Atherosclerosis and Diabetes Conferences

People with type II diabetes (formerly called adult-onset diabetes) have two to four times the risk of coronary artery disease (a cause of heart attack) and live six to seven years less than people without type II diabetes.¹ Atherosclerosis is the buildup of harmful plaque in blood vessels. Approximately 80% of deaths among diabetic patients are associated with atherosclerosis.²

Preceding type II diabetes is a condition called pre-diabetes, which is associated with insulin resistance. Some tissues may remain sensitive to insulin when others become insulin resistant. Muscle is the largest insulin-using tissue in the body. In muscular insulin resistance, the islet cells of the pancreas must produce more insulin to enable glucose to enter muscles. Although blood glucose levels remain normal, blood insulin levels are elevated.

Dr. Gerald Reaven originated the concept that insulin resistance is harmful to the cardiovascular system. When the muscles are insulin resistant, the kidneys and nervous system may remain insulin sensitive, thereby raising blood pressure due to increased sodium retention and nervous system activation.³

Water and oil (fat) do not mix, so to be carried in the watery blood circulation, fats are attached to proteins (lipoproteins). The two major forms of fat are triglycerides (used for energy) and cholesterol (used to maintain membrane structure and hormone synthesis).

Dietary fat from the intestine enters the bloodstream as chylomicron lipoproteins (which are primarily triglycerides). When chylomicrons are inadequate to supply fat for energy, the liver produces VLDL (very low-density lipoprotein) cholesterol from glucose. VLDL contains much more triglyceride than cholesterol. Enzymes (lipases) separate triglycerides from chylomicrons and VLDL into free fatty acids that cells can use for energy. But lipases are inhibited by insulin resistance.⁴ VLDL from which most triglyceride has been removed becomes LDL (low density lipoprotein) cholesterol. LDL cholesterol delivers cholesterol to tissues that have LDL receptors. Incomplete removal of triglycerides results in remnant cholesterol.

The liver also produces HDL (high density lipoprotein) cholesterol, which can return defective (oxidized or glycated) or excess cholesterol to the liver for destruction.⁵ Unlike triglycerides, which are easily eliminated by metabolism, cholesterol is persistent and can be harmful if defective.

The most common medical practice to reduce atherosclerosis and cardiovascular disease is to prescribe statin drugs to reduce LDL cholesterol.⁶ More than one fourth of all Americans over age 45 take a statin drug.⁷

This report is primarily based on the 2017 World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease held in Los Angeles and the Keystone Atherosclerosis meeting held in Taos, New Mexico, in 2018.

Blood Vessel Damage by Glucose

Peter Reaven, MD

Peter Reaven, MD (Professor, College of Medicine, University of Arizona) is concerned with the damage that glucose causes to blood vessels. Impairment of the ability of the delicate lining of blood vessels, known as the endothelium, to dilate and maintain blood flow is called endothelial dysfunction. Endothelial dysfunction leads to atherosclerosis.^8,9 Red blood cells have a lifetime of about four months, so the damage glucose does to red blood cells (glycation) indicates average blood glucose levels, measured as HbA1C (glycated hemoglobin). The higher the value of HbA1C, the greater the damage.¹⁰ Glucose damages small blood vessels more than large blood vessels.¹⁰ Glycation of small blood vessels leads to blindness and kidney failure, whereas glycation in large blood vessels leads to stroke and heart attack.¹¹

Dr. Reaven has shown that a high-fat (80%) meal of primarily saturated fat can increase blood glucose due to a temporary increase in insulin resistance.¹² Prior research suggested that saturated fat reduces insulin sensitivity more than polyunsaturated fat (such as fish oil), and that monounsaturated fat (such as olive oil) affects insulin resistance the least.¹³ More recent research suggests that insulin resistance only occurs in tissues where fat is being deposited abnormally because fat cells are too overloaded to accept more fat.¹⁴

