Lecture 25: Physiology of whole-body metabolism/key role of glucose Flashcards
1
Q
- What is the role of insulin
A
- 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.
2
Q
- What is glucagon?
A
- Glucagon is the key hormone keeping blood glucose from falling into the hypoglycaemic range.
3
Q
What is the role of fat?
A
- Fat is a major storage depot of energy and undergoes lipolysis to glycerol and free fatty acids.
- FFA are then oxidized to ketones.
4
Q
Kreb cycle allows…..
A
- 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).
5
Q
Describe glucose uptake by the brain
A
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.
6
Q
Glucose is ingested and manufactured by (PROCESSES) ___________\_and _______\_
A
Glucose is ingested and manufactured by gluconeogenesis (new glucose in liver) and glycogenenolysis (convert glycogen to glucose in muscle and liver)
7
Q
Describe the actions of insulin and glucagon
A
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.
8
Q
Insulin is ______, increases the ______of glucose, fatty acid and amino acids (transport into insulin sensitive cells).
A
Insulin is anabolic, increases the storage of glucose, fatty acid and amino acids (transport into insulin sensitive cells).
9
Q
Glucagon is _____, it increases the ______ of glucose, FA, AA from stores
A
- 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.
10
Q
- Insulin is key hormone preventing_________after eating (so it decreases blood glucose).
- Glucagon is key hormone keeping ____________
A
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).
11
Q
Describe the STRUCTURE of Islets of Langerhands
A
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
12
Q
In Islets of Langerhands…
B cells secrete….
A cells secrete….
δ cells secreted….
F cells secrete…
A
- 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
13
Q
Where are the Islets of Langerhans?
A
Pancreas
14
Q
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 _____.
A
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.
15
Q
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 __________________
A
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.
16
Q
What are somatostatins?
A
Somatostatin, also known as growth hormone-inhibiting hormone
17
Q
How are glucose transported into cells?
A
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.
18
Q
- GLUT2 found in __________\_
- GLUT4 found in ______________\_
A
- 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
19
Q
- SGLT1 found in _____
- SGLT2 found in __________
A
- 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).
20
Q
What would you observe in patients with mutations in SGLT2?
A
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.)
21
Q
Describe the steps of Insulin Release
A
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.
22
Q
After absorption, glucose enters into β-cell of pancreas via:
_________ and ______
A
After absorption, glucose enters into β-cell of pancreas via:
- Non-insulin mediated glucose uptake (NIMGU) (70%);
- GLUT2 facilitated glucose uptake for rest.
23
Q
What would you observe in a Glucokinase Mutation?
24
Q
What would you observe in a Sulphonylurea mutation?
A
Clinical: Sulphonylurea
Sulphonylureas bind to and close ATP-sensitive K+(KATP) channels on pancreatic beta cells, which increased secretion of (pro)insulin (cause hypoglycaemia).
25
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.
26
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.
27
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.
28
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.
29
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.
30
Describe the regulation of insulin
Insulin _basal secretion is pulsatile_ (9-14 minutes). Insulin turns on and off quite quickly.
* Major regulator is _glucose_ with _fast acute phase release_ (insulin burst, lost in type II diabetes) and then _slower second phase_
* Other regulators are amino acids such as arginine, glucagon, incretins, somatostatin.
Insulin release in response to:
* Increased glucose; increased glucagon,
* Vagus nerve stimulation,
* Release of arginine, incretin hormones (GLP1).
Insulin is inhibited by:
* Falling glucose,
* Sympathetic nerve stimulation,
* Release of somatostatin.
Adrenaline, growth hormone and cortisol also reduce insulin receptor number and affinity, which result in a degree of insulin resistance. Their main action however is on gluconeogenesis and glycogenolysis and _protection from hypoglycaemia_.
31
Insulin is released in response to.... and is inhibited by....
Insulin release in response to:
* Increased glucose; increased glucagon,
* Vagus nerve stimulation,
* Release of arginine, incretin hormones (GLP1).
