173 DIABETES MELLITUS
Harrison’s Manual of Medicine
ETIOLOGY Diabetes mellitus (DM) comprises a group of metabolic disorders that share the common phenotype of hyperglycemia. DM is currently classified on the basis of the pathogenic process that leads to hyperglycemia. Under this classification, the terms type 1 and type 2 DM have replaced insulin- dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM), respectively. Type 1 DM is characterized by insulin deficiency and a tendency to develop ketosis, whereas type 2 DM is a heterogeneous group of disorders characterized by variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production. Other specific types include DM caused by genetic defects [maturity-onset diabetes of the young (MODY)], diseases of the exocrine pancreas (chronic pancreatitis, cystic fibrosis, hemochromatosis), endocrinopathies (acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism), drugs (nicotinic acid, glucocorticoids, thiazides, protease inhibitors), and pregnancy (gestational diabetes mellitus).
DIAGNOSIS Criteria for the diagnosis of DM include (1) fasting plasma glucose ³7.0 mmol/L (³ 126 mg/dL), (2) symptoms of diabetes plus a random blood glucose concentration ³11.1 mmol/L (³ 200 mg/dL), or (3) 2-h plasma glucose ³ 11.1 mmol/L (³ 200 mg/dL during a 75-g oral glucose tolerance test. These criteria should be confirmed by repeat testing on a different day, unless unequivocal hyperglycemia with acute metabolic decompensation is present. Two intermediate categories have also been designated: impaired fasting glucose (IFG) for a fasting plasma glucose between 6.1 and 7.0 mmol/L (110 and 126 mg/dL) and impaired glucose tolerance (IGT) for plasma glucose levels between 7.8 and 11.1 mmol/L (140 and 200 mg/dL) 2 h after a 75-g oral glucose load. Individuals with IFG or IGT do not have DM but are at substantial risk for developing type 2 DM and cardiovascular disease in the future. The hemoglobin A1c level is useful for monitoring responses to therapy but is not recommended for screening or diagnosis of DM.
Screening with a fasting plasma glucose level is recommended every 3 years for individuals over the age of 45, as well as for younger individuals with additional risk factors (Table 173-1).
Table 173-1 Risk Factors for Type 2 Diabetes Mellitus
CLINICAL FEATURES Common presenting symptoms of DM include polyuria, polydipsia, weight loss, fatigue, weakness, blurred vision, frequent superficial infections, and poor wound healing. Acute complications of diabetes that may be seen on presentation include diabetic ketoacidosis (DKA) and nonketotic hyperosmolar state (Chap. 40).
The chronic complications of DM are listed below:
Ophthalmologic: nonproliferative or proliferative diabetic retinopathy
Renal: proteinuria, end-stage renal disease (ESRD), type IV renal tubular acidosis
Neurologic: distal symmetric polyneuropathy, polyradiculopathy, mononeuropathy, autonomic neuropathy
Gastrointestinal: gastroparesis, diarrhea, constipation
Genitourinary: cystopathy, erectile dysfunction, female sexual dysfunction
Cardiovascular: coronary artery disease, congestive heart failure, peripheral vascular disease, stroke
Lower extremity: foot deformity (hammer toe, claw toe, Charcot foot), ulceration, amputation
Optimal treatment of diabetes requires more than plasma glucose management. Comprehensive diabetes care should also detect and manage DM-specific complications and modify risk factors for DM-associated diseases. The pt with type 1 or type 2 DM should receive education about nutrition, exercise, care of diabetes during illness, and medications to lower the plasma glucose. In general, the target HbA1c level should be <7.0%, though individual considerations (age, ability to implement a complex treatment regimen, and presence of other medical conditions) should also be taken into account. Intensive therapy reduces long-term complications but is associated with more frequent and more severe hypoglycemic episodes.
In general, pts with type 1 DM require 0.5–1.0 U/kg per day of insulin divided into multiple doses. Combinations of insulin preparations with different times of onset and duration of action should be used (Table 173-2). Commonly used regimens include twice-daily injections of an intermediate insulin combined with a short-acting insulin before the morning and evening meal, twice-daily injections of an intermediate insulin and preprandial lispro insulin, and continuous subcutaneous insulin using an infusion device.
