Diabetes and Insulin

Question 0

Type 1 diabetes

Answer 0

Previously known as insulin-dependent diabetes mellitus or juvenile-onset diabetes. Accounts for about 5% of cases of diabetes mellitus. T-cell mediated destruction of pancreatic beta cells (autoimmune typically thought to be due to exposure to a viral antigen). Rapid onset, usually in childhood. Little or no insulin to secrete due to loss of beta cells. Treatment: insulin replacement.

Question 1

What are the different types of diabetes mellitus?

Answer 1

Type 1, type 2, and gestational diabetes.

Question 2

Type 2 diabetes

Answer 2

Previously known as non insulin dependent diabetes or adult onset diabetes. About 90% of diabetes mellitus. Often seen in older and more overweight individuals, family history plays a role as well. Combination of insulin resistance in target tissues and decreased insulin secretion. Insulin resistance is thought to be due to increased abdominal fat secreting cytokines and hormones. Heterogeneous polygenic condition. Gradual progression. Treatment: diet( decrease carb intake), variety of oral drugs, exercise, sometimes insulin.

Question 3

Gestational diabetes

Answer 3

Diabetes during pregnancy

Question 4

How does diabetes cause increased glucose in the urine?

Answer 4

Too much glucose in the blood leads to increase of glucose in the urine because glucose transporters that uptake glucose in the nephron
of the kidney get saturated and can’t handle the large amounts. This acts as an osmotic diuretic and water follows the glucose as it
is expelled in the urine, so you get an increase in urine volume. Polyurea and polydypsia (too much urine and excessive thrist,
respectively.)

Question 5

What are some short term side effects of too little insulin?

Answer 5

Hyperglycemia, glucose in urine, increased urine volume (hyperosmolarity causes diuresis), dehydration, ketoacidosis (metabolized troglycerides cause formation of acetone and other ketones that are biproducts of fat metabolism; cause decrease in pH), coma may result from lowered blood pH and dehydration.

Question 6

Long term effects of too little insulin

Answer 6

Long term effects on the circulatory system, especially small vessels in eye, nervous system, kidneys. Retinopathy: one of the causes of blindness in the developed world. Neuropathy: numbness or lack of motor control in the peripherals (hands and feet). Kidney disease: can also effect blood vessels in the kidneys.

Question 7

What are some effects of too much insulin?

Answer 7

Hypoglycemia. Too little glucose to the brain (can result in death). High insulin can occur from: over treatment with insulin, or PHHI (persistent hyperinsulinemic hypoglycemia of infancy)- rare, due to mutations in the ATP-dependent potassium channels. In this disease they don’t get trafficked properly to the membrane leading to constant membrane depolarization and too much insulin release. Treatment: glucose or glucagon to normalize blood glucose.

Question 8

What is retinopathy?

Answer 8

Damage to small blood vessels of the eye. Leads to blindness.

Question 9

What is neuropathy

Answer 9

Damage to peripheral nerves due to glucose-induced damage to small blood vessels.

Question 10

What are 2 ways of measuring blood glucose?

Answer 10

Two ways of measuring blood glucose: 1 is the measure of immediate levels of blood glucose which tells you what the levels are currently at, and 2 is to look at the average blood glucose over a period of time
. The latter is what is used by physicians to see if a patient is starting to acquire diabetes or whether they already have diabetes. Red blood cells have a turnover of about 120 days.

Question 11

How can average blood glucose be measured?

Answer 11

Measure levels of HbA1c, glycosylated hemoglobin. Glucose molecules react with hemoglobin, forming glycosylated hemoglobin, which remain that way throughout the 120 day lifespan of a red blood cell. Level of glycosylated hemoglobin reflects the average level of glucose to which red blood cell has been exposed to, gives an average blood glucose level over the last 3 months. Normal level is about 4-5.9%. With diabetes you want to aim for between 6-7%. Low HbA1 means fewer complications.

Question 12

What did the DCCT study reveal?

Answer 12

With intensive blood glucose level monitoring, much better maintenance of blood glucose levels was achieved. In terms of reducing the negative complications associated with diabetes, there was a lower incidence of neuropathy (60% less) and retinopathy (76% less), however there was an increase in the incidence of hypoglycemia (increased about 2-3 fold). Overall it was determined that intensive monitoring was the best option.

Question 13

What are some of the conventional treatments for diabetes?

Answer 13

Traditional: insulin injections. Short and long acting insulin, 1 to many injections per day.

Insulin pumps: control the insulin administration with a push of a button, typically right before meals.

Insulin is a peptide so it can’t be taken orally.

Question 14

What are the new directions for insulin treatment?

Answer 14

Implanted closed loop system (to monitor glucose an deliver insulin). Difficult because you want to allow for insulin release right before a meal which is hard to detect.

Inhalable insulin.

Beta cell replacement

Question 15

What is the etiology of type 2 diabetes?

Answer 15

Combination of genes and environment. Impaired insulin secretion (beta cells aren’t secreting enough) and insulin resistance (muscle and adipose tissue aren’t responding properly) both combine to give an impaired glucose tolerance which leads to type 2 diabetes.

Question 16

What’s the first line of treatment for type II diabetes?

Answer 16

Diet and exercise. More vegetables, whole grains, leaner meat.

Question 17

What is the pathogenesis of type II diabetes like?

