Lecture 7

Question 1

Where from and why is insulin secreted?

Answer 1

Insulin is secreted from the Beta cells in the islets of langerhans in response to high glucose levels

Question 2

What is a simple breakdown of the mechanism of glucose-induced insulin secretion?

Answer 2

• The transport and metabolism of glucose
• Changes in the cellular ion flux
• Initiation and calcium-dependant insulin release

Question 3

What is the full mechanism of glucose regulation by insulin?

Answer 3

• Glucose enters the cell via membrane-bound glucose transporter (GLUT2)
• It is phosphorylated to glucose 6 phosphate by glucokinase (GK)
• The Beta cell glucose sensor ‘senses’ when glucose exceeds the physiological range
• Glucose enters the glycolytic pathway and transformed into pyruvate which is metabolised in the mitochondria to ATP
• ATP triggers the closure of K+ channel which causes the depolarisation of the membrane from 70mv to 30mv
• This depolarisation opens the Ca2+ channels to open and Ca2+ to flood into the cell
• Exocytotic release of insulin happens from the ‘readily-releasable’ pool
• Some of the secretagogues used in this process are - leucine, ketoisocaproate and methyl succinate
• Some of the potentiators that are involved are - fatty acids, arginine, incretin hormones and suphonylureas

Question 4

Where is glucagon produced?

Answer 4

In the alpha cells of the pancreas

Question 5

What is glucagon and how does it work?

Answer 5

Glucagon is a hormone that acts as a counter-regulatory hormone to insulin in glucose homeostasis

It raises the concentration of glucose in the blood to prevent to brain from being starved of energy

Question 6

How is glucagon regulated?

Answer 6

Regulated via hormones, neurotransmitters and nutrients

Question 7

What is a quantitative measure of the ability of the pancreas to secrete insulin?

Answer 7

The beta cell function

Question 8

What is glucose homeostasis really measuring?

Answer 8

The beta cell function vs the insulin resistance

Question 9

What happens if you have a lipoprotein abnormality?

Answer 9

The amount of triacylglycerols goes up and the amount of HDL cholesterol goes down (type 2 diabetes)

Question 10

Why do we get fat when we have too much glucose?

Answer 10

Triacylglycerols are secreted by the liver in the form of VLDL (insulin resistance causes Triacylglycerols to increase)

Increased VLDL means there is a delay in the clearance of glucose which gets stored as adipose tissue

Question 11

What product that is released by adipocytes is also regulated by insulin?

Answer 11

Non-esterified fatty acids (NEFA)

• It is released from adipose tissue when blood glucose levels are low
• NEFA release is limited after meals by insulin
• In obesity adipose tissue decreases the effectiveness of insulin on NEFA leading to high fasting and post-prandial levels

Question 12

What is polyuria? And what is it a symptom of?

Answer 12

Often one of the first symptoms of diabetes it is having to urinate more than is usual

• Because of the hyperglycaemia the filtered load of glucose from the glomerulus exceeds the reabsorption capacity in the DCT and so glucose ends up being expelled in the urine

Question 13

What are some of the key things to know about type 1 diabetes?

Answer 13

• The body’s immune system destroys the pancreatic beta cells so no insulin is produced at all in the body
• Usually occurs in children and young adults
• Accounts for 5-10% of all diagnosed cases of diabetes
• Risk factors for this disease are autoimmune, genetic and environmental

Question 14

What are some of the key facts to know about type 2 diabetes?

Answer 14

• It accounts for 90-95% of diagnosed diabetes cases
• Usually starts with insulin resistance, cells don’t utilise insulin (so need increases) and the pancreas loses its ability to produce insulin
• Associated with older age, obesity, family history of diabetes, impaired glucose metabolism, physical inactivity and race/ethnicity

Question 15

What are some of the key facts about gestational diabetes?

Answer 15

• It requires treatment to normalise maternal blood glucose to avoid complications of the infant
• 5-10% of women who are diagnosed with gestational diabetes will go on to develop type 2 diabetes after pregnancy
• Most common in African Americans, Hispanic Americans and American Indians and women who are obese or with a family history of diabetes
• those who have gestational diabetes have a 20-50% chance of developing diabetes in the next 5-10 years

Question 16

What are some of the treatments for type 1 diabetes?

