1991) and Boston University School of Medicine (1992-1997). Dr. Freedland has developed a nutrition-centered model of disease with a special emphasis on diabetes. A staunch advocate for prescribing lifestyle changes before drugs, Dr. Freedland has written and lectured extensively on this subject.
1. Dabelea D, Hanson R, Bennett P, Roumain J, Knowler W, Pettit D. Increasing prevalence of Type II diabetes in American Indian children. Diabetologia 1998; 41:904-10.
2. Pinkney JS, Coen D.A.; Coppack, Simon; Yudkin, John S. Endothelial Dysfunction : Cause of the Insulin Resistance Syndrome. Diabetes 1997; 46:s9-s13.
3. Abraira C, Colwell J, Nuttall F, et al. A critical issue: Intensive insulin treatment and macrovascular disease. Diabetes Care 1998; 21:669-671.
4. Abraira CC, John; Nuttall, Frank; Sawin, Clark; Henderson, William; Comstock, John; Emanuele, Nicholas; Levin, Seymour; Pacold, Ivan; Lee, Hae Sook; and the VACSDM Group. Cardiovascular Events and Correlates in the Veterans Affairs Diabetes Feasibility Trial. Arch Internal Medicine 1997; 157:181-188.
5. Association AD. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 1998; 21:2180-2184.
6. Duckworth WC, McCarren M, Abraira C. Glucose control and cardiovascular complications: the VA Diabetes Trial. Diabetes Care 2001; 24:942-5.
7. Barrett-Connor E. Does hyperglycemia really cause coronary heart disease ? Diabetes Care 1997; 20:1620-1623.
8. Barrett-Connor E, Wingard DL. “Normal”blood glucose and coronary risk: dose response effect seems consistent throughout the glycaemic continuum (editorial). BMJ 2001; 322:5-6.
9. Stern M. Glycemia and Cardiovascular Risk. Diabetes Care 1997; 20:page 1501.
10. Reaven G. Role of insulin resistance in human disease. Diabetes 1988; 37:1595-607.
11. Balkau B, Shipley M, Jarrett J, et al. High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. Diabetes Care 1998; 21:360-367.
12. Haffner S, Stern M, Hazuda H, Mitchell B, Patterson J. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 1990; 263:2893-2898.
13. Mykkanen L, Kuusisto J, Pyorala K, Laakso M. Cardiovascular risk factors as predictors of type II (non-insulin-dependent) diabetes mellitus in elderly subjects. Diabetologia 1993; 36:553-559.
14. Bergman R. New concepts in extracellular signaling for insulin action: the single gateway hypothesis. Recent Prog Horm Res 1997; 52:359-85.
15. Jansson P-AE, Fowelin J, Schenck HV, Smith U, Lonnroth P. Measurement by micordialysis of the insulin concentration in subcutaneous interstial fluid. Diabetes 1993; 42:1469-73.
16. Stiel G, Ader M, Moore D, Rebrin K, Bergman R. Transendothelial insulin transport is not saturable in vivo. No evidence for a receptor-mediated process. J Clin Invest 1996; 97:1497-503.
17. Yang Y, Hope I, Ader M, Bergman R. Insulin transport across capillaries is rate limiting for insulin action in dogs. J Clin Invest 1989; 84:1620-1628.
18. Mohanty P, Hamouda W, Garg R, Aljada A, Ghanim H, Dandona P. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J Clin Endocrinol Metab 2000; 85:2970-3.
19. Facchini FS, Humphreys MH, DoNascimento CA, Abbasi F, Reaven GM. Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols. Am J Clin Nutr 2000; 72:776-9.
20. DeFronzo RF, Eleuterio. Insulin Resistance: A multifaceted syndrome responsible for NIDDM, obesity , hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14:173-194.
21. Rosetti L, Giaccari A, DeFronzo R. Glucose Toxicity. Diabetes Care 1990; 13:610-630.
22. Yki-Jarvinen H. Glucose toxicity. Endocrine Reviews 1992; 13:415-431.
23. Hempel A, Maasch C, Heintze U, et al. High glucose concentrations increase endothelial cell permeability via activation of protein kinase C. Circulation Research 1997; 81:363-371.
