Articles

Diabetes Mellitus, Type 2

Introduction

Diabetes mellitus, a term that means “the running through of sugar," was first identified in the 1st century AD. (1) The disease was described in historical text as “the melting down of flesh into urine." Diabetes mellitus is a chronic condition of insufficient insulin availability in relation to need. This can represent an absolute insulin deficiency, impaired insulin secretion, defective insulin receptors on target cells, or insulin that is inactivated before it is able to function. Diabetes mellitus is a disease in which the body does not produce or does not use insulin effectively. It is not simply hyperglycemia.

Insulin is a hormone produced in the pancreas by the beta cells in the Islets of Langerhans. Insulin secretion is regulated by blood glucose levels. It is responsible for transporting glucose (from carbohydrates) into the cells to fuel cellular metabolism and energy production. After a meal, when blood sugar increases, insulin levels rise. Between meals, when blood sugar is low, insulin levels remain low. Insulin is secreted from the pancreas directly into the liver where some is utilized and some is degraded. The rest is released into the general circulation. By facilitating the transport of glucose into the cells, insulin reduces blood sugar. Insulin also decreases the catabolism of fat stores and stimulates triglyceride synthesis. Insulin is involved in the active transport of amino acids into the cell, increasing protein synthesis. The growth and development of children is dependent on insulin.

Diabetes can affect people of any age. It increases the risk of chronic, debilitating conditions, including cardiovascular disease, retinopathy and blindness, peripheral neuropathies, vascular insufficiency and amputation, immune deficiencies, skin ulceration and wound healing disturbances, and kidney disease. The discovery of insulin in the early 20th century has afforded much progress in the diagnosis and treatment of the disease.

Diabetes is diagnosed when there is a fasting plasma glucose (FPG) of greater than 126mg/dL, or a two-hour plasma glucose (OGTT – oral glucose tolerance test) of greater than 200mg/dL. There are two forms of diabetes mellitus recognized today: type 1 (formerly referred to as IDDM, insulin dependent diabetes mellitus, or juvenile onset) and type 2 (previously called NIDDM, non-insulin dependent diabetes, or adult onset).

Ninety percent of individuals with diabetes have type 2. Most of these individuals are over 40 years old. One in five patients is over the age of 65, and 80 percent are overweight. (2) In fact, a 16 year study of over 80,000 individuals, found that overweight or obesity is the single most important predictor for this disease. (3) Many patients have elevated blood sugar levels seven to ten years before symptoms occur.

When blood sugar regulation is impaired, despite the availability of insulin, type 2 diabetes is suspected. Type 2 diabetes is characterized by elevated blood sugar and impaired insulin response. It is a non-ketotic form of diabetes. People with type 2 are not dependent on insulin to survive. The pathophysiology of type 2 diabetes is not fully understood. Three physiological abnormalities typically occur in type 2: insulin resistance, increased glucose production in the liver (hepatic gluconeogenesis), and poor beta cell function. These can occur individually or in combination.

Insulin resistance appears to be the first stage of the disease. It is defined as an inability of insulin to facilitate glucose uptake from the blood into the cells. (4) In fact, a 16 year study of over 80,000 individuals, found that overweight or obesity is the single most important predictor for this disease. (5) It is characterized by poor insulin binding at the receptor cells, particularly skeletal muscle cells. While the beta cells are able to release normal or even higher than normal amounts of insulin during this phase, glucose uptake is sluggish and blood glucose levels slowly begin to rise. Consequently, blood sugar remains elevated. As a compensatory mechanism, the pancreas initially releases more insulin, and hyperinsulinemia ensues.

This is likely the result of genetic defects that cause an inadequate number of insulin receptors and/ or an inefficient glucose transport system. Insulin resistance is due to high insulin levels, not high glucose levels. Therefore, the individual is chronically hyperglycemic. Blood glucose can be maintained within normal limits if enough insulin is produced. Eventually, though, the beta cells “burn out" and insulin resistance may progress to overt diabetes.

Many people with type 2 diabetes also produce a large amount of glucose in the liver (hepatic gluconeogenesis). This increase in hepatic glucose production is likely related to fat breakdown. When the body is not efficiently using glucose as an energy source, fat stored in adipose tissue becomes an important source of fuel. The breakdown of fat stimulates the liver to produce glucose. Because patients with type 2 diabetes are insensitive to the effects of insulin, which normally suppresses the production of glucose in the liver, this gluconeogenesis goes unchecked. Insulin sensitivity also appears to be related to weight and physical activity.

In type 2 diabetes, the ability of the beta cells to release the initial bolus of insulin needed after ingesting a meal (postprandial insulin release) deteriorates early on in the disease process. Therefore, blood glucose remains elevated for one to two hours after a large meal. As the disease progresses, the insulin release that continues following a meal worsens, resulting in pancreatic beta cell exhaustion.

Type 2 diabetes appears to be caused by genetic defects that initially result in an insensitivity to the actions of insulin and, over time, a relative lack of insulin release from the beta cells in the pancreas. However, new evidence has emerged which points to diet and lifestyle as important contributing factors to the development of the disease. A person over the age of 45 and overweight is a prime candidate for developing type 2 diabetes. Approximately 30-39 percent of Americans are obese, and many more are overweight. Research has shown a strong correlation between upper body obesity (“apple shapes") and the development of type 2 diabetes mellitus. (6)

The long-term complications associated with diabetes are serious, often life-threatening, and diagnosed in the late stages of the disease progression. These complications are due to persistent hyperglycemia from poor glucose control. Many of these chronic complications can be traced to alterations in the structure and function of blood vessels resulting in a lack of adequate blood flow. Macrovascular changes include coronary heart disease and peripheral vascular disease, and microvascular changes include retinopathy, nephropathy, and neuropathy.

Heart disease is the leading cause of diabetes-related deaths, with adults having two to four times higher heart disease death rates than adults without the disease. The risk of stroke is two to four times higher in people with diabetes. Patients with diabetes experience an accelerated rate of atherosclerosis, and some 60-65 percent of patients with diabetes have high blood pressure.

When high concentrations of glucose are present in non-insulin dependent tissues such as the lens of the eye and nerve cells, alternative methods of handling this excess glucose are used by these cells. Enzymes work to metabolize the extra glucose, causing an increase in sorbitol and fructose concentrations. This excess sugar accumulation may produce osmotic injury to these cells.

