Insulin is in our everyday vocabulary primarily because of its use in the treatment of diabetes, a disease of modern man characterized by inadequate utilization and/or secretion of insulin, which results in excessive sugar (glucose) in the blood and urine—in turn producing many harmful effects on the body.

The Physiology of Insulin. The human body is composed of many tens of trillions of cells—the basic building blocks of our bodies—with each cell functioning as a tiny biological factory contributing to the overall functioning of the body. The food we eat provides the energy that powers our vast array of cells. What we consume as food is converted into the form of food that nourishes our cells—glucose, the typical form of sugar in which dietary protein and carbohydrates are assimilated in animals. Glucose molecules are transported throughout the body via our “freeway to the cells,” the bloodstream.

Insulin—a large polypeptide molecule with a molecular weight of 5,808 daltons—is secreted into the bloodstream by the pancreatic beta cells in direct response to an increase in blood glucose concentration. It is one of the primary functions of insulin to maintain the proper blood glucose levels. It does this by allowing glucose to leave the bloodstream and enter the cells. Once the glucose is cleared from the bloodstream, the pancreas is signaled to stop its production of insulin.

On the surface (and much less so on the interior) of most all mammalian cells are insulin receptors—chemical groups or molecules that have an affinity for insulin. Each cell in the body has between 100 to 100,000 insulin receptors.1 It is rare that cells have no receptors at all. As insulin molecules circulate throughout the body via the bloodstream, they are attracted and attach to the vast quantities of receptor structures largely on the surfaces of cells.

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It is this attachment of the insulin molecules to the cells via the receptors that allows the glucose within the blood to pass into the cells, and thus provide cellular nourishment. Insulin is the “gatekeeper” of the cells, as it facilitates the diffusion (transport) of glucose across the cell membranes of the body’s many different types of cells. It is the key which fits into the receptor sites’ locks to unlock the cells and allow the cellular fuel to gain entry. In addition to the receptor-specific transfer of glucose, it is believed that insulin has a general tendency to “permeablize” the cell membranes to glucose. When insufficient insulin is produced, or the insulin receptors become insensitive to insulin molecules, the result is the disease of diabetes, a hallmark of which is hyperglycemia—an excess of glucose within the blood plasma.

Slightly over six percent of the entire U.S. population has diabetes, or approximately 18 million people. About nine percent of all Americans over the age of 20 and over 20% over the age of 65 have diabetes. However, as many as one third of all diabetics, or almost six million people, are unaware they have the disease.2 This is unfortunate, as roughly 65% of all diabetics die either from heart disease or stroke.3 In 2002, Reuters Health news reported that over 30% of all Americans are pre-diabetic.4 This is a condition in which the blood glucose levels are higher than that of a normal person, but not high enough to be classified as being diabetic.

The risk of an untimely death for a diabetic is about double that of a person without the disease.5 Observing the rapid age progression of a diabetic person has been likened to watching the normal human aging process on fast-forward. Diabetes is becoming more common among African American, Native American, and Hispanic children, adolescents and adults in comparison to Caucasians. In the U.S., the direct medical costs of the disease surpass USD $90 billion, while the indirect costs which include disability, loss of work and premature death are over $40 billion.6

Type II diabetes is also referred to as adult-onset diabetes and Non-Insulin-Dependent Diabetes Mellitus (NIDDM). It is characterized by the inefficient production and/or utilization of insulin, and is related to obesity, high cholesterol, high blood pressure, and insulin resistance. Metabolic syndrome, also called Syndrome X—a group of risk factors relating to blood sugar metabolism—is closely associated with insulin resistance syndrome (IRS). Those with metabolic syndrome are twice as likely to die of a heart attack or stroke, and are three times more likely to die prematurely. IRS is characterized by the inability of insulin molecules to attach properly to receptor sites, thus preventing or inhibiting glucose transfer into the cells. This produces the hyperglycemic excess of sugar within the blood. (Low blood sugar is referred to as hypoglycemia.) When IRS is present, much of the food consumed is stored as fat, particularly in the stomach area.

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Some of the common symptoms of diabetes include frequent urination; excessive thirst; extreme hunger; unusual weight loss; weakness and fatigue; irritability; blurred vision; difficult-to-heal skin and gum lesions; tingling or numbness in the hands and/or feet; and itchy skin.

Food, Insulin & Blood Sugar. When food is consumed, the blood glucose (sugar) levels rise. In non-diabetics, insulin allows the glucose to enter and fuel the cells. In a diabetic if the levels rise too high, too much insulin remains in the bloodstream, causing irritation and constriction of the arterial vessels which is damaging to the cardiovascular system, including the heart. It is one of the liver’s tasks to remove insulin from the blood, but excess insulin causes fatty deposits in the liver, interfering with this ability.

