Glucose homeostasis Flashcards
What is the importance of glucose?
- Important energy substrate
- Blood glucose conc normal level = 4-5 mmol/L
- If blood glucose conc falls below (hypoglycaemia), cerebral function impaired
- If blood glucose conc <2 mmol/L, unconsciousness, coma and ultimately death can result
Describe briefly the regulation of glucose and the hormones involved:
- Eat a meal. so blood glucose rises
- Insulin released to lower blood glucose
- If blood glucose too low, 4 hormones can increase it:
Glucagon, Cortisol (adrenal glands after stress), Growth hormone, Catecholamines (after stress)
1) What % people affected with diabetes mellitus in Uk?
2) What is % increase for risk of person with diabetes mellitus dying relative to an age-matched control without diabetes mellitus?
3) How much of NHS budget spend on diabetes mellitus?
4) WHat type of diabetes is most prevalent?
1) 7%
2) 34% (increased risk of macrovasuclar issues)
3) 10%
4) T2DM most, then T1DM (11%), Maturity onset diabetes of young (MODY 2-3%)
What kind of structure is the pancreas?
- It is a gland - secretes substances into bloodstream
- Retroperitonael structure (sits in retroperitonael space)
- 12-15 cm in length
- Head and tail of pancreas
Describe the secretions of the pancreas:
- 98% of pancreas generates exocrine secretions via duct to small intestine ; exocrine acinar cells ( release of secretions like amylase, lipase, protease all needed for digestion)
- 2% made up of ISLETS OF LANGERHANS (small clumps of cells) involved in glucose regulation
- 10-15% blood suply of pancreas gland diverted to these islets
What are the islet of langerhans made up of?
- Alpha cells (secrete glucagon) 30% of islet
- Beta cells (secrete insulin) 60% of islet
- Delta cells (secrete somatostatin) 10%
- Pancreatic polypeptide producing cells (pp cells) make up that 10% too (not important for glucose regulation)
- Cells work together:
Gap junctions - allow small molecules to pass directly between cells
Tight junctions - create small intercellular spaces
What kind of communication is there between the cells of islet of langerhans?
- ENDOCRINE refers to gland secreting hormone into bloodstream to exert effect on another body part
- THIS IS PARACRINE
- Not secreted via bloodstream, occurs between islet cells
Briefly describe action of pancreatic hormones?
- Insulin decreases blood glucose and stimulates growth and development (particularly important in utero)
- Glucagon increases blood glucose
- Somatostatin keeps both of these hormones in balance
What is the reaction to an increase in blood glucose, related to release of insulin? (part 1 )
- Increase in blood glucose, beta cells produce insulin
- Negative feedback for somatostatin, glucagon still produced to prevent overshoot and become hypoglycaemic
- Some amino acids, Some GI hormones, PNS activity (relaxed state so able to digest), SNS activity via beta adrenergic pathway, stimulates beta cells to make insulin
- SNS activity via alpha adrenergic pathway has inhibitory effect on beta cells
How does insulin have an effect on blood glucose concentration?
Insulin causes:
- Build up of glycogen stores (glycogenesis, occurs in liver)
- Breakdown of glucose (glycolysis)
- Increased uptake of glucose (mediated by GLUT4 ; predominantly expressed in skeletal muscles and adipocytes, resting state GLUT4 is intracellular, response to insulin GLUT4 transported to cell membrane, acts to increase glucose transport from bloodstream to cells)
- Amino acid transport increases, leads to increase protein synthesis
- Reduction in breakdown of fat(lipolysis) and increase of rate of fat being built up (lipogenesis)
What is the reacrtion to a reduction in blood glucose?
- Reduced blood glucose= alpha cells secrete glucagon, beta cells stop secreting insulon , negative feedback of somatostatin
- Some GI hormones and amino acids, SNS activity via alpha adrenergic pathway and PNS Activity cause alpha cells release glucagon
- Glucagon increases lipolysis and amino acid transport in liver which increases gluconeogenesis which increases blood glucose
- Increase hepatic glycogenolysis, glycogen reserves in liver broken down, glycogen readily mobilised form of glucose
Describe the process through which insulin is secreted by beta cells:
- GLUT2 found beta cell membranes (not insulin sensitive), has high affinity for glucose, whatever amount of glucose in bloodstream is reflected in intracellular conc of beta cells
- Glucose passes across and is converted to Glucose-6-Phosphate, mediated by glucokinase (hexokinase IV)
- Glucokinase vs other hexokinase ; it is not subject to negative feedback, it does not get inhibited by Glucose-6-P
- Converted down glycolysis pathway to ATP
- ATP closes potassium gated channels, prevented extracellular flux of potassium, increase in potassium leads to membrane depolarisation which opens calcium voltage gated channels
- Leads to influx of calcium which promotes insulin secreation via beta cell
- Continuous process not all or nothing
What is insulin and C-peptide?
- Insulin stored as pro-insulin
- Undergoes proteolytic cleavege into C-peptide and insulin (active hormone)
- C-peptide gives better indication of how much insulin individual is producing
What is the evidence of the gastrointestinal ‘incretin’ effect?
- Oral glucose is associated with enhanced insulin secretion vs intravenous glucose
- Called incretin effect; effect of gut hormones enhancing insulin secretions in response to glucose load
- Gut hormone - Glucagone like peptide-1 (GLP-1)
- Secreted in response to nutrients in gut, transcription product of pro-glucagon gene mostly from L-cell
- Stimulates insulin, suppresses glucagon, increases satiety (feeling full) short half life due to degradation from DPPG-4 inhibitor, used in treatment of diabetes
What is the insulin response in type 2 diabetes?
- IN type 2 diabetes mellitus, response gets blunted
- Given glucose, amount of insulin produced does not increase like normal - system blunted
- Beta cells after working hard for long unable to produce enough insulin for glucose load
- Glucose level stays up
- Concept of initial insulin surge is called first phase insulin release (FPIR)
Describe the insulin receptor:
- Insulin bind to extracellular domain of insulin receptor
- Once insulin binds to apha subunit, there is a conformational change in the tyrosine kinase domains of beta sub units