Retinopathy is the leading cause of new cases of blindness among adults 20 to 74 years of age. Because of increased glucose levels, blood vessels weaken and microaneurysms occur in the terminal capillaries of the retina. The retinal cells can then burst and hemorrhage. This obscures vision and can lead to detachment of the retina.

Nephropathy is the leading cause of end stage renal failure requiring dialysis. The first sign is microalbuminuria, which leads to proteinuria, and eventually end stage renal disease.

Neuropathy occurs in the periphery, manifesting as numbness and tingling, eventually leading to trauma and the development of diabetic ulcers in the extremities. Diabetes is the leading cause of nontraumatic amputations in the U.S. Autonomic changes include GI abnormalities, such as gastroparesis, chronic constipation, or diarrhea; loss of sexual function, bladder function, and cardiovascular tone.

Statistic

International Diabetes Federation, 2007.

  • Diabetes currently affects 246 million people worldwide and is expected to affect 380 million by 2025.
  • Diabetes is the fourth leading cause of global death by disease.
  • In 2007, the five countries with the largest numbers of people with diabetes are India (40.9 million), China (39.8 million), the United States (19.2 million), Russia (9.6 million) and Germany (7.4 million).
  • Each year a further 7 million people develop diabetes.
  • Each year 3.8 million deaths are attributable to diabetes.
  • Every 10 seconds two people develop diabetes.
  • Up to 80% of type 2 diabetes is preventable by adopting a healthy diet and increasing physical activity.
  • Type 2 diabetes has become the most frequent condition in people with kidney failure in countries of the Western world.
  • It is estimated that more than 2.5 million people worldwide are affected by diabetic retinopathy.
  • Cardiovascular disease is the major cause of death in diabetes, accounting for some 50% of all diabetes fatalities, and much disability.

Persatuan Diabetes Malaysia, 2007.

  • Of the nearly 1.2 million Malaysians with diabetes, more than 98% have type 2 diabetes.

Sudaram Medical Foundation, 2007.

  • It is currently estimated that there are 35 million diabetics in India. The number is expected to increase by another 60% by the year 2025.

Not available

Diabetes New Zealand, 2006.

  • Approximately 105,000 people in New Zealand have been diagnosed with Type 2 diabetes. It is estimated that 115,000 are undiagnosed.

The Center of Disease Control, National Diabetes Fact Sheet, 1998.

    60-65% of people with diabetes have High Blood Pressure (HBP). 15.7 million people have diabetes or about 5.9% of population. 10.3 million have been diagnosed with diabetes. 5.4 million people are undiagnosed. There are 798,000 new cases of diabetes diagnosed each year. 6.3 million age 65 or over or 18.4% of all people in this age group have diabetes.

Center for Disease Control and Prevention, 2003.

    Over a million adults between 18 and 79 years of age were diagnosed with diabetes in 2000.

Signs and Symptoms

[span class=alert]The following list does not insure the presence of this health condition. Please see the text and your healthcare professional for more information.[/span]

Initial symptoms of diabetes include frequent urination, thirst, fatigue and irritability. Dizziness, lethargy, irritability, loss of coordination and perspiration are marked during hypoglycemic episodes (blood glucose 250mg/dl) among insulin-dependent diabetics can lead to ketoacidosis, characterized by increased thirst, nausea, vomiting and an acetone or "fruity" odor to the breath.

General

  • Frequent urination
  • Thirst
  • Fatigue
  • Irritability
  • Episodes of hypoglycemia
  • Episodes of hyperglycemia

Treatment Options

Conventional

Currently, the basic strategies used to control elevated blood glucose in patients with type 2 diabetes include: improving insulin secretion; improving insulin sensitivity; reversing insulin resistance; regulating glucose production in the liver; reducing postprandial hyperglycemia; and preventing complications. It has been determined that many of the long-term complications can be prevented with aggressive treatment that achieves near-normal blood glucose levels.

Treatment for patients with type 2 diabetes includes diet, exercise, and drug therapy. Diet is considered to be the primary treatment approach. Maintaining ideal body weight can allow the patient to control the disease and reverse the disease’s metabolic abnormalities. Exercise can improve insulin sensitivity and help regulate glucose production in the liver. Even with diet and exercise, however, within the first five years after diagnosis, over 60 percent of patients will need oral antidiabetic agents. It is also estimated that approximately 40 percent of patients will eventually need insulin therapy.

Oral Hypoglycemic Agents

The guidelines for the use of oral therapy for the treatment of type 2 diabetes include: onset of diabetes at 40 years of age or older; obese or normal body weight; duration of diabetes of less than five years; absence of ketoacidosis; FBS less than or equal to 200mg/dL; insulin requirements of less than 40 units per day; and the absence of renal or hepatic dysfunction.

Oral drug therapy for the management of type 2 diabetes now includes more choices of agents in several drug classes, most of which work by different mechanisms of action. Sulfonylureas cause release of insulin from the pancreas and increase the sensitivity of insulin receptors; biguanides work in the liver; thiazolidinediones work in muscle tissue; glucosidase inhibitors work in the small intestine; and meglitinide causes release of insulin from the pancreas.

Oral Drugs for Treating Diabetes

First Generation
Tolbutamide 250mg, 500mg
Acetohexamide 125mg, 250mg
Tolazamide 100mg, 250mg, 500mg
Chlorpropamide 100mg, 250mg

Second Generation
Glipizide 5mg, 10mg
Glipizide extended release 2.5mg, 5mg, 10mg
Glyburide 1.25mg, 2.5mg, 5mg
Glyburide Micronized 1.5mg, 3mg, 6mg
Glimepiride 1mg, 2mg, 4mg

Alpha-Glucosidase Inhibitors
Acarbose 50mg, 100mg
Miglitol 25mg, 50mg, 100mg

Biguanides
Metformin 500mg, 850mg, 1,000mg
Metformin extended release 500mg

Meglitinides
Repaglinide 0.5mg, 1mg, 2mg

Thiazolidinediones
Rosiglitazone 2mg, 4mg, 8mg
Pioglitazone 15mg, 30mg, 45mg

Combination Products
Glyburide and Metformin 1.25/250mg, 2.5/500mg, 5/500mg

Sulfonylureas
Oral sulfonylureas are sulfonamide derivatives without antibacterial activity. They stimulate insulin secretion, increase circulating insulin levels, and increase beta cell sensitivity to glucose. (7) They are typically used as an adjunct to diet and exercise. They are only effective in patients with the ability to produce insulin. They don’t prevent beta cell loss. Therefore, sulfonylureas can become less effective over time. The second generation agents are better tolerated and have fewer drug interactions than the first generation agents. About 50 percent of patients will achieve acceptable glycemic control with the use of sulfonylureas. These agents can also be used in combination with injectable insulin.

