Type II Diabetes

Type I Diabetes

Your body doesn’t make enough insulin because your immune system destroys the cells that produce it

Type II

Your body makes insulin, but your cells don’t respond to it or your body doesn’t make enough to lower glucose levels

What causes Type II

1. Insulin resistance -> insulin-responsive tissues (like skeletal muscle, adipose tissue, liver) show reduced biological responses to normal or elevated insulin concentrations

2. Inadequeate beta-cell compensation -> pancreatic beta cells can’t sustain the extra insulin output that resistance demands, so hyperglycemia (high blood sugar) persists

Insulin responsive tissues

• Skeletal muscle

  • Largest site of glucose disposal

• Adipose tissues

  • Glucose uptake, lipid storage

• Liver

  • Glucose production

beta cells release insulin (after a meal):

• Glucose uptake by skeletal muscle and adipose tissue

• Glycogen synthesis in muscle and liver

• Glycolysis and energy storage

• Suppression of hepatic gluconeogenesis and glycogen breakdown

Net blood glucose falls

Which cells release insulin

alpha cells release glycogen (during fasting)

• Glycogen breakdown in liver

• Gluconeogeneis

• Release of glucose into the circulation

• Inhibition of hepatic glycogen synthesis and glycolysis

maintains glucose

Which cells release glucagon

Downstream insulin secretion

1. Insulin binds its receptor on the PM

2. Receptor activation: The insulin receptor undergoes autophosphorylation on tyrosine residues, activating its kinase activity.

3. IRS phosphorylation: The activated receptor phosphorylates insulin receptor substrate (IRS) proteins.

4. PI3K activation: IRS recruits and activates PI3K, which converts PIP2 into PIP3.

5. Akt activation: PIP3 helps recruit and activate Akt (protein kinase B).

6. GLUT4 translocation: Akt promotes the movement of GLUT4-containing vesicles to the cell membrane, allowing glucose to enter cells.

7. Glucose storage: Insulin signaling also promotes glycogen synthesis and inhibits glucose production by the liver.

receptor tyrosine kinases (RTKs)

What type of receptor is an insulin receptor

PI3K-AKT pathway

What is the primary downstream intracellular signaling pathway for insulin receptors

GLUT 4 is found in primarily in skeletal muscle and adipose tissue

GLUT 2 is used by the liver for glucose uptake and release

*** skeletal muscle is the largest site of glucose uptake

Where is the primary site of insulin signaling?

Glucagon receptors are Gs-coupled GPCRs

Which type of receptor is glucagon receptor?

Primary downstream effector: Adenylyl cyclase (which produces the second messenger cAMP).

activates adenylyl cyclase, raising cAMP and activating PKA. The primary site of glucagon signaling is the liver, where PKA stimulates glycogen breakdown and gluconeogenesis to raise blood glucose.

What is the primary downstream effector upon glucagon release?

Insulin vs. Glucagon

	Insulin	Glucagon
Receptor	RTK	GPCR
Main pathway	PI3K-Akt	Gs-cAMP-PKA
Primary target	Muscle, fat, liver	Liver
Blood glucose	Decreases	Increases
Main effect	Glucose uptake/storage	Glucose production/release

Exam memory trick:

• Insulin = Store glucose.

• Glucagon = Release glucose.

The primary site of glucagon signaling is the liver (hepatocytes).

Glucagon is released by pancreatic alpha cells when blood glucose is low. Glucagon binds a Gs-coupled GPCR on hepatocytes, raising cAMP and activating PKA, which stimulates glycogen breakdown and gluconeogenesis to raise blood glucose.

Where is the primary site of glucagon signaling?

Class experiment results

It aims to selectively inhibit mitochondrial complex I -> reduces ATP production, increases AMP -> increased aMP inhibits adenylyl cyclase, therefore, decreases cAMP production and decreases glucose production.

Also,

Increased AMP also activates AMPK (AMP- activated protein kinase), which decreases gluconeogenesis and improves insulin sensitivity

What is the target of type II diabetic medicine Metformin

Gαs- coupled GPCR expressed on pancreatic β cells

Similar to Glucagon receptor, GLP-1 receptor stimulates G proteins, Adenylyl cyclase, cAMP, and PKA.

While the glucagon receptor increases glucose production in hepatocytes, GLP-1 in β cells increases glucose-dependent insulin secretion

Benefit -> it increases insulin secretion when blood glucose levels are elevated

Which type of receptor is GLP-1 receptor?

Glucagon binds to its receptor on liver cells and activates glycogen phosphorylase.

During fasting, glucagon is released from alpha cells. How does it help maintaining blood glucose level?

Translocation of GLUT4-containing vesicles to the plasma membrane

In skeletal muscle and adipose tissue, insulin promotes glucose uptake primarily through which mechanism?