Type II: Non Insulin Dependent Diabetes Mellitus (NIDDM)
In the United States, about 5.2% of the population (13 million people) has diabetes; 90% of all cases are non-insulin dependent diabetes (NIDDM). Unlike Type I patients, who are always deficient in insulin, Type II patients may have insulin resistance, decreased insulin production, or increased insulin production to compensate for the insulin resistance. Type II diabetes is usually associated with obesity, a sedentary lifestyle, and a high sugar diet (as in syndrome X). Although often undiagnosed and ignored by the medical community, hyperinsulinemia is often a precursor of NIDDM. Ketoacidosis (hyperglycemic comas) seldom occurs in NIDDM.
Causal Mechanisms
There are many proposed explanations of the mechanisms involved in developing NIDDM.
High Sugar, Low Fiber Diet
The modern Western diet — high in refined sugars and fats but low in fiber — can contribute to the cause of reactive hypoglycemia. The intake of refined sugar can lead to a rapid rise in blood sugar levels, causing the pancreas to secrete insulin sometimes at a level that can result in hypoglycemia. The adrenals then secrete epinephrine and other stress-hormones to increase blood sugar back to normal. If patients continually assault their bodies with this diet, it may result in both pancreatic and adrenal exhaustion.
Obesity
Obesity is a significant factor in NIDDM, which tends to be hypertrophic and android. Hypertrophic cells are enlarged fat cells. Serum insulin levels and triglycerides regulate the deposition of fat tissue on the abdomen. Gluteo-femoral adiposite deposition is usually regulated by corticosteroids and estrogen.
Fat tissue in itself is very metabolically active, more than conventionally considered. A study at Harvard medical school found that adipocytes secrete a variety of active hormones such as tumor necrosis factor, leptins, interleukin 6, fatty acids and resistin. Resistin is thought as a chemical that induces insulin resistance since it positively correlates with insulin sensitivity. However, current research still finds the evidence as premature, since the serum resistin level of Type II patients are decreased in fasting rather than increased. Adipose tissue, once thought as a passive depot of fat, might actually be an active endocrine gland, playing a role in metabolic regulation, preventing harmful accumulation of lipids in other tissues, and the secretion of metabolically active hormones.17
Glucose Oxidation
Another postulated mechanism in NIDDM is a problem in oxidative metabolism of glucose. Glucose metabolism is regulated by pyruvate-dehydrogenase and inhibited by isomers of pyruvate-dehydrogenase kinase. Increased levels of pyruvate-dehydrogenase kinase may cause insulin-resistance in NIDDM patients and increased fatty acid oxidation. Recent studies have found that obesity can cause an insufficient down regulation of pyruvate-dehydrogenase-kinase-mRNA in people with insulin-resistance; this leads to increased levels of pyruvate-dehydrogenase-kinase, which impairs glucose oxidation and thus results in increased fatty acid oxidation.18
Other Disorders
Insulin-resistance is associated with various other disorders, including polycystic-ovary disease, liver malfunction, and cirrhosis. The oxidation of hepatic cell membranes, which occurs in cirrhosis, causes a decrease in liver function that is associated with the development of diabetes.
Increased abundance of insulin, insulin-like growth factors, and hybrid 1 receptors are found in muscles of obese patients.19-20 An increase of in-vivo insulin insensitivity has been found in both obese and hyperinsulinemic patients. Hyperinsulinemia is an independent risk factor not only for NIDDM, but also for atherosclerosis.