All of the sulfonylureas can be taken with food except for glipizide. Food delays glipizide absorption, so it is recommended that the agent be taken 30 minutes before meals.

Biguanides
Metformin is a biguanide and not chemically or pharmacologically related to the sulfonylureas. It improves insulin sensitivity without increasing insulin secretion. It also enhances glucose uptake and utilization by muscle. It decreases the liver production of glucose and decreases its intestinal absorption. By not increasing insulin secretion, it does not cause hyperinsulinemia. It also decreases blood glucose without producing hypoglycemia. It can be used as an adjunct to diet as monotherapy or in combination with other agents. It does not produce weight gain and it improves the plasma lipid profile. (8) Metformin is the only antidiabetic drug ever shown to prolong life in patients with type 2 diabetes. In the United Kingdom Prospective Diabetes Study (UKPDS) trial in 1998, metformin, when given as monotherapy, reduced all-cause mortality in obese patients by one-third.

Thiazolidinediones
Troglitazone, a member of the thiazolidinedione drug class or “glitazones", was approved in January, 1997, and made an immediate, significant impact in therapy. It was an agent reported to improve blood glucose levels by decreasing insulin resistance, not by increasing insulin secretion. It was indicated to be used as monotherapy, with insulin, or along with oral sulfonylureas. By December of that year, the FDA announced new liver enzyme monitoring guidelines to be followed which stated that patients be monitored more frequently for signs of liver injury. Subsequently, a warning about potential liver toxicity was prominently featured in the drug’s labeling, due to 35 post-marketing reports of liver injury in U.S. and Japanese patients, including liver failure that lead to one transplant and one death. The drug was voluntarily recalled by the manufacturer in March, 2000, after other drugs in its class were marketed.

In May, 1999, the FDA approved the second thiazolidinedione agent, rosiglitazone. Unlike troglitazone, rosiglitazone does not induce or inhibit CYP450 enzymes, and no significant drug-drug interactions have been noted to date. It does not appear to have the liver toxicity problems that have been associated with troglitazone. To date, there have been no reports of serious drug-induced hepatotoxicity. However, caution is still warranted and patient monitoring is still recommended.

The third thiazolidinedione to receive FDA approval is pioglitazone. It has favorable effects on the lipid profile, a potential advantage over rosiglitazone and troglitazone. Most patients will have lower triglycerides, increased HDL cholesterol, and no substantial change in LDL cholesterol. This may be important for those patients with type 2 diabetes that have elevated LDL cholesterol and are at a high risk for the development of cardiovascular disease. There were no cases of drug-induced hepatotoxicity reported during pre-marketing studies. Patient monitoring is still recommended.

Alpha-Glucosidase Inhibitors
Acarbose and miglitol are reversible inhibitors of intestinal alpha-glucosidase enzymes. By inhibiting these enzymes, they delay the digestion of complex carbohydrates (starches) into absorbable monosaccharides in the GI tract. This lowers postprandial blood glucose by slowing down the digestion and absorption of carbohydrates. These agents do not affect the absorption of simple sugars, such as glucose and lactose. Unlike sulfonylureas, they do not cause hypoglycemia, hyperglycemia, or weight gain. They do not enhance insulin secretion. Because they delay and decrease postprandial glucose levels, resulting in a smaller rise in blood glucose concentrations following meals, they may be alternative approaches for preventing postprandial hyperglycemia. They can be used with diet alone or combined with sulfonylurea or biguanide agents. They have been reported to cause a decrease in VLDL, triglycerides, and LDL-cholesterol levels. These agents are most useful for patients in the early stages of the disease who experience relatively high blood glucose levels after meals, but have relatively normal fasting blood glucose levels.

Meglitinides
Repaglinide belongs to a drug class known as the meglitinides, chemically unrelated to the sulfonylureas. It does, though, have a similar mechanism of action, increasing plasma insulin levels and decreasing glucose levels postprandially. It is the first member of a chemical class that decreases blood glucose by stimulating release of insulin from the pancreas. As with the, repaglinide relies on the presence of functioning beta cells to work effectively. It has a quick onset and short duration of action to manage the meal-related glucose load, and is less likely than long-acting sulfonylureas to have decreased efficacy with long-term use. Repaglinide can be used alone or in combination with metformin. Combined with metformin, the results achieved are better than with either agent used alone. There is no data on the use of repaglinide with other agents. Its primary disadvantage is that it must be taken multiple times daily, usually within 15 minutes of each meal. Patients who have had a poor response to a sulfonylurea are unlikely to respond to repaglinide.

Use of Insulin in Type 2 Diabetes
In the management of type 2 diabetes, it is important to individualize drug therapy. One must take into account unique patient factors and characteristics of the drug class and its specific agents. When there is little or poor response to an agent from one class, a drug from another class can be substituted and evaluated. For those patients who respond to an agent but do not reach target blood glucose levels at recommended doses, a second agent from another drug class can be added to the treatment regimen. However, achieving good control, patients are likely to have some deterioration of control over time, as type 2 is a progressive disease.

Even with the use of oral agents, postprandial hyperglycemia persists in 60 percent of patients. This secondary failure of oral agents is common. More than 25 percent of type 2 patients will require insulin to adequately control their blood sugar levels. Continual monitoring of their condition and compliance with therapy are extremely important.

