DIABETES MELLITUS

Signs and Symptoms

Moderately severe non-proliferative diabetic retinopathy in young type 1 uncontrolled diabetic patient.

Diabetes mellitus is the most common endocrine disorder and is defined as a group of disorders that exhibit a defective or deficient insulin secretory process, glucose underutilization and hyperglycemia.^1­22 Possible systemic signs and symptoms include polyuria (increased frequency of urination), polydipsia (increased thirst), polyphagia (increased appetite), glycosuria, weakness, weight loss and nephropathy.^1­18 Ophthalmic signs and symptoms may include chronic conjunctival injection; changes in corneal curvature; large fluctuations in refraction; premature cataractogenesis; nonproliferative and proliferative retinopathy; and cranial nerve III, IV or VI palsy.^1­22 Systemic complications such as kidney and cardiac disease, as well as peripheral neuropathies may be present.

Type 1 diabetes, formerly known as insulin-dependent diabetes mellitus (IDDM), also known as juvenile-onset or ketose-prone DM, usually begins by age 20 and is defined by an absolute lack of insulin caused by a reduction in the beta-cell mass of the pancreas. This may be the result of autoimmune processes and may involve genetic susceptibility.^17,18

Type 2 diabetes, formerly known as non-insulin-dependent diabetes mellitus (NIDDM), sometimes referred to as adult-onset DM, usually begins after age 40 and is a multifactorial disease that may involve improper insulin secretion, malfunctioning insulin and/or insulin resistance in peripheral tissues.^17,18 Approximately 10% of diabetic cases are type 1, and approximately 90% are type 2.^2,3

Pathophysiology

The pancreas plays a primary role in the metabolism of glucose by secreting the hormones insulin and glucagon. The islets of Langerhans secrete insulin and glucagon directly into the blood. Insulin is a protein that is essential for proper metabolism of glucose and for maintenance of proper blood glucose levels. Inadequate secretion of insulin, or inadequate structure or function of insulin or its receptors, results in impaired metabolism of glucose, other carbohydrates, proteins and fats. This is characterized by hyperglycemia and glycosuria.¹ Hyperglycemia is the most frequently observed sign of diabetes and is considered the etiologic source of diabetic complications, both in the body and in the eye.²

Glucagon is a hormone that opposes the action of insulin. It is secreted when blood glucose levels fall. Glucagon increases blood glucose concentration partly by breaking down glycogen in the liver.¹ Following a meal, glucose is absorbed into the blood. In response to increased blood glucose levels, insulin is secreted, causing rapid uptake, storage or use of glucose by the tissues of the body. Unused glucose is stored as glycogen in the liver. Between meals, when blood glucose is at minimal levels, tissues continue to require an energy source to function properly. Stored glycogen, via glucagon, is converted to glucose by a pathway known as glycogenolysis.¹ Gluconeogenesis is the production of glucose in the liver from noncarbohydrate precursors such as glycogenic amino acids.

Elevated glucose levels result in the formation of sorbitol (a sugar alcohol) via the aldose reductase pathway. Since sorbitol cannot readily diffuse through cell membranes, cell edema and changes in function can ensue.² With respect to the eye, this contributes to the evolution of premature cataractogenesis (nuclear sclerotic, senile and snowflake posterior subcapsular cateracts) and sight-threatening diabetic retinopathy (along with other pathologic changes, compromising the pericytes that line capillary walls).^5,6,9,22

An additional complication of hyperglycemia is nonenzymatic glycosylation. Nonenzymatic glycosylation is the binding of excess glucose to the amino group of proteins in the tissues.¹⁰ As a possible result, at the level of the capillary membranes, altered cell function may lead to the development of microaneurysms, vascular loops, and vessel dilation, allowing blood leakage.^2,7,8,10 Platelet aggregation secondary to these changes initiates tissue hypoxia. These changes result in the system wide accumulation of edema and in the eye increase the potential for retinal sequelae.^2,7,8,10,22

Management

Glycemic control over the course of the disease has been shown to reduce the risk of developing debilitating organ disease and retinopathy.^11,13,14,21 Blood glucose levels are of even greater importance in diabetic pregnant women, as hyperglycemia during pregnancy may initiate swift and severe progression of diabetic retinopathy.^4,15,22 Other concurrent systemic variables that may potentiate the onset of diabetic retinopathy include hypertension, nephropathy, cardiac disease, autonomic neuropathy, and ocular findings such as elevated intraocular pressure and myopia.^11,13,14

