Diabetes Protocol

Although normal fasting glucose does not directly indicate the degree of insulin resistance, impaired glucose tolerance (fasting glucose 111 to125 mg/dL) and frank diabetes (fasting glucose greater than 125 mg/dL) is a useful prognosticator. According to the Functional Medicine Research Center (Gig Harbor, WA), the best practical measure of insulin resistance and hyperinsulinemia may be fasting and two-hour postprandial serum insulin values following a 75-gram glucose challenge. Elevations above 15 mcIU/mL (fasting) and/or 50 mcIU/mL (postprandial) signify increased insulin secretion secondary to insulin resistance (Bland 2000).

Comment: It is important to note that laboratory values reflecting optimal health may be considerably lower than values used to denote Syndrome X. For example, the Life Extension Foundation believes that fasting insulin levels above 5 mcIU/mL may be a cause for concern and many respected physician/scientists are aligning with this projection.

Blood pressure may be chronically elevated, that is, consistently above 140/90 mmHg in Syndrome X patients. As few as 10 pounds of excessive weight can also indicate problems, particularly when the extra pounds are also associated with elevated blood fats and hypertension (Challem et al. 2000).

A physician will also perform liver function tests (gamma-glutamyltransferase) and evaluate the adequacy of magnesium, which is often depressed in insulin-resistant/hyperinsulinemic individuals. (Rosolova et al. 1997; Perry et al. 1998). In men, low levels of free testosterone also correlate with Syndrome X.

Clinically, the spectrum of patients with some degree of insulin resistance falls into four overlapping categories. The first category includes the individuals with a mild degree of insulin resistance (as measured by one or more of the above-mentioned criteria). Borderline laboratory values (coupled with physical exam and positive family history) may prompt the clinician to initiate diet and lifestyle changes. The second category includes the individual who clearly shows signs and symptoms of insulin resistance: central abdominal obesity, increased triglycerides, depressed HDL, elevated fasting insulin with normal glucose, and an often startling elevation in two-hour postprandial plasma insulin. This is the classic Syndrome X insulin-resistant picture with a marked compensatory hyperinsulinemia (Bland 2000).

The last two categories include the remaining insulin-resistant patients, that is, those with either impaired glucose tolerance or overt diabetes. Although these individuals are almost always insulin-resistant, they are no longer able to compensate adequately by secreting large amounts of insulin to normalize serum glucose levels. In these cases, fasting and two-hour insulin measurements are of key importance.

The third category includes the patient who is able to mount an insulin response on glucose challenge and is therefore hyperinsulinemic. This patient appears more physiologically capable of normalizing serum glucose through diet, supplementation, and other lifestyle interventions.

In the fourth category, the patient with little response to challenge is insulin-resistant as well but has apparently lost significant ability to secrete insulin. Improving insulin sensitivity continues to be of critical importance; however, additional medications to either exogenously supply or to endogenously stimulate insulin may also be necessary (Bland 2000).

Is Syndrome X Caused by Bad Genes?
If your family history includes heart attacks, hypertension, and Type II diabetes, the likelihood of being insulin resistant increases. It appears about 50% of the variability of insulin may be due to genetic propensities; the other half seems related to lifestyle. According to Dr. Gerald Reaven, author and authority on Syndrome X, of the 50% attributed to lifestyle, half may be due to a lack of fitness and half to obesity (Bogardus et al. 1985; Reaven 2000). Some researchers speculate that the genetic link may also be strongly influenced by mimicry. Offspring may (in fact) be mimicking the poor eating habits of parents, producing another generation plagued by obesity, insulin insensitivity, and diabetes.

Jeff Bland, Ph.D. (Functional Medicine Update, June 2001), explains that hyperinsulinemia is a polygene inheritance across multiple genes, not just a single gene. Research in human genetics indicates that impaired beta cell function, increased hepatic glucose production, and decreased insulin peripheral sensitivity appear to be genetic disorders exacerbated by environmental factors. According to Bland, "Environment is modifiable; genes are not."

WHAT CAUSES INSULIN RESISTANCE AND WHAT ARE THE EFFECTS?

