Insulin and Diabetes Therapeutics

Question 1

What are the short-acting insulins?

Answer 1

Lispro (Humalog), Aspart (Novolog), Glulisine (Apidra)

Question 2

What are the long-acting insulins?

Answer 2

Glargine (Lantus), Detemir (Levemir), Degludec (Tresiba)

Question 3

What GLUT transporter is Insulin-induced?

Answer 3

GLUT 4
Km= 5 mM
-expressed in skeletal muscles, adipocytes

Question 4

What GLUT transporter has the fastest Km?

Answer 4

GLUT 2
Km= 15-20 mM
-constitutive
-expressed in B-cells. liver

Question 5

What are the mechanisms of cell damage initiated by hyperglycemia?

Answer 5

-Polyol pathway
-Hexosamine pathway
-Protein Kinase C pathway
-AGE pathway

Question 6

How is NPH absorbed?

Answer 6

Neutral Protamine Hagedorn
-complexed with Protamine when injected; tissue proteases break it down to just free insulin
-slow absorption, long duration of action

Question 7

How is Lispro & Aspart absorbed?

Answer 7

-reversed position of Proline 28 and Lysine 29 (Aspart-switched to aspartate) on insulin B chain; prevents dimer and hexamer formation
-faster onset than regular insulin (5-15 minutes)

Question 8

How is Glulisine absorbed?

Answer 8

-Asn(Asparagine) 3 and Lys 29 in B chain are switched to Lys & Glutamate
-faster onset than regular insulin (5-15 minutes)

Question 9

How is Glargine absorbed?

Answer 9

Asn(Asparagine) 21 of a-chain is changed to Gly(Glycine)
2 Arg residues are added to end of B chain -changes pKa of the peptide and solubility
-slowly and steadily released from injection site over 24 hours (inject once daily)

Question 10

How is Detemir/Degludec absorbed?

Answer 10

Thr 30 of b-chain is deleted, and Lys 29(y-Glu/C16 FA in Degludec) is modified with insulation peptides to bind serum albumin extensively
-long acting 1 or 2 injections/day

Question 11

Which insulin preparation is not genetically modified?

Answer 11

NPH

Question 12

What are the sulfonylureas?

Answer 12

Tolbutamide, Chlorpropamide, Tolzamide
Glipizide, Glyburide, Glimepiride

Question 13

What are the Meglitinides “Glinides”?

Answer 13

Nateglinide (Starlix)

Question 14

What are the GLP-1 analogs?

Answer 14

Exenatide, Liraglutide (Victoza), Dulaglutide (Trulicity), Lixisenatide (Adlyxin), Semaglutide (Ozempic)

Question 15

What are the GIP receptor agonist and Biased GLP-1 receptor?

Answer 15

Tirzepatide (Mounjaro)

Question 16

What are the DPP-4 inhibitors?

Answer 16

Sitagliptin (Januvia), Saxagliptin (Onglyza), Linagliptin (Tradjenta), Alogliptin (Nesina)

Question 17

What are the a-glucosidase inhibitors?

Answer 17

Acarbose (Precose), Miglitol (Glyset)

Question 18

What are the SGLT2 inhibitors?

Answer 18

canagliflozin (Invokana), Dapagliflozin (Farxiga), Empagliflozin (Jardiance), Ertugliflozin (Steglatro), Bexagliflozin (Benzavvy)

Question 19

What are the Thiazolidinediones?

Answer 19

Rostiglitazone (Avandia), Pioglitazone (Actos)
-restricted prescribing due to cardiac toxicities
-contradindicated in heart failure later stages
-check liver function

Question 20

How does metformin reduce blood glucose levels?

Answer 20

Molecular Target: Complex 1 (ETC)
Cellular effect: Elevates [AMP], activates AMPK
Physiological effect: liver- reduced glucose export
skeletal muscle- increased glucose uptake

Question 21

How do TzDs reduce blood glucose levels?

Answer 21

Molecular target: PPARy
Cellular effect: regulation of transcription in adipose cells
Physiological effect: reduces adipokines that induce insulin resistance (resistin and TNFa)

Question 22

The toxicity of hyperglycemia results from:
A. the chemical reactivity of glucose
B. Shunting of excess glucose into the polyol and hexosamine pathways
C. Formation of AGEs and activation of receptors for AGEs
D. All of the above

Answer 22

All of the above

Question 23

How do you optimize glucose control in patients with T2DM + kidney disease (UACR >200mg/g)?

Answer 23

-SGLT2 Inhibitor w/evidence of CKD progression if eGFR > 20mL/min
-GLP-1 agonist with CV benefit if SGLT2I CI or not tolerated

Question 24

How do you manage patients with CVD/HF + T2D?

Answer 24

1st line: SGLT2 Inhibitors + GLP-1 agonists

Question 25

What are the preffered antihypertensive agents for patients with T2D?

Answer 25

ACEIs or ARBs
-use at max tolerated dose
-do not use in combo due to risk of AEs
2nd line: HCTZ, chlorthalidone, amlodipine, spironolactone

Question 26

What indicates use of antiplatelet agents in patients with diabetes?

Answer 26

-aspirin indicated as use for secondary prevention in patients with diabetes and history of past CVD (or clopidogrel 75mg/day)
-aspirin indicated as use for primary prevention in patients 50+ years old with 1 major risk factor + not at increased risk of bleeding

Question 27

What are the fasting blood glucose target and random blood glucose target?

Answer 27

Fasting: 80-130 mg/dL (ADA); <110mg/dL (AACE)
Random/postprandial: <180 mg/dL (ADA); <140mg/dL (AACE)

Question 28

What is the Egregious Eleven?

Answer 28

-factors that cause B cell damage and decrease insulin production
-B-Cell is final common denominator of B-Cell damage
Includes: Incretin effect, a-cell defect, adipose, muscle, liver, brain, colon/biome, immune dysregulation/inflammation, stomach/small intestine, kidney

Question 29

What is the diagnostic criteria for diabetes?

Answer 29

FBG: >126 mg/dL
AIC: greater than or equal to 6.5%
random glucose: 200mg/dL + symptoms
2hr postprandrial glucose: >200mg/dL during an OGTT

Question 30

What class of drugs enhance insulin secretion?

Answer 30

Sulfonylureas, Meglitinides “Glinides”

Question 31

What class of drugs enhance the incretin effect?

Answer 31

GLP-1R agonists, GLP-1 analogs, GIP receptor agonist, DPP-4 inhibitors

Question 32

What class of drugs reduce glucose absorption or increase glucose excretion?

Answer 32

a-glucosidase inhibitors, SGLT2 inhibitors

Question 33

What class of drugs reduce insulin resistance/lipotoxicity?

Answer 33

metformin (Biguanides), Thiazolidinediones (TzDs)