The initial treatment recommendation for type 2 diabetes is strict dietary control.¹⁷ Dietary regulation is set by basing the caloric intake on the patient's ideal body weight, selecting adequate sources of protein and carbohydrate, while maintaining a reasonable distribution of foods.¹⁷ When hyperglycemia persists despite dietary changes, oral hypoglycemic agents become necessary. These agents can be prescribed in small doses, adjusting the dosage to larger levels to achieve tighter control, as necessary.¹⁷

Insulin is always required for type 1 and is an option for difficult to manage cases involving type 2 diabetes.¹⁷ Conventional therapy involves the administration of an intermediate-acting insulin (NPH or lente), once or twice a day, with or without small amounts of regular insulin.¹⁷

Several studies have shown the benefits of antihypertensive treatment and glucose-lowering therapy on the prevention of macrovascular and microvascular disease.²³ However, questions remain concerning the overall balance of benefits and risks of intensive target-driven blood pressure and blood glucose control in type 2 diabetes. The Action in Diabetes and Vascular disease: PreterAx and DiamicroN modified release Controlled Evaluation (ADVANCE) study has been designed and recently engaged to provide answers concerning the value conferred by blood pressure-lowering therapy and intensive glucose control therapy in type 2 diabetes patients at high risk for cardiovascular disease.²³ In another, similar study, researchers set out to test the effects of a low-calorie diet (LCD) on body weight, lipid profile and glycemic control, finding that it is effective in improving glycemic control and blood lipids in overweight type 2 DM patients.²³

While early work has focused on improving glycemic control, new studies such as EURODIAB Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID) and new arms of older studies such as the United Kingdom Prospective Diabetes Study (KPDS) have shifted focus to observing the control of blood pressure and specifically the renin-angiotensin system (RAS) as a means of arresting diabetic sequelae.²⁴ There is a body of evidence suggesting that a local RAS, within the eye itself, may be activated upon conversion to clinically definite diabetes. This appears to be directly responsible, as well as indirectly responsible through the production of other mediators, for increasing the concentration of vascular endothelial growth factor (VEGF). VEGF is a selective angiogenic/vasopermeability factor already well implicated in the pathogenesis of diabetic retinopathy. Inhibition of angiotensin-converting enzyme appears to reduce concentrations of VEGF, with a concurrent anti-proliferative effect independent of systemic VEGF levels or blood pressure.

Angiotensin II (Ang II) type receptor blockade has been shown to reduce neovascularization independent of VEGF levels in animal models. This may be due to antagonism of activation of mitogen-activated protein kinase, which is a potent cellular proliferation stimulator by Ang II. The ramifications of this research may yield new medications whose indirect mechanisms of action may slow or arrest the pathogenesis responsible for retinopathy and other pathologic changes, not only in the eye but also throughout the body.²⁴

Currently, there are a number of large-scale trials evaluating the effects of lipid-lowering therapies in patients with diabetes.²⁵ The Lipids in Diabetes Study will hopefully provide insight for determining whether lipid lowering with a statin or fibrate medication can substantially reduce cardiovascular morbidity and mortality patients with type 2 diabetes. The Atorvastatin Study for the Prevention of coronary heart disease ENdpoints (ASPEN) is designed to compare double-blind treatment with atorvastatin against placebo in 2,250 U.S. diabetic patients without coronary heart disease, while a sister trial in the United Kingdom, the Collaborative AtoRvastatin Diabetes Study (CARDS) is enrolling 1,820 diabetic patients for completion of a British arm.²⁵ The results from these trials may provide information that will help determine the future management of diabetic dyslipidemia and indirectly all effects of systemic diabetic disease.

Clinical Pearls

• Large changes in refraction may be the first sign of diabetic disease. Often, myopic or hyperopic shifts are created as the lens swells, secondary to sorbitol effects, resulting in large refractive changes in what are otherwise noted as "stable eyes." Clinicians should avoid prescribing during this time period, instead educating patients as to why this may have occurred and ordering appropriate tests such as a fasting blood glucose.
• Cataracts (senile posterior subcapsular and snowflake posterior subcapsular) may form as well. The cataracts may mature quickly but have been documented to regress once sugar levels are stabilized.¹⁹
• The test of choice for monitoring diabetic control is the glycosylated hemoglobin test (HgbA1C).²⁰