Diabetes & Insulin

Question 1

What are the four main types of cells in the islets of the pancreas?

Answer 1

alpha cells: glucagon

beta cells: insulin

delpta cells: somatostain

pp cells: pancreatic polypeptide

Question 2

Describe the events that lead to the release of insulin from beta cells

Answer 2

At substimulatory glucose concentrations beta cells have a resting membrane potential of -60mV which is maintained by a K⁺ channels.

Glucose is transported into the beta cell via GLUT2 where is is rapidly phosphorylated by glucokinase for glycolysis.

Metabolism of glucose produces ATP which closes the K⁺ATP channel. This causes the cell to depolarise and opens VDCC and Calcum ions enter the cell.

Influx of Calcium ions releases more calcium from intracellular stores and promotes the fusion of intracellular vesicles containing insulin with the cell membane.

Insulin is released by exocytosis.

Calcium then activates K⁺ channels which cause K⁺ efflux and repolarisation

Question 3

Function of pancreatic polypeptide

Answer 3

Release is stimulated by protein meals and cholinergic reflexes

Inhibits pancreatic exocrine secretion and affects the MMC and gastric secretion

Question 4

Function of somatostatin

Answer 4

Release is stimulated by nutrients.

Inhibits the secretion of glucagon and insulin.

Question 5

Action of sulphonylureas

Answer 5

Acts on the K+/ATP channel and closes it. This promotes depolarisation of the beta cell and the release of insulin.

However the effect wears off as the beta cell mass declines.

Question 6

Describe the insulin receptor

Answer 6

RTK

Dimer linked by S-S bonds

Question 7

Define diabetes

Answer 7

A metaboic disorder characterised by chronic hyperglycaemia resulting from the inability to produce insulin or insulin insensitivity.

Question 8

Common symptoms of diabetes

Answer 8

Polydipsia

Polyuria

Weight loss (fat and protein metabolised)

Lethargy/Fatigue

Also: blurred vision, prone to infections, nausea and vomiting

Question 9

First-line treatment in someone recently diagnosed with diabetes

Answer 9

Lifestyle changes:

Low calorie diet, low cholesterol and simple sugars

Exercise (increases expression of GLUT4 in muscle and fat)

Weight reduction

Question 10

What is insulin

Answer 10

An anabolic peptide hormone

Question 11

Name three modulators of insulin release and describe their mechanism of action

Answer 11

Glucose: ATP produced during glucose metabolism closes a K⁺-ATP channel depolarising the membrane and opening VDCC. Ca²⁺ enters the cell and promotes vesicle fusion.

CCK/ACh: bind to GPCR coupled to Gq on the beta cell which stimulates PLC to cleave PIP2 to IP3 and DAG. This results in the activation of PKC which causes protein phosphorylation. This promotes insulin release.

Glucagon: binds a GPCR coupled to Ga. This activates adenylate cyclase, increasing cAMP which activtes PKA. PKA phosphorylates proteins which cause insulin release.

Somatostatin: Binds a GPCR coupled to Gi. This inhibits adenylate cyclase, inhibiting insulin release.

Epinephrine: binds to adrenergic receptors to inhibit insulin release

Question 12

What factors regulate insulin secretion?

Answer 12

The major factor that stimulates insulin secretion and biosynthesis is when the islets are exposed to glucose.

Amino acids (arginine, lysine) are potent activators of insulin release. Triggered by ATP production during metabolism

Lipids enhance glucose-stimulated insulin secretion. However lond term exposre to lipids impairs this.

Gastrointestinal peptide hormones (CCK, GLP-1, VIP, Gastrin) facilitate the release of insulin following a meal by acting through second messengers.

Glucagon (+), Somatotatin (-) and Insulin (-) regulate secretion

Parasympathetic nerves (ACh) increases insulin secretion. Sympathtetic nerves (epinephrine, norepinephrine) reduce insulin secretion.

Question 13

Describe the process of insulin biosynthesis

Answer 13

The gene for insulin is synthesised as a large precursor peptide preproinsulin which is then converted to proinsulin.

Proinsulin consists of a signal chain, A chain, B chain and a connecting peptide. This connected segment is cleaved out during the conversion to insulin.

Proinsulin is folded by S-S bonds and transported the golgi apparatus which processes the proinsulin into insulin and stores it into a secretory granule. Cleavage results in the production of insulin and C-peptide which are both secreted from the granule.

Question 14

Describe the pattern of insulin secretion following a meal

Answer 14

Insulin secretion stimulated by glucose is dose dependent. Insulin spikes occur after meals which show that there is a rapid maximal release of insulin following a meal and then levels decline as the beta cells are repolarised and the released insulin inhibits further release.

Note: If glucose is infused at a constant rate (e.g. iv administration, snacking) then a biphasic response is seen where there is a rapid early insulin peak followed by a second more slowly rising peak.

Question 15

Describe how insulin increases the uptake of glucose from the blood

Answer 15

Insulin triggers an increase in the presence of GLUT4 receptors on the cell membrane.

GLUT4 receptors are mostly stored in intracellular vesicles. Activation of the insulin receptor triggers vesicle exocytosis and targets the GLUT4 recptors to lipid rafts on the cell surface.