Nutritional Supplementation


Vitamin E

In one study, men with the lowest plasma levels of vitamin E had nearly a 4 times greater incidence of developing type 2, or non-insulin dependent diabetes. (9) The results of this study suggest that low levels of vitamin E may be one of the contributing causes of type 2 diabetes. In another study, individuals who had type 2 diabetes, found that vitamin E supplementation (900mg/day for 4 months) helped improve the action of insulin and glucose tolerance. (10)

Vitamin E could also be important because it helps to protect against many of the medical complications that often develop in individuals with type 2 diabetes. For example, people with diabetes have a greater risk of developing vascular complications such as atherosclerosis, intermittent claudication, peripheral neuropathy, and retinopathy. Vitamin E may be helpful in the prevention and treatment of these conditions. (11) , (12) , (13) , (14)


Vitamin C

Studies have reported that individuals with Type 2 diabetes have low plasma ascorbic acid levels, which is not due to inadequate dietary intake but appears to be a consequence of the disease itself. (15) Glucose and ascorbic acid have similar chemical structures, which explains why they appear to utilize a common cellular transport pathway. (16) Because individuals with diabetes usually have elevated blood glucose levels, the competition between glucose and ascorbic acid for transport into cells may cause a deficiency of ascorbic acid within various tissues and organs. (17) Thus, it has been hypothesized that elevated blood glucose levels may cause inadequate levels of ascorbic acid in leukocytes, upset inflammatory response mechanisms, and negatively impact the immune system and healing capabilities in patients with diabetes. (18)


Coenzyme Q10 (CO-Q10)

It has been suggested that a deficiency of coenzyme Q10 could lower the ability of pancreatic cells to generate mitochondrial energy, which could impair the biosynthesis of insulin. (19) This could be due to the fact that a deficiency of coenzyme Q10 could impair the function and activity of glycerol-3-phosphate dehydrogenase (G3PD). This enzyme helps control the process whereby beta cells recognize the presence of glucose and respond by producing insulin. It has been reported that G3PD underfunctions in animals and humans with type 2 diabetes. (20) Therefore, in patients with type 2 diabetes who have sub-optimal levels of coenzyme Q10, CoQ10 supplementation may improve the functioning of beta cells and the production of insulin. Physicians and patients instructed to monitor blood glucose levels very closely because improvements in insulin production will necessitate reducing the dosages of oral hypoglycemic medications accordingly.


Biotin

In an animal model, mice with non-insulin dependent diabetes were treated with biotin, which decreased post-prandial glucose levels, and improved glucose tolerance and insulin resistance. (21) These benefits may be related to the activity of glucokinase, which is an enzyme that plays an important role in regulating a variety of glucose-related metabolic processes. Biotin reportedly stimulates glucokinase enzyme activity. In a Japanese study, the administered 3 mg of biotin three times daily to patients with type 2 diabetes provided a significant lowering of fasting glucose levels without any adverse side effects. (22) Thus, it appears that biotin may be a safe nutritional product to aid in the management of type 2 diabetes.


Chromium

The influence of chromium on blood sugar regulation was first recognized in animal studies in the 1950s. In the 1970s, chromium’s importance was discovered in TPN solutions. When TPNs void of chromium were administered over a period of months, insulin resistance and elevated blood sugar levels appeared in patients. Chromium was added and blood sugar levels in TPN patients returned to normal. Various studies support that chromium has a positive effect on blood glucose levels, and recent studies report that chromium may positively impact hemoglobin A1c as well. (23)

It is thought that chromium facilitates insulin by activating the protein kinase molecules in receptor cells, therefore enhancing the uptake of glucose and other nutrients. (24) By aiding insulin utilization in the body, chromium helps to maintain muscle mass during hypocaloric dietary intake, stabilizing the basal metabolic rate. Because of the influence of insulin on thyroid hormone conversion, it has a lowering effect on cholesterol and triglycerides. By improving insulin regulation, chromium may also reduce hunger and limit food cravings. Insulin is involved in the regulation of the hypothalamic satiety center. Improving insulin response should improve satiety signals. Insulin is also vital in serotonin synthesis, a neurotransmitter linked to the craving for carbohydrates.

Several groups are at risk for reduced chromium levels. First of all, most Americans are at risk because of a diet rich in refined sugars. Individuals who eat diets high in refined sugars tend to excrete 300 percent more chromium in their urine than those whose diets are low in refined sugars. Individuals who live in countries with high levels of chromium that comes from diets rich in unrefined grains have a lower incidence of diabetes and atherosclerosis. People who exercise regularly excrete two to six times the normal amount of chromium in their urine on days of exercise. (25) Many athletes compound this problem with high-carbohydrate supplements. The elderly also tend to be at risk due to reduced absorption and inadequate intake of chromium. It is interesting to note that women tend to have a drop in chromium levels during the third trimester of pregnancy. (26)

There is a great deal of controversy over what is the best chromium to use. Chromium is biologically active only in the trivalent state in which it forms complexes with organic compounds. The most important of these complexes is glucose tolerance factor (GTF), which is comprised of trivalent chromium, niacin, glycine, glutamic acid, and cysteine. Dr. Walter Mertz of the United States Department of Agriculture researched GTF chromium. He found that chromium was a crucial part of the binding complex that allowed insulin to attach to cells. Organically bound GTF chromium is thought to be safe and well tolerated.

Chromium picolinate is another popular form of chromium that has clinical support for blood sugar regulation. (27) , (28) The majority of evidence points to the safety of the picolinate form. A recent study in lab animals reported different findings. Researchers at Dartmouth College and The George Washington Medical Center discovered that exposing ovarian cells of laboratory animals to certain doses of chromium picolinate resulted in chromosomal damage. (29) More information is needed before any true conclusion can be drawn regarding this supplement, in light of the fact that there have been studies reporting safety and efficacy.

For diabetics, adding chromium or other blood sugar regulating agents to their supplement list should be done gradually, especially if they are currently controlled on medication. Recent studies report 600mcg to 1,000mcg a day may be needed to control the type 2 diabetic. (30) With lifestyle and dietary changes, there may not be a need for an aggressive chromium dosage. If another agent is being used, its complementary activity may allow for a reduced dose of chromium.


Magnesium

Magnesium is involved in glucose metabolism and insulin secretion. (31) It is well documented that low magnesium may aggravate diabetic conditions. (32) Hypomagnesemia occurs in approximately 25 percent of diabetic patients and has been reported in type 2 diabetics. (33) Many Americans tend to be below the RDA for magnesium intake by 70-80mg. Many experts feel that the RDA for magnesium needs to be significantly increased from the current level of 350mg to as much as 700mg per day.