HISS
Glucose homeostasis is regulated both by the pancreas and the counter-regulatory responses of the adrenal gland and liver. The hormones involved include glucagon, catecholamines, growth hormone, and cortisol. The role of the liver in NIDDM has been demonstrated, in both animal and human studies. Receptors on hepatic parasympathetic nerves release nitric oxide, which causes the release of Hepatic Insulin Sensitizing Substance (HISS). HISS sensitizes skeletal muscle to absorb insulin. Animal studies have shown that the blockade of nitric oxide release causes a secondary blockade of HISS, which results in insulin resistance. 21
Low Birth Weight
Low birth weight is a contributing factor for NIDDM. Decreased fetal nutrition can lead to abnormal development of pancreas and adipose tissue, leading to hyperglycemia in adults.22 Nitric-oxide deficiency is a risk factor for both NIDDM and insulinemia.23 Levels of serum-chromium in adult diabetics have been found to be much lower than in non-diabetic subjects. However, no correlation between rate of glycemia and serum chromium levels has been found in diabetics.24
Herbicides
Exposure to herbicides during the Vietnam War, especially Monsanto’s defoliant Agent Orange (dioxin), may be associated with the development of diabetes. Agent Orange was sprayed on trees to reduce cover for North Vietnamese soldiers. About 2.6 million people served in Southeast Asia between 1962 and 1975. About 8% to 11% now have diabetes. Since diabetes increases with age, the percentage will undoubtedly rise. In 1991 the U.S. Congress passed the Agent Orange Act, which established a system for evaluating the effects on its soldiers. About 8,500 Vietnam veterans have been financially compensated, many for diabetes-related health damages under this Act.
Other diseases designated as associated with herbicides include chloracne 9 (a skin condition), soft tissue sarcoma, Hodgkin’s disease, multiple myeloma, respiratory cancers, prostate cancer, and Non-Hodgkin’s lymphoma. Spina bifida in the children of veterans is also considered grounds for compensation from the Agent Orange Act. Agent Orange is not only found in tissues of soldiers from the Vietnam war, but according to an EPA study in 1982, it is also found in the tissue of 76% of the general American public.25
Conventional Pharmaceutical Treatment [SH]
Insulin
Insulin is one type of pharmacological agent used in NIDDM. Eighty percent of the cell membranes in the body become highly permeable to glucose within seconds of insulin binding to its receptors; rapid entry of glucose ensues, which is used in the formation of substrates for metabolism. Thin diabetic patients respond quite well and have decreased microvascular complications. The disadvantages of using insulin in NIDDM patients is that they can have hypoglycemic episodes that can lead to a coma, or they can have increased risk of macrovascular complications. The use of insulin can cause weight-gain, which is a problem in perpetuating insulin resistance itself. Only a minority of patients can take insulin since it is usually not effective in obese patients.
Sulfonylurea
Sulfonylurea is another pharmacological agent used in NIDDM that works by stimulating insulin secretion from the beta cells of the pancreas. Following long-term use, it may also affect extra-pancreatic functions, such as increased peripheral sensitivity to insulin and a decreased hepatic glucose production. Sulfonylureas have the advantage that there are multiple formulations available that are relatively inexpensive.
Their effectiveness was demonstrated in a study with Glimepiride: 5,000 patients with Type II diabetes had a decrease of 43-74 mg/dL more than placebo. The administration of Glimepiride also decreased HbA1c values by 1.2-1.9%. The disadvantage of sulfonylurea use is that after initial success, sulfonylureas are completely ineffective in 30% of patients. Adequate control in the long-term use of sulfonylureas only occurred in about 20-30% of patients. Sulfonylureas are contraindicated in liver, kidney, and thyroid disease.
Primary and secondary failure can occur with all oral agents used in the treatment of NIDDM. One study showed that the rate of deaths due to heart attack was 2.5 times greater in patients who had used sulfonylureas for the treatment of glycemia than the group treated with diet alone. Currently, there are warning labels for cardiac death on all Sulfonylureas and Metformin. However, the UK study found no correlation between increased cardiovascular death and sulfonylurea use.26
Metformin
Metformin is the drug of choice for obese NIDDM patients. A Biguanide, Metformin is a pharmacological agent developed within the last few years whose mechanism is believed to potentiate insulin and increase insulin receptor sites, independent of pancreatic function. It also leads to weight-loss, which may be another contributing factor in its mechanism.
