Lecture 25: Physiology of whole-body metabolism/key role of glucose Flashcards
- What is the role of insulin
- Insulin is the key hormone preventing the uncontrolled rise in blood glucose after eating and is released from the beta cells of the islets of Langerhans. Glucose enters the beta cell and ATP is produced by glycolysis. This closes potassium channels which in turn lead to calcium influx and insulin release.
- What is glucagon?
- Glucagon is the key hormone keeping blood glucose from falling into the hypoglycaemic range.
What is the role of fat?
- Fat is a major storage depot of energy and undergoes lipolysis to glycerol and free fatty acids.
- FFA are then oxidized to ketones.
Kreb cycle allows…..
- Krebs cycle allows glucose to be formed from carbohydrate stores in muscle (via lactate), protein (via amino acids such as alanine) and fat (via glycerol).
Describe glucose uptake by the brain
Brain has obligatory requirement for glucose and consumes ~80% of whole-body glucose utilised in fasting state (110-150g/day).
- Glucose uptake by brain is NIMGU (non-insulin mediated glucose uptake).
- Cerebral function is critically dependent on maintaining glucose >3.5 mmol/l.
Glucose is ingested and manufactured by (PROCESSES) ___________\_and _______\_
Glucose is ingested and manufactured by gluconeogenesis (new glucose in liver) and glycogenenolysis (convert glycogen to glucose in muscle and liver)
Describe the actions of insulin and glucagon
Insulin and glucagon has reciprocal actions and secretion.
-
Insulin is key hormone preventing uncontrolled hyperglycaemia after eating (so it decreases blood glucose).
- Insulin is anabolic, increases the storage of glucose, fatty acid and amino acids (transport into insulin sensitive cells).
- When a person is eating, insulin will be turned on and glucagon turned off.
-
Glucagon is key hormone keeping blood glucose from falling into hypoglycaemic range (so it increases blood glucose).
- Glucagon is catabolic, increase the mobilization of glucose, fatty acid and amino acids from stores.
- In a fasting situation, glucagon will be turned on and insulin turned off.
Insulin is ______, increases the ______of glucose, fatty acid and amino acids (transport into insulin sensitive cells).
Insulin is anabolic, increases the storage of glucose, fatty acid and amino acids (transport into insulin sensitive cells).
Glucagon is _____, it increases the ______ of glucose, FA, AA from stores
- Glucagon is catabolic, increase the mobilization of glucose, fatty acid and amino acids from stores.
- In a fasting situation, glucagon will be turned on and insulin turned off.
- Insulin is key hormone preventing_________after eating (so it decreases blood glucose).
- Glucagon is key hormone keeping ____________
Insulin and glucagon has reciprocal actions and secretion.
-
Insulin is key hormone preventing uncontrolled hyperglycaemia after eating (so it decreases blood glucose).
- Glucagon is key hormone keeping blood glucose from falling into hypoglycaemic range (so it increases blood glucose).
Describe the STRUCTURE of Islets of Langerhands
Endocrine tisssue embedded within exocrine tissue (digestive enzymes released to duodenum)
- Consist of:
- β-cells core (insulin decrease glucose)
- α-cells on outer edge of islet (glucagon increase glucose)
- δ-cells scattered (somatostatin decreases insulin, also decreases GH)
- F-cells (pancreatic polypeptide for bicarbonate regulation)
- Paracrine interaction between β-cells and α-cells
Neurovascular bundle enters each islet through β-cell core (endocrine function, more concentrated in tail than body)
- Rich capillary network appearing like glomerulus with centrifugal blood flow, venous effluent to portal vein and liver
- Richly innervated by autonomic and peptidergic neurons
In Islets of Langerhands…
B cells secrete….
A cells secrete….
δ cells secreted….
F cells secrete…
- Consist of:
- β-cells core (insulin decrease glucose)
- α-cells on outer edge of islet (glucagon increase glucose)
- δ-cells scattered (somatostatin decreases insulin, also decreases GH)
- F-cells (pancreatic polypeptide for bicarbonate regulation)
- Paracrine interaction between β-cells and α-cells
Neurovascular bundle enters each islet through β-cell core (endocrine function, more concentrated in tail than body)
- Rich capillary network appearing like glomerulus with centrifugal blood flow, venous effluent to portal vein and liver
- Richly innervated by autonomic and peptidergic neurons
Where are the Islets of Langerhans?