Glucose levels rise more rapidly in diabetics, and remain elevated longer in comparison to non-diabetics. This gives rise to a host of physical problems that can occur over time, including blindness, burning foot syndrome, deafness, high blood pressure, insufficient blood circulation (especially to the lower extremities), kidney failure, nervous system diseases, periodontal (gum) disease, stroke, and a host of other complications. Diabetics are at risk of developing other illnesses and if they do, their prognosis is worse than a non-diabetic. Diabetes is the leading cause of blindness, heart attacks, kidney failure, and leg amputations, as has been widely reported.

This unchecked overabundance of glucose within the blood so characteristic in both diabetics and pre-diabetics facilitates the binding to and cross-linking with glucose-metabolic intermediates (sugars) with surrounding proteins including DNA, the material that contains the genetic instructions for the proper development and functioning of our bodies. This is the complex chemical process of glycation, and further results in a group of harmful byproducts collectively labeled advanced glycation end products (AGEs). The similar chemical process of lipoxidation occurs when sugars cross-link with lipids (fats), producing advanced lipoxidation end products (ALEs). Both the brain and heart—as well as other tissues and organs—can be severely impacted as both organs have a high lipid content, with the brain being composed mostly of fatty acids.

Once proteins and lipids become cross-linked, they become severely degraded and marginally functional. As these processes continue unchecked and the affected proteins and lipids accumulate, they emit signals which cause the production of inflammatory cytokines, cell-signaling chemicals which themselves emit further messages to increase the inflammatory cascade. This is one of the principal bases of the initiation of the inflammatory process which is so common in aging people.

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Proteins of the blood vessel linings, nerve cells, kidney, and retina are particularly vulnerable to glycation, and are typically the first to be damaged. Glycation, AGEs, lipoxidation, and ALEs are associated with all of the detrimental physical maladies discussed above, and most age-related diseases including arthritis; abnormal DNA formation (that can lead to cancer); cataracts; early aging (including wrinkling of the skin); fatigue; kidney and blood vessel damage; neurological diseases such as Alzheimer’s disease and Parkinson’s disease; and vision loss.7

Many critical cells throughout the body—including cells of the kidneys, liver, lungs, and pancreas—have on their surfaced Receptors for Advanced Glycation End Products (RAGEs).8 As AGEs from both external (food cooked at high temperatures and for long durations) and internal sources (diabetes, for example) dock with RAGEs on these vital organs, cells degrade and dysfunction and disease manifest. Free radical pathology and a decrease in antioxidant levels are mediating factors.

In addition to AGE chemistry, the related chemical process carbonylation is the origin of the “browning” effect on foods such as roasted chicken and the browning of bread into toast. Carbonylation is the result of protein oxidation and reactions of proteins with sugars, aldehydes, and products of lipid peroxidation.9 Over time, as the affected proteins accumulate in vital organs, they become progressively more damaged, causing organ dysfunction. Carbonylated proteins are visible in the aging skin as the darkened pigmented spots known as “aging spots” (lipofucin deposits), and as cataracts, the clouding of the normally-clear lens of the eye. The carbonylation “browning” process within the human body has been likened to a low temperature oven with a 65-75 year cooking cycle.

Carbonylated proteins are responsible for many age-related conditions including cardiovascular disease and neurodegenerative disorders. It is theorized that damaged proteins interfere with the cells’ ability to detect damaged DNA, thereby preventing the cellular repair of this vital material which contains the body’s genetic instructions. Additionally, damage occurs to the program which monitors orderly cell death, or apoptosis, causing damaged cells to survive and reproduce, leading to progressive chromosomal instability—which is a precursor to the development of cancerous states. As we age, about 30% of the body’s proteins become damaged by carbonylation.10 Clearly, glycation and carbonylation of proteins and lipids are two of the principal causes of aging and premature death.

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Notes

1. Rosen. Science. 273:1452-1457, 1987.
2. www.diabetes.org
3. Ibid.
4. Reuters Health. “⅓ of Americans Have Pre-diabetes Syndrome.” Aug. 27, 2002.
5. Ibid.
6. Ibid.
7. Wautier, J.L. “Advanced glycation end products, their receptors and diabetic angiography.” Diabetes Metabolism, 27(5): 536-42, 2001.
8. Wells-Knecht, K.J., et al. “Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose.” Biochemistry, 21;34(11)3702-9, March 1995.
9. Stadtman, E.R. “Protein oxidation and aging.” Science. 257(5074):1220-1224, August 28, 1992; Stadtman, E.R., et al. “Protein oxidation.” Annals of the New York Academy of Science, 899:191-208, 2000; and Berlett, B.S., et al. “Protein oxidation in aging, disease, and oxidative stress.” Journal of Biological Chemistry, 272(33):20313-20316, August 15, 1997.
10. Stadtman, 2000, as in Note 9