LECTURE 2

Control system in endocrinology: Glucose Control

Basic mechanism of blood glucose control:

Eat → Sugar Increases → Blood Glucose increase → Requires regulation

• So all tissues use glucose as their primary energy source of energy, but most of the tissues in the body can use other energy sources as well.

• However, the central nervous system can't substitute glucose. So delivery of glucose to the CNS is essential.

• CNS can use other fuels but in certain circumstances such as during embryonic development.

• We can also use glycogen to store glucose in the liver and muscle when blood glucose concentrations is in excess for future use.

• Happens through glycogen synthesis and the enzyme that's used in this process is glycogen synthase. So when glucose is in excess the

Lack of Blood Glucose:

Glucose produced via endogenous glucose production and mainly occurs in the liver but also happens in other tissues where glycogen is stored.

→ Mechanism 1: Glycogenolysis which involves glycogen phosphorylase and glycogen debranching enzyme.

• These enzymes break down storage of glycogen to release glucose back into blood.

Mechanism 2: Gluconeogenesis

• Occurs in the liver and it produces new molecules of glucose from its constituent parts.

Normal Concentrations of Blood Glucose: Normoglycemia

In the fasted State fasted state: 4 to 6 millimoles per liter of glucose in the blood.

after a meal

After a Meal: 8 or 9 millimoles per liter → Postprandial glucose concentration.

Hypoglycemia: Blood glucose concentration gets too low → below 3 millimoles per litre.

Hyperglycemia: Blood glucose over 10 millimoles

Diagnoses of Diabetes: Once you reach 11 millimoles per liter and that that is sustained.

• Glucose can be taken up and reabsorbed in the kidney.

• Excess glucose can be lost in urine → as little as 0.3 grams → An average of 160 grams taken in daily.

• Rest or glucose used up or stored as glycogen.

2 Hormones that Control Blood Glucose Concentration:

• Insulin and glucagon and these hormones act on three key tissue types: Liver + adipose tissue.

• Adipose tissue is important because it's able to break down to form the two ingredients.

• Adipose Tissue stores and releases glucose when needed.

Too much insulin produced: Rare disease called congenital hyperinsulinism.

Too much glucagon: Pushes someone to Hyperglycemia. - Can occur in diabetes, traditionally we think of diabetes as a lack of insulin but actually diabetes is also accounted for in part by an excess of glucagon, which pushes the normal glycemia towards hyperglycemia.

Fasted Situation:

• Reduction in insulin secretion because there's no glucose floating around at this point in the body.

• In the lower part of the normal range. So we've got a reduction in insulin secretion and we've

  also got an increase in glucagon secretion.

• The glucagon will act on the liver to increase endogenous glucose production.

• Could be through the breakdown of glycogen → through gluconeogenesis.

• This will increase the blood glucose levels so that the brain tissues will get their glucose requirement.

FED situation:

• Blood glucose concentration is going to increase 26-28 millimoles per liter.

• This will trigger the pancreatic beta Cells in the islets of Langerhans in the pancreas to produce insulin.

• At the same time it will reduce the secretion of glucagon because glucagon will cause endogenous glucose production.

• So glucagon will reach would be reduced so that insulin will then act on the insulin dependent

  or insulin sensitive cells.

• Muscle and adipose tissue and it will cause an increase of the uptake of glucose into those tissues thereby reducing the blood glucose concentration back towards normal glycemia.

Glucagon - like - peptide → (glp -1):

• Released from endocrine cells in the gut which responds to meals passing through the system.

• Key role in regulating blood glucose by stimulating insulin release + inhibiting glucagon release.

• Acts on beta cells + alpha cells.

GIP → Gastric inhibitory peptide:

• Released by endocrine cells in the small intestine.

• Regulates the release of insulin.

• Acts on alpha cells to inhibit glucagon.

In diabetes mellitus, there are two main types:

• Type 1: which is due to the immune system attacking the pancreas beta cells.

• Type 2, which results from issues with insulin release or sensing.

• Both types lead to a lack of insulin action, causing hyperglycemia.

• Additionally, glucagon secretion may also be imbalanced, contributing to the disease process.

• Conversely, an excess of insulin and lack of glucagon secretion can lead to severe hypoglycemia.

• We see this in the disease. I mentioned before congenital hyperinsulinism.

• Very rare disease that affects young babies.

• We also get this if a person who has diabetes and is using insulin injection to control their condition.

• If they have too much insulin, then it will also push them towards hypoglycemia and actually in particularly in type 1 diabetes mellitus, which is treated by injectable insulin. Hypoglycemia is a very very serious Problem and occurs, very frequently and can lead to something known as hypoglycemia.

