Glucose, kidneys, liver (wk 3/4)

What is Glucose

The primary source of energy for body cells, tissues, and the brain

We consume carbohydrates in our food

→ Carbs are broken down into glucose by enzymes

→ Glucose then diffuses into our cell following the concentration gradient

Is hydrophobic (repels water) -> cannot travel through membranes

• Use transport proteins

• SGLT transporters -> cotransport on ion of sodium and one molecule glucose

  • In intestine and kidneys

• GLUT (2 and 4) transporters -> allow glucose to diffuse through

  • in muscles (GLUT4)

  • fat tissue (GLUT4)

  • liver (GLUT2)

Diffusion will reduce changes in blood glucose levels (BGLs)

Brain burns the most glucose in body

Tolerance range for BGLs

Regulation Needed for BOTH Storage & Release

Glucose diffusion alone doesn't provide enough control for level BGLs

Want BGLs to stay at ~5 millimolar

Regulation after a meal (fed state)

Think: rIse = Insulin, risE = bEta

• Insulin is a Protein Encoded by the INS Gene

• Only released when BGLs are too high

Key Take Home Messages – Fed State

• Glucose is transported into cells by diffusion through glucose transporter proteins

• Negative feedback loops -> keep BGLs close to ~5 mM

• After a carbohydrate containing meal -> high BGLs -> stimulates insulin secretion into the blood from the beta cells of the pancreas

• In muscle and fat cells: insulin -> stimulates glucose uptake into the cells (through GLUT4 protein) -> glucose converted into glycogen in muscles and into fatty acids in fat cells

• In the liver: insulin -> lowers affinity glucose transporter GLUT2 at the cell surface & stimulates the storage of glucose as glycogen

  • Glucose uptake is facilitated by blood flow directly from the small intestine

    • Provides a very high glucose concentrations after a meal

Regulation in the fasted state -> before the meal

Main Glucose Source Human First 24 h

Key Take Home Messages – Fasted State

• Low BGLs -> stimulate glucagon secretion from the alpha cells of the pancreas

• In the liver

  • Glucagon -> stimulates glycogen breakdown (glycogenolysis) into glucose -> released into the blood ->maintain BGLs

  • Glucagon -> stimulates glucose synthesis (gluconeogenesis) from amino acids, glycerol and lactate -> released into the blood -> maintains BGLs

• In fat cells: glucagon -> stimulates triglyceride breakdown (lipolysis) -> releases fatty acids and glycerol into the blood for use by the liver and other organs

function of pancreas

Endocrine

• Alpha and beta islet cells secreting hormones

• Regulates BGLs

Exocrine (most function of the pancreas)

• To make enzymes for digestion

• E.g. protease, lipases

• Secrete them through their duct and it arrives in lumen of small intestines

Making Insulin and secreting

what is the Incretin Effect

• When we drink 100mL of glucose, insulin produced is higher than injecting 100mL of glucose directly into the blood (even though it spikes BGLs higher)

Due to another hormone called GLP-1

How GLP-1 works

Using GLP-1 in medicine

• We can synthesis GLP-1 and give it to people as a drug

• Ozempic contain chemically modified human GLP-1

• Used to treat diabetes by stimulating insulin secretion

Key Take Home Messages – Insulin Secretion

Insulin is produced in cells

• Regulated protein secretion starts with protein synthesis in the rough endoplasmic reticulum

• Proteins are trafficked through Golgi

• Pro-proteins (pre-matured insulin) is processed by proteases

• Insulin is packaged into vesicles ready for a stimulus to trigger their secretion

High BLGS = beta cells secrete insulin into the blood

• Via a multi-step mechanism

• Receptors -> signal transduction -> signalling cascade -> second messenger molecules (calcium) -> response

• Insulin secretion involves uptake in glucose via GLUT2 protein

• Glucose metabolised into ATP

• ATP-responsive potassium channels in the cell membrane cause membrane potential to change

• Membrane depolarisation opens of calcium channels

• Calcium levels increases in the cytoplasm

• Triggers secretion of insulin.

Glucose taken orally stimulates secretion of GLP-1 into the blood by the small intestine

• Co-stimulates the beta cells alongside glucose to maximise insulin secretion and subsequent glucose uptake in muscle and fat tissues

What is it type 1 diabetes

Is an autoimmune disease -> kills beta cells in the pancreas

• Due to production of antibodies against beta cell specific proteins (e.g. insulin)

• The immune system kills most or all of beta cells

○ Kill beta cells = lack or complete absence of insulin

• Patients cannot store glucose in muscle or fat tissue

○ Lead to high BGLs if not controlled

○ Leads to high glucose in urination since there is no other way to get rid of glucose

• Mostly first diagnosed in younger people

  • Environmental factors are strong contributors to getting this disease

  • With identical twins, only 20-30% both have type 1 diabetes

Symptoms of type 1 diabetes

• Frequent Urination: kidneys work overtime to excrete excess glucose.

• Excessive Thirst: Constant urination leads to dehydration

• Weight Loss: Without insulin, the body breaks down muscle and fat tissue, leading to weight loss

• Fatigue: Muscle cells are not receiving the glucose needed for energy, resulting in extreme lethargy

Progression of Type 1 Diabetes

Treatment for type 1 diabetes

Type II Diabetes symptoms

How it is developed: type 2 diabetes

Liver, muscle and adipose tissue becomes resistant to the effects of insulin

• Signalling inside cell when insulin binds to receptor is not as effective

• Cascade is not as great

• Insulin resistance

Pancreas loses the capacity to secrete enough insulin in response to glucose

• Beta cells have to increase amount of insulin they secrete to get the normal response of insulin

• Challenging to produce all this extra insulin

• Causes them to die -> could lead you to end up being like in type 1 diabetes

Type 1 vs Type 2 Diabetes