Until recently, one of the most popular explanations regarding insulin resistance was that some individuals are born with bad cellular receptors, which ultimately require the overproduction of compensatory insulin. According to information in The Institute of Nutritional Science Journal (Whiting 2000), diabetic patients may be born with a genetic fault that causes their bodies to overproduce insulin when sugar or sugar-forming foods are consumed. As excesses of insulin wash over the delicate insulin-receptors located on cell membranes, the powerful hormone robs more and more of the receptors' sensitivity. If the insulin saturation becomes too extreme, the receptors can be totally burned out. Reckless carbohydrate consumption exacerbates this sequence.

During insulin resistance, the pancreas is aware of the hyperglycemia (mounting glucose in the bloodstream) and, in an effort to correct the malfunction, discharges copious amounts of insulin as a compensatory gesture. Although this homeostatic mechanism allows glucose to enter the cell, hyperinsulinemia results. Unfortunately, a number of drugs prescribed to treat Type II diabetes stimulate the pancreas to produce more and more insulin. This approach temporarily lowers blood glucose levels but at the expense of the insulin receptor. Although debated, some contend that a surplus of insulin in the bloodstream causes more medical complications than an excess of glucose.

It is important to note that the cell is surrounded by a plasma membrane composed of a double layer of phospholipids. This double layer of lipids provides a site of dissolution for molecules that are soluble in lipids. Protein molecules float in the phospholipids, adding structural support, membrane channels, carrier molecules, enzymes, and receptor molecules. The binding of insulin to its receptor in the cell membrane is the first step in a metabolic cascade that results in a glucose uptake in insulin-sensitive tissue.

Historically, the cell membrane has been regarded as the most dynamic feature of the cell. It has become increasingly clear that alterations in membrane lipid composition and membrane fluidity influence pivotal cellular functions such as the transport of substances across the cell membrane and the activity of receptors (Adamo et al. 1988). By contributing to the sluggish transport and irresponsiveness of the receptor, altered membrane activity can be an important factor leading to Type II diabetes. Nutritional imbalances that might be affecting the integrity of the cell membrane should be a principal focus of treatments targeted at hyperinsulinemia (Kinnunen et al. 1991).

So which one of the explanations regarding damage occurring at the insulin receptor is most reliable? Does the lack of receptor sensitivity occur because of an unstable plasma membrane, a genetic disadvantage, or abusive consumption of carbohydrates? In truth, any one of the premises or a combination thereof can damage the receptor's responsiveness. A positive finding is that the insulin receptor is resilient. When insulin concentrations in the bloodstream are reduced, the receptor may be able to reestablish sensitivity, resulting in better blood sugar control with only a fraction of the insulin previously required.

What are the Risks Imposed by Hyper- and Hypoglycemia?

Diabetes independently imposes such stress upon the heart and vascular system that the diabetic frequently succumbs from a cardiovascular event rather than the disease itself. In the Cardiovascular protocol in this book (Diabetes and Syndrome X sections), diabetes-induced damage to the heart and blood vessels (the major complication arising from abnormal blood glucose levels) is thoroughly described and will not be repeated in this protocol. The reader is strongly advised to read those sections for valuable information regarding the role unstable blood glucose plays in heart and vascular disease.

Most healthy individuals maintain postabsorptive blood glucose levels of 90-100 mg/dL. Even after fasting or overeating, blood glucose levels seldom fluctuate lower than 60 or over 160 mg/dL. Unstable diabetics lack the homeostatic control to maintain blood glucose within a normal range; subsequently, blood glucose levels can oscillate from hyperglycemia to hypoglycemia within a few hours.

The effects of too much or too little blood glucose or insulin in the bloodstream are usually as diverse as they are serious. For example, chronic hyperinsulinemia causes tissues to receive insulin that do not require it. Renal glomeruli (kidney structure composed of blood vessels or nerve fibers), ocular lens, and peripheral nerves are among those tissues most damaged. Kidney disease (17 times more frequent among diabetic patients), cardiovascular disease, gangrene, retinopathy, and damage to the nervous system are relatively common in chronically unstable diabetic patients. Another grim finding is that hyperglycemia impairs the activity of nitric oxide, resulting in endothelial dysfunction. This, in turn, causes vasoconstriction, smooth muscle proliferation, platelet activation/aggregation, and leukocyte adherence to the endothelium (Adrie 1996; Cooke et al. 1997; Federici et al. 2002).

