DEFINITIONDiabetes mellitus (DM) refers to a syndrome of hyperglycemia resulting from many different causes. It can be classi ed into type 1 (formerly insulin-dependent diabetes mellitus [IDDM]) and type 2 (formerly noninsulin-dependent diabetes mellitus [NIDDM]). Because insulin-dependent and noninsulin-dependent refer to the stage at diagnosis, when a type 2 diabetic needs insulin, he or she remains classi ed as type 2 and does not revert to type 1.

The American Diabetes Association (ADA) de nes DM as (1) a fasting plasma glucose 126 mg/dL, (2) a nonfasting plasma glucose 200 mg/dL, or (3) glucose 200 mg/dL in the 2-hour sample in an oral glucose tolerance test (OGTT). Fur-thermore, a value of 100 mg/dL of fasting blood sugar is the upper limit of normal for glucose. A fasting glucose between 100 and 126 mg/dL is classi ed as impaired fasting glucose (IFG). CAUSEIdiopathic diabetes

TYPE 1 DIABETES MELLITUS Hereditary factors1. Islet cell antibodies (found in 90% of patients within the rst year of diagnosis)2. Higher incidence of HLA types DR3, DR43. 50% concordance in identical twins Environmental factors: viral infection (possibly coxsackie virus, mumps virus)TYPE 2 DIABETES MELLITUS Hereditary factors: 90% concordance in identical twins Environmental factor: obesity

Diabetes secondary to other factors Hormonal excess: Cushings syndrome, acromegaly, glu-cagonoma, pheochromocytoma Drugs: glucocorticoids, diuretics, oral contraceptives Insulin receptor unavailability (with or without circulat-ing antibodies) Pancreatic disease: pancreatitis, pancreatectomy, hemo-chromatosis Genetic syndromes: hyperlipidemias, myotonic dystro-phy, lipoatrophy Gestational diabetes

DIFFERENTIAL DIAGNOSIS Diabetes insipidus Stress hyperglycemia Diabetes secondary to hormonal excess, drugs, pancreatic disease

PHYSICAL FINDINGS AND CLINICAL PRESENTATION Physical examination varies with the presence of complica-

tions and may be normal in early stages. Diabetic retinopathy

Nonproliferative (background diabetic retinopathy)1. Initially: microaneurysms (Fig. 2851), capillary dilation, waxy or hard exudates, dot and ame hemorrhages (Fig. 2852), arteriovenous (AV) shunts

2. Advanced stage: microinfarcts with cotton-wool exudates, macular edema Proliferative retinopathy: characterized by formation of new vessels (Fig. 2853), vitreal hemorrhages, brous scar-ring, and retinal detachment

Cataracts and glaucoma occur with increased frequency in diabetics.

Peripheral neuropathy: patients often complain of paresthe-sias of extremities (feet more than hands); the symptoms are symmetrical, bilateral, and associated with intense burn-ing pain (particularly during the night). Mononeuropathies involving cranial nerves III, IV, and VI, intercostal nerves, and femoral nerves are also common. Physical examination may reveal the following:

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285 Section 11: Endocrine and metabolic disorders

Chapter 285 Diabetes mellitus

A

B

Fig 2851Nonproliferative diabetic retinopathy with microaneurysms. A, Small dot hemorrhages, microaneurysms, hard (lipid) exudates, circinate retinop-athy, an intraretinal microvascular abnormality, and macular edema. B, Fluorescein angiography of the eye shown in A. Microaneurysms are seen as multiple dots of hyper uorescence, but the dot hemorrhages do not uoresce. The foveal avascular zone is minimally enlarged.(From Yanoff M, Duker JS: Ophthalmology, 2nd ed. St. Louis, Mosby, 2004.)

DISORDERS OF CARBOHYDRATE AND LIPID METABOLISM

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Chapter 285: Diabetes mellitus 285

Retinalhemorrhages

Cottonwool spots

Fig 2852Background diabetic retinopathy with cotton-wool spots and retinal hemorrhages.(Courtesy of Dr. James Tiedeman.)

Fig 2853Neovascularization. A, Neovascularization of the disc with some brous proliferation. B, Neovascularization elsewhere.(From Yanoff M, Duker JS: Ophthalmology, 2nd ed. St. Louis, Mosby, 2004.)

A

B

1. Decreased pinprick sensation, sensation to light touch, and pain sensation2. Decreased vibration sense3. Loss of proprioception (leading to ataxia)4. Motor disturbances (decreased DTR, weakness and atro-phy of interossei muscles). When the hands are affected, the patient has trouble picking up small objects, dressing, and turning pages in a book.5. Diplopia, abnormalities of visual elds

Autonomic neuropathy GI disturbances: esophageal motility abnormalities, gas-troparesis, diarrhea (usually nocturnal) GU disturbances: neurogenic bladder (hesitancy, weak stream, and dribbling), impotence Orthostatic hypotension: postural syncope, dizziness, light-headedness

Nephropathy: pedal edema, pallor, weakness, uremic ap-pearance. Diabetic kidney changes are described in Figure 2854. Early diabetic glomerulopathy is shown in Figure 2855.