Lowering LDL Cholesterol with Drugs

Paul Jellinger, MD

Paul Jellinger, MD (Endocrinologist, Memorial Health Care Network, Fort Lauderdale, Florida) endorses the leading medical strategy for reducing atherosclerosis—that is, by lowering LDL cholesterol. He believes that the average American level of LDL cholesterol of 130 mg/dL is not healthy. Healthy newborns, native hunter-gatherers, and healthy primates living in the wild have half that level of LDL cholesterol or less.¹⁵ Statin drugs are the most common means of lowering LDL cholesterol, but more than 40% of patients taking high doses of statin drugs fail to lower LDL cholesterol below 70 mg/dL.¹⁶ In a careful analysis of many studies, those who achieved low levels of LDL cholesterol with statin therapy had a 44%–56% lower risk of a major cardiovascular event.¹⁶ Adding ezetimibe (a non-statin drug that reduces absorption of dietary cholesterol from the intestine) to statin therapy reduces cardiovascular disease risk.¹⁷ Adding the non-statin Repatha^® (evolocumab), a PCSK9 inhibitor, to statin therapy also reduces atherosclerotic plaque volume more than statin therapy alone.¹⁸ The original cost of Repatha was $14,000 a year. The price was recently reduced to around $5,900 a year. Since most insurance plans won’t cover it, Repatha is cost-prohibitive for most people.

Gene Therapy to Lower LDL Cholesterol

Kiran Musunuru, MD, PhD, MPH

Kiran Musunuru, MD, PhD, MPH (Associate Professor, Perelman School of Medicine, University of Pennsylvania) is interested in using gene therapy to reduce LDL cholesterol. People with a hereditary PCSK9 defect have approximately 30%-40% lower levels of LDL cholesterol and an 88% reduction in coronary artery disease risk.¹⁹ Dr. Musunuru has used CRISPR-Cas9 gene editing and gene therapy to disrupt PCSK9 and reduce blood cholesterol in normal laboratory mice.¹⁹

Angiopoietin-like proteins (ANGPTLs) inhibit the enzymes (lipases) that break-up triglyceride fats.²⁰ Humans who have inherited genetic mutations that result in lower levels of the ANGPTL3 form of ANGPTL have been shown to have less triglyceride and LDL cholesterol in their blood, as well as an approximate one-third reduction in odds of coronary artery disease.²¹ Use of an antibody against ANGPTL3 in healthy human volunteers with elevated triglycerides and LDL cholesterol has been shown to lower the LDL cholesterol as much as 23% .²² Dr. Musunuru wants to use gene therapy to reduce ANGPTL3 as well as PCSK9 in humans.

Remnant Cholesterol as Cardiovascular Disease Risk

Anne Tybjaerg-Hansen, MD, DMSc

Anne Tybjaerg-Hansen, MD, DMSc (Clinical Professor, University of Copenhagen, Denmark) is concerned about the role of remnant cholesterol in the development of atherosclerosis. Remnant cholesterol is a term for all cholesterol-containing particles exclusive of HDL and LDL cholesterol. Remnant cholesterol causes more atherosclerosis than LDL cholesterol.

Remnant cholesterol contains about 40 times more cholesterol than LDL cholesterol,²³ and is associated with chronic inflammation.²⁴ Every increment of elevated remnant cholesterol increases the risk of heart attack.²⁵ The extent to which blood triglycerides (fats) rise after a meal corresponds with elevated remnant cholesterol and cardiovascular disease.^26,27

Reducing Inflammation to Reduce Cardiovascular Disease

Paul Ridker, M.D.

Paul Ridker, M.D. (Professor of Medicine, Harvard University, Boston, Massachusetts) led an important clinical trial aimed at reducing cardiovascular disease death by reducing inflammation. Although oxidized LDL cholesterol may induce atherosclerosis, high levels of LDL cholesterol have the capacity to form crystals, which leads to inflammation.²⁸ Cholesterol crystals are typically found in atherosclerotic plaque, not only causing inflammation, but also inducing plaque rupture.²⁹ Patients benefit the most from statin therapy when both LDL cholesterol and inflammation are reduced.³⁰ Dr. Ridker’s clinical trial showed that treating patients with an antibody against the inflammatory cytokine interleukin 1-beta (IL-1B) substantially reduced the incidence of heart attack and stroke.³¹ But the treated patients suffered more deaths from infection; consequently there was no difference in the death rate between the treated and untreated patients.³¹

Insulin Resistance Indicates Cardiovascular Disease Risk

Nadir Ali, MD

Nadir Ali, MD (Cardiologist, Clear Lake Regional Medical Center, Webster, Texas) believes that insulin resistance is a better indicator of cardiovascular disease risk than LDL cholesterol.³² Insulin resistance leads to endothelial dysfunction, which leads to atherosclerosis.³³