Pancreas
Clinical: Pancreatitis
If a person gets pancreatitis, digestive enzymes are released into pancreas tissue and damage pancreas. This can include damage to the _______, and subsequent development of _____.
Clinical: Pancreatitis
If a person gets pancreatitis, digestive enzymes are released into pancreas tissue and damage pancreas. This can include damage to the islets of Langerhans, and subsequent development of diabetes.
Clinical: Somatostatin and Pituitary Tumour Treatment
______analogues are used in treatment of patients with pituitary tumours that produce too much _______.
A side use can be for type II diabetes, because somatostatin will also be __________________
Clinical: Somatostatin and Pituitary Tumour Treatment
Somatostatin analogues are used in treatment of patients with pituitary tumours that produce too much growth hormone.
A side use can be for type II diabetes, because somatostatin will also be decreasing insulin release, also decreasing growth hormone release.
What are somatostatins?
Somatostatin, also known as growth hormone-inhibiting hormone
How are glucose transported into cells?
Glucose transport into cells via active glucose transporters (non-insulin mediated and insulin mediated glucose transport).
GLUT1-7 transporters are transport proteins at different cells in the body that facilitate glucose uptake
- GLUT1 found in erythrocytes and brain (non-insulin mediated glucose uptake NIMGU)
- GLUT2 found in pancreas (__β-cells__) and liver **
- GLUT3 found in neurons (and placenta)
- GLUT4 found in fat and muscle (insulin-mediated glucose **uptake and present in vesicles) (also exercise-induced to reduce glucose, e.g. patients with diabetes can get hypoglycemic during exercise)
GLUT1-7 has no homology with sodium-glucose like transporters (SGLT1-2).
- SGLT1 found in small intestine
- SGLT2 found in kidneys to reabsorbed glucose (into blood) in proximal nephron.
- GLUT2 found in __________\_
- GLUT4 found in ______________\_
- GLUT2 found in pancreas (__β-cells__) and liver
- GLUT4 found in fat and muscle (insulin-mediated glucose uptake and present in vesicles) (also exercise-induced to reduce
- SGLT1 found in _____
- SGLT2 found in __________
- SGLT1 found in small intestine
- SGLT2 found in kidneys to reabsorbed glucose (into blood) in proximal nephron.
GLUT1-7 has no homology with sodium-glucose like transporters (SGLT1-2).
What would you observe in patients with mutations in SGLT2?
Clinical: SGLT2
Patients with SGLT2 mutations appear with glucose in their urine but their blood glucose is normal.
SGLT2 inhibitor is a new class of drug used in treatment of diabetes. This lowers threshold of having glucose in your urine, so that even if their blood glucose is <10, they will secrete glucose in their urine due to SGLT2 inhibition.
The threshold of having urine glucose is a blood glucose of ~10, meaning if your blood glucose is <10 you won’t have glucose in your urine. (this is why using glucose in the urine is a bad diagnostic test, because if the diabetic person has a blood glucose of 9 they still won’t have glucose in their urine.)
Describe the steps of Insulin Release
After absorption, glucose enters into β-cell of pancreas via:
- Non-insulin mediated glucose uptake (NIMGU) (70%);
- GLUT2 facilitated glucose uptake for rest.
After entering β-cell, glucose undergoes glycolysis to form ATP. (glucokinase phosphorylate glycose to glucose-6-phosphate).
- This results in closure of ATP-sensitive potassium channels resulting in cell depolarisation.
- Calcium then enters via voltage gated channels increasing intracellular calcium which triggers insulin translocation and exocytosis (hence insulin release).
Note that glucagon-like peptide (GLP) receptor in beta cells respond to GLP1 (incretin hormone produced by intestine) that induce insulin, so decrease in blood glucose.
After absorption, glucose enters into β-cell of pancreas via:
_________ and ______
After absorption, glucose enters into β-cell of pancreas via:
- Non-insulin mediated glucose uptake (NIMGU) (70%);
- GLUT2 facilitated glucose uptake for rest.
What would you observe in a Glucokinase Mutation?
What would you observe in a Sulphonylurea mutation?
Clinical: Sulphonylurea
Sulphonylureas bind to and close ATP-sensitive K+(KATP) channels on pancreatic beta cells, which increased secretion of (pro)insulin (cause hypoglycaemia).
What would you observe in a Clinical KATP Channel mutation
Clinical: KATP Channel Mutation
- Inactivating mutation means K channel cannot close (hypofunction), cannot produce insulin, hence hyperglycaemia (diabetes-like).
