Endocrine: Insulin and Glucagon, Diabetes

What happens to insulin levels after eating a meal?

• insulin is secreted by pancreatic beta cells due to a rise in blood glucose concentration

What occurs in the liver after eating a meal?

• insulin is secreted

• this accelerates the uptake of blood glucose into the liver by GLUT2.

• The catalytic sites of glucokinase (a hexokinase) become filled with glucose

• The increase in glucose 6-phosphate (glucose) coupled with insulin action (activates glycogen synthase) leads to a build-up of glycogen stores

What effect does insulin have on the liver?

• insulin decreases hepatic gluconeogenesis

What role does the liver play in blood glucose concentration?

The liver helps to limit the amount of glucose in the blood during times of plenty by storing it as glycogen in times of scarcity.

What occurs in muscle and fat after eating a meal?

• insulin is secreted by pancreas and binds to insulin receptors on muscle and adipose cells

• the resulting ‘signal transduction’ leads to the recruitment of GLUT4 from intracellular vesicles to the cell surface

• GLUT4 proteins are integrated into the cell membrane allowing glucose to be transported into the cell

What effects does insulin have on fat and muscle cells?

• insulin increases glucose uptake into fat and muscle

• insulin stimulates glycogen synthesis

• insulin stimulates storage of triglyceride in adipose tissue

• insulin increases protein synthesis

What are the effects of feeding on the liver?

1. after feeding glycogen synthesis in the liver increases, gluconeogenesis decreases and protein synthesis increases

What are the effects of feeding on fat?

1. after feeding lipogenesis (metabolic formation of fat) increases and lipolysis decreases

What are the effects on muscle after feeding?

1. after feeding glycogen synthesis increases, gluconeogenesis decreases, protein synthesis increases, a switch to carbohydrate oxidation occurs

What are the effects of feeding in the blood?

• after feeding glucose becomes too high, ketones and amino acids and fatty acid concentrations decrease.

What happens when blood sugars are low in the body?

1. Reduced uptake of glucose via GLUT1

2. Reduced ATP production in alpha cell mitochondria

3. ATP-sensitive potassium channels close, the efflux of potassium (K+) is reduced.

4. Causes depolarisation of the cell membrane which, in turn opens voltage-dependent Ca2+ channels allowing influx of Ca2+.

5. Intracellular Ca2+ levels increase, causing exocytosis of glucagon granules from the alpha cells

What is glucagon and what does it do?

• glucagon is a hormone released from the alpha cells of the pancreas

• glucagon inhibits fatty acid synthesis by diminishing the production of pyruvate.

• glucagon stimulates gluconeogenesis in the liver and blocks glycolysis.

• it mobilises glucose, fatty acids and amino acids from stores into the blood.

What organ is the main target of glucagon?

• The main target of glucagon is the liver.

What is the effect of fasting on the liver?

1. On the liver; glycogen synthesis decreases, gluconeogenesis increases and protein synthesis decreases.

What is the effect of fasting on fat?

1. On fat; lipogenesis decreases and lipolysis increases

What is the effect of fasting on muscle?

1. On muscle; glycogen synthesis decreases, gluconeogenesis increases, protein synthesis decreases, switch to lipid oxidation.

What is the effect of fasting on the blood?

1. glucose concentration decreases, ketone concentration and fatty acids increases and amino acids decrease.

What is the effect of fasting on the brain?

• gets ATP from ketone bodies instead of glucose

What is diabetes?

• a medical condition whereby a person has chronically raised blood glucose concentrations

• due to either deficiency of the hormone insulin and/or resistance to its action

What are 6 types of diabetes and their causes?

• type I (autoimmune)

• type II (obesity-related)

• type 3c (diabetes secondary to pancreatic disease)

• LADA (late onset autoimmune diabetes)

• MODY (maturity onset diabetes of the young - rare inherited form of type II)

• secondary diabetes (e.g. Cushing’s syndrome)

Why does Diabetes Type I occur?

• islets of Langerhans in the pancreas are completely or nearly all destroyed in diabetes type I

• absolute insulin deficiency

What medical complications can occur if diabetes type I is left untreated?

• absolute insulin deficiency; leads to uncontrolled gluconeogenesis, failure of glucose uptake into muscle and fat, use of alternative fuels (fatty acid) and the development of hyperglycaemia, ketoacidosis, eventual coma and death if untreated.

What would a blood sample of a person with untreated type I diabetes look like and why?

In the blood; glucose, ketones and fatty acid concentrations would be higher than normal.

1. In the liver; glycogen synthesis decreases, protein synthesis decreases and gluconeogenesis increases. = glucose released

2. In fat; lipogenesis fall and lipolysis increases. = fatty acids released

3. In muscle; glycogen synthesis decreases, gluconeogenesis increases, protein synthesis decreases. Switch to lipid oxidation (fat burning). = ketones released as by product

How many genes are involved with Type I diabetes?

• at least 18

What is ‘HLA’ diabetes?

"HLA diabetes" refers to the genetic predisposition to Type 1 Diabetes (T1D), which is strongly linked to genes in the human leukocyte antigen (HLA) complex on chromosome 6.

What is hypoglycaemia and what are its symptoms?

• excess of insulin -usually occurs in treatment of diabetes

• can occur with rare insulin secreting pancreatic tumour

• blood glucose falls (less than 2 mmol/L)

• sympathetic response (sweating, tachycardia, hunger)

• confusion and coma as brain starved of glucose

What causes diabetes Type II?

• type II diabetes is caused by Insulin resistance; peripheral tissues are not responsive to insulin; higher levels of insulin are required in order to keep blood glucose within the normal range.

• genetic component

• exacerbated by obesity and physical inactivity

What gene has been linked to higher risk of diabetes type II?

• FTO and related genes - this variant increases risk; associated with 3kg additional weight if two copies of variant are present (about 16% of UK population have thus)

Explain the mechanism by which insulin resistance develops:

• peripheral tissues are hit with frequent and high levels of insulin due to blood sugar spikes.

• insulin receptors on target cells become less responsive to insulin as they become ‘exhausted’ (downregulation)

• So higher levels of insulin are required in order to keep blood glucose within the normal range.

• the pancreatic beta-cells initially compensate for insulin resistance by increasing production (hyperinsulinemia), thereby maintaining normal blood glucose levels.

• however, in most patients with type 2 diabetes, the pancreatic beta-cell function progressively declines, leading to hyperglycaemia and clinical diabetes.

What age group, body weight and ethnicity are more at risk from diabetes type II?

• over 40

• overweight or obese

• south asian

What does complete absence of insulin result in?

• ketoacidosis

• brain oxidises fats in order to make ATP, ketones are produced as by-product.

• makes blood acidic

What is the treatment for diabetes?

• type I = lifelong insulin therapy (injections or pump), regular blood sugar monitoring, carbohydrate counting, a healthy diet, and exercise

• type II = Treatment for Type 2 Diabetes focuses on lifestyle changes (diet, exercise, weight loss) and medications like metformin, with other drugs (GLP-1 agonists, SGLT2 inhibitors), or insulin added as needed.