A study of more than 100,000 healthy individuals showed insulin resistance to be highly predictive of cardiovascular disease, but levels of LDL cholesterol were not predictive.³⁴ Another study divided 208 healthy people into three groups based on levels of insulin resistance. After an average of 6.3 years, not a single age-related disease was seen in the third with the least insulin resistance, whereas 18% of the group in the highest third developed at least one incidence of stroke, cancer, high blood pressure, coronary heart disease, or type II diabetes.³⁵

Insulin resistance before the onset of diabetes typically results in normal blood glucose levels because the pancreas compensates by secreting more insulin. But insulin resistance is not the same in all tissues. Insulin is a hormone that promotes growth, so high blood levels of insulin may worsen atherosclerosis.³⁶

In Japan and Norway, death from cardiovascular disease is lower in women with high cholesterol, compared to men.³⁷ LDL cholesterol reduces death from infectious disease because LDL cholesterol adheres to bacteria and viruses, reducing their toxicity.³⁷

TMAO Causes Atherosclerosis

Michael Petriello, PhD

Michael Petriello, PhD (Fellow, University of Kentucky College of Medicine) is interested in organic pollutants and the role of TMAO (trimethylamine N-oxide) in cardiovascular disease. TMAO is associated with the unpleasant odor of decomposing dead fish. Elevated levels of TMAO in humans contribute to atherosclerosis. Intestinal microbiota produce TMAO from foods such as eggs, liver, beef, and pork.³⁸ Vegans and vegetarians typically do not have these microbiota and do not produce TMAO when fed red meat experimentally.³⁹ Dr. Petriello has shown that dioxin-like organic pollutants PCBs (polychlorinated biphenyls) can substantially increase TMAO formation in the liver.⁴⁰

Industrial PCB production was banned in the U.S. in 1979,⁴¹ but PCBs resist degradation, thereby persisting in the environment and accumulating in the fat of humans and animals (notably in the fat of animals eaten by humans, amplifying the effect in humans).⁴² Persistent organic pollutants (including DDT, which was banned in the U.S. in 1972)⁴³ and phthalates (which can leech from plastic containers) accumulate in fat tissue, disrupting hormone function and increasing obesity.⁴⁴ Nitrates in processed meats (sausages, salami, bacon) cause endothelial dysfunction, insulin resistance, and atherosclerosis.⁴⁵ Red meat increases the risk of ischemic stroke.⁴⁵

Dr. Petriello advocates a vegetarian diet and notes that green tea can inhibit intestinal absorption of dietary lipids and increase the excretion of PCBs.⁴⁶

Insulin Resistance in the Liver

Sudha Biddinger, MD, PhD

Sudha Biddinger, MD, PhD (Assistant Professor of Pediatrics, Harvard Medical School, Boston, Massachusetts) uses mice as experimental models to understand atherosclerosis and diabetes. Insulin resistance can affect many different organs and tissues to different degrees and with different effects.⁴⁷ Dr. Biddinger has genetically modified mice so they are insulin resistant in the liver, but not in other tissues. These mice developed severe atherosclerosis within three months, whereas normal mice do not.^47,48 In a follow-up experiment, she showed that these mice exhibit reduced cholesterol synthesis, demonstrating that a key effect of insulin on the liver is to increase cholesterol synthesis.⁴⁹ Statins inhibit the cholesterol synthesizing enzyme in the liver.⁵⁰

Dr. Biddinger has also shown that the enzyme which produces the pro-atherogenic substance TMAO in the liver is inhibited by insulin, but that the enzyme is increased in insulin resistance.⁵¹

Two Signs of Pre-diabetes

Foo Siew Hui, MD

Foo Siew Hui, MD (Endocrinologist, Hospital Selayang, Selagor, Malaysia) is interested in pre-diabetes. Roughly a quarter of people with signs of prediabetes progress to type II diabetes within three to five years.⁵² Only 3.4% of prediabetic patients report that their physicians informed them of having prediabetes, either because the physicians did not diagnose the prediabetes or because of the poor memory of the prediabetic patients.⁵³

