Type 1 DM Flashcards
What are the major markers for type 1 DM?
Staples: Anti-GAD, anti- IA-2, IAA, and, recently, AnT8A
best prediction if all 4 are present, but 95% of pts with DM1 have at least 1 antibody present.
What is the major mechanism of pathogenesis of type 1 DM?
CELL MEDIATED IMMUNITY (even though we look for autoantibodies)
What are some general characteristics of LADA? (frequency, body weight, insulin needs, likelihood of ketosis)
about 12% of pts with "type 2 DM" decreasing freq with age generally non-obese higher HbA1C for age greater insulin requirement at 6 yrs (94% vs. 14%) aka latent autoimmune diabetes not usually ketosis prone
What do we think about the pathogenesis of LADA>
a type 1 DM like process but with multiple hits and recoveries in an overall downward spiral
usually don’t knock out enough cells to be prone to ketosis
What are the genetic predispositions to type 1 DM?
HLA type: DR3 and DR4 (in the lecture he lists DQ2-DR3 and DQ8-DR4). HLA accounts for about 60% of the genetic risk
insulin gene may also be important
What are some viral associations with Type I DM?
Rubella- type 1 is associated with congenital rubella syndrome
coxsachie B
mumps
rotavirus
describe the progression of type 1 DM
starts with a genetic predisposition and normal insulin release
at some point, you develop autoantibodies (which AREN’T pathogenic) and the progressive loss of insulin release
At some point, the patient will have abnormal glucose and overt diabetes. At the start, the patient will still have C peptide, which is a cleavage product of insulin and a good marker for insulin release. If they come to medical attention at this point, they may be misdiagnosed, because it looks like they have hyperglycemia in the setting of insulin release. Later, however, C peptide will go away as insulin production falls further.
If you treat early, you may have a honeymoon phase where symptoms and biochemical abnormalities subside- but the disease is still there and will return within months to years
What does glucose do, physiologically?
glucose comes into the body. it can be put in fat cells, liver, and skeletal muscle. glucose also goes to the brain- but this is done independent of insulin levels.
if there is a glucose deficiency, skeletal muscle, fat and liver cells break things down. liver is also able to synthesize glucose, and is regulated by insulin and glucugon.
What are some events in the pathogenesis of DKA?
an absolute insulin deficiency causes increased lipolysis (without insulin, the body thinks it is glucose deficient)
this increases free fatty acids
excess FFAs in liver are metabolized to acteyl CoA
In pathogenic states, Acetyl CoA may be metabolized to ketone bodies: ketogenesis, which increases ketogenesis, which reduces the alkali reserve. it can cause ketoacidosis
this is exacerbated by increased release of glucugon (no insulin to prevent it from being released), though glucugon excess is not required for DKA. somatostatin, which blocks glucugon but will have no impact on insulin in a pt with type 1 DM, is helpful in these pts.
How does absolute insulin deficiency lead to hyperglycemia? what are some consequences of hyperglycemia in terms of symptoms?
without insulin, you see decreased glucose uptake/utilization, increased gluconeogenesis, and increased glycogenolysis
all of these cause hyperglycemia
hyperglycemia causes glycosuria, which is an osmotic diuretic. Water and electrolytes are lost in the urine and cause dehydration.
What are the ketones? what is the result?
ketones: acetoactetate (an acid). acetoacetate can be converted to beta-hydroxybutyric acid or acetone (acetone is neutral, not acidic)
acetone is not an acid but is often meausred
overproduction of glucose results in osmotic diuresis
What is the regulation for ketone production? Why don’t all FFAs in the liver cause ketosis and acidosis? (use specific enzyme names and their relationships with glucugon)
usually, FFAs in the liver are converted to triglycerides in the cytoplasm
For ketosis to occur, FFAs mus be made to Acetyl CoA.
FFA-CoA must be transported to the mitochondria.
entry of fatty acids longer than 12 carbons is regulated by carnitin palmitoyltransferase I (CPT-I).
CPT-1 is on the outer mitochondrial membrane and converts acyl-CoA to a transportable fatty acylcarnitine.
CPT2 takes the carnitine off so that the fatty acid can undergo ketogenesis
Malonyl CoA inhibits CPT1 and prevents ketosis.
glucagon decreases malonyl CoA production, thereby increasing CPT activity and increasing kenogenesis
What are the lab features of DKA?
high glucose, volume depletion, which exacerbates DKA, anion gap acidosis (because ketoacids are unmeasured anions)
high serum K but low total body K
low serum Na (because of osmotic diuresis from hyperglycemia)
What regulates fatty acid oxidation in the liver?
number of FFAs in the liver (high in insulin deficient states due to an inability to inhibit lipolysis) and ability of the liver to oxidize the fatty acids (due to excess glucugon, which reduces malonyl CoA and increases CPT1’s ability to transport fatty acids into mitochondrial for oxidation)
What are the biochemical steps in ketogenesis?
acetocaetyl-CoA to HMG CoA by HMG-CoA synthase
HMG CoA to acetoacetate by HMG CoA lyase
Acetoacetate to acetone (non-enzymatic decredation) or to D-beta hydroxybutyrate by D-beta hydroxybutyrate dehydrogenase