Hyperglycemia and excesses of ineffective insulin cause rampant free-radical activity, lipid peroxidation, glycation (the pathological union of protein and sugar), and increased inflammation (Sears 1999). Impotence, depression, cataracts, glaucoma, atherosclerosis, and dementia often negatively impact a diabetic's quality of life. Subjects with Type II diabetes have a 1.9 relative risk of both dementia and Alzheimer's disease and that risk jumps to 4.3 among patients receiving insulin (Ott et al. 1999). It is hypothesized that vascular disease or the nonvascular effects of diabetes could explain the increased risk of dementia. It was also pointed out that both hyperglycemia and hypoglycemia are thought to have adverse effects on the brain. (Relative risk denotes the chance of a disease developing among members of a population exposed to a factor compared to a similar population not exposed to the factor.)

The degree and duration of hyperglycemia appear to dictate the frequency and pathological intensity of complications arising from diabetes. People with Type II diabetes generally are not prone to ketosis and acidosis, but extremely high blood glucose levels pose another significant endangerment: a coma, usually the result of dehydration, which if left untreated is fatal about 50% of the time. (This type of coma is termed hyperosmolar, hyperglycemic, nonketotic coma.) Troublesome physical events quickly mount against an uncontrolled diabetic, shortening life expectancy by about one-third compared to the nondiabetic population.

Blood Glucose/Insulin Equation

High blood glucose/high insulin levels =
accelerated aging and an increased risk of
premature death
Normal blood sugar/normal insulin levels =
healthier individuals with greater chance
for longevity

An unstable diabetic faces additional challenges if blood glucose levels become too low (hypoglycemia). For example, normal brain function requires 6 mg of glucose an hour, which can only be delivered if arterial blood contains over 50 mg/dL of glucose. Dizziness and blurred vision are symptoms of hypoglycemia, but if blood glucose levels truly plummet, unconsciousness can result. (Extremes at either end of the glycemic scale can result in loss of consciousness.)

Factors that Provoke Low Blood Glucose Levels

Dietary carelessness (excesses of refined carbohydrates or foods high on the glycemic index) can cause hypoglycemia. Sugary treats can cause blood glucose levels to rocket, followed by a rapid fall. (See the section in this protocol devoted to the Glycemic Index for a more in-depth look at insulin-provoking foods.)
Stress-induced hypoglycemia occurs when frustration and arousal command the adrenal glands to release cortisol and adrenaline. Increased hormonal activity causes a precipitous rise in blood sugar, followed by an abrupt plunge. Hypoglycemic individuals often report varying degrees of panic and terror, a response likely orchestrated by the action of adrenaline. Overwhelming fatigue results as the body absorbs the stress of the glucose seesaw.
Using insulin when insulin is not indicated, too much insulin even when insulin is justified, or oral insulin-inducing diabetic medications can produce the same blood glucose swings.

GLUCOSE, INSULIN, AND GLUCAGON

Major control of blood glucose levels is achieved through actions of the hormones insulin and glucagon. The slightest rise in plasma glucose leads to a decrease in glucagon secretion and an increase in insulin secretion. The reverse occurs when plasma glucose levels fall. A network of interrelated responses from the liver, pancreas, pituitary, adrenal, and thyroid glands joins forces to ensure that the rate of glucose entry into the blood is balanced by its rate of withdrawal (Pike et al. 1984).

