Tolbutamide

Early detection may lead to a decrease in the severity of complications.

As primary eyecare providers, most of us are familiar with the ocular implications of diabetes mellitus (DM), but this complex systemic disease affects much more than just the eyes. Proper diagnosis and management often entail dialogue with the patient's primary care physician, so we must all be familiar with the essentials of this disease. By providing this service, we can help in earlier detection of DM, which may ultimately lead to a decrease in the severity of complications associated with this disease.

The basics

Diabetes is classically defined as "a group of metabolic diseases characterized by hyperglycemia, resulting from defects in insulin secretion, insulin action or both." Ultimately, it alters the body's ability to metabolize carbohydrates. Chronic hyperglycemia resuits in fats and proteins causing widespread damage throughout the body. This elevated blood sugar eventually causes damage to the eyes, kidneys, nerves, heart and blood vessels.

The pathophysiology of the disease involves two hormones: insulin and glucagon, which are respectively secreted by the alpha and beta cells of the islets of Langerhans of the pancreas. These two hormones work together to maintain a homeostatic mechanism for blood glucose levels. Insulin enters the blood stream shortly after a person ingests food, particularly those rich in carbohydrates. When the body needs glucose, insulin facilitates its use to meet the body's needs. Any excess glucose converts to glycogen, which is stored in the liver or muscle, or as fatty tissue; the net effect of insulin is to lower blood glucose concentration.

Glucagon opposes the effects of insulin. This hormone is secreted during fasting states by the alpha cells of the Islet of Langerhans. The overall effect of glucagon is to elevate blood glucose levels by one of three mechanisms:

1. Glycogenolysis ( breakdown of stored glycogen in the liver to make glucose)

2. Gluconeogenesis (conversion of non-glucose substrates into glucose)

3. Glucose sparing (a process in which ketones are formed in the liver).

Classification

Diabetes falls into one of two categories: type-1 and type-2. More than nomenclature, these types of diabetes are distinct in terms of etiology, pathogenesis, clinical presentation and treatment.

Type-1. Type-1 diabetes accounts for approximately 10% of all diabetes cases. Patients with type-1 diabetes are typically young, thin and undergo a progressive loss of endogenous insulin leading to hyperglycemia. Type-1 DM is characterized by an autoimmune process, which causes beta cell destruction, usually leading to absolute insulin deficiency. This sub-category of diabetes was formerly known as "insulin-dependent diabetes" because the patient depended on insulin administration for survival. The peak incidence is between ten and 13 years of age. In fact, 95% of patients with type-1 diabetes mellitus are diagnosed before the age of 25.

Physicians often diagnose these patients after they experience an abrupt onset of symptoms. The classic triad of symptoms includes the three Ps:

1. Polydipsia (increased thirst)

2. Polyphagia (increased hunger)

3. Polyuria (increased urination).

These patients are prone to ketoacidosis, a lifethreatening complication caused by severe insulin deficiency, that can cause diabetic coma and death.

Type-2. Accounting for more than 90% of the total disease population, type-2 diabetes is the more common form. This type involves two major pathogenetic mechanisms: impaired islet-cell function (impaired insulin secretion) and impaired insulin action (insulin resistance or decreased insulin sensitivity). Insulin resistance happens when normal concentrations of insulin elicit a less-than-normal biologic response. When this patient eats a meal, some insulin secretion still occurs, but at reduced levels.

Patients who have type-2 diabetes usually aren't dependent on insulin to prevent ketosis or maintenance of life (thus it was called non-insulin-dependent diabetes), but insulin is commonly necessary to maintain reasonable blood glucose concentrations.

Type-2 diabetes typically occurs in people who are older than 40, are obese and/or have a family history of diabetes. Unlike type-1 diabetes, in which the symptoms are pronounced, the onset of type-2 diabetes is gradual. Doctors often diagnose type-2 diabetes in asymptomatic patients during routine physical examinations when their laboratory work shows elevated blood glucose levels.

Diagnosing diabetes

A definitive diagnosis of diabetes is usually based on any one of the following criteria:

* Elevated plasma glucose (greater than 200mg/dL or 11.2mmol/L) along with the classic signs and symptoms of diabetes and unexplained weight loss (type-I) or obesity (type-2)

* A fasting plasma glucose (FPG) value of 126mg/dL (7.0mmol/L) or greater on at least two separate tests

* Oral glucose tolerance test values at two hours, and at least one other sampling during the exam, greater than 200mg/dL.

Of the major tests, fasting plasma glucose is the most common one used to aid in proper diagnosis. The physician performs this after the patient fasts for at least eight hours, usually in the morning before a patient has breakfast. In this test, the patient ingests a 75g glucose load dissolved in water and the doctor checks his blood glucose levels after two hours. Risk factors include obesity, first-degree relatives with diabetes mellitus, hypertension, hypertriglyceridemia or previous evidence of impaired glucose homeostasis.

Glycated hemoglobin

Measurements of this hemoglobin, also called glycosylated hemoglobin, glycohemoglobin, hemoglobin AIc or hemoglobin Al, will help you evaluate the stable linkage of glucose to minor hemoglobin components. It is believed that this link is a function of the tightness of glycemic control. Because glycated hemoglobin levels are highly correlated to adverse clini-cal outcomes like retinopathy, this test is commonly used to monitor glycemic control in patients with diagnosed diabetes.

In most cases, this test is not used in the initial diagnosis because there is currently no agreement on standardization. So, a variety of measurement methods and normal ranges are utilized. The major advantage to using glycated hemoglobin is that the specimen can be collected regardless of when the patient last ate.

