Diabetes mellitus
I. General principles
Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
This metabolic disorder is accompanied by hypertension and hypercholesterolemia in half of the adult diabetic patients, increasing the risk for the development of diabetic-induced complications.
II. Classification of Diabetes:
DM is classified into four clinical classes2:
Type 1 diabetes accounts for <10% of all cases of DM and results from a cellular-mediated autoimmune destruction of the cells of the pancreas. This form of diabetes is characterized by severe insulin deficiency. Exogenous insulin is required to control blood glucose, prevent diabetic ketoacidosis (DKA), and preserve life.
Type 2 diabetes accounts for >90% of all cases of DM. Type 2 DM is initially characterized by insulin resistance followed by failure of cells to compensate for the increased insulin requirements. Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity. Frequency varies in different ethnic groups.
Other specific types of DM include those that result from genetic defects in insulin secretion or action, exocrine pancreatic disease, pancreatectomy, endocrinopathies (e.g., Cushing syndrome, acromegaly), drugs, and other syndromes.
Gestational DM complicates approximately 4% of all pregnancies and usually resolves after delivery, although affected women remain at an increased risk for development of type 2 DM later in life.
III. Diagnosis:
Thediagnosis of DM can be established using any of the following criteria.
1) Plasma glucose of 126 mg/dL or greater after an overnight fast. This should be confirmed with a repeat test.
2) Symptoms of diabetes and a random plasma glucose of 200 mg/dL or greater.
3) Oral glucose tolerance test that shows a plasma glucose of 200 mg/dL or greater at 2 hours after a 75-g glucose load.
Diagnosis of prediabetes. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) refer to intermediate states between normal glucose tolerance and DM type 2. IFG and IGT are risk factors for type 2 diabetes and micro- and macrovascular complications.
IGT is defined by a 2-hour oral glucose tolerance test plasma glucose from 140 mg/dL to 199 mg/dL.
IFG is defined by fasting plasma glucose of 100 mg/dL to 125 mg/dL.
Lifestyle modification is recommended for persons with IGT or IFG, but the rationale for drug therapy has not been established.
IV. Principles of Management:
The therapeutic goals are alleviation of symptoms, achievement of metabolic control, and prevention of acute and long-term complications of diabetes.
Glycemic control is set at the same goal for type 1 and type 2 diabetes: average preprandial capillary blood glucose values of 90-130 mg/dL, postprandial capillary blood glucose values <180 mg/dL, and HbA1c of <7% or as close to normal as possible while avoiding significant hypoglycemia.
This degree of glycemic control has been associated with the lowest risk for long-term complications in patients with type 1 as well as type 2 DM.
An individualized, comprehensive diabetes care plan is necessary to accomplish these goals.
Assessment of glycemic control consists of the following:
Self-monitoring of capillary blood glucose (SMBG) is an important tool in preventing hypoglycemia and adjusting medications to reach glucose goals. It is recommended for all patients but especially for patients treated with insulin. SMBG should be carried out three or more times a day for patients using multiple insulin injections.
HbA1c provides an integrated measure of blood glucose profile over the preceding 2-3 months; it should be obtained approximately every 3 months or at least twice a year in well-controlled patients. Any suspicion of a discordant HbA1c level should be followed up by assessment of the self-monitoring blood glucose technique, hemoglobin level, and hemoglobin electrophoresis. Normal HbA1c levels in population studies are 4%-6% using the Diabetes Control and Complications Trial (DCCT) assay.
Ketonuria grossly reflects ketonemia. All DM patients should monitor urine ketones using Ketostix or Acetest tablets during febrile illness or persistent elevated glucose (>300 mg/dL) or if signs of impending DKA (e.g., nausea, vomiting, abdominal pain) develop.
Patient education
Dietary modification.
Exercise improves insulin sensitivity, reduces fasting and postprandial blood glucose, and offers numerous metabolic, cardiovascular, and psychological benefits in diabetic patients.
Medications for diabetes are more effective when instituted as part of a comprehensive management approach that includes diet and exercise.
Treatment of type 1 DM requires lifelong insulin replacement.
Insulin preparations. After SC injection, there is individual variability in the duration and peak activity of insulin preparations and day-to-day variability in the same subject
Insulin type Onset of action (hr) Peak effect (hr) Duration of activity (hr)
Rapid acting
Lispro, aspart, glulisine 0.25-0.50 0.50-1.50 3-5
Regular 0.50-1.00 2-4 6-8
Intermediate acting
NPH 1-2 6-12 18-24
Lente 1-3 6-12 18-26
Long acting
Ultralente 4-6 10-16 24-48
Glargine 4-6 Nonea 18
Detemir 3-4 ~20

The achievement of these goals requires individualized therapy and a comprehensive approach that incorporates lifestyle and pharmacologic interventions. Several considerations should be taken into account before choosing oral agents (Table 21-2) in patients with type 2 DM:
Oral therapy should be initiated early in patients that failed glycemic control after a short-term trial of diet and exercise.
Monotherapy with maximum doses of insulin secretagogues, metformin, or thiazol-idinediones yields comparable glucose-lowering effects.
The glucose-lowering effects of insulin secretagogues are observed within days, but approximately 20% of patients do not respond to these agents. In contrast, the maximum effects of metformin or thiazolidinediones may not be observed for several weeks.
A second or third agent including insulin should be added if no response is achieved with monotherapy.
Glycemic control with monotherapy is less likely to occur in patients with very high glucose readings (>240 mg/dL) at the time of diagnosis.12 Combination therapy or insulin should be considered as first line for these patients
Drug Daily dosage range Dose(s)/d Duration of action (hr) Main adverse effects
Insulin secretagogues sulfonylureas
First generation Hypoglycemia, weight gain
Tolbutamide 0.5-2.0 g 2-3 12
Acetohexamide 0.25-1.5 g 1-2 12-24
Tolazamide 0.1-0.5 g 1-2 12-24
Chlorpropamide 1.25-20.0 mg 1 36-72
Second generation
Glyburide 5-40 mg 1-2 16-24
Glipizide 1.8 mg 1-2 12
Glimepiride 1 24
Rapid acting Hypoglycemia, weight gain
Nateglinide 60-360 mg 2-4 1-2
Repaglinide 1-16 mg 2-4
Biguanide Gastrointestinal (GI) intolerance, lactic acidosis
Metformin 1.0-2.5 g 2-3 6-12
α-Glucosidase inhibitors GI intolerance, flatulence
Acarbose 75-300 mg 3 NA
Miglitol 75-300 mg 3 NA
Thiazolidinediones Fluid retention, congestive heart failure, hepatotoxicity, weight gain
Rosiglitazone 2-8 mg 1-2 12-24
Pioglitazone 15-45 mg 1 24