Type II Diabetes

Question 1

What is Type II diabetes?

Answer 1

Insulin resistance, hyperinsulinemia, and hyperglycemia, which can lead to beta-cell dysfunction

Question 2

How do sulfonylureas work?

Answer 2

Secretagogues that bind K-ATP channels, leading to insulin release

Question 3

Tolbutamide, chlorpropamide, and acetohexamide differ from glyburide, glipizide, and glimepiride in what way?

Answer 3

The former three are first generation secretagogues while the latter three are second generation (having a shorter half life, fewer side effects, and more potency)

Question 4

How do sulfonylureas stimulate glucose-induced insulin secretion?

Answer 4

Sulfonylureas bind the K-ATP channel, causing influx of K+, which leads to an influx of Ca2+, which stimulates exocytosis of insulin from its granules

Question 5

What adverse effects are seen with sulfonylureas?

Answer 5

Hypoglycemia (most likely glyburide, chlorpropamide, and glipizide, least likely tolbutamide)
Hyponatremia (chlorpropamide)
Weight gain
Potential cardiovascular complications

Question 6

What class of medication are repaglinide and nateglinide in?

Answer 6

Non-sulfonylurea secretagogues, meglitinide analogues

Question 7

Why do meglitinide analogues produce less cardiac side effects compared to sulfonylureas?

Answer 7

They are more selective for the beta-cell K-ATP channel than the cardiac K-ATP channel

Question 7

How do alpha-glucosidase inhibitors work?

Answer 7

Competitive inhibitor of intestinal alpha-glucosidase, decreasing absorption of monosaccharides and, therefore, postprandial glucose rise

Question 7

What class of medications do acarbose, miglitol, and voglibose belong to?

Answer 7

Alpha-glucosidase inhibitors

Question 8

What must be considered with alpha-glucosidase inhibitors?

Answer 8

Least effective oral antidiabetic drug
Needs to be taken with the first bite of food
Significant GI complications, specifically flatulence
Hypoglycemic episodes require glucose
Won’t cause hypoglycemia on their own

Question 9

What class of medications are rosiglitazone, pioglitazone, and troglitazone in?

Answer 9

Thiazolidinediones

Question 10

How do thiazolidinediones work?

Answer 10

Agonism of peroxisome-proliferator-activated receptor gamma (PPAR-gamma), which promotes uptake and storage of fatty acids into adipose tissue and, therefore, improving muscle insulin sensitivity. Can take 6-12 weeks to work.

Question 11

What adverse effects are associated with thiazolidinediones?

Answer 11

Fluid retention can aggravate pre-existing heart failure
Cardiovascular complications limit use of rosiglitazone and pioglitazone
Weight gain due to increased fat storage in adipocytes

Question 12

What class of medication is metformin in?

Answer 12

Biguanides

Question 13

How does metformin work?

Answer 13

The exact mechanism is unknown

Thought to decrease glucose production in the liver*, but could be related to AMPK (through inhibition of ACC and melanoyl CoA), inhibition of glucagon signaling in the liver, or promoting glucose uptake by skeletal muscle

Question 14

What are some clinical considerations of metformin?

Answer 14

Does not cause hypoglycemia
Weight neutral
GI symptoms (usually transient)
Lactic acidosis (phenformin)
Vitamin B12 deficiency (usually given Ca2+ supplements to mitigate this)

Question 15

Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and bexagliflozin are considered what class of medication?

Answer 15

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Question 16

How do SGLT2 inhibitors work?

Answer 16

SGLT2 is the primary mediator of glucose reabsorption in the kidneys. Decreasing its function decreases glucose reabsorption by 50-60% (due to compensation by SGLT1)

Question 17

Which SGLT2 inhibitor shows some SGLT1 inhibition?

Answer 17

Canagliflozin

Question 18

What are advantages of SGLT2 treatment?

Answer 18

Does not cause hypoglycemia
Can be used with other therapies
Effective at all stages of Type II diabetes
Beneficial effects on the cardiovascular system (empagliflozin)*

Question 19

What are disadvantages of SGLT2 treatment?

Answer 19

Increased genital and urinary tract infections due to increased glucose content*
May increase hepatic glucose production (deactivation of alpha-islet cells tricks the body into thinking there is hypoglycemia, responding by increasing glucagon)
May increase ketoacidosis (may be the cause of cardioprotective effects)*
Increased risk of amputation (canagliflozin)*

Question 20

What is the incretin effect?

Answer 20

Oral glucose stimulates a greater response by beta-cells than intravenous glucose

Question 21

What class of medications do exenatide, liraglutide, albiglutide, lixisenatide, dulaglutide, and semaglutide belong to?

Answer 21

GLP-1 receptor agonists (resistant to DDP-4)

Question 22

How must GLP-1 receptor agonists be administered?

Answer 22

Injection

Question 23

What are some advantages of GLP-1 agonist treatment?

Answer 23

Weight loss (liraglutide is approved for obesity, semaglutide is being used for weight loss) Less risk of hypoglycemia (no promotion of insulin when glucose levels are low or normal) Reduced cardiovascular risk (except lixisenatide and exenatide)

Question 24

What are disadvantages to GLP-1 agonist treatments?

Answer 24

Nausea Diarrhea Vomiting Increased heart rate* Pancreatitis* Hypoglycemia IF co-prescribed with sulfonylureas

Question 25

What class of medications contains sitagliptin, vildagliptin, saxagliptin, alogliptin, and linagliptin?

Answer 25

DPP-4 inhibitors

Question 26

What are some advantages to treatment with DDP-4 inhibitors?

Answer 26

Less risk of hypoglycemia Oral rather than injectable (unlike other incretin-based therapies like GLP-1 agonists)

Question 27

What are some disadvantages to DDP-4 treatments?

Answer 27

Nausea Diarrhea Vomiting Pancreatitis* Hypoglycemia IF co-prescribed with sulfonylureas Increased risk of hospitalization for heart failure (saxagliptin) No weight loss (unlike GLP-1 agonists) Don't improve CV outcomes DDP-4 degrades many peptides, many of which we are still learning about (potential for other effects?)