Insulin is inhibited by:
* Falling glucose,
* Sympathetic nerve stimulation,
* Release of somatostatin.
32
Decribe the inter-organ communication with Beta Cells
* _Instestine_: GLP1 (increase insulin)
* _Liver_: glucagon, which stimulates kisspeptin (decrease insulin)
* _Adipocyte_: leptin (increase insulin), adiponectin (increase insulin sensitivity), resistin (insulin resistance)
* _Bone_: leptin binds to osteoclasts to stimulate osteocalcin (increase insulin)
* _Muscle_: IL6 (increase insulin sensitivity)
* _CNS_: autonomic innervation
33
_Clinical: High Blood Sugar In Morning for Type II Diabetes_
Patients with type II diabetes has \_\_\_\_\_\_blood sugar in the morning even though they haven’t eaten. That is because \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
_Clinical: High Blood Sugar In Morning for Type II Diabetes_
Patients with type II diabetes has higher blood sugar in the morning even though they haven’t eaten. That is because when we are physiologically waking up at ~4am, GH and cortisol are released, which makes you insulin resistant.
* In a normal person, you produce a bit more insulin in pulses, so when you actually wake up your blood sugar will be normal;
* But in a patient with type II diabetes, the _pulsatile release of insulin doesn’t work and so they wake up with high blood sugar._
34
![]()*\_\_\_\_\_\_\_Regulate Glucose Homeostasis Through Effects on Islet Cell Function*
![]()***_Incretins_ Regulate Glucose Homeostasis Through Effects on Islet Cell Function***
35
Describe the role of Incretins
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 re_sponse 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.
36
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.
37
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._
38
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)
39
Describe the insulin metabolic action of fat
* Insulin increases triglyceride storage, inhibits lipolysis (↓hormone sensitive lipase), which inhibits FFA production, therefore inhibits ketone production
40
Describe the insulin metabolic action on protein
* Insulin is anabolic so it increases transport of amino acid into liver and muscle (store energy)
41
What happens to glucose (% -wise) once we absorb it?
**Energy Storage And Use**
50% of glucose load burned for energy (H2O and CO2), 5% becomes glycogen and 45% is stored as fat. Glycogen is available for immediate glucose needs and fat for “slower” needs.
42
What happens to excess carbohydrate?
**Carbohydrates**
Excess carbohydrate (1-2% stored energy) is _stored as glycogen (75% in muscle and 25% in liver)._ *Glycogen is a complex hydrated polymer of glucose molecules with highly branched spherical structure.*
* Glyconeolysis results in glucose release (rapid available for instant energy). Glycogen stores are ~500g resulting in storage of ~2000kcal.
* When glycogen stores have been depleted, excess energy consumed is fat.
43
Where is fat stored?
Fat (20-30% body weight but 70-80% stored energy) is stored in _adipocytes_ which are _hormonally active_ and produce such diverse hormones as adiponectin, resistin, leptin and TNF alpha. Lipolysis results in release of:
* _Free fatty acids_ (oxidised to _ketone bodies_, which can be utilized as energy);
* _Glycerol_ (transported to liver and into _Krebs_ cycle)
44
How do we stored Protein?
Protein (20% stored energy) has _no specific depots_ and is constantly turned over via protein hydrolysis resulting in release of amino acids which can be reused for:
* Gluconeogenesis,
* Oxidised for energy (Krebs cycle),
* Reincorporated into proteins.
45
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.
46
What is glucogenesis?
Gluconeogenesis is the formation of new molecules of glucose
47
Define glycolysis
Glycolysis is the breakdown of glucose to pyruvate, which enters the Krebs cycle to produce ATP.
48
What is Glycogenolysis?
Glycogenolysis is the breakdown of _glycogen_ which can then:
* Used for _energy_ (muscle)
* Glycolysis of muscle glycogen anaerobically creates ATP via pyruvate. Lactate is formed from pyruvate and can be later converted back to glucose in liver via Cori cycle.
* Shock or septic patients produce increased lactate due to anaerobic metabolism of their muscles. High levels of lactate in blood can cause lactic acidosis.
