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Diabetes Mellitus:

Laboratory Diagnosis

C H A P T E R

DIABETES MELLITUS

Diabetes mellitus is a chronic metabolic disorder with

vascular components that is characterized by disturbances

in carbohydrate, lipid and protein metabolism. So,

hyperglycemia and glycosuria reflect the major metabolic

lesion in carbohydrate metabolism, with secondary

metabolic disturbances in proteins (gluconeogenesis) and

lipids (ketosis and hypercholesterolemia).

With hyperglycemia, renal glycosuria occurs with

an osmotic diuresis (polyuria) ultimately leads to

dehydration and associated polydipsia (increased thirst).

Glycogenolysis and gluconeogenesis (protein depletion)

are augmented to generate glucose that contributes to or

sustains hyperglycemia. Muscle glycogen cannot contribute glucose directly to the blood because of the absence

of glucose-6-phosphatase. A failure of glucose to penetrate

adipose tissue cells mobilizes fat and produces a rise in

the free fatty acid and triglycerides in the liver. A diabetic

fatty liver may result from the absence of lipoprotein

synthesis when protein synthesis is compromised by

accelerated gluconeogenesis (negative nitrogen balance).

When glucose oxidation is impaired, fatty acids form the

major source of energy and generate an excess of acetyl

coenzyme A that cannot be oxidized to water and carbon

dioxide or be disposed of in other metabolic routes. The

condensation of two carbon fragments of acetyl coenzyme

A results in formation of ketone bodies, ketonemia

and ketonuria. The three ketone bodies are acetone, β

hydroxybutyric acid and acetoacetic acid. Ketoacidosis is

the hallmark of potentially fatal complications of diabetes

mellitus.

Classification and Causes of Diabetes

Primary

¾ Maturity-onset (adult) type

¾ Growth-onset (juvenile) type

¾ Hyperpituitarism

• Pituitary basophilism

• Acromegaly.

¾ Hyperadrenalism

• Cortical: Cushing’s syndrome, aldosteronism

• Medullary: Pheochromocytoma.

¾ Hyperthyroidism

¾ Iatrogenic

• Corticosteroids and ACTH

• Growth hormone

• Thyroid extract and triiodothyronine.

Destruction of Pancreatic Islets

¾ Surgical removal of pancreas

¾ Hemochromatosis

¾ Fibrocystic disease of pancreas

¾ Neoplasm.

Miscellaneous

¾ Diuretics and derivatives (thiazide therapy)

¾ Stress reactions, surgery and pregnancy

¾ Starvation and low carbohydrate intake.

The course of the disease can be divided into four

stages:

1. Prediabetes

2. Suspected diabetes

3. Chemical or latent diabetes

4. Overt diabetes.

Diabetes Mellitus: Laboratory Diagnosis 435

The period from birth until the first evidence of the

disease characterizes prediabetes. In suspected diabetes,

the patient displays an abnormal glucose tolerance test

(GTT) or even diabetic symptoms after stressful influences

(e.g. obesity, pregnancy, trauma and infections), but

usually is normal in all respects. In chemical or latent

diabetes, there are no signs or symptoms of disease but

an abnormal GTT or fasting hyperglycemia are evident

when the patient is not under stress. With overt diabetes,

symptoms of polyuria, polydipsia and weight loss (and

possibly ketoacidosis) are often associated with fasting

hyperglycemia and glycosuria. For diagnosis of diabetes

in individuals with marked glucose intolerance, the

provocative tests should not be performed (as in an

insulin requiring diabetic). In patients who have neither

glycosuria nor fasting hyperglycemia—in these individuals

provocative tests may be needed to demonstrate impaired

glucose tolerance. Glycosuria associated with ketonuria is

almost always pathognomonic of diabetes mellitus.

Screening Tests

These include urine and blood glucose estimations:

Urine Glucose (Methods Mentioned Elsewhere)

While evaluating glycosuria, it should be remembered that

venous “true glucose” must exceed 180 mg% of blood before

any glucose will spill over into urine (renal threshold). In

diabetic nephropathy, the renal threshold may be elevated

considerably (very little filtration apparatus left, i.e.

glomeruli) even in the presence of hyperglycemia. Also,

the renal threshold increases with age, and in some elderly

patients no glycosuria will be present with serum levels of

200 mg% of glucose.

