Pathogenesis of DM Flashcards
1
Q
Normal regulation of blood glc
A
- Insulin suppresses hepatic glc production and stimulates glc utilization by tissues that express GLUT4 (most important is skeletal muscle)
- Diabetes develops when you make less insulin than you need
2
Q
How insulin is released
A
- B cells in pancreas have high capacity GLC transporter and highly active glucokinase
- All glc that enters the cell is converted to ATP, which is essentially used as a marker for ECF glc levels
- As ATP builds up in B cells it inhibits a K channel, thus leading to depolarization of the cell
- Depending on the degree of depolarization, insulin release is induced (more depolarized, more insulin is released)
- GLP1 works by amplifying this pathway, but the pathway must still be intact for this to have an effect (e.g. GLP only helps T2 diabetics who have functioning B cells)
3
Q
Dx of diabetes
A
- Fasting glc >126
- 75 g glc load leads to plasma glc >200
- Random plasma glc >200 w/ Sx of hyperglycemia (thirst, polyuria, weight loss, blurred vision)
- HbA1c >6.5%
4
Q
T1 diabetes
A
- Due to autoimmune process that destroys beta cells
- Pts have complete absence of endogenous insulin and they will develop diabetic ketoacidosis unless treated w/ exogenous insulin
- Only treatment for T1 is insulin
- Associated w/ DR3/4 mutations
- Mostly seen first in childhood
- <10% of all diabetes
- Have no insulin or C peptide (cleaved off pro-insulin to make insulin)
5
Q
T2 diabetes
A
- Insulin resistance w/ relative insulin deficiency
- Many causes of insulin resistance, most common being obesity (due to increased lipid content in liver and SkM, which reduces insulin action at these sites)
- These pts have some beta cells and still make insulin, but its not enough to compensate for their needs
- The insulin they do make is enough to regulate lipolysis, thus they rarely develop ketoacidosis
- Have insulin and C peptide (cleaved off pro-insulin to make insulin) in low amounts
6
Q
Maturity onset diabetes of the young (MODY)
A
-Autosomal dominant form of diabetes that is non-immune related
7
Q
Gestational diabetes
A
- Pregnancy is a state of acquire insulin resistance
- Complications include over weight baby and mother has an increased risk of developing T2 diabetes after the pregnancy
8
Q
Clinical presentation of T1
A
- Acute onset of Sx, antecedent illness (viral syndrome) common
- There is a honeymoon phase early on, in which there is little or no insulin Rx required, due to some endogenous insulin present (B cell destruction incomplete but ongoing)
- Progression: markers of autoimmunity detected-> acute insulin sensitivity is lost (normal glc)-> overt diabetes
9
Q
Clinical presentation of T2
A
- Gradual onset, same temporal pattern (over 4-7 years_
- > 80% of pts are obese
- Insulin levels may be normal, but are low compared to the amount the pt would need to overcome their insulin resistance
- Insulin resistance is the inability of SkM and liver to use insulin to uptake glc (SkM/fat) and suppress glc production (liver)
10
Q
Pathogenesis of T2 1
A
- How obesity can lead to T2: adipose tissue (esp. w/ high amounts) releases FAs and cytokines that contribute to insulin resistance
- These factors phosphorylate IRS1/2 inappropriately
- Normally IRS1/2 are phosphorylated at a Tyr residue once insulin binds to its receptor
- This activates IRS to activate IP3, leading to GLUT4 placement in the membrane and increasing glc uptake
11
Q
Pathogenesis of T2 2
A
- When there are high levels of FAs and cytokines (esp TNFa), there is activation of phosphokinase C and subsequent phosphorylation of ser and thr residues on IRS
- The phosphorylation of these residues cause conformational changes to IRS resulting in concealed tyr residues and thus inactivation of IRS
- This results in an inability of insulin receptors to communicate the movement of GLUT4 to the cell membrane and thus insulin resistance
12
Q
Pancreatic B cell defect 1
A
- Many people have insulin resistance, but only 20-30% develop T2
- Thus a second defect (B cell defect) is present in those who develop T2
- These pts have a failure of B cell compensation, in that glc-stimulated insulin secretion is impaired
- People w/ insulin resistance and don’t have diabetes have B cells that compensate by increasing B cell mass and insulin secretion
- People who develop diabetes have a loss of B cell mass and decreased insulin secretion
13
Q
Pancreatic B cell defect 2
A
- In part due to glc toxicity (desensitizes B cells to elevated glc levels) and B cell exhaustion (B cells release all insulin and cannot release anymore until glc levels are brought down)
- Rx of insulin resistance allows B cells to rest, to make more insulin, and restores the balance of insulin-glc matching
- Insulin resistance is Rx by weight loss, exercise, insulin-sensitizing medications
14
Q
Hepatic glc overproduction
A
- Fasting hyperglycemia (hallmark of diabetes) is due to increased production of glc by the liver
- Mostly results from GNG rather than glycogenolysis
- Mechanism is not known, but thought to be from increased FA delivery to liver during fasting
15
Q
Glucose toxicity
A
- Elevated glc levels contribute to insulin secretory defect and insulin resistance by desensitizing the pancreas to high glc levels
- A positive feedback loop of high glc levels leading to blunted insulin response which feeds back to keeping the glc levels high
- When caught early on pills are usable to control blood glc, insulin release and insulin sensitivity
- But later the problem is so profound on insulin is usable as a Rx