* Used for _gluconeogenesis_ (liver and kidney, can convert glycogen to glucose)
49
What is Protein Hydrolysis?
Protein hydrolysis is the breakdown of _proteins_ to _amino acids_ (alanine in muscle) which enters the _Krebs cycle_ for _gluconeogenesis_ or are oxidized directly to ATP.
50
What is lipolysis?
Lipolysis is the breakdown of _fat_ to _glycerol_ (used for gluconeogenesis via Krebs cycle) and _FFA_ (cannot enter Krebs cycle, so oxidised to ketone bodies as energy)
* The brain can’t change instantly from using glucose as an energy source to ketones for energy. It takes ~16-18 hours for the brain to start transforming ketones into energy.
51
What are ketones?
Ketones (volatile, makes breath smell) are produced via _oxidation of FFA._
**_K_**etone products include aceto acetate, acetone and beta hydroxybutyrate (acidotic) (measure in blood for diabetic ketoacidosis).
Ketones are _utilized as fuel_ for _muscle_ and the _liver **acutely**_, but not acutely for the brain or red blood cells. (note that brain and red cells cannot oxidise FFA to ketones, but adapt over time to use ketone bodies during times of starvation.)
52
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).
53
What are normal individual response to hypoglycaemia?
As _blood glucose starts falling_, autonomic system activates _hypothalamus_ to stimulate:
* 1) Pancreas _releases glucagon_, which increase blood glucose
* 2) Adrenal gland r_eleases adrenaline_ (sweat, tremor), which is a _potent activator of glycogenolysis and gluconeogenesis_.
* 3) Pituitary gland release growth hormone and _ACTH_. ACTH will also stimulate adrenal gland to release cortisol.
The person is aware of hypoglycaemia and starts to eat.
54
Describe what happens when someone with Type 1 Diabetes is hypoglycaemic
Hypoglycaemic disorder is very regular because it’s difficult to match insulin injections to normal physiology.
* Patient _stops producing ANS_ response to recurrent _hypoglycaemia_.
* Hypothalamus now perceives low blood glucose as normal because it is low too frequently.
* Patient now develop _hypoglycaemia unawareness._
* First response to hypoglycaemia will now be severe _neuroglycopenia_, and patient will not be aware before that.
* Brain cannot adapt to low glucose, therefore results in _convulsions and coma/death._
After about 4-5 years of diabetes, patient may _also stop producing glucagon i_n response to hypoglycaemia (when there is too much injections of insulin) (3-5 times injection/day).
* This is because glucose levels are going down due to _too much exogenous insulin_
* Alpha cells sense increased insulin, therefore not produce glucagon.
These patients are doubly vulnerable, their _hypothalamus does not respond to hypoglycaemia_ (no ANS response) and _pancreas does not produce glucagon_ (too much insulin injection). Therefore, they have _poorer counter-regulatory mechanisms_, meaning they will get more and more vulnerable to severe hypoglycaemic episodes.
55
Type 1 Diabetic patients are doubly vulnerable, their hypothalamus \_\_\_\_\_\_\_\_\_\_\_\_and pancreas \_\_\_\_\_\_\_\_\_\_\_\_\_. Therefore, they have poorer counter-regulatory mechanisms, meaning they will get more and more vulnerable to severe hypoglycaemic episodes.
These patients are doubly vulnerable, their **_hypothalamus_** does not respond to hypoglycaemia (no ANS response) and **_pancreas_** does not produce glucagon (too much insulin injection). Therefore, they have poorer counter-regulatory mechanisms, meaning they will get more and more vulnerable to severe hypoglycaemic episodes.
56
What are some causes of hypoglycaemia?
* _Too much insulin_ in patients with diabetes (most common)
* _Sulphonylurea therapy_ (close K+ channel, opens Ca2+ channel, produce insulin)
* _Insulinoma_ (rare tumour in pancreas that overproduce insulin)
* _Severe hormone deficiency_ such as Addison’s disease (rare cortisol deficiency)
