B5.002 - Diabetes Mellitus Physiology Flashcards
what is DM
group of metabolic disorders that share a common feature of hyperglycemia
describe T1DM
destruction of beta cells - absolute insulin insufficiency
autoimmune
idiopathic
usually occurs at young age
describe T2DM
resistance to insulin and relative insulin insufficiency
classically called adult onselt
genetic and lifestyle factors
rank which ethnicities have the highest to lowest risk of DM
hispanic F non hispanic black F hispanic M non hispanic black M non hispanic white F non hispanic white M
90% of pts with newly diagnosed diabetes re what
overweight or obese
what is the most important stimulator of insulin secretion
glucose
what yields the best plasma insulin response, IV or oral insulin
oral, indicating alimentary mechanisms in addition to the arterial blood sugar concentration regulate insulin secretion
what are the core defects in T2DM
beta cell dysfunction
insulin resistance
more than 80% of pts progressing to T2DM are what
insulin resistant
what tissue is the major player in insulin resistance
skeletal muscle
describe the 2 major methods of glucose transport into skeletal muscle
insulin receptor is stimulated
muscle contraction
describe hepatic insulin resistance
NAFLD, ectopic lipids decrease sensitivity to insulin
what defines steatosis
> 5% of liver comprised of fat
hyerglycermia is linked to what
oxidative stress and CVD
insulin secretion is inversely related to what
insulin sensitivity
how are plasma glucose levels regulated
by alterations in insulin secretion relative to the underlying level of insulin sensitivity
what are measures of insulin sensitivity
OGTT >200 = DM, >150 = IGT Mixed meal tolerance test continuous glucose monitors fasting lood glucose (100-125 elevated; >126 = DM) HOMA >3 insuline resistance hyerinsulinemic euglycemic clamp
fasting glucose levels
<100 normal
100-126 pre diabetic
>126 diabetic
OGTT levels
<140 normal
140-200 pre diabetic
>200 diabetic
what are IFG and IGT
IFG - impaired fasting glucose
IGT - impaired glucose tolerance
what is HbA1C
glucose chemically linked to Hb
excellent, good and bad HbA1C
4-6 excellent
7-8 good
9-14 action suggested
what are components leading to beta cell failure
chronic hyperglycemia glucotoxicity lipotoxicity oversecretion of insulin to compensate high circulating free fatty acids
what are incretins
GLP-1, GIP
as much as 50% post prandial insulin release dependent on incretins
describe how GLP-1 works
upon ingestion of food GLP-1 is secreted from L cell in the intestine this stimulates insulin secretion suppresses glucagon secretion slows gastric emptying reduces food intake increases B cell mass and maintains B cell function improves insulin sensitiviy enhances glucose disposal
describe GLP-1 levels in T2DM
they are lower either due to decreased production or increased production of DPP-4
cellular mediators of insulin secretion
gut peptides (GLP-1, GIP) glucose
biguanides MOA
activates AMP kinase
decreases hepatic glucose production
advantages of biguanides
extensive experience
no hypoglycemia
weight neutral
low cost
disadvantages of biguanides
GI
Lactic acidosis
B12 deficiency
SU/Meglitinides MOA
closes KATP channels
increases insulin secretion
advantages of SU/Meglitinides
extensive experience
decreased microvascular risk
low cost
disadvantages of SU/meglitinides
hypoglycemia
weight gain
low durability
TZDs MAO
PPAR gamma activator
increased insulin sensitivity
advantages of TZDs
no hypoglycemia
durability
decreased TGs
increased HDL
disadvantages of TZDs
weight gain
edema/CHF
bone fractures
high cost
a-GIs MOA
inhibits alpha glucosidase
slows carbohydrate absorption
advantages of a-GIs
no hypoglycemia
nonsystemic
decreased post prandial glucose
disadvantages of a-GIs
GI
dosing frequency
modest decrease in a1c
DPP-4 inhibitors MOA
inhibits DPP-4
increases GLP-1, GIP
advantages of DPP-4i
no hypoglycemia
well tolerated
disadvantages of DPP-4i
modest dec in a1c
urticaria
high cost
GLP-1 receptor agonist MOA
activates GLP-1 R
increases insulin decreaes glucagon
decreased gastric emptying
increased satiety
advantages of GLP-1 RA
weight loss
no hypoglycemia
disadvantages of GLP-1RA
GI
medullary ca
injectable
high cost
amylin mimetics MOA
activates amylin receptor
decreasesd glucagon
decreased gastric emptying
increased satiety
advantages of amylin mimetics
weight loss
decreased PPG
disadvantages of amylin mimetics
GI modest dec in a1c injectable hypo w insulin dosing frequency high cost
bile acid sequestrants MOA
bind bile acid
dec. hepatic glucose production
advantages of bile acid sequestrants
no hypoglycemia
nonsystemic
dec post prandial glucose
dec CVD events
disadvantages of bile acid sequestrants
GI
modest dec in a1c
dosing prequency
high cost
dopamine 2 agonist MOA
activates DA receptor
modulates hypothalamic control of metabolism
increased insulin sensitivity
advantages fo dopamine 2 agonists
no hypoglycemia
disadvantages of dopamine 2 agonists
modest dec in a1c dizziness/syncope nausea fatigue high cost
do treatments stay constant over time?
no all get worse
what is the downside to using HbA1C as the measure of interest for treatment
it doesnt capture short term changes in glycemic control and dose not distinguish pre and post prandial conditions
what is the primary cause of T2D
inactivity
what volume of activity is needed to offset T2D?
> 3500 steps/day
how does chronic exercise and weight loss affect DM
evidence of improved beta cell fxn
rank types of physical activity in order of best to worst at lowering a1c
aerobic
resistance
combined
