Diabetes Mellitus

Question 1

In the endocrine pancreas, the islets of Langerhans, which type of endocrine cells produce insulin.

Answer 1

B cells

Question 2

Serum concentrations of hemoglobin A1C.

Answer 2

A glycosylated hemoglobin that serves as a marker of glycemia. (HbA1c)

Question 3

Type 1 diabetes mellitus

Answer 3

A form of chronic hyperglycemia caused by immunologic destruction of pancreatic B cells.

Question 4

Type 2 diabetes mellitus

Answer 4

A form of chronic hyperglycemia initially caused by resistance to insulin; often progresses to insulin deficiency.

Question 5

Proinsulin

Answer 5

An 86-amino acid single-chain polypeptide.

Question 6

Cleavage of proinsulin and cross-linking result in?

Answer 6

2-chain 51-peptide insulin molecule
&
31-amino-acid residual C-peptide.

Neither proinsulin
nor C-peptide appears to have any physiologic actions.

Question 7

Insulin receptor

Answer 7

• A transmembrane kinase.

- Phosphorylates itself and a variety of intracellular proteins when activated by the hormone.

Question 8

Action of Insulin in the Liver.

Answer 8

• Increases the storage of glucose as glycogen in the liver, this involves:
  1. The insertion of additional GLUT2 glucose transport molecules in the cell plasma membrane.
  2. Increased synthesis of the enzymes pyruvate kinase, phosphofructokinase, and glucokinase.
  3. Suppression of other enzymes.
• Insulin decreases protein catabolism.

Question 9

Action of Insulin on Skeletal muscle.

Answer 9

1. Insulin stimulates glycogen synthesis and protein synthesis.
2. Glucose transport into muscle cells is facilitated by insertion of GLUT4 transporters into cell plasma membranes.

Question 10

Action of Insulin on Adipose tissues.

Answer 10

• Facilitates triglyceride storage by:
  1. Activating plasma lipoprotein lipase.
  2. Increasing glucose transport into cells via GLUT4 transporters.
  3. Reducing intracellular lipolysis.

Question 11

How is human insulin manufactured?

Answer 11

By bacterial recombinant DNA technology.

Question 12

Rapid-Acting insulin preparations.

Answer 12

• Insulin Lispro.
• Insulin Aspart.
• Insulin Glulisine.

> Early peaks of activity.
Have small alterations in their primary amino acid.
Do not affect interaction with insulin receptor.
Subcutaneously injected immediately before meals.
Preferred in infusion devices.
Used in uncomplicated diabetic ketoacidosis.

Question 13

Short-Acting Insulin preparations.

Answer 13

-Regular Insulin.

> Intravenously only in emergencies.
Subcutaneously in maintenance regimens.
Requires administration 1hr or more before a meal.

Question 14

Intermediate-Acting Insulin preparations.

Answer 14

• Neutral Protamine Hagedorn Insulin or NPH Insulin.
• Protamine.
  >NPH Insulin is often combined with regular and rapid-acting insulin.

Question 15

Long-Acting Insulin preparations.

Answer 15

• Insulin Glargine.
• Insulin Detemir.

> Provide a peak-less basal insulin level lasting more than 20 hr.
Helps control basal glucose levels without producing hypoglycemia.

Question 16

Hazards of Insulin use

Answer 16

• Hypoglycemia: detrimental in advanced renal disease, elderly, and children under 7 yr.
• The most common form of insulin-induced immunologic complication is the formation of antibodies to insulin or noninsulin protein contaminants, which results in resistance to the action of the drug or allergic reactions.

Question 17

Established groups of oral antidiabetic drugs for Type 2:

Answer 17

1. Insulin Secretagogues.
2. Biguanide Metformin.
3. Thiazolidinediones.
4. Alpha-Glucosidase inhibitors.

Question 18

Mechanism and effects of Insulin Secretagogues.

Answer 18

• Stimulate the release of endogenous insulin > by promoting closure of potassium channels in pancreatic B-cell membrane > channel closure depolarizes the cell > triggers insulin release.
• Do not act in patients who lack functional pancreatic B cells.
• Chemical class = Sulfonylureas.
• 2nd generation sulfonylureas: Glyburide, Glipizide, Glimepiride; more potent.
• 1st generation sulfonylureas: Tolbutamide, Chlorpropamide.

Question 19

Repaglinide

Answer 19

• A meglitinide (Insulin Secretagogue)

- Rapid onset - Short duration

Question 20

Nateglinide

Answer 20

• A D-phenylalanine derivative (Insulin Secretagogue)

- Rapid onset - Short duration

Question 21

Toxicities of insulin secretagogues.

Answer 21

• Glyburide and glipizide; since highly potent, can cause hypoglycemia.
• Tolbutamide and chlorpropamide extensively bind to serum proteins, may enhance hypoglycemic effects.
• Weight gain.

Question 22

Biguanides

Answer 22

Metformin

Question 23

Biguanides; mechanism and effects

Answer 23

• Metformin (a primary member); reduces postprandial and fasting glucose levels.
• Biguanides inhibit hepatic and renal gluconeogenesis.
• Stimulate glucose uptake and glycolysis in peripheral tissues.
• Slowing of glucose absorption from GIT tract.
• Reduction of plasma glucagon levels.

Question 24

Molecular mechanism of Biguanide reduction in hepatic glucose production.

Answer 24

It appears to involve activation of an AMP-stimulated protein kinase.

Question 25

Insulin resistance and Biguanides.

Answer 25

Metformin reduces endogenous insulin production through enhanced insulin sensitivity.