Foot ulcers (Fig. 2856): occur in 15% of diabetics (an-nual incidence, 2%) and are the leading causes of hospi-talization. They are usually secondary to peripheral vascu-

lar insuf ciency, repeated trauma (unrecognized because of sensory loss), and superimposed infections often lead-ing to gangrene (Fig. 2857). If a diabetic foot ulcer has been present for weeks and foot pulses are palpable, neu-ropathy should be considered a major cause. Neuropathy can be detected with a simple examination of the lower extremities using a 10-g mono lament to test sensation. Prevention of foot ulcers in diabetics includes strict glu-cose control, patient education, prescription foot wear, intensive podiatric care, and evaluation for surgical inter-ventions.

Neuropathic arthropathy (Charcots joints): bone or joint deformities (Fig. 2858) from repeated trauma (secondary to peripheral neuropathy).

Necrobiosis lipoidica diabeticorum: plaquelike reddened ar-eas with a central area that fades to white-yellow found on the anterior surfaces of the legs. In these areas, the skin be-comes very thin and can ulcerate readily (Fig. 2859).

LABORATORY TESTS Diagnosis is made on the basis of the following tests and

should be con rmed by repeated testing on a different day:1. Fasting glucose 126 mg/dL (ADA criterion)2. Nonfasting plasma glucose 200 mg/dL

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285 Section 11: Endocrine and metabolic disorders

Fig 2855Early diabetic glomerulopathy with slight hypercellularity and a mild increase in the mesangial matrix (H&E).(Courtesy of Dr. Benjamin Sturgill.)

Glomerulus

Increasedcellularityand mildincreasein matrix

Normal glomerulus Basement membrane thickening

Mesangial proliferation Nodular sclerosis

Diabetic changes in the kidney

Bowman'scapsule

Afferentarteriole Efferent

arteriole

Mesangium

Expandedmesangium

Fig 2854Diabetic changes in the kidney. Illustrated here are the progressive changes in the renal glomerular architecture that occur in the diabetic kidney.(From Besser CM, Thorner MO: Comprehensive Clinical Endocrinology, 3rd ed. St. Louis, Mosby, 2002.)

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Chapter 285: Diabetes mellitus 285

Fig 2856Neuropathic plantar ulcer in diabetic osteoarthropathy.(From Hochberg MC, Silman AJ, Smolen JS, et al [eds]: Rheumatology, 3rd ed. St. Louis, Mosby, 2003.)

Fig 2857Diabetic gangrene.(From Swartz MH: Textbook of Physical Diagnosis, 5th ed. Philadelphia, WB Saunders, 2006.)

A B

Fig 2858Diabetic osteoarthropathy. A, Fragmentation and severe osteolysis on the articular surfaces of the rst metatarsophalangeal joint. B, The pro-cess has healed, with moderate deformation of the articular surfaces.(From Hochberg MC, Silman AJ, Smolen JS, et al [eds]: Rheumatology, 3rd ed. St Louis, Mosby, 2003.)

Fig 2859Necrobiosis lipoidica. Shown is a chronic lesion with ulceration and crusting.(Courtesy of the Institute of Dermatology, London.)

Use of glycosylated hemoglobin (HbA1c) level is generally not recommended for diagnosis because of lack of standard-ization of HbAlc values and the imperfect correlation be-tween HbAlc and fasting plasma glucose levels. However, some physicians use this test to make the diagnosis of dia-betes mellitus if the random plasma glucose is 200 mg/dL and the HbAlc level is 2 SDs (standard deviations) above the laboratory mean.

Screening for diabetic nephropathy by measuring microalbu-minuria is recommended in all patients with diabetes. It can be accomplished by any of the following three methods:1. Measurement of the albumin-to-creatinine ratio in ran-dom spot urine collection. This is the easiest method to administer in the of ce setting because it is an easy assay to perform in most laboratories; the physician simply orders Urine for microalbumin level.

2. Measurement of a 24-hour urine collection for albumin, creatinine clearance3. Timed (4-hour or overnight) urine collection

The diagnosis of microalbuminuria should be based on two or three elevated levels within a 3- to 6-month period because there is a marked variability in daily albumin excretion and possible transient elevations in urine albumin from short-term hyperglycemia, exercise, severe hypertension, and other illnesses, such as sepsis and CHF. Patients with overt ne-phropathy do not need screening for microalbuminuria

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285 Section 11: Endocrine and metabolic disordersbecause the level of protein in the urine is high enough to be detected on routine urinalysis.

