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Is Hyperglycemia the Major Culprit in Diabetes or Simply a Marker of Endothelial

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

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.

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