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chapter 22
Metabolic Homeostasis
and amputation, and macrovascular disease such as
atherosclerosis.
Etiologic Classification o f Diabetes Mellitus
In the new system of classification the arabic numerals
1 and 2 are used in place of roman numerals I and II.
The previously used terms, i.e., insulin-dependent diabetes
(IDDM) and non-insulin-dependent diabetes (NIDDM),
are no longer used.
Type 1 Diabetes Mellitus
This disorder is primarily
caused by autoimmune destruction of pancreatic /3 cells.
However, in some patients evidence of autoimmunity may
not be present and the cause of the destruction of the
fi
cells may be undetermined (idiopathic). Type 1
diabet-
ics are insulin-dependent and prone to ketoacidosis. The
anti-/3-cell antibodies may be directed against many dif-
ferent antigens but the major ones are insulin and glutamic
acid decarboxylase (GAD). The antibodies appear in the
plasma during the preclinical stage; in high-risk individu-
als the presence of the autoantibodies, e.g., antibodies to
GAD can have predictive value in predicting development
of diabetes mellitus. The inheritance of type 1
diabetes
mellitus does not follow simple Mendelian inheritance and
appears to be a polygenic disease with environmental fac-
tors playing a role in its initiation. It has been proposed
that some infectious agents (e.g., coxsackie virus) may
trigger the autoimmune destruction of
ft
cells by molecu-
lar mimicry.
Type 2 Diabetes Mellitus
This is the most prevalent
form of diabetes and is characterized by both an insulin
secretion defect and insulin resistance. Maturity-onset di-
abetes of the young (MODY), attributable to mutations of
the glucose kinase gene (discussed earlier), may also be
classified as type 2 diabetes mellitus. Obesity is a con-
tributory factor and may predispose to insulin resistance
with eventual development of type
2
diabetes mellitus.
The precise mechanism by which obesity leads to in-
sulin resistance in the target tissues is not understood.
However, in several animal models (e.g.,
o b /o b
mouse,
d b /d b
mouse) mutations have been identified that cause
both obesity and diabetes mellitus. Unlike type 1
diabetes
mellitus, type 2 is not an autoimmune disease. Studies
with monozygotic twins have revealed a 90% concor-
dance rate for type
2
diabetes mellitus, suggesting the
involvement of genetic factors in the development of the
disease.
Gestational Diabetes Mellitus (GDM)
Glucose in-
tolerance that is first recognized during pregnancy is clas-
sified as GDM. The prevalence of GDM varies among
ethnic groups. Studies of predominately white women
have shown that the prevalence of GDM is between 4%
and 7%. GDM is associated with an increase in mater-
nal and fetal neonatal morbidity. The clinical risks may
include macrosomia (excessive fetal growth) associated
with complications of labor and delivery, jaundice, respira-
tory distress syndrome, hypocalcemia, and polycythemia.
Thus, proper diagnosis (discussed later) with appropriate
intervention and treatment is required during the antepar-
tum period of GDM. The causes of macrosomia in GDM is
attributed to multiple disturbances that occur in both ma-
ternal and fetal metabolism. Fetal hyperinsulinemia due to
increased delivery of maternal glucose may be one of the
contributory factors. Two additional risks associated with
GDM have been identified in epidemiological studies:
1. Persons exposed to GDM
in utero
have an increased
risk of obesity, and
2. GDM increases the risk of development of type 2
diabetes mellitus between 5 and 16 years after the
index pregnancy.
Specific Mutations That Cause Diabetes Mellitus
This group of disorders is relatively uncommon and in-
clude mutations in genes that affect various aspects of
yS-cell function including mitochondrial DNA and the in-
sulin receptor gene; these disorders have been discussed
earlier.
Endocrinopathies
Excessive production of insulin
counterregulatory hormones can cause diabetes mellitus.
Examples include excessive production of growth hor-
mone (
acrom egaly
), cortisol (
C u sh in g’s syn drom e
), epine-
phrine
(ph eoch rom ocytom a),
and glucagon (
glu cago-
nom a).
Miscellaneous Causes of Diabetes Mellitus
These
include diseases of the exocrine pancreas (e.g.,
cystic
fi-
brosis, hem ochrom atosis, p a n crea titis
) and drug-induced
causes (e.g., thiazides, glucocorticoids).
Diagnosis of Diabetes Mellitus
Since diabetes mel-
litus is a heterogeneous group of metabolic disorders
characterized by hyperglycemia, the diagnosis involves
first excluding other causes of hyperglycemia. For exam-
ple, all of the endocrinopathies that have other pathog-
nomonic features, such as acromegaly, Cushing’s syn-
drome, glucagonoma, and pheochromocytoma, should be
identified with appropriate diagnostic procedures. After
excluding all such causes of hyperglycemia, the diagnosis
of type
1
or type
2
diabetes mellitus should be consid-
ered. The diagnostic criteria for diabetes mellitus are given