Question 26

What drug can restore fertility in anovulatory women with polycystic ovary disease (PCOD) and evidence of insulin resistance?

Answer 26

Metformin

Question 27

Toxicities of Biguanides.

Answer 27

• No hypoglycemia.
• No weight gain.
• GIT distress; nausea, diarrhea.
• Lactic acidosis especially in renal or liver disease, alcoholism or conditions predisposing to tissue anoxia and lactic acid production (chronic cardiopulmonary dysfunction)

Question 28

Thiazolidinediones; Mechanism.

Answer 28

• Rosiglitazone & Pioglitazone.
• Increase target tissue sensitivity to insulin by activating the Peroxisome Proliferator-Activated Receptor-gamma nuclear Receptor (PPAR-V Receptor)
• PPAR-V Receptor, nuclear receptor, regulates transcription of genes encoding proteins involved in carbohydrate and lipid metabolism.

Question 29

Thiazolidinediones; Effects.

Answer 29

Effects:

• Increase glucose uptake in muscle and adipose tissue.
• Inhibit hepatic gluconeogenesis.
• Effect lipid metabolism and body fat distribution.
• Reduce fasting and postprandial hyperglycemia.

Question 30

Thiazolidinediones; Toxicities.

Answer 30

-Rare hypoglycemia.
-Can cause fluid retention,
which presents as mild anemia and edema and may increase the risk of heart failure.
-Rosiglitazone increases risk of myocardial infarction.
*The original thiazolidinedione (troglitazone) was removed from the market because of hepatotoxicity.
-Female patients taking thiazolidinediones appear to have an increased risk of
bone fractures.
-Pioglitazone and troglitazone induce cytochrome
P450 activity (especially the CYP3A4 isozyme) and can reduce the serum concentrations of drugs that are metabolized by these enzymes (eg, oral contraceptives, cyclosporine).

Question 31

Alpha-Glucosidase Inhibitors; Mechanism & Effects.

Answer 31

• Acarbose & Miglitol are carbohydrate analogs that act within the intestine to inhibit alpha-glucosidase.
• Alpha-glucosidase: an enzyme necessary for the conversion of complex starches, oligosaccharides, and disaccharides to the monosaccharides that can be transported out of the intestinal lumen and into the blood stream.
• Lack an effect on fasting blood sugar.

Question 32

Alpha-Glucosidase Inhibitors; Toxicities.

Answer 32

-Flatulence
-Diarrhea
-Abdominal pain
All resulting from increased fermentation of unabsorbed carbohydrate by bacteria in the colon.

Precaution: Patients taking an α-glucosidase inhibitor who experience hypoglycemia should be treated with oral glucose (dextrose) and not sucrose, because the absorption of sucrose will be delayed.

Question 33

Pramlintide

Answer 33

Injectable synthetic analog of amylin. Amylin contributes to glycemic control by activating high-affinity receptors involved in both glycemic control and osteogenesis.

• Suppresses glucagon release.
• Slows gastric emptying.
• Works in the CNS to reduce appetite.

SE:
-Hypoglycemia and GIT disturbances

Question 34

Exenatide

Answer 34

Glucagon Like Peptide-1 (GLP-1), a member of the incretin family of peptide hormones, which are released from endocrine cells in the epithelium of the bowel in response to food.
The GLP-1 receptor is a G protein coupled receptor (GPCR) that increases cAMP and also increases the free intracellular concentration of calcium.
-Retards gastric emptying.
-Exenatide, a long-acting injectable peptide analog of GLP-1, is used in combination with metformin or a sulfonylurea for treatment of type 2 diabetes.

SE:
-Fatal acute pancreatitis.

Question 35

Sitagliptin

Answer 35

-Sitagliptin is an oral inhibitor of dipeptidyl peptidase-4 (DPP-4), the
enzyme that degrades GLP-1 and other incretins.
-Like exenatide, sitagliptin promotes insulin release, inhibits glucagon secretion, and has an anorexic effect.

SE:
-The most common adverse effects associated with
sitagliptin are headache, nasopharyngitis, and upper respiratory tract infection.

Question 36

Canagliflozin

Answer 36

• The sodium-glucose transporter 2 (SGLT2) accounts for 90% of renal glucose reabsorption, and its inhibition causes glycosuria and lowers glucose levels in patients with type 2 diabetes.
• The SGLT2 inhibitors canagliflozin and dapagliflozin are approved for clinical use.

SE:

• The main adverse effects are increased incidence of genital infections and urinary tract infections.
• The osmotic diuresis can also cause intravascular volume contraction and hypotension.

Question 37

Because type 2 diabetes often involves both insulin resistance and inadequate insulin production, _____

Answer 37

it may be necessary to combine an agent that augments insulin’s action (metformin, a thiazolidinedione, or an α-glucosidase inhibitor) with one that augments the insulin supplies (insulin secretagogue or insulin).

Question 38

Glucagon; Chemistry, mechanism and effects.

Answer 38

• A protein hormone secreted by the A cells of the endocrine pancreas.
• Acting through G protein-coupled receptors in heart, smooth muscle, and liver.
• Glucagon increases heart rate and force of contraction, increases hepatic glycogenolysis and gluconeogenesis, and relaxes smooth muscle. The smooth muscle effect is particularly marked in the gut.

Question 39

Glucagon; Clinical uses.

Answer 39

-Glucagon is used to treat severe hypoglycemia in diabetics, but its hyperglycemic action requires intact
hepatic glycogen stores.
-Intramuscular or Intravenous.
*In the management of severe β-blocker overdose, glucagon may be the most effective method for stimulating the depressed heart because it increases cardiac cAMP without requiring access to β receptors