• Unawareness where that patient isn't able to detect the symptoms of hypoglycemia, which are normally quite prominent and this can be really dangerous because it means they don't realize they've got hypoglycemia and very serious hypoglycemia can result in coma and death as well. So that's actually a very serious complication of overuse.

Islets of Langerhans:

• Clusters of cells in the pancreas that produce hormones like insulin and glucagon.

• These hormones help regulate blood sugar levels in the body.

• The pancreas is an important organ located in the abdomen, and it's divided into different parts like the head, body, and tail.

• Tumors in the pancreas can be challenging to remove, especially if they're in the head.

• The islets of Langerhans make up around 1% of the pancreatic mass, while the rest, about 99%, is the exocrine tissue with acinar cells and ducts.

• Within the islets, there are different cells like the pancreatic beta cells that produce insulin, the alpha cells that produce glucagon, and the Delta cells that produce somatostatin.

• These cells work together to regulate the release of insulin and glucagon.

• Additionally, there are Epsilon cells that secrete ghrelin and PP cells that secrete pancreatic polypeptide, although they are less common and not as involved in glucose regulation.

• The islets of Langerhans are well supplied with blood to quickly respond to changes in blood glucose levels.

  Structure and these vessels are responsible for moving glucose and amino acids and

The blood flow through the islets of Langerhans is crucial for the movement of glucose, amino acids, and hormones like adrenaline, GLP-1, and GIP:

• This blood supply allows the cells in the islets to respond to chemical messengers effectively.

• The flow of blood and fluid within the islets is vital for paracrine and autocrine signaling between different cell types, like beta cells secreting insulin and interacting with alpha and Delta cells.

• Additionally, the islets are well supplied with nerve fibers from the sympathetic, parasympathetic, and enteric nervous systems, which further regulate their function.

Autocrine response:

• Insulin can reduce its own secretion as well as from other beta cells.

• It's not just blood glucose levels that control these islets; there are other factors at play too.

• The structure of the islet allows these factors to influence hormone secretion.

• Human and mouse islets differ in structure, with human islets having fewer beta cells but more alpha cells, which may help humans avoid hypoglycemia better than rodents.

• Humans seem to have developed mechanisms to protect against hypoglycemia more effectively.

Insulin + Glucagon:

• Insulin helps make glycogen, which is a storage form of glucose, while glucagon breaks down glycogen to release more glucose.

• Insulin is produced by beta cells in the pancreas and is made up of a single polypeptide chain. The insulin molecule is connected by disulphide linkages, and enzymes in the pancreas help cleave insulin from c-peptide.

• This process happens in secretory granules in the pancreatic beta cells. The effects of insulin are well-known, but the role of c-peptide is still being studied.

• Insulin undergoes first-pass metabolism in the liver, which reduces its concentration in the blood, unlike c-peptide.

At the Insulin Receptor:

• When insulin binds to the insulin receptor, it triggers the activation of the intrinsic tyrosine kinase, leading to a cascade of signaling events in the cell involving PI3 kinase, PDK one, and AKT.

• This signaling pathway has various effects on the cell, such as promoting protein synthesis, cell survival, and cell proliferation.

• One crucial action of insulin in glucose metabolism is the translocation of glucose transporters, specifically GLUT4, to the cell surface membrane.

• This allows glucose to enter the cell when needed, aiding in glucose homeostasis.

• The process ensures that glucose is available for metabolism to produce ATP and can be stored as glycogen through glycogenolysis or glycogen synthesis.

• On the other hand, glucagon, produced by the alpha cells of the pancreatic islets, plays a role in regulating glucose levels through a different mechanism.

• It's synthesized from a preproglucagon gene and undergoes processing by proconvertase enzymes to become active.

• Glucagon is super important for what we call the counter regulatory response to hypoglycemia.

• Basically, it's what the body does to bring us back to a normal low blood sugar state.

• Glucagon plays a crucial role in this process. If we don't have enough glucagon, our response to hypoglycemia won't be effective, which can be seen in diseases like congenital hyperinsulinism in infancy.

• In that condition, glucagon binds to its receptors in the liver, leading to an increase in cyclic AMP and activation of protein kinase A.

• This results in boosting endogenous glucose production from the liver through glycogenolysis and gluconeogenesis. Glucagon also increases lipolysis, breaking down adipose tissue to produce glycerol and free fatty acids, which the liver uses to ramp up gluconeogenesis.

• This collaboration between adipose tissue and the liver helps increase glucose production in response to low blood sugar levels.