Answer 16

• insulin (first line therapy) however can be used n v advanced type 2 when the beta cells disappear
• can have an islet cell transplant

Question 17

What are some of the treatments for type 2 diabetes?

Answer 17

• Lifestyle modification (reduction in carb and lipid intake, taking regular exercise)
• Sulphonylureas (medications such as gliclazide and metformin) that stimulate the beta cells to produce insulin
• Medications called prandial glucose regulators that stimulate the beta cells to produce more insulin (short acting)
• GLP-1 (mediciations such as bydureon, ozempic and trulicity) also lower blood glucose through enhanced insulin release

Question 18

What are inherited metabolic diseases?

Answer 18

The are diseases in which someone is lacking a specific enzyme to convert one compound to another in the body

Question 19

What are some of the routine lab tests that are taken to start the investigation into metabolic disorders?

Answer 19

• Glucose test (hypoglycaemia is a presenting symptom in many disorders)
• Ammonia (hyperammonaemia can be signs of a defect in the urea cycle)
• Acid-base status test (metabolic acidosis found in many disorders, respiratory alkalosis can be caused by a defect in the urea cycle)
• Lactate test
• Liver function test [including clotting]
• Creatine kinase test (increased in long chain fatty acid oxidation defects and muscle glycogen storage diseases)

Question 20

What are some of the key facts about glucose testing?

Answer 20

• Blood test is much more reliable than other methods, urine glucose levels are rarely used these days
• Low or high blood glucose can contribute to fainting or unconsciousness
• Hypoglycaemia is a presenting feature of many disorders - Organic acidurias, fatty acid oxidation disorders and carbohydrate disorders

Question 21

What is an example of a glucose deregulation disease and what happens?

Answer 21

Pompe disease

• The GAA enzyme that breaks glycogen down to glucose is defective and so causes a glycogen build up leading to health problems

Question 22

What are some of the key facts to know about ammonia routine lab tests?

Answer 22

• Hyperammonaemia is a medical emergency and needs immediate medical intervention and treatment (levels >200umol/L)
• If high levels are found this can be indicative of organic acidurias and urea cycle defects

Question 23

What are some of the key facts about the routine lab test acid base status?

Answer 23

• Acidosis - pH too low
• Alkalosis - pH too high
• Can be respiratory with not enough or too much CO2 in the lungs (respiratory alkalosis is an early sign of urea cycle disorders)
• Metabolic acidosis is found in many disorders

Question 24

What are some of the key facts about routine lab testing for lactate?

Answer 24

• Usually lactate is only high if due to hypoxia, shock or seizure so if the lactate levels found are high without these happening it can be a sign of an inherited metabolic disorder

Question 25

What are some of the facts about the routine lab liver function tests?

Answer 25

• Liver dysfunction can be the result of many inherited metabolic disorders
• Galactosemia can show major signs of liver dysfunction

Question 26

What are some of the key facts about testing creatine kinase in a routine lab test?

Answer 26

• Local storage of ATP keeps levels steady
• If levels of CK are high this usually indicates there is muscle damage however can also be caused by long chain fatty acid oxidation disorders and muscle glycogen storage diseases

Question 27

What are some of the key facts about the routine lab testing of lipids?

Answer 27

• They test for cholesterol, non-HDL, HDL, triglycerides and LDL
• If the tests come back elevated this can be due to glycogen storage diseases

Question 28

What are some of the key facts about the routine lab testing of urate?

Answer 28

• Can be increased in glycogen storage diseases

- Can be decreased if there is a molybdenum cofactor deficiency

Question 29

What are some of the diseases that are screened during the NHS newborn blood spot screening programme?

Answer 29

• Sickle cell disease
• Cystic fibrosis
• Congenital hypothyroidism
• Phenylketonuria
• Medium chain acyl-CoA dehydrogenase deficiency
• Maple syrup urine disease
• Isovaleric acidaemia
• Glutaric aciduria type 1
• Homocystinuria

Question 30

What happens when a person has phenylketonuria and what can be done about it?

Answer 30

• The phenylalanine levels in the body become elevated due to a defect in an enzyme called phenylalanine hydroxylase which would usually convert it into tyrosine
• Levels of tyrosine become lowered
• This can cause seizures, intellectual disability etc
• This can be managed through a very strict and restrictive diet of. Low phenylalanine foods and there are 2 medication treatments that are now available