Week 1: Pathogenesis of Diabetes Mellitus Flashcards
1
Q
Normal regulation of blood sugar
A
- Insulin lowers blood glucose via:
- suppression of hepatic glucose production
- stimulation of glucose utilization by tissues w/ GLUT4: skeletal muscle, adipose tissue, cardiac muscle - Insulin sensitivity varies among normal people
- white males have greatest sensitivity
- puberty, obese, 3rd trimester pregnancy have low insulin sensitivity - B cell function varies according to body’s insulin needs
- insulin resistant people have to make a lot more insulin
- if don’t make enough insulin than needed, will have diabetes
2
Q
Regulation of insulin secretion on cellular level
A
- glucose enters via high capacity GLUT2 transporter in beta cell. metabolized via high capacity glucokinase to ATP
- ATP shuts down outward rectifying K+ channel, which holds cell hyper polarized at -90mV. Shutting down the channel makes cell less negative and depolarizes at -60mV
- depolarization release insulin
3
Q
Insulin signaling and stimulation of glucose uptake: cellular level
A
- insulin binds to receptor on cell membrane, causes autophosphorylation of receptor
- phosphorylated insulin receptor acts as a kinase to stimulate phosphorylation of IRS1 and IRS2 (signaling molecules in cytoplasm)
- activated IRS1 and 2 stimulate production of PI-3-kinase, which through unknown ways, stimulates intracellular vesicles containing GLUT4 to move to cell surface
4
Q
Diagnosis of Diabetes mellitus
A
One of the following
- elevated blood glucose level with symptoms of hyperglycemia
- fasting serum or plasma glucose>126 mg/dl
- 2 hour glucose level>200mg/dl during 75 g oral glucose tolerance test
- HbA1C>6.5%
5
Q
Classification of Type 1 vs Type 2 DM
A
- Type 1: hyperglycemia due to severe or absolute insulin deficiency. Beta cell defect alone
- Type 2: hyperglycemia due to insulin resistance with relative insulin deficiency. Beta cell defect with insulin resistance.
6
Q
Clinical characteristics of Type 1 DM
A
- inherited susceptibility: HLA gene important, but not only genes involved
- acute onset of symptoms
- recent viral illness common
- immune markers present at onset: circulating evidence for antibodies directed against beta cell antigens
- “honeymoon” period
- most common in children/teens and people of european descent
- can develop DKA
7
Q
Pathogenesis of Type 1 diabetes
A
- first have genetic risk
- precipitating event: believed to be virus associated
- immune markers appear, beta cell mass starts to decrease
- insulin response reduced
- glucose is elevated
- then insulin becomes absent as beta cell mass decreases to nothing
8
Q
Rx for Type 1 DM
A
- Secondary therapy (insulin replacement: exogenous insulin. Pancreas transplant and islet transplant are temporary
- primary therapy: has not worked using immunosuppressive drugs
9
Q
Characteristics of type 2 DM
A
- some, often great, degree of resistance to their own insulin
- many causes of insulin resistance: obesity most common. lipid reduces insulin action on glucose uptake in muscle and glucose production in liver
- relative insulin deficiency compared to increased needs
- make some insulin, rarely develop DKA
- more than 90% of DM is Type 2. Most common in ppl of African, Native American, Asian origin.
- gradual onset: normal to impaired glucose tolerance to overt diabetes
10
Q
intracellular mechanisms for insulin resistance
A
- fatty acids and inflammatory cytokines such as TNF-a cause chronic phosphorylation via phosphokinase C of molecules in the insulin signaling cascade (IRS1 and 2) at the wrong place (serine and threonine)
- these block activating phosphorylations on tyrosine that normally mediate insulin signaling
11
Q
Pancreatic b-cell defect in DM Type 2
A
progressive beta cell defect may be caused by
- beta cell exhaustion early on
- rising glucose levels, toxic effects of chronic hyperglycemia
12
Q
Hepatic glucose overproduction in DM type 2
A
- fasting hyperglycemia due to increased production of glucose by the liver
- mainly results from gluconeogenesis than glycogen breakdown
- liver in overt diabetes is resistant to glucose and insulin
- mechanisms not completely known. May be due to increase FFA delivery to the liver
13
Q
Summary of causes of hyperglycemia in Type 2 DM
A
- insulin resistance
- pancreatic beta cell defect
- hepatic glucose overproduction
14
Q
visceral fat and insulin resistance
A
- visceral fat has more insulin resistance than subcutaneous adiposity. visceral fat may be better at releasing FFA
- people with the highest central abdominal fat had lowest insulin sensitivity
15
Q
Hormonal products of adipose tissue
A
- increase with obesity, block insulin action
- leptin, TNF-a, Il-6, Resistan - decreases with obesity, enhances insulin action
- adiponectin: found more in small skinny fat cells
