Insulin, Glucagon, and DM

Question 1

Where is glucagon and insulin produced?

Answer 1

In the islet of Langerhans in the pancreas
Beta cells = insulin
Alpha cells = glucagon

Question 2

How is insulin synthesize and stored?

Answer 2

It’s synthesized as a preprohormone, cleaved to prohormone in ER, and packaged into vesicles by the Golgi apparatus as insulin and connecting C peptide

Question 3

Are insulin and glucagon protein bound in circulation?

Answer 3

No, therefore they have a relatively short half life (5-10min)

Question 4

Generally speaking, what stimulates insulin secretion?

Answer 4

an abundance of nutrients, as insulin promote nutrient uptake by the body

Question 5

What are some examples of rapid, intermediate, and delayed effects of insulin?

Answer 5

Rapid: glucose, amino acid, and K+ uptake
Intermediate: protein anabolism, inhibition of protein catabolism
Delayed: gene transcription

Question 6

Describe the insulin receptor

Answer 6

It’s a tetramer.
Has 2 alpha subunits that are extracellular and 2 beta subunits in the phospholipid bilayer. Insulin binds to the alpha subunits –> leads to tyrosine activation of the beta subunits –> autophosphorylation of the intracellular components –> further phosphorylation of activating enzymes

Question 7

What are the effects of insulin on carbohydrate metabolism in the muscles?

Answer 7

• promotes muscle glucose uptake by GLUT4
• GLUT4 otherwise stored in vesicle in the cytoplasm
• glucose into muscle –> glycolysis & oxidation –> stored as glycogen
• exercise can also translocate GLUT4 independent of insulin

Question 8

What are the effects of insulin on hepatic carbohydrate metabolism?

Answer 8

• increase glucose uptake via glucokinase induction
• increased phosphorylation of glucose to glucose-6-phosphate
• increased glycogen synthesis by activating glycogen synthase
• decrease hepatic output of glucose: 1. inhibits glycogenolysis by inhibition glycogen phosphorylase, 2. decrease exit of glucose by inhitibting glucose-6-phosphatase, and 3. inhibits gluconeogenesis by inhibiting amino acid uptake by the liver & by decreasing key enzymes in gluoneogenesis
• enhances synthesis of fatty acids: 1. increase glucose flow to pyruvate –> acetyl Co-A, and 2. converts acetyl Co-A to Malonyl-CoA, a rate limiting step in fatty acid synthesis

Question 9

What are the effects of insulin on carbohydrate metabolism in adipose tissue?

Answer 9

• facilitate glucose uptake
• metabolize glucose to alpha-glycerol phosphate
• provides glycerol for esterification to triglycerides for storage

Question 10

What are the effects of insulin on carbohydrate metabolism in the brain?

Answer 10

very little effect!

Question 11

What are the effects of insulin on fat metabolims?

Answer 11

• inhibits hormone sensitive lipase: decrease rate of lipolysis and release for fatty acids in the blood stream
• increase glucose transport into fatty tissue –> metabolize glucose to alpha-glycerol phosphate –> stored as triglyceride
• inhibits lipoprotein lipase: this enzyme is present in the capillary walls, therefore prevents splitting of triglycerides into fatty acids

Question 12

What are the effects of insulin on hepatic lipid metabolism?

Answer 12

• promotes synthesis and inhibits oxidation of fatty acids
• conversion of acetyl-CoA to malonyl-CoA inhibits carnitine acyltransferase, which is responsible for taking fatty acids from cytoplasm to the mitochondria for beta oxidation and conversion into ketones
• insulin in anti-ketogenic

Question 13

What’s the effect of insulin on protein?

Answer 13

• anabolic
• increases protein synthesis by increasing gene transcription and translation
• also inhibits protein catabolism

Question 14

How is insulin secretion controlled?

Answer 14

• major one = glucose feedback to beta cells

Question 15

Other than blood sugar level, what else can increase insulin secretion?

Answer 15

1. amino acids
2. GI hormones, esp gastric inhibitory polypeptide and glucagon-like polypeptide
3. other hormones, like growth hormone and cortisol –> they antagonize insulin
4. autonomic nervous system: sympathetic (alpha-adrenergic) inhibits insulin secretion; parasympathetic increases insulin secretion

Question 16

Where is glucagon produced?

Answer 16

In the alpha cells in the pancreas - islet of Langerhans

Question 17

What’s the main action of glucagon?

Answer 17

increase blood sugar concentration when it’s low in the bloodstream

Question 18

How is the action of glucagon achieved?

Answer 18

Upon binding to the hepatic glucagon receptors –> activation of adenylyl cyclase –> generation of 2nd messenger cAMP –> activates protein kinas A activation –> downstream effects

Question 19

How does glucagon increase blood sugar level?

Answer 19

1. promote glycogenolysis –> activation of glycogen phosphorylase, and simultaneous inhibition of glycogen synthase
2. inhibits glycolysis in the liver –> glucose-6-phosphate rises –> more released from the liver
3. promote gluconeogenesis. Increases amino acid uptake by the liver and increases activities of key gluconeogenic enzymes –> delayed and protracted actions to promote glucose output by the liver

Glucagon also inhibits acety-CoA carboxylase (so no Malonyl-CoA production), and also inhibits carnitine acyltransferase –> therefore, more beta oxidation of fat in the mitochondria –> ketogenic

4. promote fatty acid beta oxidation

Question 20

What’s the most important controller of glucagon secretion?

Answer 20

blood sugar level
- hypoglycemia will stimulate glucagon secretion

Question 21

What are some other factors that can increase glucagon secretion?

Answer 21

• amino acids: both glucagon and insulin secretion are increased after a protein meal, but less so for glucagon if there is also glucose ingestion. Simultaneous secretin minimizes the risk of hypoglycemia
• fasting
• exercise
  Secretion is stimulated by Beta adrenergic stimulation and inhibited by alpha adrenergic stimulation. It’s secreted when the sympathetic system is activated (opposite of insulin)

Question 22

What’s the role of somatostatin?

Answer 22

It inhibits both glucagon and insulin secretion
- decreases GI motility, secretion, and absorption
- delays assimilation of nutrients by GI, and utilization of absorbed nutrients

Question 23

What are the two types of diabetes?

Answer 23

Type 1 = insulin dependent
Type 2 = insulin independent

Question 24

What’s the cause of type I diabetes mellitus?

Answer 24

• impaired secretion of insulin
• autoimmune against the beta cells, or due to viral destruction

Question 25

What are the 3 major effects of insulin deficiency?

Answer 25

1. hyperglycemia
2. Depletion of proteins
3. depletion of fat stores and increased ketogenesis

Question 26

What are the results of the fundamental derangement caused by type I diabetes?

Answer 26

• glucosuria, diuresis, hypovolemia, hypotension
• hyperosmolality, dehydration, PD
• hyperphagia with weight loss, lethargy
• acidosis –> diabetic coma
• hypercholesterolemia

Question 27

What are the results of the fundamental derangement caused by type II diabetes?

Answer 27

• hyperglycemia
• accelerated lipolysis and ketogenesis don’t usually occur

Question 28

How does glucose stimulate insulin release?

Answer 28

Glucose from bloodstream goes through the GLUT2 transport of the beta cell –> becomes glucose-6-phophate via glucokinase (rate limiting step) –> turns into ATP –> closes Na/K ATPase –> depolarization of the cell –> opening of the Ca2+ channel –> influx of Ca2+ –> exocytosis of insulin