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Section 11: Endocrine and metabolic disorders

DISORDERS OF CARBOHYDRATE AND LIPID METABOLISM

Chapter 285 Diabetes mellitus

2. Advanced stage: microinfarcts with cotton-wool exudates,
macular edema
Proliferative retinopathy: characterized by formation of
new vessels (Fig. 2853), vitreal hemorrhages, brous scarring, and retinal detachment
Cataracts and glaucoma occur with increased frequency in
diabetics.
Peripheral neuropathy: patients often complain of paresthesias of extremities (feet more than hands); the symptoms
are symmetrical, bilateral, and associated with intense burning 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:

DEFINITION

Diabetes mellitus (DM) refers to a syndrome of hyperglycemia

resulting from many different causes. It can be classied into
type 1 (formerly insulin-dependent diabetes mellitus [IDDM])
and type 2 (formerly noninsulin-dependent diabetes mellitus
[NIDDM]). Because insulin-dependent and noninsulindependent refer to the stage at diagnosis, when a type 2 diabetic
needs insulin, he or she remains classied as type 2 and does
not revert to type 1.
The American Diabetes Association (ADA) denes 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). Furthermore, 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 classied as impaired fasting glucose
(IFG).

CAUSE
Idiopathic diabetes

TYPE 1 DIABETES MELLITUS

Hereditary factors
1. Islet cell antibodies (found in 90% of patients within the
rst year of diagnosis)
2. Higher incidence of HLA types DR3, DR4
3. 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, glucagonoma, pheochromocytoma

Drugs: glucocorticoids, diuretics, oral contraceptives
Insulin receptor unavailability (with or without circulating antibodies)
Pancreatic disease: pancreatitis, pancreatectomy, hemochromatosis
Genetic syndromes: hyperlipidemias, myotonic dystrophy, lipoatrophy
Gestational diabetes

DIFFERENTIAL DIAGNOSIS

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

PHYSICAL FINDINGS AND CLINICAL PRESENTATION

Fig 2851

Nonproliferative diabetic retinopathy with microaneurysms. A, Small dot

hemorrhages, microaneurysms, hard (lipid) exudates, circinate retinopathy, an intraretinal microvascular abnormality, and macular edema.
B, Fluorescein angiography of the eye shown in A. Microaneurysms are
seen as multiple dots of hyperuorescence, but the dot hemorrhages
do not uoresce. The foveal avascular zone is minimally enlarged.

916

Physical examination varies with the presence of complications 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

(From Yanoff M, Duker JS: Ophthalmology, 2nd ed. St. Louis, Mosby,
2004.)

Chapter 285: Diabetes mellitus

285

Cotton
wool spots

Retinal
hemorrhages

B
Fig 2852

Fig 2853

Background diabetic retinopathy with cotton-wool spots and retinal

hemorrhages.

Neovascularization. A, Neovascularization of the disc with some brous

proliferation. B, Neovascularization elsewhere.

(Courtesy of Dr. James Tiedeman.)

(From Yanoff M, Duker JS: Ophthalmology, 2nd ed. St. Louis, Mosby,
2004.)

1. Decreased pinprick sensation, sensation to light touch,

and pain sensation
2. Decreased vibration sense
3. Loss of proprioception (leading to ataxia)
4. Motor disturbances (decreased DTR, weakness and atrophy 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, gastroparesis, 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 appearance. 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 (annual incidence, 2%) and are the leading causes of hospitalization. They are usually secondary to peripheral vascu-

lar insufciency, repeated trauma (unrecognized because

of sensory loss), and superimposed infections often leading to gangrene (Fig. 2857). If a diabetic foot ulcer has
been present for weeks and foot pulses are palpable, neuropathy should be considered a major cause. Neuropathy
can be detected with a simple examination of the lower
extremities using a 10-g monolament to test sensation.
Prevention of foot ulcers in diabetics includes strict glucose control, patient education, prescription foot wear,
intensive podiatric care, and evaluation for surgical interventions.
Neuropathic arthropathy (Charcots joints): bone or joint
deformities (Fig. 2858) from repeated trauma (secondary
to peripheral neuropathy).
Necrobiosis lipoidica diabeticorum: plaquelike reddened areas with a central area that fades to white-yellow found on
the anterior surfaces of the legs. In these areas, the skin becomes very thin and can ulcerate readily (Fig. 2859).

