M2- lecture 12: Type 2 diabetes

Question 1

what is type 2 diabetes characterized by

Answer 1

• insulin resistance,

hyperinsulinemia and hyperglycemia (b/c of excess hepatic glucose production)

Question 2

what happens to beta cells as T2D progresses

Answer 2

beta cell dysfunction and destruction

Question 3

what are 5 ways to lower glucose in T2D

Answer 3

• increase insulin secretion
• increase insulin sensitivity
• decrease hepatic glucose production

insulin -independent methods:

• increase glucose excretion
• prevent dietary glucose absorption

Question 4

what is a secretagogues

Answer 4

a substance stimulating secretion

Question 5

what secretagogues are used in T2D?

Answer 5

• 1st gen and 2nd gen sulfonylureas and 3rd gen

- non sulfonylureas secretagogues

Question 6

what are three 1st gen sulonylureas

Answer 6

– Tolbutamide, Chlorpropamide, Acetohexamide

Question 7

what are three 2nd gen sulonylureas

Answer 7

• -Glyburide [or glibenclamide] (Diabeta®, generics)
• -Glipizide (Glucotrol®)
• -Glimepiride (Amaryl®) (some ref say this is 3rd gen)

Question 8

how do sulfonylurea secretagogues work in T2D?

Answer 8

• 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

Question 9

WHAT ARE AE of sulfonylurea secretagogues?

Answer 9

• hypoglycemia ( Glyburide, chlorpropamide, and glipizide)
• weight gain
• hyponatremina - low Na+(chlorpropamide)
• CV complications

Question 10

which gen of sulfonylurea secretagogues have lowest risk of drug-drug interactions?

Answer 10

2nd gen

Question 11

what are 2 non-sulfonylurea secretagogues?

Answer 11

• Repaglinide (GlucoNorm®)

* Nateglinide (Starlix®)

Question 12

what is the MOA of Non-sulfonylurea Secretagogues?

Answer 12

– 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

Question 13

what are non-sulfonylurea secretagogues?

Answer 13

– Derivatives of benzoic acid or phenylalanine

-meglitinide analogues

Question 14

what are 3 α-glucosidase inhibitors?

Answer 14

– Acarbose
– Miglitol
– Voglibose

Question 15

what is the MOA of α-glucosidase inhibitors?

Answer 15

– 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

Question 16

what are some clinical considerations of α-Glucosidase Inhibitors?

Answer 16

– 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

Question 17

which are the least potent diabetes drugs?

Answer 17

α-Glucosidase Inhibitors

Question 18

what are 3 Thiazolidinediones?

Answer 18

• –Rosiglitazone (Avandia®)
• – Pioglitazone (Actos®)
• – Troglitazone (Rezulin®

Question 19

what is the MOA of Thiazolidinediones?

Answer 19

–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

Question 20

what are AE of Thiazolidinediones?

Answer 20

Fluid retention (can aggravate pre-existing heart failure)

– Cardiovascular (… and now cancer) complications limiting use of rosiglitazone and pioglitazone

– Weight gain

Question 21

what are AE of α-Glucosidase Inhibitors?

Answer 21

– Significant GI complications (flatulence)

– Hypoglycemic episodes require FREE glucose

Question 22

what drug class does metformin belong to?

Answer 22

biguanides

Question 23

WHAT is the first line of therapy for T2D?

Answer 23

metformin

Question 24

what is the brand name for metformin

Answer 24

glucophage

Question 25

what is the MOA of metformin?

Answer 25

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

Question 26

how does metformin decrease hepatic lipid content?

Answer 26

1) metformin activates AMPK which inhibits ACC…increasing fat oxidation 2) inturn hepatic lipid content decreases

…LOOK AT SLIDE 20 +21 FOR VISUAL

Question 27

What are clinical considerations of metformin?

Answer 27

– 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