Control of blood glucose and the endocrine pancreas

Question 1

How does glucose get into cells?

Answer 1

There are two main groups. Sodium-glucose cotransporters (SGLTs) and a family of glucose transporters (GLUTs)

• It uses secondary active transport
• SGLT 1: glucose absorption from the gut
• SGLT 2: glucose reabsorption from the kidney (PCT

Glucose from the lumen gets absorbed into the epithelial cell of the gut along with sodium ions against the concentration gradient. There is a lower sodium ion concentration gradient in the cell as it is being actively transported out. As glucose builds up in the epithelial cell, then it will diffuse out via the other end through GLUT2 into the blood.

Question 2

What are the two important GLUT transporters?

Answer 2

GLUT 2 (liver, kidney, pancreas, gut) - low affinity: glucose equilibrates across the membrane
-Glucose-dependent insulin release in the pancreas (insulin independent) 

GLUT 4 (muscle and adipose tissue) - medium affinity. Insulin recruits transporters.
-Insulin-dependent uptake of glucose into cells 
They are translocated in the presence of insulin. They are not ordinarily there

Question 3

What are the Islets of Langerhans?

Answer 3

Clusters of endocrine cells surrounded by exocrine pancreas

Question 4

What cells are in the Islets of Langerhans

Answer 4

alpha (A) cells - glucagon
beta (B) cells - insulin
delta cells - somatostatin (GH inhibiting hormone)

Question 5

Explain stages of insulin synthesis

Answer 5

Firstly preproinsulin is made (original transcript). Then the signalling sequence is removed in the rough er, leaving proinsulin.

Transfer to Golgi apparatus

Peptidases break off C-peptide, leaving an A and B chain linked by disulfide bonds,

One mole of C peptide is secreted for each mole of insulin

Question 6

What arteries supply the pancreas?

Answer 6

Branches of the coeliac and the superior mesenteric

Question 7

How is insulin released into the circulation

Answer 7

From the pancreas into the hepatic portal vein where it goes to the liver. Half of the secreted insulin is metabolised in its first pass; the remainder is diluted in the peripheral circulation.

Question 8

How do you measure levels of insulin?

Answer 8

Measuring the C-peptide is a more accurate index of insulin secretion in the peripheral circulation (not metabolised by the liver)

Question 9

What factors regulate insulin secretion?

Answer 9

Positive
Plasma glucose
Amino acids
Parasympathetic nervous system
Glucagon (local paracrine effect in the islets of Langerhans)
Incretin hormones (not directly but enhance secretion of insulin in response to a rise in glucose)

Negative
Alpha-adrenergic (sympathetic)
Somatostatin

Question 10

What factors regulate glucagon secretion?

Answer 10

Positive
Amino acids
Beta-adrenergic (sympathetic)
Parasympathetic

Negative
Plasma glucose
Somatostatin
Insulin

Question 11

How do beta cells sense a rise in glucose?

Answer 11

It has no glucose receptor but the GLUT2/glucokinase can be thought of as a sensor. The effector is a rise in ATP due to glucose oxidation.

Question 12

How does an increase in plasma glucose levels cause insulin to be released?

Answer 12

Glucose enters the beta cell via GLUT2 at a rate proportional to the rise in plasma glucose. As it enters, it is immediately metabolised by glucokinase to G6P, keeping the concentration gradient going. Then through glycolysis and oxidative phosphorylation, ATP is produced. ATP rise in the cell causes KATP channel to close. (KATP channel has an internal sub-unit sensitive to ATP. When ATP binds to the sub-unit, it closes, so potassium ion efflux is switched off.) This reduces potassium ion leakage which has a depolarising effect on the cell membrane. This, in turn, activates voltage-gated calcium channels. Calcium enters which is the signal that causes vesicle mobilisation and secretion.

Question 13

Why do FFAs and Amino acids also cause secretion of insulin?

Answer 13

They can also produce ATP through oxidative phosphorylation. Anything that can cause depolarization can also promote insulin release.

Question 14

What is an insulin receptor?

Answer 14

It is a member of the tyrosine kinase superfamily

Question 15

How does an insulin cause a reaction at its receptor?

Answer 15

It starts many protein activation cascades such as the translocation of GLUT-4 transporters to the plasma membrane and influx of glucose, glycogen synthesis, glycolysis and fatty acid synthesis.

Works through modulating enzyme phosphorylation and gene transcription.

Question 16

How do counter-regulatory hormones act principally?

Answer 16

Through the activity of PKA, which phosphorylates key enzymes in metabolic pathways.

Question 17

How does insulin work primarily?

Answer 17

Causes dephosphorylation of the same enzymes

Question 18

What is type 1 diabetes?

Answer 18

Absolute insulin deficiency (due to the destruction of insulin-producing pancreatic beta cells)

Question 19

What is type 2 diabetes?

Answer 19

Variable combination of insulin resistance and insulin insufficiency

Question 20

What are the figures for diagnosing hyperglycemia?

Answer 20

Random plasma glucose ≥ 11.1 mmol L-1
Fasting plasma glucose ≥ 7.0 mmol L-1
Oral glucose tolerance test (OGT) ≥ 11.1 mmol L-1

Question 21

How to measure glycaemic control?

Answer 21

Glycosylation of haemoglobin. Less than 6.5% is good.

Question 22

Name a few drugs and how they work for T2DM

Answer 22

-SGLT2 inhibitors: promote glucose excretion via the kidney
-Sulfonylureas: bind and close KATP channels, depolarize B cell releasing insulin
-Incretin targeting drugs: potentiate insulin release in response to rising plasma glucose
DPP-4 inhibitors (prevent the breakdown of natural incretins)
Synthetic GLP-1 analogues