How is diabetes mellitus best characterized?
a deficiency of insulin secretion or action resulting in hyperglycemia and the probable development of complications over time. While DM is characterized by elevated levels of glucose in blood there is a reduction (shortage) of glucose inside the cells.
What is another name for Type I Diabetes Mellitus? Is it more severe than Type II?
Insulin dependent (IDDM) and it is the more severe form of diabetes. Type 1 DM accounts for about 10% of all cases of DM.
What is IDDM characterized by? Can it be immune mediated?
characterized by an absolute deficiency of insulin. Associated with an autoimmune mediated destruction or degeneration of the pancreatic islet beta (B) cells.
What is believed to be the most likely cause of Type I Diabetes (IDDM)?
Coxsackievirus B4 (CVB4), an environmentally acquired Enterovirus (Picornaviridae). Type 1 is considered to be an "immune sequel" disorder in that it occurs after an immune response to antigen that is not related to the actual disease!
In regards to HLA What are some genetic "determinants" of IDDM?
Increased risk of Type 1 IDDM (IDDM1) has been repeatedly linked to inheritance of HLA-A8, HLA-W16, HLA-DR3, HLA-DR4 and HLA-DQw8 markers.
How does having the HLA alleles that predispose one to IDDM lead to IDDM?
The presence of these markers will facilitate viral infections (such as CV) which results in humoral immunization. These antibodies are able to destroy the viral antigen but also "crossreact" with similar ("heterologous") antigens that also occur on human cells. This is the etiology of the so called "autoantibodies".
What type of autoantibodies do the majority of Type I diabetics present with?
microinsulin autoantibodies, islet cell autoantibodies, glutamic acid decarboxylase (GAD65) autoantibodies, and tyrosine phosphatase IA-2 and IAR autoantibodies.
What are microinsulin autoantibodies (MIAA) and on what patient population are they found in?
Antibodies to insulin. Presence indicates ongoing destruction of β islet cells. Found predominantly, though not exclusively, in young children (<5 years) developing Type 1 diabetes.
What other type of antibodies are microinsulin autoantibodies (MIAAs) similar to?
appear to be identical to insulin antibodies that commonly develop with insulin therapy. In insulin-naive (untreated) patients, the prevalence of autoantibodies to insulin is almost 100% in very young individuals and almost absent in patients with adult onset of Type 1 diabetes.
What are heterologous antibodies?
antibodies originally made to other antigens (e.g. viruses) that become so-called autoantibodies due to their being similar sequenced self-proteins on beta islet cells.
What are two types of Islet Cell Autoantibodies (ICA) pertinent to IDDM?
IA2 & IRA
What two types of beta islet cell antigens show high specificity in diagnosis of Type I DM?
- IA2 & IAR. IA2 (aka ICA512) a protein tyrosine phosphatase. Helps to regulate cell metabolism and signal transduction across the cell membrane. IAR (islet antigen related) - also on beta islet cells. Relatively homologous to IA2.
What are Glutamic Acid Decarboxylase 65 & 67? Where are they found? And what is there role in Type I DM?
Enzyme isoforms found in islet cells. GADs catalyze conversion of L-glutamine to gamma amino butyrate (GABA), an inhibitory neurotransmitter. Within the 590 amino acids of GAD there are a number of amino acid sequences that also occur in at least 17 different viruses, especially protein PC2 of CVB4. These heterologous regions permit antibodies made to viral antigens to cross react with the human sequences and damage or destroy the cells carrying GAD 65 and 67.
What is the single most sensitive marker for identifying persons at risk for developing diabetes?
Anti-GADs. Can appear as many as 10yrs prior to disease onset.
What percentage of IDDM patients present with the following autoantibodies: IA2, GAD 65 & 67?
IA2: 50-75% of Type I diabetics at & prior to disease onset. GAD 65 &67: 70-90% of prediabetics & Type I diabetics. NOTE: 7-10% of Type 2 diabetics (>35yo) have anti-GADs.
What are the clinical symptoms of Type 1 DM?
Hyperglycemia. Abrupt onset of symptoms often following viral infection & proneness to ketosis. These pts require insulin treatment to prevent ketosis & sustain life. History of rapid weight loss accompanied by polyphagia, polydipsia, polyuria and neurological symptoms including confusion, disorientation and loss of consciousness.
What are some laboratory findings common to both Type 1 & 2 diabetes?
hyperglycemia, polyuria, increased serum osmolality, increased urine osmolality and specific gravity.
Differential findings that distinguish Type I from Type 2 include?
ketonemia, ketonuria, acidosis (acidemia and aciduria) and electrolyte imbalance including an increased anion gap.
What complications will IDDM patients develop over time?
renal, cardiac, retinal, neurological and microvascular complications.