Vanadium

Vanadium is a trace mineral essential for plant nutrition, but its role in human nutrition remains unclear. It is a known co-factor in enzymatic functions. High concentrations of vanadium are found in the kidneys, liver, and bone. Fat cells temporarily store vanadium for quick release into the body. Its application in the treatment of type 2 diabetes has received attention in the scientific community. Supplementation with vanadyl sulfate and other vanadium compounds has been reported to markedly improve a number of clinical measures of diabetes. It appears that vanadium mimics the effects of insulin, resulting in decreased gluconeogenesis, an increase in the activity of glycolytic enzymes, and an increase in glycogen production. (34) , (35)

Animal studies have demonstrated that vanadium administered to diabetic rats restores elevated blood glucose to normal ranges. Subsequent studies have reported that vanadyl sulfate not only lowers blood glucose in diabetic animals, but cholesterol and triglycerides as well. (36) Furthermore, the hypoglycemic effect of vanadium may have a sustained effect. In one study, diabetic rats remained euglycemic for as long as 20 weeks after withdrawal from treatment, indicating that vanadium may exert a protective role over the pancreatic beta cells. (37)

Human studies are encouraging. Type 2 diabetics given oral vanadyl sulfate (50mg twice daily for four weeks) in a single-blind, placebo-controlled study had a nearly 20 percent drop in fasting blood glucose in one study. (38) Minor gastrointestinal upset was the only reported adverse effect. In another study, supplementation with 100mg of vanadyl sulfate daily for three weeks resulted in improved insulin sensitivity in hepatic and peripheral tissue. (39) There is additional evidence that vanadium may have applications in the management of insulin dependent diabetes.

Vanadium pentoxide and vanadyl sulfate are active, absorbable forms of vanadium.


Alpha-Lipoic Acid (ALA)

Alpha-lipoic acid (ALA) is an antioxidant substance produced by the body. ALA is also known as alpha-lipoate or thiotic acid. Lipoates are small water and fat-soluble molecules that are easily absorbed from the gastrointestinal tract. It has been recognized recently for its role in cardiovascular disease, as well as a potential adjunctive therapy for AIDS patients. (40) Alpha-lipoic acid has also demonstrated a positive effect on insulin and blood sugar metabolism for type 2 diabetics. (41) Lipoates have been reported to increase insulin-mediated glucose uptake and insulin sensitivity among type 2 diabetics in clinical trials. (42) , (43) ALA reportedly improved glucose metabolism in insulin-resistant skeletal muscle in one study, indicating its potential in restoring glucose availability. (44)

ALA may also be a promising antihyperglycemic agent for diabetics who suffer glucose overproduction by inhibiting hepatic fatty acid oxidation and gluconeogenesis. (45) In addition, ALA’s antioxidant properties are reportedly effective in the treatment of diabetic neuropathy. (46) In a recent single blind, placebo-controlled study, 97.5 percent of diabetic subjects treated with a 200 ml intravenous solution daily for three weeks reported an improvement of neuropathy symptoms. The response rate of the control group was 40 percent. (47) These mechanisms are enhanced over several weeks of intake and can be used in conjunction with other glycemic agents.


Zinc

Zinc deficiency is associated with a number of metabolic disorders, including impaired glucose tolerance, insulin degradation, decreased insulin potency, and reduced pancreatic insulin content. (48) In clinical studies, diabetic animals and humans with zinc deficiencies have demonstrated improved glucose tolerance when supplemented with zinc. (49) , (50) Zinc plays a role in the regulation of insulin production by the pancreas and glucose utilization by muscle and fat cells. Zinc also serves as a component in glucose transport and in gene expression of insulin receptors.


Cyclo (His-Pro)

Cyclo hispro, a thyrotropin releasing hormone metabolite, is thought to be a useful agent in improving blood sugar regulation. (51) Cyclo hispro has potential for individuals with hypoglycemia, diabetes, and impaired glucose tolerance (IGT). It has been documented that individuals with diabetes have impaired intestinal zinc absorption and low plasma zinc levels. Both animal and human studies suggest that this extract influences intestinal zinc absorption mechanisms. Zinc deficiency has been associated with reduced pancreatic insulin content, decreased insulin potency, IGT, and increased insulin degradation. (52) This extract not only contains high levels of zinc, but also several cofactors reported to stimulate intestinal zinc absorption.

In a recent controlled clinical trial, cyclo hispro was administered to 22 male subjects with type 2 diabetes. After three months, the treatment group reportedly exhibited significantly diminished fasting blood glucose levels and fasting plasma insulin levels. The placebo control group demonstrated no significant changes. In addition, the treatment group had slight decreases in serum cholesterol and LDL and increased plasma zinc concentrations. The results of the study demonstrated the potential of cyclo hispro extract with zinc in managing insulin and glucose metabolism among type 2 diabetics. (53)

Improving zinc utilization is important because it plays a role in over 300 different enzymatic functions. Most importantly for the diabetic, it is involved in wound healing, immune function, and skin integrity.

Herbal Supplementation


Gymnema

Gymnema is a rain forest vine found in Central and Southern India, which has a long tradition in the treatment and management of diabetes. The Indian name is Gurmar, which means, “sugar destroyer". Its use has been documented in Ayurvedic medical texts for over 2,000 years in the treatment of “sweet urine". Gymnema is gaining popularity with clinicians utilizing natural therapy protocols in the management of diabetes, hyperinsulinemia, and impaired glucose tolerance. The leaves of gymnema are thought to increase insulin secretion, and several studies report control of hyperglycemia in moderately diabetic laboratory animals. (54) , (55) A decrease in body weight was also reported. Gymnema reportedly produced blood glucose homeostasis and increased the activity of the enzymes involved in the utilization of glucose by insulin dependent pathways. (56)

Human studies have reported a significant reduction in blood glucose during therapy with gymnema. (57) , (58) A reduction in glycosylated hemoglobin and glycosylated plasma proteins has also been reported, with a reduction in conventional drug dosage. In studies, patients with diabetes were able to discontinue conventional drugs and maintain their blood glucose homeostasis with gymnema alone. (59) Researchers suggest that beta cells may be regenerated and/or repaired in type 2 diabetics on gymnema supplementation. (60) They support their claim by the appearance of increased endogenous insulin levels in the serum of individuals after gymnema supplementation. Other studies report that gymnemic acids suppress the elevation of blood glucose levels by inhibiting glucose uptake in the intestine. (61)