- Activating mutation means K channel close all the time (hyperfunction) to induce insulin, hence hypoglycaemia.
What would you observe in patients with mutations in Glucagon-Like Peptide
Clinical: Glucagon-Like Peptide 1
Glucagon-like peptide 1 (GLP1) is used in diabetes as long acting injections to induce insulin so reducing blood glucose.
Describe the steps of Insulin synthesis
Preproinsulin is a long chain, which consists of chain A, B and C.
Proinsulin is made from preproinsulin with signal sequence cleaved.
- It has no particular biological actions;
- Bsome patients with pancreatic tumours producing too much insulin preferentially produce proinsulin, which in excess can cause hypoglycaemia.
Insulin has chain A and B connected by disulphide bonds.
- A chain binds to insulin receptor.
- It is made from proinsulin with chain C (C peptide) cleaved.
- For every molecule of insulin released, a C peptide (biomarker) is also released.
What are the clinical implications of the C Peptide
Clinical: C Peptide
C peptide has no biological function, but can measure its level as a marker to ensure level of insulin production.
- C peptide is measured when patients present with spontaneous hypoglycaemia, such as distinguishing factitious hypoglycaemia and insulin producing tumour.
- If factitious hypoglycaemia (caused by unneeded injections of insulin), then low C peptide level.
- If tumour that is producing insulin, then high C peptide level.
Therefore, we can measure C peptide level and insulin level at the same time in assessment.
Describe the clinical implication of the B chain in preproinsulin
Clincial: B Chain
Because chain B has positive charge, we can modify it for short acting and long acting insulin drugs.
_______Regulate Glucose Homeostasis Through Effects on Islet Cell Function
Incretins Regulate Glucose Homeostasis Through Effects on Islet Cell Function
Ingestion of food leads to _______gut hormones release such as __________which results in:
______________ and _________
Ingestion of food leads to incretin gut hormones release such as GLP-1 (glucagon-like peptide), which results in:
- Reduce glucagon release from alpha cells.
- Increase insulin release from beta cells.
This response to GLP1 are glucose dependent. This means the higher the glucose, more GLP1 signal (to decrease blood glucose). When glucose levels go back down to normal level, the response is switched off.
Describe how Insulin signalling works
Circulating insulin binds to cell surface insulin receptors (not needed by brain or red blood cells)
- This results in phosphorylation cascade (no details) and translocation of GLUT4 proteins to plasma membrane;
- This allows glucose to enter muscle and fat cells thus reducing blood glucose.
Describe the insulin metabolic action on Carbohydrates
- Liver: insulin i_nhibits glyogenolysis and gluconeogenesis_ (inhibit glucose production)
- Muscle: insulin increases glucose transport into muscles, then glycolysis (utilized by muscles)
- Adipose tissue (same as muscle)
Describe the insulin metabolic action of fat
- Insulin increases triglyceride storage, inhibits lipolysis (↓hormone sensitive lipase), which inhibits FFA production, therefore inhibits ketone production
Describe the insulin metabolic action on protein
- Insulin is anabolic so it increases transport of amino acid into liver and muscle (store energy)
Describe the Kreb Cycle
Carbohydrates are digested to glucose. Glucose enters cells and then undergoes controlled sequence of two dozen steps catalyzed by enzymes.
Glucose is oxidized to pyruvate (glycolysis) then acetyl Co-A, which feeds into Krebs cycle to produce 38 ATP for energy.
Krebs’ cycle is active in every cell with mitochondria except red blood cell which lacks mitochondria. It is the link between carbohydrate (gluconeogenesis), lipid (lipogenesis) and protein (amino acid) metabolism.
What are some consequences of Insulin Deficiency?
(TYPE 1 DIABETES)
With prolonged and profound insulin deficiency (type 1 diabetes):
- 1) Hormone sensitive lipase is very active results in fat lipolysis and formation of ketones which are acidic
- 2) Glycogenolysis is uncontrolled, so increasing glucose production and hepatic glucose output.Protein hydrolysis is unchecked and amino acids enters uncontrolled Krebs cycle and results in uncontrolled gluconeogenesis.
- 3) Finally, GLUT4 (insulin-dependent activation) is inactive, there is no glucose uptake, and therefore hyperglycaemia results.
This condition is called diabetic ketoacidosis (uncontrolled glucose and ketone production results in acidosis).
