4.7 - Glucose Homeostasis

Question 1

What is the importance of glucose?

Answer 1

• important energy substrate
• particularly true for the CNS - if BGC falls much below normal levels of 4-5 mmol/L (hypoglycaemia), then cerebral function is increasingly impaired
• if BGC <2 mmol/L, unconsciousness, coma and ultimately death can result

Question 2

What does persistent hyperglycaemia result in?

Answer 2

Diabetes mellitus

Question 3

What hormones are secreted to increase blood glucose?

Answer 3

• glucagon
• cortisol
• GH (growth hormone)
• catecholamines

Question 4

What does the body secrete to decrease blood glucose?

Answer 4

Insulin

Question 5

What % of people are affected with diabetes mellitus in the UK?

Answer 5

7%

Question 6

What is the % risk increase of a person with diabetes mellitus dying relative to an age-matched control without diabetes mellitus?

Answer 6

34%

Question 7

How much of the NHS budget is spent on diabetes mellitus?

Answer 7

10%

Question 8

What is the most prevalent form of diabetes?

Answer 8

• type 2 diabetes
• type 1 is 11% of all diabetes
• maturity onset diabetes of the young (MODY) is 2-3% of all diabetes

Question 9

What kind of structure is the pancreas?

Answer 9

Retroperitoneal structure

Question 10

What collections of cells make up the pancreas and what do they do?

Answer 10

• exocrine acinar cells - most of the pancreas (98%) generates exocrine secretions via duct to small intestine e.g. amylase and protease
• islets of Langerhans - small clumps of cells within pancreatic tissue (2%)
• even though they only make up 2%, 10-15% of pancreatic blood supply is given to them showing their importance

Question 11

What cells make up the islets of Langerhans?

Answer 11

• alpha cells - secrete glucagon
• beta cells - secrete insulin
• delta cells - secrete somatostatin (and pancreatic polypeptide - irrelevant here)
• there are gap junctions between these cells that allow small molecules to pass directly between cells - paracrine communication
• there are also tight junctions that create small intercellular spaces with proteins that help coordinate response of the different cell types

Question 12

How do the pancreatic hormones interact with each other and with blood glucose?

Answer 12

• insulin stimulates growth and development (especially in utero) and reduces BGC
• glucagon increases BGC
• somatostatin inhibits both in a negative feedback loop to keep them in balance and ensure we are not oversecreting either

Question 13

What stimulates beta cells to produce insulin?

Answer 13

• the increase in BGC itself
• some amino acids from food
• some GI hormones
• parasympathetic nervous system activity
• sympathetic nervous system has both inhibitory effect via alpha-adrenergic pathway and a weak stimulatory effect via beta-adrenergic pathway

Question 14

How does the pancreas react to an increase in BGC?

Answer 14

• beta cells stimulated to produce insulin
• some glucagon produced by alpha cells to make sure we have the right balance and do not overshoot with insulin and become hypoglycaemic
• somatostatin produced in negative feedback loop
• these are all required to ensure BGC does not continue to rise beyond physiological values

Question 15

How does insulin regulate BGC?

Answer 15

• build up of glycogen stores (increase glycogenesis)
• breakdown of glucose (increase glycolysis)
• increased glucose uptake/transport into cells via GLUT4 - one of family of glucose transporters mainly found in skeletal muscle and adipocytes that moves from being intracellular to being in cell membrane to take up glucose from blood into cell
• increases amino acid transport and therefore protein synthesis
• decrease in lipolysis and increase in lipogenesis

Question 16

What stimulates alpha cells to produce glucagon?

Answer 16

• decrease in BGC itself
• some amino acids
• some GI hormones
• parasympathetic nervous system activity
• sympathetic nervous system activity via alpha-adrenergic pathway

Question 17

How does the pancreas react to a decrease in BGC?

Answer 17

• alpha cells produce glucagon
• beta cells stop producing insulin altogether
• somatostatin is produced by delta cells to keep glucagon in check

Question 18

How does glucagon increase BGC?

Answer 18

• increases lipolysis which releases more glucose and so more gluconeogenesis occurs = more glucose in blood
• increases amino acid transport into liver which increases rate of gluconeogenesis
• increases hepatic glycogenolysis

Question 19

How do beta cells detect glucose levels and know when to make insulin?

Answer 19

1. beta cells have GLUT2 transporters which is NOT insulin sensitive and has a very high affinity for glucose = our blood glucose passes through it into beta cells constantly, so blood and intracellular glucose concentrations are monitored
2. glucose in beta cell is converted into glucose-6-phosphate by glucokinase (hexokinase IV) –> glucokinase is not subjective to negative feedback = G6P does not inhibit the enzyme = continual conversion of glucose –> G6P so G6P levels = glucose levels
3. G6P converted to ATP through glycolysis
4. ATP closes potassium gated channels so prevents extracellular flux of K+
5. K+ remains intracellularly, and this relative increase leads to membrane depolarisation
6. this opens Ca2+ voltage gated channels –> Ca2+ influx = promotes secretion of stored insulin in beta cell

• this is a graded response as BGC will vary throughout the day so insulin is secreted at different levels too

Question 20

In what form is insulin stored?

Answer 20

• stored as proinsulin, which has some degree of activity but by proteolytic cleavage is split into C-peptide and insulin
• measuring endogenous C-peptide is a good indicator for insulin as insulin is very unstable assay and C-peptide can be stable for up to 30min when samples sent to lab

Question 21

What is the gastrointestinal incretin effect?

Answer 21

• GI hormones enhance insulin secretion = when glucose is ingested orally vs IV, there is higher plasma insulin in oral vs IV even though plasma glucose is the same (as GI system involved in digestion when orally)

Question 22

What is glucagon like peptide-1 (GLP-1)?

Answer 22

• gut hormone secreted in response to nutrients in gut
• transcription product of pro-glucagon gene, mostly from L-cell in distal part of colon
• increases satiety (feeling of fullness)
• stimulates insulin, suppresses glucagon
• short half-life due to rapid degradation from DDP4 enzyme
• used in treatment of type 2 diabetes - sufferers have reduced GLP-1 reserves, helping people with obesity feel full can help reduce their insulin insensitivity as they eat less

Question 23

What is the first phase insulin release (FPIR) in normal people vs those with T2DM?

Answer 23

• FPIR is the first spike in insulin following increase in BGC
• normal people - marked increase in insulin after IV glucose challenge, then BGC goes down and thus so does insulin
• T2DM - this response is blunted so it is not just that cells are resistant to insulin, but also beta cells cannot produce enough to counteract glucose load after working hard for a long time = no marked increase

Question 24

What is the insulin receptor?

Answer 24

• insulin binds to the extracellular domain of insulin receptor at the alpha-subunit
• causes a conformational change in the tyrosine kinase
  domains of the beta-subunits
• enables GLUT4 transport from intracellular into the membrane