Gymnema has also been reported to selectively suppress the neural responses to sweet taste stimuli. (62) , (63) , (64) Because gymnema leaf powder has an anesthetizing effect on the taste buds which can last for several hours, some researchers feel that gymnema may be a potential agent in weight reduction and sweet cravings. (65) A recent study reports significant serum cholesterol lowering effects of gymnema. (66) Gymnema may potentially be used in athletes to develop a higher ratio of lean muscle mass to body fat. This may be due to the reported increase of insulin output associated with long-term use of gymnema. Increased insulin output and utilization encourages the uptake of amino acids into muscle tissue. Another study found that gymnema was effective and safe for the reduction of excess weight, BMI and also promoted healthy blood lipid levels. (67)


Bitter Melon

Bitter melon or karela fruit has long been used in South America and the Orient as not only a food but also as a febrifuge, abortifacient, emmenagogue, vermifuge, antiviral, emetic, anthelmintic, and antidiabetic agent among other uses. (68) Recent studies have focused on the beneficial properties of the fruit in diabetes and hyperinsulinemia, HIV viral infection, and certain cancers. (69) , (70)

Bitter melon has been reported to significantly improve glucose tolerance in humans. (71) , (72) The currently accepted hypotheses regarding hypoglycemic activity is claimed to be mediated through an insulin secretagogue effect or through an influence on enzymes involved in glucose metabolism. (73) Research indicates that molecules with insulin-like bioactivity may be present in bitter melon seeds. (74) A few studies suggest that the hypoglycemic mechanism of action of bitter melon could be partly attributed to increased glucose utilization in the liver rather than an insulin secretion effect. (75) A recent laboratory study reported a significant reduction of fasting blood glucose levels observed in diabetic rats, but no hypoglycemic activity in the treated normal rats. (76) Bitter melon also demonstrated considerable lowering of serum cholesterol and triglycerides in the treated diabetic group. There was a significant improvement in hepatic glycogen level in treated diabetic rats, with a return of close to normal levels after the treatment with bitter melon. There have been negative reports as to the ability of bitter melon extracts to lower blood sugar levels in laboratory animals. (77) , (78) It is recommended that a standardized extract of bitter melon always be used.


Evening Primrose

Evening primrose oil (EPO) is rich in gamma-linolenic acid which is an omega-6 fatty acid. (79) , (80) Omega-6 fatty acids reportedly reduce the arachidonic acid cascade and decrease inflammation through inhibiting the formation of inflammatory mediators in this process. Supplementation with essential fatty acids such as EPO has been reported to prevent zinc deficiency, thereby potentially improving immunity. (81) Fatty acids are an important part of normal homeostasis. The human body can produce all but two fatty acids - omega-3 and omega-6 fatty acids. Both must be obtained through the diet or by the use of supplements. Obtaining a balance of these two fatty acids is essential. Essential fatty acids are needed for building cell membranes, and are precursors for production of hormones and prostaglandins. Modern diets tend to be lacking in quality sources of fatty acids.

Diabetics who do not convert linoleic acid to gamma-linolenic acid will need a quality source of GLA. (82) , (83) This is said to be essential for proper nerve function and for the prevention of diabetic neuropathy. (84) , (85) Evening primrose oil was reported to be beneficial in effecting the course of diabetic neuropathy by decreasing microvascular problems associated with diabetes. (86) , (87)

Acupuncture & Acupressure

Acupuncture
Zhu Xiou Feng used acupuncture treatment for 246 diabetes patients. He chose Zu San Li (S 36), San Yin Jiao (Sp6), Qu Chi (LI11), and other points according to the symptoms of the patients. He used gental manipulation, leaving the needles in the points for thirty minutes, and also combined with moxibustion for five minutes for each point once a day, with one month as one treatment unit. After one to four treatment units, 154 patients received substantial progress, 83 cases showed progress, 9 patients showed no response. The total effectiveness rate is 96.3%. (88)

Guo Shui Chi used acupuncture to treate type 2 diabetes for 60 patients. He divided his patients into three groups according to the differentiation theory in Chinese medicine. He applied acupuncture needles to Ge Shu (B17), Pi Shu (B20), Zu San Li (S36), Chi Ze (L5), Di Ji (Sp8), San Yin Jiao (Sp6), etc. once a day, with ten treatments as one treatment unit. 27 patients showed substantial results, 23 showed progress and 10 patients showed no change. The effectiveness rate is 83.34%. (89)

Li Dong Ling, et al. used acupuncture treatment treating 29 patients of type 2 diabetes. According to the Chinese medicine theory, these patients all belong to defiency qi and ying condition. The method he used is a combination of acupuncture and diet. The main acupuncture points are He Gu (LI4), Fu Liu (K7), and Da Zhui (D14), leaving the needles in the points for twenty minutes for each time. 11 patients showed substantial progress, 16 patients showed progress and 2 showed no response. (90)

Combination of Acupuncture and Herbal Therapy
Fan Guan Jie observed a group of patients using a combination of acupuncture and herbal treatment. This group of people all belong to type 2 diabetes along with hyperlipidemia. He used Qi Hai (Ren6), Zhong Wan (Ren 12), Pi Shu (B20), Shen Shu (B23), etc. acupuncture points once a day, with five times as one treatment unit. Patients rest two days between acupuncture treatment units. Meanwhile, the herbal formula is given to the patients. It contains Ren Shen (Ginseng), Sheng Di (Rehmannia), Sha Shen(Adenophora), E Zhu (Zedoaria), Da Huang (Rhubarb), Wei Mao, San Qi (Notoginsing), and Gan Cao (Licorice). All the patients received a positive response on the level of cholesterol, triglycerides, and HDL. Among these three, the greatest change is in the triglyceride level. The combination of both acupuncture and herbs showed better results than the control group. (91)

Electrical Stimulation Therapy
Feng Sheng Li, et al. used impulse low-frequency of electro-stimulation for 45 patients of type 2 diabetes. The name of the apparatus used is called CDJ-E Diabetes Theraputic Apparatus. The main acupuncture points used are Zhong Wan (Ren 12), Zu San Li (S36), and Yong Quan (K1). The electrode is applied to the points adjusting the frequency and strength of stimulation according to the patient's feelings. The patients were stimulated four minutes per point, once a day, with thirty times as one treatment unit. The glucose level two hours after a meal was decreased on an average by .44mmol/L, compared to non-treatment (P

Traditional Chinese Medicine

Diabetes Mellitus, Type 2

Extensive information regarding the treatment of this health condition using Traditional Chinese Medicine is available through the link above.