The pancreas, detecting excess glucose in the bloodstream, takes immediate steps to counter the glucose rise by supplying the hormone insulin. Insulin, in turn, is responsible for marshaling glucose to the receptor site for cellular entry. Stimulating glucose transport into muscle and adipose tissue is a crucial component of the physiologic response to insulin. However, the pancreas demonstrates its diversity by also supplying the hormone glucagon (produced from the alpha cells in the islets of Langerhans). Glucagon has the opposite effect of insulin. Glucagon summons the release of glycogen (the stored form of glucose) from the liver to form glucose when blood sugar levels become too low, a process referred to as glycogenolysis (the breaking down of glycogen). The secretion of glucagon is stimulated by a state of hypoglycemia and the growth hormone from the anterior pituitary gland.

Glycogen (glucose stored in the liver) is a major force in glucose control, but it is the liver (receiving instructions from hormones and neural stimuli) that holds dominion over glycogen pathways. By both supplying glucose when blood levels are low and accepting glucose when blood levels are high, the hepatocytes (liver cells) become key participants in glucose/glycogen homeostatic mechanisms. It should be noted that the muscles stockpile about two-thirds of glycogen but use most of this supply to provide for their own energy requirements. The liver stores the remaining one-third, releasing it when blood levels of glucose are no longer adequate to meet metabolic demand (Hamilton 1988). Normally, an adult will have about three-fourths of a pound of glycogen (340 grams) stored in the liver and muscles at one time (Krause et al. 1984).

The Insulin-Liver Connection
Internal checks and balances, warranting safe blood glucose levels, are as vital as they are amazing. A status favoring neither hyper- nor hypoglycemia occurs through the interaction of hormonal and neural stimuli, as illustrated by the following examples:

Insulin's primary action in the hepatic (liver) cell is the inhibition of glucagon-mediated activity by
Blocking glycogenolysis (the degrading of glycogen to form glucose) as well as inhibiting gluconeogeneis (the formation of glucose from noncarbohydrate sources, such as lactate, pyruvate, glycerol, and certain amino acids) (Pike et al. 1984).
Removing the glucagon block on liver glycogen synthase. An increased conversion of glycogen synthase to its active form explains a part of the known effect of insulin on glucose uptake by the liver cell (Villar-Palasi et al. 1971; Pike et al. 1984).
Another action of insulin is induction of the activity of glucokinase, increasing the uptake of glucose by the liver when plasma glucose levels are elevated (Czech 1980). The Therapeutic Section of this protocol describes how biotin works synergistically with insulin to increase the activity of glucokinase, an enzyme responsible for the first step in glucose utilization (Murray 1996). Glucokinase, with the help of ATP, catalyzes glucose to glucose 6-phosphate, an intermediate in carbohydrate metabolism.
Epinephrine, an adrenal medulla hormone, and thyroxin, a hormone secreted by the thyroid gland, also stimulate glycogenolysis, the breakdown of glycogen to supply a ready source of glucose. Glucocorticoids, particularly cortisol, tend to increase glucose production by the liver cells and decrease glucose utilization in both muscle and fat cells. These actions are inclined to counteract the effects of insulin and subsequently increase blood glucose concentrations.

Comment: In a postabsorptive state, blood glucose concentrations are ideally maintained within a normal range of 80-100 mg/dL by glycogenolysis (the formation of glucose from glycogen) and gluconeogeneis (the formation of glucose from noncarbohydrate sources). Since liver glycogen capacity is rather limited, the ability of liver cells to tap more extensive sources of ultimate glucose (gluconeogenesis) is keenly important. Both mechanisms, glycogenolysis and gluconeogenesis, occur within the liver cell, but under certain circumstances such as starvation, the kidney is equally important in providing glucose from noncarbohydrate sources. In a healthy individual (even during periods of fasting or overeating) blood glucose levels remain remarkably constant because of the efficiency and rapidity of these systems (Unger 1981). It should be noted that the most vital function of glucagon is to maintain plasma glucose at a level adequate for the function of the central nervous system regardless of energy intake or energy expenditure.

Maintaining a healthy liver (capable of fully participating in blood glucose control) is vital. Please consult the Therapeutic Section of this protocol to read about silymarin, a liver protector and hypoglycemic agent.

Diabetes Protocol Pg (1) (2) (3) (4) (5) (6) (7) (8) (9) (10)

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