M2- lecture 12: Type 2 diabetes Flashcards
what is type 2 diabetes characterized by
- insulin resistance,
hyperinsulinemia and hyperglycemia (b/c of excess hepatic glucose production)
what happens to beta cells as T2D progresses
beta cell dysfunction and destruction
what are 5 ways to lower glucose in T2D
- increase insulin secretion
- increase insulin sensitivity
- decrease hepatic glucose production
insulin -independent methods:
- increase glucose excretion
- prevent dietary glucose absorption
what is a secretagogues
a substance stimulating secretion
what secretagogues are used in T2D?
- 1st gen and 2nd gen sulfonylureas and 3rd gen
- non sulfonylureas secretagogues
what are three 1st gen sulonylureas
– Tolbutamide, Chlorpropamide, Acetohexamide
what are three 2nd gen sulonylureas
- -Glyburide [or glibenclamide] (Diabeta®, generics)
- -Glipizide (Glucotrol®)
- -Glimepiride (Amaryl®) (some ref say this is 3rd gen)
how do sulfonylurea secretagogues work in T2D?
- Agents bind to and inhibit K-ATP channels…. PREVENTS K+ EFFLUX, INDUCES DEPOLARIZATION…ACTIVATES CA2+ CHANNELS AND CA2+ INFLUX —>LEADING TO EXOCYTOSIS OF INSULIN FROM INSULIN GRANULES
- May also reduce hepatic clearance of insulin
WHAT ARE AE of sulfonylurea secretagogues?
- hypoglycemia ( Glyburide, chlorpropamide, and glipizide)
- weight gain
- hyponatremina - low Na+(chlorpropamide)
- CV complications
which gen of sulfonylurea secretagogues have lowest risk of drug-drug interactions?
2nd gen
what are 2 non-sulfonylurea secretagogues?
- Repaglinide (GlucoNorm®)
* Nateglinide (Starlix®)
what is the MOA of Non-sulfonylurea Secretagogues?
– Bind to a different site of the K-ATP channel
– More selective for the beta cell K-ATP channel than the cardiac K-ATP channel
what are non-sulfonylurea secretagogues?
– Derivatives of benzoic acid or phenylalanine
-meglitinide analogues
what are 3 α-glucosidase inhibitors?
– Acarbose
– Miglitol
– Voglibose
what is the MOA of α-glucosidase inhibitors?
– Competitive inhibitor of intestinal α-glucosidase, an enzyme responsible for
breakdown of disaccharides (e.g. sucrose, maltose)
– bc of inhibition—>Delays and decreases absorption of monosaccharides
– Reduces postprandial glucose rise
what are some clinical considerations of α-Glucosidase Inhibitors?
– Least effective oral antidiabetic drug
– Take with meal (first bite of food)
– Does not cause hypoglycemia
– Significant GI complications (flatulence)
– Hypoglycemic episodes require FREE glucose
which are the least potent diabetes drugs?
α-Glucosidase Inhibitors
what are 3 Thiazolidinediones?
- –Rosiglitazone (Avandia®)
- – Pioglitazone (Actos®)
- – Troglitazone (Rezulin®
what is the MOA of Thiazolidinediones?
–INSULIN SENSITIZERS:
VIA PUTTING FAT WHERE IT SHOULD BE IN ADIPOSE TISSUE… WHICH INCREASES SENSITIVITY
– Agonists of peroxisome-proliferator-activated receptor gamma (PPAR!, nuclear receptor highly expressed in adipose tissue)
– Promote uptake & storage of fatty acids into adipose tissue (prevents excess fat from being stored in other
organs)
– Improves muscle insulin sensitivity
what are AE of Thiazolidinediones?
Fluid retention (can aggravate pre-existing heart failure)
– Cardiovascular (… and now cancer) complications limiting use of rosiglitazone and pioglitazone
– Weight gain
what are AE of α-Glucosidase Inhibitors?
– Significant GI complications (flatulence)
– Hypoglycemic episodes require FREE glucose
what drug class does metformin belong to?
biguanides
WHAT is the first line of therapy for T2D?
metformin
what is the brand name for metformin
glucophage
what is the MOA of metformin?
NOT KNOWN…BELIEFS ARE:
• Decreases glucose production in the liver (hepatic gluconeogenesis)
–related to AMPK,
– inhibits glucagon signaling prevents glucagon from activating hepatic gluconeogenesis
–promotes glucose uptake by skeletal muscle
how does metformin decrease hepatic lipid content?
1) metformin activates AMPK which inhibits ACC…increasing fat oxidation 2) inturn hepatic lipid content decreases
…LOOK AT SLIDE 20 +21 FOR VISUAL
What are clinical considerations of metformin?
– Does not cause hypoglycemia
– Weight neutral or no weight gain
– GI symptoms most common side effect
– Lactic acidosis (phenformin)… BUT NOT REALLY A CONCERN W/ METFORMIN.
– CAN INTERFERE W/ Vitamin B12 absorptioN
