Lecture 25: Physiology of whole-body metabolism/key role of glucose Flashcards Preview

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Flashcards in Lecture 25: Physiology of whole-body metabolism/key role of glucose Deck (56)
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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?

A

Clinical: Glucokinase Mutation

Mutations of glucokinase gene for this enzyme can cause unusual forms of diabetes (cannot utilise glucose so hyperglycaemia).

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
Q

What would you observe in a Clinical KATP Channel mutation

A

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
Q

What would you observe in patients with mutations in Glucagon-Like Peptide

A

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
Q

Describe the steps of Insulin synthesis

A

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
Q

What are the clinical implications of the C Peptide

A

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
Q

Describe the clinical implication of the B chain in preproinsulin

A

Clincial: B Chain

Because chain B has positive charge, we can modify it for short acting and long acting insulin drugs.

30
Q

Describe the regulation of insulin

A

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
Q

Insulin is released in response to…. and is inhibited by….

A

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
Q

Decribe the inter-organ communication with Beta Cells

A
  • 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
Q

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 _____________________

A

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
Q

_______Regulate Glucose Homeostasis Through Effects on Islet Cell Function

A

Incretins Regulate Glucose Homeostasis Through Effects on Islet Cell Function

35
Q

Describe the role of Incretins

A

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
Q

Ingestion of food leads to _______gut hormones release such as __________which results in:

______________ and _________

A

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
Q

Describe how Insulin signalling works

A

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
Q

Describe the insulin metabolic action on Carbohydrates

A
  • 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
Q

Describe the insulin metabolic action of fat

A
  • Insulin increases triglyceride storage, inhibits lipolysis (↓hormone sensitive lipase), which inhibits FFA production, therefore inhibits ketone production
40
Q

Describe the insulin metabolic action on protein

A
  • Insulin is anabolic so it increases transport of amino acid into liver and muscle (store energy)
41
Q

What happens to glucose (% -wise) once we absorb it?

A

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
Q

What happens to excess carbohydrate?

A

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
Q

Where is fat stored?

A

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
Q

How do we stored Protein?

A

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
Q

Describe the Kreb Cycle

A

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
Q

What is glucogenesis?

A

Gluconeogenesis is the formation of new molecules of glucose

47
Q

Define glycolysis

A

Glycolysis is the breakdown of glucose to pyruvate, which enters the Krebs cycle to produce ATP.

48
Q

What is Glycogenolysis?

A

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
Q

What is Protein Hydrolysis?

A

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
Q

What is lipolysis?

A

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
Q

What are ketones?

A

Ketones (volatile, makes breath smell) are produced via oxidation of FFA.

Ketone 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
Q

What are some consequences of Insulin Deficiency?

A

(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
Q

What are normal individual response to hypoglycaemia?

A

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
Q

Describe what happens when someone with Type 1 Diabetes is hypoglycaemic

A

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
Q

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.

A

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
Q

What are some causes of hypoglycaemia?

A
  • 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)