Diet & Lifestyle

Diabetes and obesity have increased significantly over the past 50 years in the United States. People don’t eat enough fresh foods, and there are fewer micronutrients in the soil (like chromium and vanadium) where food is grown. Fad diets of high protein, low or high fat, and low or no carbohydrates are not the answer. While this type of diet may help take weight off initially, it is not a long-term answer. Carbohydrates alone are not the culprit, because humans were eating carbohydrates long before these problems arose. It is true, however, that people are eating excessive amounts of carbohydrates, and it would be better to moderate that intake.

There are several ways to support and potentially improve insulin regulation through natural agents, but the real key is to modify the dietary selection of foods. In general, the American diet consists of a large amount of carbohydrates, especially refined carbohydrates. People limit their intake of fresh vegetables and fruits, and quality sources of protein and legumes, and they do not take in adequate sources of essential fats. As of 1985, the typical American diet was 46 percent carbohydrates, 43 percent fat (poor quality), and only 11 percent protein. With the average American eating approximately 150 pounds of sugar a year, it is apparent that there is a continual demand for more insulin production. The average person drinking two “big gulp" drinks a day is receiving approximately 54 teaspoons of sugar. Using diet drinks does not work either because of their sodium content. This is particularly a problem for diabetics with hypertension. While current research shows that dietary fat and cholesterol are definite problems, this situation is compounded by the continuous, elevated intake of carbohydrates simultaneously with fats. Dietary fat is stored under the influence of excessive insulin release during a repeated high-carbohydrate load.

Many experts over the years have acclaimed the low-fat, high-carbohydrate diet. The problem with this diet has been that it does not result in weight loss. In fact, excessive carbohydrate intake has been linked to elevated LDL cholesterol and triglycerides. (92) This conclusion makes sense when realizing what mechanisms are involved metabolically under a continuous high-carbohydrate load. The other deceiving aspect is that many prepared foods may be labeled low fat, but are loaded with refined sugars, which aggravate the insulin response mechanism, and therefore, fat storage.

The obvious first step is to eat foods that will least aggravate insulin response. This will not only benefit the diabetic, but many individuals wanting to lose weight will notice a positive effect from this approach as well. The first concept to understand is the glycemic index, the fact that certain foods actually cause a sharper rise in insulin release than others. The glycemic index was first developed to help diabetics control postprandial insulin blood sugar regulation, since this is the most difficult aspect of controlling blood sugar. Foods that do not cause a rapid rise in blood sugar will not aggravate the insulin response. For example, in the past, it was thought that all complex carbohydrates were equal. It is now known that different grains have varying glycemic responses. It is valuable to consider the glycemic index when looking at foods that contain varying amounts of carbohydrates. Proteins and fats have virtually no glycemic factor.

Legumes: Virtually all legumes have a moderate glycemic index. They also provide a source of water-soluble fiber that is valuable for lowering cholesterol. They also provide phytoestrogens, which may provide health benefits.

Vegetables: Some vegetables have a high glycemic index and should be used in moderation if one is trying to actively control blood sugar. The most prominent of these are white potatoes (baked), carrots, beets, and turnips. However, if an individual is eliminating other sources of refined sugar in the diet and is reducing the amount of complex carbohydrates (breads and pastas), he/she should be able to use these vegetables with moderation.

Dairy products: Most dairy products have a low glycemic index. However, some people do not tolerate dairy well.

Fruits: Fruits are generally in the middle of the road in terms of glycemic index, but dried fruits, which are concentrated, rank higher. Drinking fruit juices will definitely aggravate blood sugar response and is known to contribute to triglyceride response. Therefore, fruit juices should be limited or diluted with three-fourths water.

Most sweeteners such as honey, molasses, sugar, and white grape juice concentrate tend to have a high glycemic index. Rice syrup and granulated rice sweeteners are also acceptable alternatives. There is some evidence that aspartame may aggravate insulin resistance over time.

Grains: Many of the grain sources such as rice, wheat, and corn tend to have a high glycemic index, but grains such as buckwheat, millet, barley, rye, and bulgur are actually quite low. For successful weight loss and blood sugar control, this group of foods should be used in moderation. Also, the addition of fats such as olive oil or butter (in moderation) can slow the glycemic index.

Fiber: Fiber is an important part of the diet for a number of reasons. It is well known that fiber helps prevent constipation. However, fiber also controls sugar and cholesterol levels and aids in the prevention of colon cancer and diverticulitis. Most individuals with diabetes/insulin resistance do not realize that they run a 75 percent risk of developing atherosclerosis. Reducing cholesterol levels through the use of fiber is one way to combat this problem.

Fiber is the indigestible part of plant food that acts as roughage for the body. There are two types of fiber. Water-soluble fiber is found in fruits, vegetables, and legumes in the form of guar, pectin, and gums. These products form a gel in the digestive tract that allows for a food to be held longer, resulting in a slow rise in blood sugar. This type of fiber also aids in lowering cholesterol. Insoluble fiber is made of cellulose, hemicellulose, and lignins, and can be found in grains and bran. This food also takes longer to be broken down and used for energy, but its main value is in adding bulk and preventing constipation.

Food Nutrient Groups and Their Importance in Insulin Regulation

Proteins: Protein is a vital part of every individual’s diet. It is needed for the growth and rebuilding of tissues. Proteins are made of amino acids. These amino acids are absorbed through the small intestine and distributed as needed. The body can manufacture most amino acids, but there are eight essential amino acids that must be obtained through the diet. These eight can best be found in sources such as eggs, poultry, fish, and meat. Nuts, seeds, legumes, and grains can provide some of these essential amino acids as well. For the sedentary individual, an average of about 0.8 grams/kilogram body weight is normal; for the more active individual or aerobic enthusiast, 1.2 grams/kilogram may be needed. For the individual who engages in anaerobic or weight or strength-related exercises, as much as 1.7 to 1.8 grams/kilogram body weight may be needed. Protein intake is invaluable for tissue healing and maintaining anabolic function in the body.

