Hypoglycemic Agents

Question 1

Describe the production of insulin from mRNA to final product and the relevance of the C peptide.

Answer 1

Insulin is produced as a prepro hormone. In the golgi apparatus the proinsulin is cleaved into insulin. The cleavage byproduct is C-peptide, which can be used to measure insulin production.

Question 2

Describe the different forms of insulin.

Answer 2

Insulin can occur as a monomer, dimer, or hexamer. The hexamer is complexed with two Zn atoms. The storage form is closer to hexamer, while the active form is a monomer.

Question 3

Describe how glucose, alpha-2, and beta-2 receptors effect insulin secretion.

Answer 3

Glucose enters pancreatic islet beta cells through the GLUT 2 transporter. It is phosphorylated to G6P by glucokinase, and used to create ATP. The production of ATP causes inactivation of the ATP-sensitive potassium channel, leading to activation of voltage-gated calcium channels and release of intracellular calcium. Secretory granules fuse with cellular membranes. Alpha-2 inhibits teh secretion of insulin, while beta-2 stimulates insulin secretion.

Question 4

Describe the phases of insulin secretion with constant glucose infusion with respect to individuals who are healthy, with DM1, and with DM2.

Answer 4

Healthy - Spike with initial infusion, and a lower spike with continued infusion

DM 1 - no spikes

DM 2 - no initial spike

Question 5

How does insulin induce transport of glucose into cells?

Answer 5

Insulin receptor activation causes PI3K-mediated fusion of vesicle containing membrane bound GLUT4 transporters with cellular membranes. Can also increase synthesis of GLUT1 and GLUT 4 transporters

Question 6

List the rapidly-acting insulin preparations and why they have this property

Answer 6

Lispro, aspart, glulisine

Two amino acids are switched to prevent aggregation of insulin monomers

Question 7

List the short-acting insulin preparations

Answer 7

regular insulin

Question 8

List the intermediate insulin preparation and how it acheives this

Answer 8

NPH is insulin complexed with a protamine and Zn.

Question 9

Describe the two ultra-long-acting insulin preparations and how they work.

Answer 9

Glargine - complexed with Zn and altered so it precipitates in neutral subcutaneous tissue

Detemir - complexed with a fatty acid side chain so it associates with albumin

Question 10

Describe the four different insulin regimens discussed in the DSA

Answer 10

1. Conventional - twice daily Regular/NPH mixtures
2. Intensive Therapy - RAI/NPH followed by regular insulin and NPH separately
3. Intensive Therapy - Regular bolus insulin before meals with BID or QID long-actining insulin
4. Continuous subcutaneous insulin infusion

Question 11

Describe split-mixed insulin regimens

Answer 11

Insulin is administered in preparations of R/NPH before breakfast and dinner or bedtime. Typically, the doses will be a larger portion of NPH than regular insulin

Question 12

What is the Dawn Phenomenon

Answer 12

Both normal and diabetic patients have an increased requirement for insulin in the morning due to hyperglycemia induced by evening cortisol.

Question 13

What are the possible adverse reactions of insulin therapy?

Answer 13

Hypoglycemia, lipoatrophy, and lipohypertrophy

Question 14

How should you correct DKA

Answer 14

Normal saline infusion along with insulin therapy

Question 15

Describe the treatment approach of DM2 with respect to 1st line, and alternate therapies.

Answer 15

Initial therapy - lifestyle modifications and metformin

Most individuals fail monotherapy and must utilize a combination therapy.

Question 16

Describe the effects of metformin on metabolism of glucose, weight, blood sugar, and cholesterol

Answer 16

Metformin reduces hepatic gluconeogenesis and increases peripheral uptake of glucose, while decreasing intestinal absorption. It does not cause weight gain or HYPOGLYCEMIA. Reduces LDL, cholesterol, and triglycerides.

Question 17

What are the ADRs and CIs of metformin?

Answer 17

ADR - metallic taste and anorexia

CI - renal and hepatic failure along with those predisposed to lactic acidosis (cardiac failure and hypoxic lung disease)

Question 18

Describe the multiple MOAs of sulfonylureas?

Answer 18

Sulfonylureas induce the release of insulin by blocking ATP-sensitive K+ channels. They also cause increased expression of insulin receptors and glucose transporters while inhibiting hepatic gluconeogenesis.

Insulin levels will eventually return to baseline, but blood glucose will be maintained.

Question 19

What are the second generation sulfonylureas?

Answer 19

Glimepiride, Glipizide, glyburide

Question 20

What are the uses of sulfonylureas?

Answer 20

Sulfonylureas are typically used in situation where patients fail to normalize blood glucose with metformin. They are used in combination therapy. Ideal patients are over 30 years old with some beta-cell function and a blood sugar below 300.

Note: Replacing one sulfonylurea for another is ineffective in achieving a response.

Question 21

What are the adverse effects of sulfonylureas?

Answer 21

Hypoglycemia (especially renal/hepatic function impaired), aplastic anemia, agranulocytosis, and cholestatic jaundice.

Question 22

What are non-sulfonylurea secretagogues? Give two examples.

Answer 22

Meglitinides. Repaglinide and Nateglinide.

Question 23

Describe the MOA and administration of Meglitinides.

Answer 23

These drugs bind the ATP-sensitive potassium channel receptor at a different site than sulfonylureas. They can be taken orally before meals, but must be skipped if the meal is skipped.

Question 24

What are the ADRs of CIs of meglitinides?

Answer 24

Comparable to sulfonylureas

Question 25

What are a1-glucosidase inhibitors? Describe their MOA, ADRs, and CIs?

Answer 25

MOA - These oligosaccharides bind and block brush border enzymes inhibiting post-prandial spike in glucose

ADR - GI disturbance leading to poor patient compliance

CIs - IBD, partial bowel obstruction, colonic ulcers, DKA, or cirrhosis

Question 26

What is a prototype thiazolidinedione?

Answer 26

Pioglitazone

Question 27

Describe the MOA of TZDs?

Answer 27

TZD’s bind transcription factors increasing the sensitivity of target tissues to insulin

Question 28

What are the ADRs of TZDs?

Answer 28

Weight gain, edema, mild anemia, and possible MI (long-term)

Question 29

What are the therapeutic uses of amylin analogs (pramlintide)?

Answer 29

Used in patients on large amounts of insulin who experience large glucose swings.

Question 30

What are the ADRs of pramlintide?

Answer 30

GI disturbances, hypoglycemia, dizziness, lethargy, and additional daily injections

Question 31

What are the MOAs of GLP-1 analogs (Exenatide)?

Answer 31

Increase glucose-dependent release of insulin
Prevent glucagon release
Suppress appetite

Question 32

What are the therapeutic uses of exenatide?

Answer 32

Use with metformin and/or sulfonylurea

Question 33

What are the ADRs of GLP-1 analogs?

Answer 33

GI disturbances and additional daily injections

Question 34

What are DPP-4 inhibitors?

Answer 34

These inhibit the breakdown of GIP and GLP-1.

Question 35

What are the ADRs of DPP-4 inhibitors?

Answer 35

Anaphylazis, Stevens-Johnson Syndrome, Hepatic Failure

Question 36

What is the MOA and ADR of SGLT-2 inhibitors?

Answer 36

MOA - Block the resorption of glucose in the kidneys

ADR - increased risk of genital mycotic infections and UTIs