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For what disease are the glucose-lowering drugs (aside from insulin)?

Type 2 diabetes.
(they don't work for T1D)


What 4 organs that are targeted by glucose-lowering drugs? What is the goal of drugs targeting these organs?

Liver - decrease gluconeogenesis
Pancreas - increase insulin secretion, decrease glucagon secretion/signaling
Skeletal muscle - increase glucose uptake (insulin sensitivity)
Gut - decrease carb absorption, increase incretins


What are 4 advantageous effects that you want in glucose lowering drugs?

Weight neutral or causes weight loss.
Does not cause hypoglycemia.
Infrequent administration.
Oral administration (instead of injection).


3 ways glucose-modifying drugs can cause weight gain?

Reversal of osmotic diuresis.
Reversing "relative starvation."
Causing water retention.


Biguanides: What's the most notable one? MoA?
Adverse effects?

MoA: activate AMPK, reduce gluconeogenesis in liver (also increases liver insulin sensitivity?)
Adverse effects: Anorexia/nausea/diarrhea, lactic acidosis. (slowly increase dose to avoid these effects)
Efficacy: Lowers A1c up to 2 percentage points.


What is an insulin secretogogue? What are 2 drug classes that do this?

Insulin secretogogues induce pancreas to secret insulin.


Sulfonylurea MoA?
Notable contraindications?
Adverse effects?

In beta cells, sulfonylurea closes ATP-dependent (i.e. ATP-inhibited) K+ channels -> depolarization (more positive membrane voltage) --> insulin release. Acts for 12-24 hrs.
Notable contraindications include DKA (because there's no insulin to promote the release of), renal impairment (it's metabolized renally).
Adverse effects: Hypoglycemia, hunger, weight gain (because there's more insulin).


Note that meglitinides and sulfonylureas have about the same MoA. What's the main difference between sulfonylurea and meglitinides?

Meglitinides are shorter-acting (3-4 hours). Taken before meals, but can cause post-prandial hypoglycemia.


Thiazolidinedione effect? MoA?

Effect: Sensitizes muscle, adipose, liver to glucose (more glucose uptake).
MoA: Binds PPAR-gamma nuclear receptor -> increased transcription of GLUT-4.


Good things about thiazolidinedione? Bad things?

Good: Doesn't cause hypoglycemia. Relatively effective (can lower A1c by about 1.8 percentage points).
Bad: Causes hypervolemia -> bad when pt has renal failure or heart disease. Also rough on liver.


What do alpha-glucosidase inhibitors do?
Adverse effects?

Delay absorption of carbs from gut, and increase GLP-1 response to feeding.
Flatulence, bloating. (probably like lactose intolerance: if you don't eat it, your GI flora will, and make gas)


Review: Where are GLP-1 and GIP made?

The gut. (specifically, mostly in the distal ileum)


3-4 effects of GLP-1?

Increases insulin, decreases glucagon.
Slows gut motility.
Induces satiety.


Why do GLP-1 / GIP have such short half-lives?

They're degraded by peptidases in the small intestine.


What do Gila monsters have to do with diabetes treatment?

Their (poisonous) saliva contains a GLP-1 analogue, exanetide, that has a longer half-life than GLP-1 and can be given subcutaneously.


Does exanetide work well?

Yep. You can see the incretin effect come back. It's pretty cool.


What's nice about the action of exanetide and liraglutide (GLP-1 analogues) that makes them safer?

Their action is glucose dependent, thus they won't cause hypoglycemia.
(also people lose weight... possibly due to effects on GI motility and satiety)


Other than giving a GLP-1 analogue, what's a way to increase incretins?

Inhibit their breakdown by inhibiting DPP-IV.


How to SGLT2 inhibitors work?
One drug in this class?
Adverse effects?

Block glucose resorption in the kidney - it gets peed out.
Adverse effect: Because there's more glucose in urine, way easier to get UTIs, vulvovaginal yeast/mycotic infections, and causes polyuria.


Can you use these drugs in combination?

Yep, pretty much all of them in various combinations except for meglitinides and sulfonylurias, as these have the same MoA.