Nitric oxide (NO)
A diabetic environment high in free radicals and low in antioxidants may disrupt endothelial function. A highly active regulatory organ, the endothelium senses and assesses signals to which it is constantly exposed by the blood, and responds by secreting factors that affect blood vessels’ tone and structure. 26 On the endothelial cell’s surface specific receptors sense such changes as shear stress or force of blood turbulence acting on the endothelium as it flows by, oxidized LDLs, and inflammatory mediators. The endothelial receptors use a number of pathways to translate signals from their environment and make adjustments. One of these, the L-arginine pathway, generates nitric oxide (NO), a gas that protects the vessel wall’s health. 148 When endothelial cells produce NO, it dilates (opens) blood vessels and delivers more blood. Nitric oxide also combats oxidation and can be depleted or elevated in diseases related to endothelial dysfunction. Concentrations of NO were found to be higher in a group of patients with insulin resistance, possibly because the endothelium was compensating to overcome the unfavorable effects of insulin resistance and high insulin concentration (hyperinsulinemia). 149
Adequate intracellular supplies of L-arginine are believed to be critical in forming enough NO. Though plenty of L-arginine usually seems to be available, small supplements may increase the endothelium’s production of NO in patients with high cholesterol and diabetes, 150 and long-term supplementing with l-arginine has been shown to improve endothelial function in the small arteries that supply the heart. 151 Supplementing also shows promise in preventing atherosclerosis-related heart disease 152, 153 .
When production of NO is inhibited, the endothelium triggers secretion of adhesion molecules that attract white blood cells and cause them to stick to the endothelial surface along the blood-vessel wall. This sequence is part of inflammation, but NO also prevents inflammation by keeping circulating white blood cells from attaching to vessel walls.
Throughout the body tiny blood clots commonly form but are quickly broken down and rendered harmless. Clots are of course necessary to protect against significant bleeding, but syndrome X (metabolic syndrome) and diabetes heighten the tendency for blood to clot, and increase risk for stroke and myocardial infarction (MI). Measures of body fat are strongly associated with circulating levels of fibrinogen, 154 which plays a critical role in clotting. Even those who apparently are healthy but whose blood insulin is high have been found to impair ability to dissolve blood clots (fibrinolysis). The endothelium is mainly responsible for the delicate balance of fibrinolysis. Plasminogen activator (tPA), a natural tissue enzyme that dissolves blood clots, is used in treating patients suffering from acute heart attack. Fat cells as well as endothelial cells secrete plasminogen activator inhibitor-1 (PAI-1), which increases with obesity and, as its name implies, inhibits plasminogen activator. 94 Damaged or dysfunctional endothelial cells also are linked to increased PAI-1. When PAI-1 is over-expressed, blood clots (thromboses) form more readily, a major event leading to atherosclerosis. But NO helps keep PAI-1 under control and so prevents life and limb-threatening thromboses, life-threatening clots that can wholly occlude a blood vessel. 155
Risks in “improving” control of blood glucose
Elevated insulin by itself is a predictor of CHD and death. 129, 156-159 Injected insulin, drugs, and diets that raise insulin concentrations are harmful. Adverse effects include: cost, patient inconvenience, consumption of medical resources, hypoglycemia, weight gain, early worsening of angiopathy 160 and lipid profiles, increased blood pressure, 161 162 drug side effects, and unknown drug interactions. In the United Kingdom Prospective Diabetes Study fasting insulin levels at nine years were higher in patients assigned to sulfonylurea and insulin therapy than those assigned to conventional therapy, 163 placing them at higher risk for CHD. 164 Sulfonylurea therapy in the University Group Diabetes Program study also was associated with an increase in cardiovascular events. 165 A 1997 study demonstrates that insulin therapy requires expensive resources and is rarely effective in decreasing risk of severe complications. 166 Commenting on the 1997 article, the American Diabetes Association’s chief scientific and medical officer comments, “Intuitively, people thought, of course if you give insulin, people will do better. But this shows we’re not doing so great.”
Patients are encouraged to think they can make up for that extra- rich dessert simply by injecting a little extra insulin to avoid “risking” higher blood glucose. 167, 168 This mindset is a risky proposition. In fact, studies such as the Veterans Affairs Cooperative Study on Glycemic Control and Complications in Diabetes Mellitus, examined intensive treatment with oral drugs, insulin, or both —compared to those treated less aggressively. They found that more people who were intensively treated and had “more improved” blood glucose concentrations (as reflected by HbA1c) died, 4 and fibrinogen levels were increased which increases the risk of thrombosis and CHD. 169 “Better” control of blood sugar with medication also carries a risk for dangerously low blood glucose (hypoglycemia) a condition that leaves patients prone to act bizarrely, lose consciousness, and suffer brain damage or death. Recurrent hypoglycemia can result in cognitive dysfunction and non-cognitive psychological abnormalities.
Self-monitoring blood glucose remains open to debate. While for some patients self-monitoring may improve blood glucose, in patients not treated with insulin, self-monitoring is associated with higher HbA1c levels and psychological burden. 170 In a meta-analysis of four randomized controlled studies comparing the effects of glucose monitoring with no self-monitoring, the authors concluded, “The results do not provide evidence for clinical effectiveness of an item of care with appreciable costs. Further work is needed to evaluate self-monitoring so that resources for diabetes care can be used more efficiently.” 171 Meanwhile, self-monitoring is not widely practiced 172, 173 I am not saying it is not important to monitor blood glucose, but it is, perhaps, more important to educate our patients and ourselves and appreciate that glucose is but one marker of and contributor to a diffuse, complex disease and not an isolated target to be treated in a vacuum.