Table 173-2 Pharmacokinetics of Insulin Preparations
Pts with type 2 DM may be managed with diet and exercise alone or in conjunction with oral glucose-lowering agents, insulin, or a combination of oral agents and insulin. The classes of oral glucose-lowering agents and dosing regimens are listed in Table 173-3. A reasonable treatment algorithm for initial therapy proposes either a sulfonlyurea or metformin as initial therapy because of their efficacy, (1–2% decrease in HbA1c), known side-effect profile, and relatively low cost (Fig. 173-1). Metformin has the advantage that it promotes mild weight loss, lowers insulin levels, improves the lipid profile slightly, and does not cause hypoglycemia when used as monotherapy, though it is contraindicated in renal insufficiency, congestive heart failure, any form of acidosis, liver disease, or severe hypoxia, and should be temporarily discontinued in pts who are seriously ill or receiving radiographic contrast material. Combinations of two oral agents may be used with additive effects, with stepwise addition of bedtime insulin or a third oral agent if adequate control is not achieved. As endogenous insulin production falls, multiple injections of intermediate-acting and short-acting insulin may be required, as in type 1 DM. Individuals who require >1 U/kg per day of intermediate- acting insulin should be considered for combination therapy with an insulin- sensitizing agent such as metformin or a thiazolidinedione.
Table 173-3 Oral Glucose-Lowering Agents
FIGURE 173-1. Glycemic management of type 2 diabetes. See text for discussion. *See text about use as monotherapy. The broken line indicates that biguanides or insulin secretagogues, but not a glucosidase inhibitors or thiazolidinediones, are preferred for initial therapy.
The morbidity and mortality of DM-related complications can be greatly reduced by timely and consistent surveillance procedures (Table 173-4). A routine urinalysis may be performed as an initial screen for diabetic nephropathy. If it is positive for protein, quantification of protein on a 24-h urine collection should be performed. If the urinalysis is negative for protein, a spot or timed collection for microalbuminuria should be performed (present if 30–300 µg/mg creatinine on spot collection or 30–300 mg/d on timed collection on two of three tests within a 3–6 month period). Conditions that transiently increase albumin excretion must be excluded to avoid a false diagnosis. If the urinalysis has been negative for protein in the past, testing for the presence of microalbumin should be performed on an annual basis. A resting ECG should be performed in adults, with more extensive cardiac testing for high- risk pts. Therapeutic goals to prevent complications of DM include management of proteinuria with ACE inhibitor therapy, bp control (<130/85 mmHg if no proteinuria, <120/80 if proteinuria), and dyslipidemia management [LDL <2.6 mmol/L (<100 mg/dL) HDL >0.9 mmol/L (>35 mg/dL), triglycerides <2.6 mmol/L (<200 mg/dL)].
Table 173-4 Guidelines for Ongoing Medical Care for Patients with Diabetes
Management of the Hospitalized Patient The goals of diabetes management during hospitalization are avoidance of hypoglycemia, optimization of glycemic control, and transition back to the outpatient diabetes treatment regimen. Individuals with type 1 DM undergoing general anesthesia and surgery, or with serious illness, should receive continuous insulin, either through an IV insulin infusion or by SC administration of a reduced dose of a long- acting insulin. Short-acting insulin alone is insufficient to prevent the onset of diabetic ketoacidosis. Oral hypoglycemic agents may need to be discontinued in individuals with type 2 DM at the time of hospitalization. A low dose of intermediate-acting insulin can be used to keep glucose levels to <13.9 mmol/L (<250 mg/dL). An insulin infusion or a reduced dose (by 30–50%) of long- or intermediate-acting insulin and short-acting insulin (held, or reduced by 30–50%), with infusion of a solution of 5% dextrose, should be administered when pts are NPO for a procedure. Those with DM undergoing radiographic procedures with contrast dye should be well hydrated before and after dye exposure, and the serum creatinine should be monitored after the procedure.
For a more detailed discussion, see Powers AC: Diabetes Mellitus, Chap. 333, p. 2109, in HPIM-15.