Rice- Non Insulin Hypoglycemics GLPs, DPP4s, SGLT2s

What are the 2 main incretin hormones?

GLP1, GIP

Incretin effect

Oral glucose produces greater insulin secretion than IV glucose

Is the incretin effect larger or smaller in normal VS. T2D patient?

the incretin effect is diminished in a T2D vs. normal patient

GLP-1 is a ____ AA peptide hormone

30

GLP-1 is secreted by endocrine ___ cells in the intestine

L

GLP-1 and Glucagon are related in the fact that they are made by the same ___ called ____

gene

proglucagon

If GLP-1 and glucagon are made by the same gene, how are they so different in effects?

This is due to processing the gene in different cells

glucagon is made from pancreatic ___ cells, where GLP-1 is made from endocrine ____ cells in the small intestine

alpha

L

GLP-1 incretin hormone:

Increase glucose-dependent insulin _____ , decrease ______, delays gastric _____, ______ satiety

increase glucose-dependent insulin secretion, decrease glucagon, delays gastric emptying, increase satiety

Incretin hormones overall stimulate the ___ phase of insulin release from the pancreas and inhibit ____ release

1st

glucago

GIP is considered an

incretin

T/F Incretins are released due to IV glucose that allow insulin response to meal size

False, Oral glucose

Where does GLP-1 bind to, to elicit a response?

GLP-1 Receptor on pancreatic beta cells

Where is the GLP-1 Receptor?

Pancreatic Beta cells

While not proven in humans yet, GLP-1 has been shown to preserve ____ cells, which may lead to preservation of these cells

Beta

When does GLP-1 coupling to GLP-1 Receptor work?

When glucose is present

Since GLP-1s only work when glucose is present, this avoids ______

hypoglycemia

The GLP-1/GLP-1R pathway and the Glucokinase pathway in the beta cell join together at ______ synthesis

proinsulin

The reason why we cant use enodengous GLP-1 for medication is that it has a t1/2 of ___ minutes

2

What enzyme proteolytically cleaves GLP-1, making the t1/2 so short?

DPP4 (dipeptidyl peptidase 4)

Exenatide brand names

Byetta, Bydureon

Exenatide is ___ AA long, and an analogue of ______.

39, extendin-4

Exenatide is an analogue of extendin-4, which was naturally extracted from the saliva of the ____

gila monster

Exenatide has been pulled from the market due to its short _____

t 1/2 (2-4hours)

Lixisenatide brand

Adylyxin

Like Exenatide, Lixisenatide is derived from the ____ peptide too

extendin

Lixisenatide is a ___ amino acid peptide

44

Lixisenatide Structural Modifications:

1. ___ --> ____ on Position 2 (blocks DPP4)

2. String of 6 Cterminal _____ residues

Ala to Gly, Lys

Compared to Exenatide, Lixisenatide is not a natural peptide anymore. This can cause issues with ....

immunogenicity

Liraglutide brand

Victoza

What was the 1st GLP-1 made with recombinant human DNA ?

Liraglutide (Victoza)

Liraglutide Structural Modifications:

1. ___--> ____ at Position 34

2. Attatchment of C16 ______ (palmatic acid) with a glutamic acid spacer at Lys 26

Arg to Lys

fatty acid

The attatchment of the fatty acid in Liraglutide prevents ____ from degrading and promotes binding to ____

DPP4

Albumin

Liraglutide is the first long acting GLP-1R agonsit with a dose of ___ daily

once

Liraglutide has a black box warning for this type of cancer

thyroid

Dulaglutide brand

Trulicity

1st ever approved GLP1 agonist

Exenatide

What GLP-1 RA is considered a recombinant fusion protein

Dulaglutide (Trulicity)

Dulaglutide structural modifications:

1. 2 identical, disulfide linked temrinal ____ sequences

2. ____ on an human immunoglobulin, ___

GLP-1

Fc, IgG

Dulaglutide has a once ____ administartion

weekly

Semaglutide brands

ozempic, wegovy

Semaglutide structural modifications:

1. ____ acid at P8

2. ____ at P4

3. _____ chain addded to Lys26

2-aminoisobutyric

Arginine

fatty diacid

When a fatty acid chain is added to a GLP-1 it can serve 2 purposes:

DPP4 blockage and albumin binding

Semaglutide is a once ____ injection

weekly

GLP-1 stands for

glucagon like peptide -1

GIP stands for

glucose dependent insulinotropic peptide

Tirzepatide brand names

Mounjaro, Zepbound

Tirzepatide is a _____ drug with ___ and ____ combined

Chimera

GLP-1, GIP

Tirzepatide is a once ____ injeciton

weekly

T/F Tirzepatide has the greatest weight loss compared to other GLP-1RAs

True because its a dual GIP/GLP1RA

T/F Compared to semaglutide, tirzepatide you take less dose, but can achieve higher weight loss

true

GLP-1 RA leads to weight ____

loss

Orforglipron (Foundayo) is unique in the sense that it is not a ____ but it is a ____ drug

peptide, small molecule

Orforglipron binds the _____ site of the GLP-1 Receptor whereas endogenous GLP-1 binds the orthosteric binding site

allosteric

Orforglipron is a once ____ medication with no food or water restrictions

daily

___% of weight loss is obsevered with Orforglipron

12-13

Dipeptidyl peptidases are proline-specific aminopeptidases, and they cleave ____ dipeptides at N terminus

X-proline

What Dipeptidyl peptidase specifically rempves N terminal 2 amino acids from GLP-1 in the gut muscosa to inactivate it?

DPP-4

What specific DPP inhibitor was designed for GLP-1 longevity?

DPP-4 Inhibitor

DPP inhibitors were designed for DPP4 specificity and not DPP_ or _ because of serious side effects

8, 9

suffix for DPP4 inhibitors

-gliptin

DPP4 inhibitors increase the amount of _____ GLP1 in circulation

endogenous

Are DDP4 inhibitors glucose dependent

YES

DPP4s are considered weight ____

neutral

Do DPP4s acts on the GLP1 Receptor?

Not at all

DPP4 outcomes:

1. decrease _____ release

2. increase _____ secretion

3. delay gastric ______

overall decrease blood glucose levels

glucagon

insulin

emptying

Which DPP4 inhibitor has the most DDIs?

Saxagliptin (Onglyza)

Sitagliptin brand

Januvia

Out of the 4 DPP4 inhibitors, 3 of them are non covalent binders. Which 1 is a covalent binder

Saxagliptin (Onglyza)

Out of the 4 DPP4 inhibitors, 3 of them are eliminated renally/urine . Which 1 is metablized via CYP3A4/5?

Saxagliptin (Onglyza)

Sitagliptin structure

Beta aminoamide

The Trifluorophenyl group in Sitaglitpin binds to the ___ pocket in DPP4, while Trifluoromethyl group binds to the ____ pocket

S1

S2

Saxagliptin is ___ times more potent than Sitagliptin

10

Saxagliptin binds to the ____ site of DPP4 (Ser610)

Active

Saxagliptin structure

aminoacylpyrrolidine with cyano substituent (CN)

Out of the 4 DPP4 inhibitors, 3 of them make inactive metabolites . Which 1 makes active metabolites

Saxagliptin (Onglyza)

Linagliptin brand

Trajendta

Linagliptin structure

xanthine analogue

Where does Linagliptin bind non covalently on DPP4?

S1 pocket

Alogliptin brand

Nesina

Alogliptin structure

pyrimidinedione analogue

One unique thing about Alogliptin is that it has ___% bioavailability

100

SGLT2i are considered weight ____

loss

SGLT2 receptor is responsible for __% of glucose reabsorption while SGLT1 is ___% in the nephron

90

10

SGLT2 resides only in the ___

nephron (proximal tubule)

SGLT1 resides in the ____ and the ____

nephron (distal tubule) and intestine

SGLT stands for

sodium dependent glucose transporter

SGLT reabsorb ____

glucose

In drug making, we specifically want to inhibit SGLT_ not SGLT_ because.....

2

1

can lead to diarrhea, dehydration, glucose galactose malaborption in the small intestine

SGLT inihbitors were first mase from a natural substance called ___ which is from _____

Phlorizin

bark of apple roots

Phlorizin is considered a O glycoside with 2 parts:

B-glucose and aglycone

The problem with Phlorizin is that is was a SGLT inhibitor but ______, with bad bioavailability, rapid hydrolysis and GI effects

NON selective 1 and 2

Canagliflozin (Invokana) structual modifications to Phlorizin:

1. ___ to resist hydrolysis and improve bioavailability

2. ___ selective for SGLT2, not 1

C-glycoside

aglycone

SGLT2i suffix

-flozin

With SGLT2i, you should take in the _____ with or w/o food

morning before a meal

Canagliflozin is metabolized via _____ with enzymes ____ and ____ to form ____ glucuronides

O-glucuronidation

UGT1A9, UGT2B4

inactive

Should you use SGLT2i in Type 1 treating ketoacidosis?

no

Should you use SGLT2i in severe renal impairment

no

Should you use SGLT2i with UGT enzyme inducers?

no

Can SGLT2i cause serious UTIs?

Yes