The effectiveness of metformin has been demonstrated in pharmacological studies. In one study, 228 patients had an HbA1c value of 9.43%; after 3 months of treatment it decreased to 8.7%; after 6 months to 8.3%; after 9 months to 8.72%. Notice the slight rise in HbA1c value after long-term administration of metformin. Metformin is often prescribed following secondary failure of sulfonylureas; however, many physicians find this to be rarely effective.
The most common side effect of Metformin is diarrhea. It also decreases absorption of vitamin B12 and folic acid. Patients with diabetic neuropathy may have symptoms associated with both diabetes and a vitamin B12 deficiency due to the use of Metformin. Metformin is contraindicated in kidney disease. It is important to determine whether the hyperglycemia or the pharmacological agent will present more problems to a patient with diabetic nephropathy. A rare fatal complication of Metformin is lactic acidosis.27-29
Alpha-glucosidase Inhibitors
A newly developed pharmacological agent used in the treatment of NIDDM is an alpha-glucosidase inhibitor. It works in the small intestine by delaying postprandial glucose absorption by inhibiting the enzyme glucosidase.
In a study of 1,027 patients given alpha-glucosidase inhibitors, a significant decrease in blood sugar levels was found. However, one-third of the patients could not take the drug for one year due to gastrointestinal side effects. Thus, it has marginal clinical relevance. The disadvantage of this drug is that it is costly and has many side effects.30
Cautions, Contraindications, and Side-Effects
Pharmacological drugs have been demonstrated to be effective in decreasing glycosylated-hemoglobin and in the complications of diabetes. However, great improvement still needs to be made in the ability of patients to achieve tight control of blood-sugar levels. Due to the amount of side effects, the use of oral pharmacological agents should be assessed when administering drugs to NIDDM patients. Both hyperglycemia and NIDDM pharmacological agents may cause tissue-damage; for example, kidney damage can be caused by hyperglycemia or by the use of Sulfonylureas and Biguanides. Thus, it is important to determine which is more damaging to the patient, hyperglycemia or drug therapy.
There is also suspicion that the sulfonylureas are toxic to the pancreas. Sulfonylureas are contraindicated in patients with liver, thyroid, and kidney disease. These three organs are all involved in diabetes, the liver having its function in producing receptor sites, the thyroid having its function in preventing excessive weight gain, and the kidneys in maintaining blood pressure control. When kidney function is impaired by hyperglycemia or pharmaceuticals, there is a progressive deterioration of blood pressure control, which is important for diabetics. In the UK study, patients were divided into a tight blood pressure control group and a group with less tight control of their blood pressure. The average blood pressure in the tight control group was 144/82 and in the less tight control group 154/87. Some of the tight control group needed three to four pharmacological agents to achieve this blood pressure level. The tight blood pressure control group had a decrease in almost all microvascular complications: a 25% decrease in diabetic related endpoints; a 32% decrease in deaths related to diabetes; a 44% decrease in strokes; and a 39% decrease in microvascular endpoints. The tight control group had a significant difference compared to the less tight control group in along-term perspective of the patient’s life.
There are many reported hypoglycemic deaths due to the use of oral hypoglycemics. Other adverse effects include jaundice, decreased RAI-uptake of the thyroid, weight-gain, chronic hyperinsulinemia, severe insulin resistance, and perhaps beta cell exhaustion.
SIADH (syndrome of inappropriate anti-diuretic hormone secretion) can also occur in the use of sulfonylureas. This side effect is manifested by water-retention and hyponatremia. Since many diabetic patients have edema due to nephropathy, pharmacological agents must be ruled out as another cause of the edema in these patients. One patient of mine, who had diabetic nephropathy, lost all edema in her legs after discontinuing Glyburide (a sulfonylurea drug) and using a combination of herbs – jambul, devil’s club, globe artichoke, milk thistle, and nopal.
Despite the use of pharmaceutical drugs for Type II diabetes in the last 30 years, less than 25% of NIDDM patients have been able to achieve normal glycosylated hemoglobin levels, regardless of the mode of treatment. Elevated glycosylated hemoglobin and poor glycemic control are associated with increased mortality. Thus, if mortality due to diabetes is to be decreased, advances in more effective treatments are necessary.31
