Glucose Homeostasis

Question 1

Importance of Glucose + Normal Blood Glucose levels

Answer 1

Glucose is an important ENERGY SUBSTRATE
very important for CNS - if undergo hypoglycaemia (blood glucose levels less than 4-5mmol/L) then cerebral function is increasingly impaired
If blood glucose concentration <2 mmol/L - unconsciousness, coma and death

Question 2

Importance of Glucose Regulation

Answer 2

Glucose is closely regulated
Feedback system needed for regulation
Persistent hyperglycaemia results in Diabetes Mellitus

Question 3

Hormones important for blood glucose regulation

Answer 3

Insulin
Glucagon 
Cortisol 
Growth Hormone 
Catecholamines

Question 4

Name the Diabetes Mellitus Phenotypes in order of prevalence

Answer 4

Type 2 Diabetes Mellitus (T2DM) - most prevalent
Type 1 Diabetes Mellitus (T1DM)
Maturity onset Diabetes of the young (MODY) - least prevalent

Question 5

Pancreas

Answer 5

Important in pathogenesis of diabetes Mellitus
Pancreas gland is a retroperitoneal structure
98% generates exocrine secretions such as amylase, lipase, professes needs for digestion via duct to small intestine (exocrine acinar cells)
2% made up of islets of Langerhans which are involved in glucose regulation

Question 6

Islet of Langerhans

Answer 6

30% alpha-cells -> glucagon
60% beta-cells -> insulin
10% delta-cells -> somatostatin
Work together to make sure glucose regulation is maintained using
Gap Junctions: allow small molecules to pass directly between cells
Tight Junctions: create small intercellular spaces
Paracrine Communication between islet cells NOT ENDOCRINE COMMUNCATION

Question 7

General Action of Pancreatic Hormones

Answer 7

Insulin stimulates growth and development and reduces blood glucose
Glucagon increases blood glucose
Somatostatin acts as a negative feedback hormone to control insulin and glucagon levels

Question 8

Reaction to increase in Blood Glucose

Answer 8

As blood glucose levels increase, direct effect on beta-cells to produce insulin. Negative feedback with regards to somatostatin to control insulin levels and some glucagon is produced to make sure hypoglycaemia doesn’t occur
AAs, GI hormones, PNS activity increases beta-cell activity
SNS activity via beta increases activity while via alpha decreases activity of beta-cells

Question 9

How does insulin decrease blood glucose levels?

Answer 9

Causes:
Build up of glycogen stores
Breakdown of glucose
Increased uptake of glucose into cells via GLUT4
(Altogether decreases blood glucose levels)

Question 10

What are other actions of insulin?

Answer 10

Increases amino acid transport and protein synthesis

Increases rate of lipogenesis and decrease is lipolysis

Question 11

Reaction to reduction in Blood Glucose

Answer 11

Decrease in blood glucose levels cause alpha cells to release glucagon , insulin production is completely switched off at beta cells and again negative feedback mechanism of somatostatin from delta cells acting as a counter-regulatory hormone
AAs, GI hormones, PNS activity and SNS activity via the alpha pathway increases alpha cells activity and releasing glucagon

Question 12

How does glucagon increase blood glucose levels?

Answer 12

Glucagon increases rate of lipolysis and so releases glucose allowing more gluconeogenesis to occur and so increasing blood glucose levels
Also increases amino acid transport to liver, increasing rate of gluconeogenesis
Increased rate of hepatic glycogenolysis in the presence of glucagon (glycogen reserves in liver is broken down to increase glucose levels)

Question 13

What is GLUT2 and how does it work?

Answer 13

GLUT2 is not insulin sensitive but Glucokinase is thought to be the main glucose transporter.
GLUT2 is receptor found on beta cells membranes with a high affinity for glucose. So glucose passes through the GLUT2 receptors to mirror the concentration inside and outside the cell.

Question 14

Glucokinase and its role?

Answer 14

Conversion of glucose to glucose-6-phosphate is mediated by the main glucose sensor glucokinase. It is not subject to negative feedback (amount of glucose-6-phosphate does not affect the rate of conversion) and so there is a continual conversion. Glucose-6-phosphate is then converted into ATP. Glucose-6-phosphate amount gives an indication of how much glucose is in our beta cells. Extracellular glucose = Intracellular glucose = Intracellular ATP levels

Question 15

How is insulin released from beta cells?

Answer 15

Glucose transported into beta cells via GLUT2 to mirror glucose levels. Converted into Glucose-6-phosphate using glucokinase. Then turned into ATP. High levels of ATP closes potassium gated channels causing potassium to remain intracellular. This relative increase in K+ leads to membrane depolarisation which opens Ca2+ voltage gates channels. This in turn leads to an influx of calcium which promotes insulin secretion via the beta cells.

Question 16

Insulin storage and formation of active form

Answer 16

Stores as Proinsulin and undergoes proteolytic cleavage into two compounds C-Peptide and Insulin (the active form)

Question 17

Importance of C-peptides

Answer 17

Breakdown product of proinsulin. To help assess amount of endogenous insulin better to measure C-peptide levels. This is because insulin is a very unstable assay while C-peptides are much more stable.

Question 18

The ‘Incretin’ effect

Answer 18

Relates to gastrointestinal effect which is observed when glucose load is ingested. Evidence comparing intravenous and oral glucose - healthy human given same amounts of glucose but differently (rate of change of glucose is literally the same) however looking at insulin levels when give same glucose amounts the oral glucose is associated with an enhanced insulin secretion whereas the intravenous one has much lower levels. This is known as the ‘Incretin’ effect. This is the effect of gut hormones on insulin secretion in response to a glucose load.

Question 19

Glucagon Like Peptide - 1

Answer 19

Gut hormone 
Secreted in response to nutrients in gut
Transcription product of pro-glucagon gene, mostly from L-cell (found in distal parts of colon)
Stimulates insulin
Suppresses glucagon
Increases satiety
Short half life due to rapid degradation from enzyme dipeptidyl peptides-4 (DPPG-4 inhibitor)
Used in treatment of diabetes

Question 20

First Phase Insulin Release (FPIR)

Graph

Answer 20

At normal glucose tolerance:
Given glucose challenge, insulin shoots ups so glucose goes down and stays down.
Type 2 Diabetes Mellitus:
When given glucose challenge, insulin level up slight (beta cells after working hard are unable to produce enough insulin to counteract that glucose load) and glucose levels also remain high. -> first phase insulin release

Question 21

The Insulin Receptor

Answer 21

Insulin binds to the extracellular domain of the insulin receptor. Once insulin binds to the alpha-subunit, there is a conformational change in the tyrosine kinase domains of the beta-subunits.
Diagram of insulin receptor