Increases number of receptors helps facilitate the influx of glucose into the cell

Question 16

Name four things that affect glucagon secretion

Answer 16

The primary regulator of glucagon secretion is low blood glucose

Amino acids, ACh, Nor, and Eph also increase glucagon secretion

Fatty acids, Somatostatin and Insulin inhibit glucagon secretion.

Question 17

Name four common types of diabetes

Answer 17

Type 1 diabetes (autoimmune, insulin dependent)

Type 2 diabetes (non-insulin dependent)

Gestational diabetes

MODY

Question 18

What is the cause of type 1 diabetes?

Answer 18

Type 1 diabetes is caused by autoimmune destruction of the beta cells within the islets of the pancreas.

Destruction is progressive and therefore only presents when there is significant depletion of cells.

Treated with exogenous insulin

Question 19

How do insulin and glucagon detemine metabolic status?

Answer 19

Insulin and glucagon have opposing effects and therefore relative levels of each hormone in the blood determines the metabolic response.

In the fed state, insulin is released from beta cells and so there is a high insulin:glucagon ratio which promotes anabolic effects and inhibits metabolism.

Glucagon is secreted in response to nutrient supply, and levels remain relatively contant throughout the day. In the starved state the insulin:glucagon ratio is low which promotes catabolic activities to increase glucose levels.

Question 20

What is the normal fasting glucose concentration?

Answer 20

5.5 - 6.5 mmol/L

Over 7 is a sign of type 2 diabetes

less than 2.5 mmol/L is a sign of hypoglycaemia

Question 21

Describe an oral glucose tolerance test

Answer 21

A zero time (baseline) blood sample is drawn.

The patient is then given a measured dose of glucose solution to drink

Blood is drawn at 2 hours to assess how fast glucose has been cleared from the blood.

In a patient with diabetes, glucose levels will be above the normal level after two hours. in normal patients gluose leves is reduced. Diabetic patients may also have a high starting glucose blood concentraion.

Question 22

General effects of medication used to treat diabetes

Answer 22

Increase insulin output (sulphonylureas)

Decrease glucose production (Biguanides - metformin)

Increase insulin sensitvity

Decrease carbohydrate absorption

Question 23

Name four sites of insulin resistance

Answer 23

pre-receptor: abnormal insulin molecule, insulin receptor antibodies

receptor: decreased number or affinity of insulin receptors

post-receptor: defects in signal transduction or activity of key enzymes

glucose transport: deficient or defective glucose transporters

Question 24

Name four substances that control the release of glucagon

Answer 24

Glucose: low levels of blood glucose stimulate glucagon release

CCK: secreted in response to protein in the small intestine. Potent stimulator of glucagon

Amino acids: presence in the blood and oral protein stimulate release

Parasympathetic (ACh and VIP): stimulate release

Question 25

What is gestational diabetes?

Answer 25

Any degree of glucose intolerance with with onset or recognition during pregnancy. Normally during the late second trimester

In some woment he pancreas is unable to respond to the increased metabolic demands of pregnancy, thus blood glucose increases.

Condition ususally results after parturition but may result in type 1 or type 2 diabetes.

Question 26

Complications of gestational diabetes

Answer 26

Macrosomia: abnormally large foetus

Increased rate of spontaneous abortions

Increased risk of congential abnormalities

Infant hyperglycaemia during pregnancy can lead to beta cell hyperplasia to compensate. Neonatal hypoglycaemia.

Question 27

Name five major actions of glucagon on metabolism?

Answer 27

The major actions of glucagon are on the liver and work to increase blood sugar levels

1. Increases glycogenolysis by activating glycogen phosphorylase and inhibitng glycogen synthase
2. Inhibits pyruvate kinase, which decreases PEP levels so pyruvate and glucose levels are increased
3. Increases gluconeogenesis by increasing the uptake of alanine and glutamine which are used for gluconeogenesis and degrading hepatic proteins. Amino acid metabolism into glucose increases urea production
4. Promotes lipolysis which increases [FFA]
5. Ketogenesis from FFA which can be used as a metabolic fuel

Question 28

What are the stages in insulin action?

(Phased responses of insulin receptor activation)

Answer 28

1. Insulin binds to insulin receptors on the cell surface and causes microaggregation of the receptors
2. Receptor activation intiates early responses:
   Change in membrane potential
   Activation of protein kinase cascades and production of second messengers
   Increase in GLUT4 transporters on the plasma
3. Hormone receptor complex is internalised, downregulating the insulin receptor
4. Delayed responses (post receptor events):
   Growth and gene expression
   Protein synthesis
   Inhibition of lipolysis
   Glycogen synthesis

Question 29

Describe the cellular biochemical changes that occur in ketoacidosis

Answer 29

Insulin deficiency means that blood glucose cannot be metabolised or stored effciently. The body therefore begins to metabolise proteins and TAG for gluconeogenesis, resulting in hyperglycaemia.

Increased blood glucose levels alter the osmotic potential of the blood, water leaves the cells, causing intracellular dehydration. K+ is lost from the cells

Excess acetyl-CoA produced from b-oxidation of FFAs is used for ketogenesis. Some is used as an energy source by the brain. Increased ketones in the blood causes metabolic acidosis, resulting in extracellular dehydration.

Frequency of urination is increased, excess ketones, glucose and ions are excreted. There is a loss of Na+ ions from the body.