Thursday, November 15, 2012

TYPE 1 DIABETES MELLITUS AND ITS AETIOLOGY

Formerly called Insulin dependent diabetes mellitus (IDDM). Accounts for about 5-10% of diabetes.  Occurs due to beta cell destruction leading to absolute insulin deficiency, so that patient requires exogenous supply of insulin. It is characterized by hyperglycemia severe cachexia (if untreated), dehydration and ketoacidosis. It is apparent within week or month, i.e., early and abrupt onset of symptoms in childhood and adolescence (polyuria, polydipsia and weight loss). About 75% acquire the disease and are diagnosed before 30 years of age but in remainder can occur in any age.

Fig. Type 1 Diabetes mechanism
LADA is rare subtype of type 1 diabetes. Individual develop diabetes insidiously and respond initially to treatments other than insulin, like sulphonylureas. Some patients with autoimmune type 1 diabetes although have ketoacidosis, but has sufficient islet cells reserve for some months after the diagnosis to remain ketosis free on little or even no insulin (so called honeymoon period). Some patients with type 2 diabetes may become ketosis prone as beta cell failure progresses from being relative to being absolute due to islet cell exhaustion or destruction, particularly in conditions of increased insulin requirement such as systemic sepsis. The acceleratory hypothesis of type 2 diabetes predisposing to type 1 diabetes via islet cell stress and high prevalence of co-aggregation of features of both types of diabetes is called double diabetes effect.  Some patients have no evidence of autoimmunity and are classified as type 1 idiopathic.

For the confirmation of type 1 (autoimmune) diabetes quantification of anti-glutamic acid decarboxylase (GAD) antibodies and/or islet cell antibodies (ICA) may be helpful. These antibodies are also present in 2% of normal individuals. But in individuals with these antibodies are at increased risk of diabetes. 

AETIOLOGY

Fig. Cause of Type 1 Diabetes
Type 1 diabetes results from autoimmune (CMI, mostly T cell) attack of pancreatic β cells. Many factors are associated with this dysfunction. The islet cells have a chronic mononuclear cell infiltrate, called insulitis. The autoimmune process begins months or years before clinical presentation, and an 80% to 90% reduction in the volume of beta cell is required to induce symptoms. The process of β cell destruction takes many months and occurs in cycles of deterioration and remission. The remission period with normal β cell function is called honeymoon period and it lasts for 6 month upto 24 months. Although the main defect is autoimmune destruction of β cells but insulin resistance also develops due to formation of anti insulin antibodies and other mechanisms like obesity.

ANTIBODIES

The most practical markers of beta cell autoimmunity are circulating antibodies that can be detected in serum years before the onset of hyperglycemia. The best characterized antibodies are;

  1. Islet cell cytoplasmic antibodies (ICA): These reacts with a sialoglycoconjugate antigen present in the cytoplasm of all endocrine cells of the pancreatic islets. These are seen in some normal persons but occur in 75-85% of T-1 diabetics. 
  2. Insulin autoantibodies (IAAs): High titer IAAs are present in children who develop T-1 diabetes, >90% of children <5 years with diabetes has IAA. IAA can develop even in human insulin therapy. IAA also occurs in very few normal individuals.
  3.  Antibodies to the 65-kD isoform of glutamic acid decarboxylase (GAD65): These are found up to 10 years before the onset of type 1 diabetes and present in most of newly diagnosed diabetics. These antibodies can be used to determine the likelihood of conversion of type 2 to type 1.
  4. Insulinoma-associated antibodies (IA-2A and IA-2βA): These antibodies are directed against two tyrosine phosphatases, are present in more than 50% of diabetics.
  5. Autoantibody markers of immune destruction are present in 85% to 90% of immune mediated diabetics when fasting hyperglycemia is detected. Some individuals with type 2 diabetes phenotype also have ICA, particularly GAD65A. This condition has been termed Latent autoimmune diabetes of adulthood (LADA). The presence of multiple autoantibodies is associated with >90% risk of immune mediated diabetes.
Diabetes is multigenic trait and several works has demonstrated certain genetic markers associated with high prevalence of type 1 diabetes. Most of these genetic markers are found in chromosome no. 6 in HLA complex. E.g. HLA-DQR4 has RR upto 90, HLADR4 has RR 7. Other chromosomes are insulin gene regulatory locus in chromosome 11, Ig heavy chain gene in chromosome 14.

Environmental factors are also involved in initiating diabetes. Viruses like rubella, mumps, etc. have been implicated. Other factors suggested are chemicals and cow’s milk. 
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