A fasting serum lipid panel, serum creatinine, and electro-lytes should be obtained annually on all adult diabetic patients.

TREATMENT Diet

Calories1. The diabetic patient can be started on 15 cal/lb of ideal body weight; this can be increased to 20 cal/lb for an ac-tive person and 25 cal/lb if the patient does heavy physical labor.2. The calories should be distributed as 50% to 60% carbo-hydrates, less than 30% fat, with saturated fat limited to less than 10% of total calories, and 15% to 20% protein.3. The emphasis should be on complex carbohydrates rather than simple and re ned starches and on polyunsaturated instead of saturated fats in a ratio of 2:1. Seven food groups1. The exchange diet of the ADA includes protein, bread, fruit, milk, and low- and intermediate-carbohydrate vegetables.2. The name of each exchange is meant to be all-inclusive (e.g., cereal, muf ns, spaghetti, potatoes, rice are in the bread group; meats, sh, eggs, cheese, peanut butter are in the protein group).3. The glycemic index compares the rise in blood sugar after the ingestion of simple sugars and complex carbohydrates with the rise that occurs after the absorption of glucose. Equal amounts of starches do not produce the same in-crease in plasma glucose (pasta equal in calories to a baked potato causes less of an increase than the potato). Thus, it is helpful to know the glycemic index of a particular food product.4. Fiber: insoluble ber (bran, celery) and soluble globular ber (pectin in fruit) delay glucose absorption and attenu-ate the postprandial serum glucose peak. They also appear to lower the elevated triglyceride level often present in un-controlled diabetics. A diet high in ber should be empha-sized (20 to 35 g/day of soluble and insoluble ber). Other principles1. Modest sodium restriction to 2400 to 3000 mg/day. If hypertension is present, restrict to less than 2400 mg/day; if nephropathy and hypertension are present, restrict to less than 2000 mg/day.2. Moderation of alcohol intake (two drinks or less/day in men, one drink/day or less in women)3. Non-nutritive arti cial sweeteners are acceptable in mod-erate amounts.

Exercise increases the cellular glucose uptake by increasing the number of cell receptors. The following points must be considered: Exercise program must be individualized and built up slowly. Insulin is more rapidly absorbed when injected into a limb that is then exercised; this can result in hypoglycemia.

Weight loss: to ideal body weight if the patient is over-weight

Screenings for nephropathy, neuropathy, and retinopathy When the previous measures fail to normalize the serum

glucose, oral hypoglycemic agents (e.g., metformin, gli-tazones, or a sulfonylurea) should be added to the regimen in type 2 DM. The sulfonamides and the biguanide metfor-min are the oldest and most commonly used classes of hy-poglycemic drugs. Metformins primary mechanism is to decrease hepatic glucose output. Because metformin does not produce hypo-glycemia when used as a monotherapy, it is preferred for most patients. It is contraindicated for patients with renal insuf ciency. Sulfonylureas and repaglinide work best when given be-fore meals because they increase the postprandial output of insulin from the pancreas. All sulfonylureas are contraindi-cated for patients allergic to sulfa. Acarbose and miglitol work by competitively inhibiting pancreatic amylase. Small intestine glucosidases delay gas-trointestinal absorption of carbohydrates, thereby reducing alimentary hyperglycemia. The major side effects are atu-lence, diarrhea, and abdominal cramps. Pioglitazone and rosiglitazone increase insulin sensitivity and are useful in addition to other agents in type 2 diabetics whose hyperglycemia is inadequately controlled. Serum transaminase levels should be determined before starting therapy and monitored periodically. Insulin is indicated for the treatment of all type 1 and type 2 DM patients who cannot be adequately controlled with diet and oral agents. Pramlintide (Symlin), a synthetic analogue of human amylin (a hormone synthesized by pancreatic beta cells and cosecreted with insulin in response to food intake), can be used as an adjunctive treatment for patients with type 1 or type 2 DM who inject insulin at mealtime. Exenatide (Byetta), a synthetic peptide that stimulates release of insulin from pancreatic beta cells, can be used as adjunctive therapy for patients with type 2 DM. It is not indicated in type 1 DM and is contraindicated in patients with severe renal impairment. Combination therapy of various hypoglycemic agents is commonly used when monotherapy results in inadequate glycemic control. Continuous subcutaneous insulin infusion (CSII, or in-sulin pump) provides better glycemic control than conven-tional therapy and comparable with or slightly better con-trol than multiple daily injections. It should be considered for diabetes presenting in childhood or adolescence and during pregnancy. Low-dose aminosalicylic acid (ASA) to decrease the risk of cerebrovascular disease is bene cial for diabetics older than 30 years with other risk factors (hypertension, dyslip-idemia, smoking, obesity). Strict lipid control (low-density lipoprotein [LDL] 70 mg/dL) is indicated for all diabetics. Use of statins is usually necessary to achieve therapeutic goals.

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