Diabet

Secondary, or other specific types of diabetes mellitus are the result of many causes including:

1. Maturity onset type diabetes of the young (MODY) was previously considered to be a third form of type 2 diabetes. However, with the discovery of specific mutations leading to MODY, it is now classified under secondary or other specific types of diabetes. MODY is characterized by onset prior to age 25. All cases to date have shown impaired β-cell function. Patients may also exhibit insulin resistance and late β-cell failure. Evidence indicates that mutations in 10-12 different genes have been correlated with the development of MODY. Mutations in the 6 genes described here are all clearly correlated to MODY:

MODY1: the transcription factor identified as hepatic nuclear factor-4α (HNF-4α). This gene is also called transcription factor-14 (TCF14). Expression of HNF-4α is associated with the growth and normal functioning of the pancreas. Genes known to be regulated by HNF-4α include the insulin gene, glucose-6-phosphatase, GLUT2, the liver pyruvate kinase isoform (L-PK) which is also expressed in the pancreas, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), aldolase B and thermogenin (uncoupling protein, UCP).

MODY2: pancreatic glucokinase

MODY3: the transcription factor HNF-1α. This gene is also called hepatocyte transcription factor-1 (TCF1). HNF-1α is known to regulate expression of the HNF-4α gene and also the GLUT2 and L-PK genes.

MODY4: the homeodomain transcription factor insulin promoter factor-1 (IPF-1). This gene is more commonly called PDX1 derived from pancreas duodenum homeobox-1.

MODY5: the transcription factor HNF-1β. This gene is also called hepatocyte transcription factor-2 (TCF2). HNF-1β is a critical regulator of a transcriptional network that controls the specification, growth, and differentiation of the embryonic pancreas. In humans, mutations in the HNF-1β gene are associated with pancreatic hypoplasia, defective kidney development and genital malformations.

MODY6: the bHLH transcription factor NeuroD1. NeuroD1 was first identified as a neural fate-inducing gene. The hamster β2 gene, shown to regulate insulin transcription is identical to NeuroD1 so the gene is often called NeuroD/β2.

2. Pancreatic disease: Pancreatectomy leads to the clearest example of secondary diabetes. Cystic fibrosis and pancreatitis can also lead to destruction of the pancreas.

3. Endocrine disease: Some tumors can produce counter-regulatory hormones that oppose the action of insulin or inhibit insulin secretion. These counter-regulatory hormones are glucagon, epinephrine, growth hormone and cortisol.

a. Glucagonomas are pancreatic cancers that secrete glucagon.

b. Pheochromocytomas secrete epinephrine.

c. Cushing syndrome results in excess cortisol secretion.

d. Acromegaly results in excess growth hormone production.

4. Drug-induced diabetes; treatment with glucocorticoids and diuretics can interfere with insulin function.

5. Anti-insulin receptor autoantibodies (Type B insulin resistance).

6. Mutations in the insulin gene.

7. Mutations in insulin receptor gene which lead to the syndromes listed below. Two clinical features are common in all syndromes that result from mutations in the insulin receptor gene: acanthosis nigricans and hyperandrogenism (the latter being observed only in females).

a. Donohue syndrome (also referred to as Leprachaunism)

b. Rabson-Mendenhall syndrome

c. Type A insulin resistance

8. Gestational diabetes; this syndrome sets in during pregnancy and usually resolves itself following childbirth.

9. Many other genetic syndromes have either diabetes or impaired glucose tolerance associated with them; lipoatrophic diabetes, Wolfram syndrome, Down syndrome, Klinefelter syndrome (XXY males), Turner syndrome, myotonic dystrophy, muscular dystrophy, Huntington disease, Friedreich ataxia, Prader-Willi syndrome, Werner syndrome, Cockayne syndrome, and others such as those indicated above