Screening appropriately

Although there is some variability in screening criteria, many practitioners routinely screen any patient over the age of 45 and, if normal, repeat this screening at three-year intervals. Patients are tested at an earlier age or more frequently if one or more of the following criteria are met:

* Obesity (120% of desirable body weight or greater, or a body mass index of 27kg per m2 or more)

* A first-degree relative with diabetes mellitus

* African-American, hispanic or Native American decent

* Women who have delivered a baby weighing more than 4,032g (9Ib), or who were diagnosed with gestational DM during pregnancy

* Hypertension

* A high-density lipoprotein level of 35mg per dL (0.90mmol per L) or lower and/or a triglyceride level of 250mg per dL (2.83mmol per L) or higher.

Systemic complications

The chronic complications of diabetes include accelerated vascular disease, neurologic deficits, and other organ-specific degenerative processes. The vascular dis ease consists of both microangiopathy and macroangiopathy. The former is a disease of the capillaries specifically associated with diabetes. It's characterized by thickening of capillary basement membranes and manifests clinically mostly in the retina and kidney. The latter is an accelerated form of atherosclerotic disease of the arteries that usually manifests clinically in the coronary arteries, cerebral arteries and peripheral vessels of the lower extremities.

Management options

Although there is some overlap, the management protocol for type-1 and type-2 diabetes differs in many ways.

Type-I diabetes. Because patients who have type-1 diabetes suffer from relative or absolute loss of insulin, they require insulin injections. Insulin therapy regimens vary greatly based on patients' clinical condition, meal times, exercise schedule and waking/sleeping patterns.

Most practitioners use one of three therapeutic approaches to insulin therapy:

1. Conventional therapy. This involves one or two daily injections of intermediate-acting insulin alone or in conjunction with rapid-acting insulin.

2. Multiple subcutaneous injections. This technique requires a rapid-acting insulin shot before each meal along with either intermediate or long-acting insulin at bedtime. The advantage is tighter glycemie control than is achieved with conventional therapy.

3. Continuous subcutaneous insulin infusion. This involves a battery-powered insulin pump to inject insulin into the abdominal wall. A basal rate of insulin infusion occurs throughout the day with additional amounts delivered before each meal. The patient usually checks her glucose level before eating and programs the insulin pump accordingly.

Type-2 diabetes. Although many patients use medications and even insulin, the cornerstone of therapy for type-2 diabetes is proper nutrition, weight loss and exercise. Patients must attain and maintain ideal body weight, reduce intake of fats, increase intake of high-fiber carbohydrates (e.g., bran, beans, fruits and vegetables), reduce intake of refined sugars and salt and restrict alcohol consumption.

Five different oral drug classes are available for the management of type-2 diabetes. Because these classes work by different mechanisms, many patients are on two or three combinations.

1. Sulfonylureas. This group includes tolbutamide (Orinase, Pharmacia & Upjohn), tolazamide (Tolinase, Pharmacia & Upjohn), acetohexamide (Dymelor, Eli Lilly), chlorpropamide (Diabinese, Pfizer), glyburide (Diabeta, Aventis, Micronase and Glynase, Pharmacia & Upjohn), glipizide (Glucotrol, Glucotrol XL, Pfizer) and glimepiride (Amaryl, Aventis). Sulfonylureas bind to receptors on the pancreatic b-cell, causing a cascade of reactions that lead to insulin secretion.

2. Meglinitides. The mechanism of action of the two available metiglinides, repaglinide (Prandin, Novo Nordisk) and nateglinide (Starlix, Novartis), is similar to the way Sulfonylureas stimulates pancreatic insulin release. But, the meglinitides have a shorter half-life, which results in brief stimulation of insulin release. Patients take these medications at each meal to decrease postprandial blood glucose.

3. Biguanides. Metformin (Glucophage, Bristol Myers Squibb) lowers blood glucose primarily by inhibiting hepatic glucose production and secondarily by enhancing peripheral muscle glucose uptake. It also helps to combat insulin resistance, which may help decrease the risk of cardiovascular disease.

4. a-Glucosidase inhibitors, aGlucosidase enzymes, found in the small intestinal epithelium, break down complex starches into oligo- and mono-saccharides and glucose for easier absorption. The medications, acarbose (Precose, Bayer) and miglitol (Glycet, Bayer), inhibit the enzymes that delay carbohydrate absorption. This decreases the postprandial glucose elevation, but has little or no effect on fasting glucose levels.

5. Thiazolidinediones. Medications such as Rosiglitazone (Avandia, Smith Kline Beecham) and Pioglitazone (Actos, Takeda Pharmaceuticals America) increase insulin sensitivity and glucose use in peripheral tissues, mainly in muscle and fat. Experts don't completely understand their novel mechanism of action, but thiazolidinediones may help suppress glucose synthesis in the liver.

Patient education

As with any other disease, patient education is vital in longterm diabetes management. This is a chronic disease that the patient will have to deal with for the rest of his or her life. In addition to taking prescribed medications, the patient must constantly monitor diet and exercise in order to maintain proper glycemie control.

with Deepak Gupta, O.D., F.A.A.O.

by Deepak Gupta, O.D., .F.A.A.0. and Sonia Gupta, Rp.H., M.S.

Dr. CiLipta practices full scope optometry in Stamford, Conn. He's also clinical director of The Center for Keratoconus at Stamford Ophthalmology. E-mail Deegup4919@hotmail. com.

Ms. Gupta is a clinical pharmacist who has years of both retail and hospital pharmacy experience.

Copyright Boucher Communications, Inc. Sep 2005
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