Fasting Blood Sugar

For this, plasma is the blood fraction of choice. Fasting

plasma glucose values in excess of 120 mg% (true glucose)

are considered indicative of diabetes mellitus; values

between 110-120 mg% are equivocal and should be

confirmed with a GTT. The 2 hours postprandial (PP) test

should be done instead of fasting glucose levels. Emotional

hyperglycemia from secretion of epinephrine as well as

cerebral lesions (skull fractures, tumors, vascular accident,

and encephalitis) and carbon monoxide poisoning, often

provoke hyperglycemia and glycosuria, must be considered

in the evaluation of blood glucose measurements.

Two-hours Postprandial Blood Glucose

After an overnight fast (12 hours), the patient is given

a breakfast of 100 g of carbohydrate or a 100 g glucose

load. Previous to the test, the patient should have been

on an adequate carbohydrate diet (300 g daily) and all

medications that influence glucose tolerance should

have been discontinued 3 days prior to the test. Two

hours later [2 hours PP or PC, post cibum] a single blood

sample is withdrawn for analysis. A value within normal

limits makes the diagnosis of diabetes mellitus unlikely,

plasma glucose values in the range of 120-140 mg% are

suspicious and in excess of 140 mg% (true glucose),

diagnosis is most likely and should be confirmed by GTT.

The limitations of a single 2 hours PP glucose value

include the following:

1. Slow absorption, which may delay the peak.

2. Rapid absorption with early hyperglycemia, rapid

fall in concentration of blood glucose (due to insulin

release), and then a second hyperglycemic peak

due to the effects of counter regulatory responses

(epinephrine, glucagon, growth hormone).

3. Errors in timing specimen collection.

Diagnosis and Classification of Diabetes

Mellitus: New Criteria

New recommendations for the classification and diagnosis

of diabetes mellitus include the preferred use of the terms

“type 1” and “type 2” instead of “IDDM” and “NIDDM”

to designate the two major types of diabetes mellitus:

simplification of the diagnostic criteria for diabetes

mellitus to two abnormal fasting plasma determinations:

and a lower cutoff for fasting plasma glucose [126 mg per

dL (7 mmol per L) or higher] to confirm the diagnosis of

diabetes mellitus. These changes provide an easier and

more reliable means of diagnosing persons at risk of

complications from hyperglycemia. Currently, only one

half of the people who have diabetes mellitus have been

diagnosed. Screening for diabetes mellitus should begin at

45 years of age and should be repeated every three years in

persons without risk factors, and should begin earlier and

be repeated every 3 years in persons without risk factors,

and should begin earlier and be repeated more often in

those with risk factors. Risk factors include obesity, firstdegree relatives with diabetes mellitus, hypertension,

hypertriglyceridemia or previous evidence of impaired

glucose homeostasis. Earlier detection of diabetes mellitus

may lead to tighter control of blood glucose levels and a

reduction in the severity of complications associated with

this disease.

Diabetes mellitus is a group of metabolic disorders

with one common manifestation: hyperglycemia. Chronic

hyperglycemia causes damage to the eyes, kidneys, nerves,

heart and blood vessels. The etiology and pathophysiology

436 Concise Book of Medical Laboratory Technology: Methods and Interpretations leading to the hyperglycemia, however, are markedly

different among patients with diabetes mellitus, dictating

different prevention strategies, diagnostic screening

methods and treatments. The adverse impact of

hyperglycemia and the rationale for aggressive treatment

have recently been reviewed.

In June 1997, an international expert committee released

a report with new recommendations for the classification

and diagnosis of diabetes mellitus. These new recommendations were the result of more than two years of collaboration

among experts from the American Diabetes Association

and the World Health Organization (WHO). The use of

classification systems and standardized diagnostic criteria

facilitates a common language among patients, physicians,

other healthcare professionals and scientists.

Previous Classification

In 1979, the National (American) Diabetes Data Group

produced a consensus document standardizing the

nomenclature and definitions for diabetes mellitus.

This document was endorsed one year later by WHO.