24. Vlassara H. Recent progress in advanced glycation end products and diabetic complications. Diabetes 1997; 46, Suppl. 2:S19-S25.
25. Vane JA, Erik; Botting Regina. Regulatory functions of the vascular endothelium. The New England Journal Of Medicine 1990; 323:27-36.
26. Cooke JP. The endothelium: a new target for therapy. Vasc Med 2000; 5:49-53.
27. Carter AMG, P.J. Vascular homeostasis, adhesion molecules, and macrovascular disease in non-insulin dependent diabetes mellitus. Diabetic medicine 1997; 14:423-432.
28. Collier A, Rumley A, Rumley A, et al. Free radical activity and hemostatic factors in NIDDM patients with and without microalbuminuria. Diabetes 1992; 41:909-13.
29. Yudkin JS, Panahloo A, Stehouwer C, et al. The influence of improved glycaemic control with insulin and sulphonylureas on acute phase and endothelial markers in Type II diabetic subjects. Diabetologia 2000; 43:1099-106.
30. Yudkin JS. Abnormalities of coagulation and fibrinolysis in insulin resistance. Evidence for a common antecedent? Diabetes Care 1999; 22 Suppl 3:C25-30.
31. Rebrin K, Steil G, Mittleman S, Bergman R. Casual Linkage between Insulin Suppression of Lipolysis and Suppression of Liver Glucose Output in Dogs. Journal of Clinical Investigation 1996:741-749
32. Stehouwer CDAN, J.J.P.; Zeldenrust; G.C.; Hackeng, W.H.L.; Donker, A.J.M.; Den Ottlander, G.J.H. Urinary albumin excretion, cardiovascular disease , and endothelial dysfunction in non-insulin-dependent diabetes mellitus. The Lancet 1992; 340:319-323.
33. Axelrod L. Insulin, prostaglandins, and the pathogenesis of hypertension. Diabetes 1991; 40:1223-27.
34. Chatzipanteli KR, Sheila; Axelrod, Lloyd. Coordinate Control of Lipolysis by Prostaglandin E2 and Prostacyclin in Rat Adipose Tissue. Diabetes 1992; 41:927-935.
35. Greene D, Stevens M. The sorbitol-osmotic and sorbitol-redox hypotheses, Ch 89. In: LeRoith D, Taylor S, Olefsky J, eds. Diabetes Mellitus. Philadelphia: Lippincott-Raven Publishers, 1996:801-809.
36. Frank H, Levin E, Hu R-M, Pedram A. Insulin stimulates endothelin binding and action on cultured vascular smooth muscle cells. Endocrinology 1993; 133:1092-1097.
37. Oliver F, de la Rubia G, Feener E, et al. Stimulation of endothelin-1 expression by insulin in endothelial cells. J Biol Chem 1991; 266:23251-23256.
38. Takahashi K, Ghatei M, Lam H-C, O’Halloran D, Bloom S. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 1990; 33:306-310.
39. Natarajan R, Rosdahl J, Gonzales N, Bai W. Regulation of 12-lipoxygenase by cytokines in vascular smooth muscle cells. Hypertension 1997; 30:873-9.
40. Antonipillai I, Nadler J, Vu E, Bughi S, Natarajan R, Horton R. A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease. J Clin Endocrinol Metab 1996; 81:1940-5.
41. Natarajan R, Gu J-L, Rossi J, et al. Elevated glucose and angiotensin II increase 12-lipoxygenase activity and expression in porcine aortic smooth muscle cells. Proc Natl Acad Sci USA 1993; 90:4947-4951.
42. Raheja BS, Shaukat; ; Phatak, Raghunath; Rao, Madhubala. Significance of the N-6/N-3 Ratio for Insulin Action in Diabetes. Annals New York Academy of Sciences 1993; 683:258-271.
43. Celermajer DS, Sorensen K, Ryalls M, et al. Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents. J Am Coll Cardiol 1993; 22:854-8.