Despite improving blood glucose concentrations in patients with type 2 diabetes by using either insulin or an oral drug (sulfonylurea), Yudkin and colleagues were unable to show improvement in markers of endothelial dysfunction (von Willebrand factor, cellular fibronectin, thrombomodulin, tissue plasminogen activator, soluble E-selectin or soluble intercellular adhesion molecule-1 or in urinary albumin excretion rate) after either treatment period. 29 In another study forty-three patients with type 2 diabetes and glycosylated hemoglobin (HbA1c) greater than 8.9 percent were randomized to either improved glycemic control or usual control for 20 weeks. 174 Despite significant lowering of HbA1c in the improved group (IC) there was no improvement in endothelial function as determined by measuring brachial artery flow-mediated dilatation. Furthermore, in the IC group weight increased by 3.2 kg after 20 weeks compared to less than 1.0 kg for the unimproved HbA1c group.
In 1998, an ancillary study of the Diabetes Control and Complications Trial (DCCT) suggested that using insulin to tightly control glucose in patients with type-1 diabetes increases body fat and worsens risk factors for CHD (elevated triglycerides, more cholesterol in small dense LDL sub-fractions, lower HDL levels, and higher blood pressure) by increasing insulin resistance. 161 This sequence is very similar to that observed in patients with type-2 diabetes whose bodies make insulin but whose cells are resistant to it, suggesting that excessive use of insulin to lower or “improve” blood glucose may actually increase the risk for CHD. 175
United Kingdom Prospective Diabetes Study (UKPDS) — a different perspective
Currently hailed as a landmark inquiry, the UKPDS followed 5,102 patients with newly diagnosed type-2 diabetes in twenty-three British healthcare centers for an average of ten years. The study was designed to determine whether intensively applying drugs to lower blood glucose would lessen complications from diabetes. Although the small blood vessels supplying the eyes and kidneys seemed to improve somewhat, lowering blood glucose did not significantly improve the complications caused by atherosclerosis involving the large blood vessels that supply the heart, brain, and legs.
The UKPDS is fraught with problems. Drugs were administered in combinations, patients were crossed over into different treatment groups, and the diet group was not kept pure because 80 percent of them ultimately received one or more drugs. It is also unclear which diet was followed. Such confusion prompted the American Diabetes Association (ADA) to comment in December 1998 “the prevalence of treatment crossovers and additions reduces our confidence in the differences observed, or not detected, among the various pharmacological agents.” One subgroup assigned to receive a commonly prescribed combination of two drugs (a sulfonylurea and metformin) had a 96 percent increase in diabetes-related deaths and a 60 percent increase in death from any cause. And yet, the ADA’s position statement concludes that “nothing should stop practitioners from pursuing the American Diabetes Association’s goals for glycemia…,” 5 which supports tight control with drugs.
What about microvascular disease?
Elevated glucose causes the blood to become more viscous, which especially affects the small blood vessels supplying the eyes and kidneys. These tiny blood vessels have endothelial cells that differ a bit from those in larger vessels, and these changes in the blood are more likely to increase the pressure (transcapillary pressure). Consequent transcapillary passage of macromolecules, including leakage of plasma protein may ensue, 176, 177 which may explain microalbuminuria in diabetes. Also, high extracellular glucose concentration directly increases vascular endothelial growth factor (VEGF), which induces angiogenesis and increases endothelial permeability and dysfunction. 178 This can lead to microvascular disease of the eye with neovascularization and retinopathy. 179 In the UKPDS the main effect of glucose control after 10.5 years was only a 3/1,000 reduction in photocoagulation for retinal disease (from 1.1% in the standard arm to 0.8% in the intensive arm). Glucose control did not have an effect on clinical end points, such as visual acuity. 6
Lowering blood glucose with drugs may improve microvascular conditions, 5, 180 181 182 but, in many cases, for only a short time. Although glucose impairs endothelial cells, neither quickly lowering blood glucose by itself, nor tight control, have been shown to prevent continuing damage to the endothelial cells in the large blood vessels supplying heart and brain, nor does it lower insulin or improve inflammation. 165 4, 5, 7 Glucose control in the UKPDS failed to show a significant improvement in macrovascular diseases. One needs to reverse these afflictions to make a difference in the goals that really count — decreasing heart disease, stroke, leg amputation, prolonging life, and improving its quality. Different endothelial processes may contribute to atherombotic disease of the larger blood vessels. For example, macrovascular endothelial cells seem to be more affected by LDL oxidation than those of the microvasculature. 183 Drugs may have a function but the answer is not simply better drug therapy, but better-informed nutrition along with moderate exercise and avoiding cigarette smoke.
Here’s the secret: If you administer too much insulin or other drugs to lower blood glucose, you may pay a price —if insulin levels go up you can end up with worse endothelial dysfunction and insulin resistance and make patients fatter and sicker.
Despite, or perhaps by, implementing insulin therapy in patients with type 2 diabetes we are worsening macrovascular disease. This is supported by the following report from diabetesincontrol.com,(November 14, 2001, Issue 78) “The number of lower-extremity amputations among diabetic patients in the U.S .increased from 36,000 in 1980 to 86,000 in 1996…Fifty-five percent of deaths in people with diabetes are caused by cardiovascular disease.” Likewise we are not very successful. The immediate and often angry response to this is often, “So what would you do, not treat them and let their eye disease deteriorate?” No. Lower blood glucose by methods that have been proven safe—lifestyle changes. The reply—“That’s not very easy to do.” Therein lays the challenge we will explore. There is no other rational choice, just like there is no magic pill, nor is there likely to ever be one.
We will continue our journey toward appreciating that first and second line treatments must be lifestyle changes and not drugs. In the next section we will explore the roles of macronutrients and nutritional intervention in preventing and reversing Type 2 diabetes and endothelial dysfunction.