LABORATORY TESTS

Diagnosis is made on the basis of the following tests and

should be conrmed 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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Section 11: Endocrine and metabolic disorders

Diabetic changes in the kidney

Normal glomerulus

Basement membrane thickening

Bowman's
capsule

Mesangium

Afferent
arteriole

Efferent
arteriole

Mesangial proliferation

Nodular sclerosis

Expanded
mesangium

Fig 2854
Diabetic 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.)

Glomerulus

Increased
cellularity
and mild
increase
in matrix

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

918

Chapter 285: Diabetes mellitus

285

Fig 2858
Diabetic osteoarthropathy. A, Fragmentation and severe osteolysis on
the articular surfaces of the rst metatarsophalangeal joint. B, The process has healed, with moderate deformation of the articular surfaces.

Fig 2856
Neuropathic plantar ulcer in diabetic osteoarthropathy.

(From Hochberg MC, Silman AJ, Smolen JS, et al [eds]: Rheumatology,

3rd ed. St Louis, Mosby, 2003.)

(From Hochberg MC, Silman AJ, Smolen JS, et al [eds]: Rheumatology,

3rd ed. St. Louis, Mosby, 2003.)

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

Use of glycosylated hemoglobin (HbA1c) level is generally

not recommended for diagnosis because of lack of standardization of HbAlc values and the imperfect correlation between HbAlc and fasting plasma glucose levels. However,
some physicians use this test to make the diagnosis of diabetes 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 microalbuminuria 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 random spot urine collection. This is the easiest method to
administer in the ofce setting because it is an easy assay to
perform in most laboratories; the physician simply orders
Urine for microalbumin level.

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

2. Measurement of a 24-hour urine collection for albumin,

creatinine clearance
3. 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 shortterm hyperglycemia, exercise, severe hypertension, and other
illnesses, such as sepsis and CHF. Patients with overt nephropathy do not need screening for microalbuminuria

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because the level of protein in the urine is high enough to be

detected on routine urinalysis.
A fasting serum lipid panel, serum creatinine, and electrolytes should be obtained annually on all adult diabetic
patients.

TREATMENT

920

Diet
Calories
1. The diabetic patient can be started on 15 cal/lb of ideal
body weight; this can be increased to 20 cal/lb for an active person and 25 cal/lb if the patient does heavy physical
labor.
2. The calories should be distributed as 50% to 60% carbohydrates, 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 rened starches and on polyunsaturated
instead of saturated fats in a ratio of 2:1.
Seven food groups
1. 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, mufns, 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 increase 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 attenuate the postprandial serum glucose peak. They also appear
to lower the elevated triglyceride level often present in uncontrolled diabetics. A diet high in ber should be emphasized (20 to 35 g/day of soluble and insoluble ber).
Other principles
1. 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 articial sweeteners are acceptable in moderate 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 overweight

Screenings for nephropathy, neuropathy, and retinopathy

When the previous measures fail to normalize the serum
glucose, oral hypoglycemic agents (e.g., metformin, glitazones, or a sulfonylurea) should be added to the regimen
in type 2 DM. The sulfonamides and the biguanide metformin are the oldest and most commonly used classes of hypoglycemic drugs.
Metformins primary mechanism is to decrease hepatic
glucose output. Because metformin does not produce hypoglycemia when used as a monotherapy, it is preferred for
most patients. It is contraindicated for patients with renal
insufciency.
Sulfonylureas and repaglinide work best when given before meals because they increase the postprandial output of
insulin from the pancreas. All sulfonylureas are contraindicated for patients allergic to sulfa.
Acarbose and miglitol work by competitively inhibiting
pancreatic amylase. Small intestine glucosidases delay gastrointestinal absorption of carbohydrates, thereby reducing
alimentary hyperglycemia. The major side effects are atulence, 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 insulin pump) provides better glycemic control than conventional therapy and comparable with or slightly better control 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 benecial for diabetics older
than 30 years with other risk factors (hypertension, dyslipidemia, 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.