There are two somewhat distinct signs of pre-diabetes: (1) In impaired fasting glucose, a person who has fasted eight hours will show abnormally high blood glucose (100 to 125 mg/dL), and (2) In impaired glucose tolerance, a person who has been administered a standard quantity of glucose (75 grams) will show elevated blood glucose (140 to 199 mg/dL) when tested in two hours.⁵³ Although some people with prediabetes have both signs, most do not. Nearly four times as many people with pre-diabetes have impaired glucose tolerance rather than impaired fasting glucose.⁵³

People with only impaired glucose tolerance have skeletal muscle insulin resistance, whereas people with isolated impaired fasting glucose have insulin resistance in the liver.⁵⁴ Some people with metabolic abnormalities have both of these conditions.⁵⁵ Physical inactivity and poor diet have been found to be associated with impaired glucose tolerance, whereas smoking has been found to be associated with impaired fasting glucose.⁵⁶

Fructose, Uric Acid, and Metabolic Syndrome

Richard Johnson, MD

Richard Johnson, MD (Professor of Medicine, University of Colorado) has linked the development of metabolic syndrome and obesity due to the sugar fructose to the elevation of uric acid by fructose.⁵⁷ (Table sugar is composed of equal parts glucose and fructose). Uric acid causes endothelial dysfunction and insulin resistance. Consumption of sugar averaged four pounds per year in England in 1700, which is far less than the 150 pounds per person of sugar and high fructose corn syrup now consumed annually in the U.S.⁵⁸ Dr. Johnson’s team has shown that fructose induces obesity by causing resistance to the hunger-suppressing hormone leptin.⁵⁹ His team was able to induce metabolic syndrome in overweight, healthy men in only two weeks by administering fructose.⁶⁰ His team showed that fructose causes fat to accumulate in the liver, linking fructose to non-alcoholic fatty liver disease (NAFLD), a condition affecting 20%- 30% of adults in the U.S.⁶¹

His team has also shown that, in mice, high salt consumption increases fructose production, leading to obesity, insulin resistance, and fatty liver.⁶²

Concluding Remarks

Most medical professionals are intent on lowering LDL cholesterol as much as possible to prevent atherosclerosis despite the fact that cholesterol is a component of all cell membranes and is required to synthesize many hormones. Nearly one fourth of cholesterol in the body is in the brain, where it is required for mental function.^63,64 Notably, cholesterol is an essential component of myelin (facilitating communication between brain cells), and cholesterol is required for synaptic plasticity (required for learning).⁶⁵

Clinical trials showing the cardiovascular benefits of cholesterol-lowering drugs do not distinguish between lowering oxidized cholesterol or non-oxidized cholesterol. People with oxidized LDL cholesterol may benefit while others do not.

People with small, dense LDL cholesterol have much more atherosclerosis than those with large LDL cholesterol.⁶⁶ Small, dense LDL cholesterol is more easily oxidized and glycated, and a high-carbohydrate diet has been shown to specifically increase small, dense LDL cholesterol.⁶⁷ Insulin resistance promotes small, dense LDL particle formation.⁶⁸

Many studies show that oxidized LDL cholesterol leads to atherosclerosis.^69,70 But many scientists do not believe that oxidized LDL causes atherosclerosis because of poorly designed clinical trials in which antioxidants failed to reduce cardiovascular disease.⁷¹ A notable example is the failure of alpha-tocopherol to reduce cardiovascular disease in a clinical trial based on ignorance of the fact that gamma-tocopherol is more important than alpha-tocopherol for reducing atherosclerotic oxidation and that alpha-tocopherol supplementation displaces gamma-tocopherol.⁷² A less publicized study showed that N-acetylcysteine reduces cardiovascular disease.⁷³

High LDL cholesterol blood levels are widely regarded as indicating a risk factor for atherosclerosis, but coronary artery calcium directly measures atherosclerosis.⁷⁴ Whether or not blood LDL cholesterol is elevated, people shown not to have coronary artery calcium may not need to be taking statins.⁷⁵

Not discussed directly in this article is a protein on the surface of LDL called apolipoprotein B (ApoB). ‘Higher levels of ApoB pose a greater risk for atherosclerosis than just elevated LDL cholesterol itself: Life Extension advocates for a level under 80 mg/dL (< 80ng/dL).

Those who have an annual Male or Female Blood Test panel offered by Life Extension learn their apolipoprotein B status and can take corrective actions to lower it. More about apolipoprotein B and the many ways to reduce it will soon be published in this magazine.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

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