05: Alternative Energy and Metabolic Disease

Why is oxidative phosphorylation a constant process

• Glycolysis is inefficient

• Cells can only store a few minutes of energy

What happens if oxidative phosphorylation stops and pyruvate builds up

Converted to lactic acid → drop in pH → glycolysis stops

What ensures that glycolysis can keep going even if oxidative phosphorylation cannot

Lactic acid is transported out of the cell and dumped into tissues

What is the key for oxidative phosphorylation to happen

Adequate supply of oxygen

What endergonic process converts lactic acid back to glucose for muscle function

Cori cycle

After a period of anaerobic metabolism, how quickly does restoring oxygen work

Very quickly, and it allows lactic acid to rapidly be reconverted to pyruvate to be fed into the CAC

What happens to excess glucose if glycogen stores are maxed out

It is shunted off to be stored as fat by the pentose phosphate pathway

Where does the pentose phosphate pathway happen

In liver and fat cells

Gluconeogenesis

The synthesis of glucose form non-CHO precursors

Does the body prefer to get alternative energy from gluconeogenesis or glycogenolysis

Glycogenolysis

Which species is constantly doing gluconeogenesis

Ruminants (VFAs!)

Triggers for gluconeogenesis

• Low BG

• Stress hormones

How do stress hormones stimulate gluconeogenesis

Mobilizes proteins → deamination → used in liver for glucose synthesis

Diagnostics that test blood glucose

• HbA1c

• Fructosamine

• Blood glucometer

How does HbA1c evaluate BG

Longer term test taking a 3 month average of how much glucose an RBC sits in

How does fructosamine evaluate BG

Medium term test that tests for how much glycated albumin is in the blood

How does a glucometer evaluate BG

Spot check for how much glucose is in the blood

How does the body ensure adequate distribution of blood to the tissues

Perfusion/demand matching that will send blood to areas with low oxygen/high metabolism

What is the most common final electron acceptor of the ETC

O₂

How have some animals adapted to use glycolysis more than your average mammal

They have a more efficient glycolytic pathway

Most clinically relevant metabolic disease

Diabetes → dysregulated glucose control

Type 1 diabetes

Autoimmune damage to the beta cells of the pancreatic islets of Langerhans; irreversible

Type 2 diabetes

Peripheral tissues don’t respond to insulin; reversible

How do insulin concentrations change as type 2 diabetes progresses

There will initially be a lot of insulin in the blood because a high BG stimulates release from the pancreas. As the cells get overworked, they burn out and die, making end stage type 2 look like type 1

Major cells of the pancreatic islets of langerhans

• α

• β

• δ

• PP

• ε

What comes from the α cells

Glucagon

Glucagon action

Increases rate of glycogenolysis and gluconeogenesis in response to low BG

What comes from the β cells

Insulin and amylin

What comes from the δ cells

Somatostatin

Somatostatin action

Suppresses insulin and glucagon release

What comes from the PP cells

Pancreatic polypeptide

Pancreatic polypeptide action

CCK antagonist → inhibits digestion

What comes from the ε cells

Ghrelin

Which cell type is most common in the pancreatic islets of langerhans

β

In what form is insulin produced in the cell

Pre-pro-insulin

How is pre-pro-insulin converted to insulin

Cleaved to pre-insulin after synth in the ER → cleaved to insulin in the golgi apparatus

What is cleaved from pro-insulin to form insulin

C peptide

Function of C peptide

Get a grant to answer that question

Clinical relevance of C peptide

Can be measured in the blood to measure the production of endogenous insulin, even if the patient is on exogenous insulin

Insulin receptor type

Receptor tyrosine kinase

How do RTK receptors work

Autophosphorylation of the attached tyrosine kinases promote further phosphorylation and activation of downstream proteins

Molecular signaling pathway that causes insulin release

GL absorbed into blood → enters β cells via GLUT 2 → GL converted to G6P → oxidized to form ATP → closes K⁺ channel → depolarized membrane → Ca⁺⁺ VGC opens → Ca⁺⁺ causes insulin vesicles to be released

Why is insulin release not a constant rate after eating (why is the graph wonky)

There is a huge insulin dump right after a meal because of stored vesicles, causing a huge spike in insulin. Then the insulin drops as the cellular machinery kicks in to synthesize more insulin

How does insulin cause BG to drop

Signals for cells to translocate more GLUT to their membranes to increase GL uptake

How long does the GLUT stay at the membranes

As long as insulin is bound (insulin dependent)

Effects of insulin secondary to glucose uptake

• Increased membrane permeability

• Altered metabolic activity for hours-days

What glucose transporter is used by muscles

GLUT4

How does insulin affect glycogen metabolism

• Inactivates glycogen phosphorylase, promoting glycogen storage

• Activates glycogen synthase, promoting glycogen synthesis

How does insulin affect protein metabolism

Promotes protein synthesis and inhibits protein catabolism

How is insulin key for growth

It has a synergistic effect with growth hormone, and normal growth isn’t seen unless both hormones are released