The two major types of diabetes mellitus were given

names descriptive of their clinical presentation: “insulindependent diabetes mellitus” (IDDM) and “noninsulindependent diabetes mellitus” (NIDDM).

Diabetes mellitus that is characterized by absolute insulin deficiency

and acute onset, usually before 25 years of age, should now be

referred to as type 1 (not type I, IDDM or juvenile) diabetes mellitus.

However, as treatment recommendations evolved, correct classification of the type of diabetes mellitus became

confusing. For example, it was difficult to correctly classify

persons with NIDDM who were being treated with insulin.

This confusion led to the incorrect classification of a large

number of patients with diabetes mellitus complicating

epidemiologic evaluation and clinical management. The

discovery of other types of diabetes with specific pathophysiology that did not fit into this classification system

further complicated the situation. These difficulties, along

with new insights into the mechanisms of diabetes mellitus, provided a major impetus for the development of a

new classification system.

The National Diabetes Data Group also established

the oral glucose tolerance test (using a glucose load

of 75 g) as the preferred diagnostic test for diabetes

mellitus. However, this test has poor reproducibility, lacks

physiologic relevance and is a weaker indicator of longterm complications compared with other measures of

hyperglycemia. Furthermore, many high-risk patients are

unwilling to undergo this time-consuming test on a repeatbasis. The new diagnostic criteria also address this issue.

Changes in the Classification System

The new classification system identifies four types of

diabetes mellitus: type 1, type 2, other specific types and

gestational diabetes. Arabic numerals are specifically used

in the new system to minimize the occasional confusion of

type “II” as the number “11”. Each of the types of diabetes

mellitus identified extends across a clinical continuum of

hyperglycemia and insulin requirements.

Any patient with two fasting plasma glucose levels of 126 mg per dL

(7.0 mmol per L) or greater is considered to have diabetes mellitus.

Type 1 diabetes mellitus (formerly called type I, IDDM or

juvenile diabetes) is characterized by beta cell destruction

caused by an autoimmune process, usually leading to

absolute insulin deficiency. The onset is usually acute,

developing over a period of a few days to weeks. Over 95%

of persons with type 1 diabetes mellitus develop the disease

before the age of 25, with an equal incidence in both sexes

and an increased prevalence in the white population.

A family history of type 1 diabetes mellitus, gluten

enteropathy (celiac disease) or other endocrine disease

is often found. Most of these patients have the “immunemediated form” of type 1 diabetes mellitus with islet cell

antibodies and often have other autoimmune disorders,

such as Hashimoto’s thyroiditis, Addison’s disease, vitiligo

or pernicious anemia. A few patients, usually those of

African or Asian origin, have no antibodies but have

a similar clinical presentation; consequently, they are

included in this classification and their disease is called

the “idiopathic form” of type 1 diabetes mellitus.

Type 2 diabetes mellitus (formerly called NIDDM,

type  II or adult-onset) is characterized by insulin

resistance in peripheral tissue and an insulin secretory

defect of the beta cell. This is the most common form of

diabetes mellitus and is highly associated with a family

history of diabetes, older age, obesity and lack of exercise.

It is more common in women, especially women with

a history of gestational diabetes. Insulin resistance and

hyperinsulinemia eventually lead to impaired glucose

tolerance. Defective beta cells become exhausted, further

fueling the cycle of glucose intolerance and hyperglycemia.

The etiology of type 2 diabetes mellitus is multifactorial

and probably genetically based, but it also has strong

behavioral components.

The etiologic classifications of diabetes mellitus are

listed in Table 17.1.

Diabetes Mellitus: Laboratory Diagnosis 437

TABLE 17.1: Etiologic classification of diabetes mellitus

Types of diabetes mellitus of various known etiologies

are grouped together to form the classification called

“other specific types.” This group includes persons with

genetic defects of beta-cell function (this type of diabetes

was formerly called MODY or maturity-onset diabetes

in youth) or with defects of insulin action; persons with

diseases of the exocrine pancreas, such as pancreatitis or

cystic fibrosis; persons with dysfunction associated with

other endocrinopathies (e.g. acromegaly); and persons

with pancreatic dysfunction caused by drugs, chemicals or

infections.