Answer 17

Impaired insulin secretion leads to hepatic insulin resistance. Leading to excessive glucose production so more glucose enters the blood. High plasma glucose (hyperglycemia) cause excretion of glucose in the urine and impairs glucose clearance in the muscle and fat cells (also insulin resistant now) so less glucose can enter the peripheral tissues.

Question 18

What are the oral drugs for type 2 diabetes?

Answer 18

Insulin sensitizers: biguanides, thiazolidinediones. Drugs that make the body make better use of insulin that is produced and help promote gene transcriptional events that insulin would normally promote.

Insulin secretagogues: sulfonylureas, megliginides, GLP-1 agonist, DPP-4 inhibitor. Increase insulin secretion from beta cells in the pancrease.

Inhibitors of carbohydrate absorption: alpha-glucosidase inhibitors. Decrease carbohydrate absorption.

Question 19

Biguanides (Metformin)

Answer 19

Most widely prescribed insulin sensitizers and first line of drug therapy for type II diabetes. MOA: antihyperglycemic: corrects elevated glucose output by liver by decreasing hepatic gluconeogenesis. Decreases absorption of glucose in the intestinal tract. Increases sensitivity to insulin, and increases utilization of glucose by peripheral tissues. Exact mech unknown. Discovered from goats rue in the Middle Ages. May act as an antagonist to glucagon signaling by inhibiting adenyly cyclase, this reducing glucagon-mediated glucose output from the liver. May activate 5AMP-activated protein kinase (AMPK) in liver and muscle, which plays a role in the metabolism of fats and glucose.

Question 20

Thiazolidinediones (pioglitazone)

Answer 20

Agonist for type 2 nuclear receptor. Agonist for PPAR gamma: Peroxisome proliferator-activated receptor gamma. Nuclear hormone receptor superfamily. PPAR gamma heterodimerizes with RXR, bins to hormone response elements, regulates transcription of genes. The normal ligand for this receptor is free fatty acids and eicosanoids (prostaglandins, leukotrienes). So it’s normal activity is involved in the regulation of free fatty acids. Modulates transcription of insulin-sensitive genes involved in glucose and lipid metabolism (increases their transcription). Increases insulin sensitivity in liver and muscle, has a slow onset of action (1-2 months for max effect).

Question 21

What are some side effects of thiazolidinediones

Answer 21

Usually used in combo with sulfonylurea, metformin, or insulin, but can be used alone. Pioglitazone (actos): increased risk of bone fractures. Rosiglitazone (avandia): increased risk of bone fractures; increased risk of congestive heart failure and heart attack. Restricted access. Troglitazone: withdrawn due to hepatic side effects. Other side effects include fluid retention leading to risk of cardiac heart failure. Transcriptional regulators effect so many tissues that there are bound to be undesired effects .

Question 22

Secretagogue

Answer 22

Induced insulin release from pancreatic beta cells. Sulfonylureas or meglitinides bind directly to the ATP-dependent potassium channels and inactivate them, causing depolarization leading to insulin release from beta cells. ATP not needed.

Question 23

ATP-sensitive potassium channel

Answer 23

Channel activity is regulated by ATP/ADP ratio. ADP or ATP binds to nucleotide binding folds of sulfonylurea receptor subunits and promotes channel opening. ATP binds to an inhibitory site on Kir6.2 subunits and promotes channel closing. Sulfonylurea drugs bind to the sulfonylurea subunit and cause channel closing. 4 pore forming subunits and 4 accessory forming subunits for the channel.

Question 24

Tolbutamide

Answer 24

Older sulfonylurea drug for type 2 diabetes that causes weight gain, hypoglycemia, and can contribute to the depletion of insulin in beta cells.

Question 25

What does the membrane depolarization in beta cells look like?

Answer 25

Action potential bursts. Potassium channels are important in maintaining resting potential and sodium channels are important in maintaining the action potential peaks. The long duration is due to calcium channels because they don’t inactivate very fast. Calcium influx is what leads to insulin release.

Question 26

Incretin pathway

Answer 26

Beta cells can sense levels of glucose in the blood, but Incretin hormones released by the gut can sense when food is first being taken in. GLP-1 is a peptide and potent antihyperglycemic hormone from the GI tract: increases te release of insulin and decreases the release of glucagon, decreases nutrient absorption by slowing gastric emptying and contributed to satiety. Activates GLP-1 receptor in beta cells, acting through Gs and cAMP and PKA to promote insulin release. When plasma glucose is in the normal fasting range, GLP-1 no longer stimulates insulin release so it’s not likely to cause hyperglycemia. GLP-1 is rapidly degraded (<2min) inactivated by dipeptidyl peptidase-4 (DPP-4).

Question 27

How can GLP-1 be used therapeutically if it’s so short lasting?

Answer 27

Long lasting GLP-1 agonists (s.c.) or DPP-4 inhibitors (oral) are used for type 2 diabetes. Can also use GLP-1 analogs to make it last longer. Derived from saliva of hela monsters, these are peptides so they need to be injected subcutaneously.

Question 28

Alpha-glucosidase inhibitors (acarbose, miglitol)

Answer 28

Inhibit and delay carbohydrate absorption in the small intestine. These are saccharides that are competitive inhibitors of enzymes needed to digest carbohydrates. Decrease the rate of carb digestion so smaller rise in glucose after a meal. Can be used for both type 1 and type 2 diabetes. May cause Gi side effects, flatulence, indigestion.