Carbohydrates: Carbohydrates is the class of foods that tend to be overconsumed. They are easy to obtain, are filling, and tend to be gratifying (like desserts). They are an energy source that eventually gets broken down into sugar. There are complex and simple sugars. Simple sugars are found in fruit and fruit products, white and brown sugar, maple syrup, and honey. These simple sugars definitely tend to aggravate insulin response. Carbohydrates are the main fuel for serotonin production and a principle reason for the late night craving for sweets that occurs for so many individuals. Because of its fiber content, fruit, however, does have the advantage of being broken down in the stomach, with the sugar released over time. However, fruit should not be overeaten, since it does contain, in some cases, a large amount of fructose. Complex carbohydrates provide the advantage of fiber, but too many complex carbohydrates, especially the high glycemic index ones, will have a negative effect on metabolism. Significant carbohydrate intake should come from vegetable sources.

Fats: Fats are an essential part of the diet. Americans eat poor sources of dietary fat for the most part. Most of the fats come from margarine, partially hydrogenated oils, or oils that have been commercially heated and are oxidized. Monounsaturated fats, such as olive oil, benefit by helping to control cholesterol. The use of omega-3 fatty acids, especially from vegetable sources (flax seed), can provide benefits. Because of the shortage of quality oils in the diet, most people are actually deficient in essential fatty acids. In particular, the omega-3 fatty acids seem to be an issue. These fatty acids are important as regulators of inflammatory pathways and for the health of nerve tissue, as well as being key nutrients for the health of every cell in the body.

Exercise: Along with dietary responsibility, exercise is the most important step diabetics can take toward tighter blood sugar control. Today, there is more stress and less physical activity than even a generation ago. As Diabetes Care recently reported, exercise improves cardiovascular risk in diabetic patients. Regular exercise improved cardio-respiratory endurance, insulin sensitivity, and HDL cholesterol, while decreasing LDL cholesterol levels. (93) Of course, it is well established that exercise also helps to regulate blood sugar levels. At a minimum, diabetics should get 30 minutes of some form of exercise at least four days a week, but more would be beneficial. Anyone who is over 40, or a brittle diabetic, and has not been exercising, should seek medical advice and supervision before initiation of any exercise program.

Clinical Lab Assessment

Some of the following laboratory testing can provide information necessary for diagnosis and treatment. In addition, the tests listed may also give insight to functional metabolism and functional nutrient status in the body.

Organic Acids

Organic acids analysis is a useful method for measurement of biochemical intermediates in urine. These intermediates can offer information about key enzyme functions and nutrient competence (amino acids, nutrient cofactors, minerals and fatty acids). Several examples can be cited:

    Elevations of pyruvate, lactate, á-hydroxybutyrate, and â-hydroxybutyrate indicate impairment in enzyme functions relative to carbohydrate metabolism.

    Elevation of tricarballylate suggests functional magnesium deficiency, which can impact glycemic response mechanisms due to bacterial pathogens.

    Elevation of vanilmandelate reflects elevations in epinephrine, an aggressive antagonist of insulin.

    Detoxication and dysbiosis markers in organic acids suggest the relative competence of the liver and gastrointestinal tract to detoxify insulin, a critical process in carbohydrate metabolism.

Fructosamine

This is a measure of glycosylated serum proteins (primarily albumin) implicated in the formation of glycosylated hemoglobin. Because albumin has a circulatory half-life of 20 days, the amount of fructosamine reflects hyperglycemic periods within the previous few weeks. Thus, blood or urine glucose provides information about immediate diabetic control, fructosamine about short-term control, and HbA1c about long-term control.

Glucose

High blood glucose is suggestive of type 1 insulin-dependent diabetes mellitus (IDDM). Type 2 non-insulin-dependent diabetes mellitus (NIDDM) is often associated with a lower glucose, but with an increased fasting insulin level in serum. Blood glucose levels vary in response to food intake, stress, physical exertion, and various disorders. Elevations of serum glucose should lead to confirmatory testing such as fasting insulin, serum phosphorus, magnesium, hemoglobin A1c, and/or fructosamine.

Glucose Tolerance Test (GTT)

This evaluation is sometimes employed when a diagnosis is uncertain. The GTT can be performed with an oral glucose load, or in cases where gastrointestinal absorption may be variable (gastroenterostomy, thyrotoxicosis, or sprue and other malabsorption syndromes), it can be performed with an intravenous loading dose. Pretreatment with glucocorticoids (e.g., cortisone) can increase the GTT sensitivity; this is known as the Cortisone-Glucose Tolerance Test. Measuring insulin at the same time as glucose can offer significant additional information regarding insulin response, further contributing to a more accurate assessment of function in carbohydrate metabolism. The Glucose-Insulin Tolerance Test (GITT) can be useful in contrasting insulin deficiency with cellular insulin insensitivity abnormalities.

Hemoglobin A1c (glycosylated hemoglobin)

When exposed to high glucose levels, the hemoglobin molecule irreversibly acquires a glucose-derived segment on the beta chain. Elevated HbA1c levels reflect poor diabetic control in the previous three to five weeks. Following the stabilization of glycemic levels, HbA1c levels will return to normal in about three weeks. HbA1c can provide information missed in spot checks of urine or serum glucose. Insulin-sensitive IDDM individuals may have undetected periods of hyperglycemia, alternating with post-insulin periods of normoglycemia or hypoglycemia. Episodic or chronic hemolysis will result in low HbA1c values. Old red cells have higher A1c levels than young cells. Any condition that results in a higher proportion of young RBCs will result in an A1c value that is not necessarily a true reflection of glucose management.

Urine Glucose

Screening of random or postprandial urine specimen for reducing substances is the most widely used and simplest procedure used to diagnose diabetes. Clinitest color reactions are semiquantitative, while glucose oxidase test strips provide a gross assessment of urine glucose. If reducing substances are present, a check for ketone bodies is usually done to determine if diabetic acidosis is present.

Clinical Notes

Dietary changes must be emphasized for the diabetic patient. In addition, there are multiple considerations such as nutrient status for magnesium, essential fatty acids, zinc, and organic acids testing to determine fungal involvement in the gut, circulatory support, antioxidant support, and cardiovascular support. These all need to be considered in addition to suggesting nutritional support for maintaining tighter control of blood sugar. When recommending any agent that may alter blood sugar metabolism, it is best to titrate the dose slowly over a few weeks so that blood sugar regulation is gradually altered.

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