DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 43–2
Different Forms of Diabetes Mellitus
I. Type 1 diabetes β-cell destruction, usually leading to absolute insulin deficiency)
A. Immune-mediated
B. Idiopathic
II. Type 2 diabetes (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly
insulin secretory defect with insulin resistance)
III. Other specific types of diabetes
A. Genetic defects of β cell function characterized by mutations in:
1. Hepatocyte nuclear transcription factor (HNF) 4α (MODY 1)
2. Glucokinase (MODY 2)
3. HNF-1α (MODY 3)
4. Insulin promoter factor-1 (IPF-1; MODY 4)
5. HNF-1β (MODY 5)
6. NeuroD1 (MODY 6)
7. Mitochondrial DNA
8. Subunits of ATP-sensitive K + channel
9. Proinsulin or insulin sequence conversion
B. Genetic defects in insulin action
1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome
4. Lipodystrophy syndromes
C. Diseases of the exocrine pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis,
fibrocalculous pancreatopathy, mutations in carboxyl ester lipase
D. Endocrinopathies—acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism,
somatostatinoma, aldosteronoma
E. Drug- or chemical-induced—Vacor (a rodenticide); see Table 43-3
F. Infections—congenital rubella, cytomegalovirus
G. Uncommon forms of immune-mediated diabetes—“stiff-person” syndrome, anti-insulin receptor antibodies
H. Other genetic syndromes sometimes associated with diabetes—Wolfram’s syndrome, Down’s syndrome, Klinefelter’s
syndrome, Turner’s syndrome, Friedreich’s ataxia, Huntington’s chorea, Laurence-Moon-Biedl
syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome
IV. Gestational diabetes mellitus (GDM)
MODY- maturity onset of diabetes of the young. Copyright 2010 American Diabetes Association. From Diabetes Care, Vol. 33 (Suppl 1), 2010; S62.
Reprinted with permission from the American Diabetes Association.
as autoimmune adrenal insufficiency (Addison’s disease),
autoimmune thyroid disease (Graves’ and
Hashimoto’s disease), pernicious anemia, vitiligo, and
celiac sprue.
The concordance of type 1 diabetes in genetically identical
twins is 40-60%, indicating a significant genetic component. The
major genetic risk (40-50%) is conferred by HLA class II genes
encoding HLA-DR and HLA-DQ (and possibly other genes with the
HLA locus). Candidate gene association studies and recently
genome-wide association studies have identified >20 additional loci
that confer genetic susceptibility to type 1 diabetes (INS, PTPN22,
CTLA4, and IL2RA, among others) (Concannon et al., 2009).
However, there clearly is a critical interaction of genetics and an
environmental or infectious agent. Most individuals with type 1
diabetes (~75%) do not have a family member with type 1 diabetes,
and the genes conferring genetic susceptibility are found in a significant
fraction of the nondiabetic population.
Genetically susceptible individuals are thought to have a normal
β cell number or mass until β cell–directed autoimmunity develops
and β cell loss begins. The first physiological abnormality that
is detectable in affected subjects is loss of the first phase of glucosestimulated
insulin secretion. Prior to this, islet cell autoantibodies
can be detected in the serum (known autoantigens include insulin,
glutamate decarboxylase, protein tyrosine phosphatase IA-2[ICA-
512], and zinc transporter 8 [SLC30A8]). The initiating or triggering
stimulus for the autoimmune process is not known, but most
favor exposure to viruses (enterovirus, etc.) or other ubiquitous environmental
agents. Histological examinations of human pancreata
during the prediabetic period and at presentation are quite limited,
but animal models of type 1 diabetes show a T cell infiltrate with a