Lecture 14 - Glucose homeostasis Flashcards

1
Q

What is the endocrine system?

A
  • Responsible for maintaining homeostasis in the body – like the nervous system
  • Consists of cells, tissues and organs that secrete hormones as a primary or secondary function
  • Uses chemical signalling in the form of hormones that are transported primarily by the bloodstream
  • Hormones result in autocrine (affects the cells that secreted it), paracrine (affects neighbouring cells) and long-distance (other parts of the body)
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2
Q

The pancreas is an organ of the

A

Endocrine system

  • Role in the body: regulation of macronutrient digestion for metabolism/energy homeostasis by releasing various digestive enzymes and hormones
  • Exocrine and endocrine function
  • Exocrine function: the secretion of digestive enzymes into the small intestine to aid in the digestion of carbohydrates, proteins and fats
  • Endocrine function: production and secretion of hormones into the bloodstream to regulate glucose metabolism
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3
Q

What are the two main types of pancreatic cells?

A

Acinus: aids in the exocrine function
* Cluster of acinar cells
* Secretes digestive enzymes
* Produced as inactive forms and stored in zymogen granules (protects pancreatic cells from destruction)
o Amylase: breaks down carbohydrates
o Lipase: breaks down lipids
o Trypsinogen: breaks down proteins
* Stimulated by acetylcholine and cholecystokinin
Ductal cells:
* Produces an aqueous secretion containing bicarbonate
* Helps neutralise acidic stomach contents by increasing bicarbonate as needed
* Stimulated by secretin, as well as acetylcholine and cholecystokinin

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4
Q

What is the anatomy of the pancreas?

A

Acinus
>cluster of acinar cells, secrete digestive enzymes into the pancreatic duct

Islets of Langerhans
>secrete hormones into the bloodstream
>alpha cells
>beta cells
>exocrine acinus

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5
Q

What are the Islets of Langerhans

A
  • The islets of Langerhans are scattered throughout the pancreas and make up only about 1-2% of its total mass. They are composed of several types of cells, including alpha cells, beta cells, delta cells, and gamma cells and epsilon cells
  • Beta cells are the most abundant type of cell in the islets of Langerhans and are responsible for the production and secretion of insulin.
  • Alpha cells are responsible for the production and secretion of glucagon, which is another hormone that helps to regulate blood glucose levels.
  • Delta cells secrete somatostatin, which helps to regulate the release of insulin and glucagon by the alpha and beta cells.
  • The islets of Langerhans are a critical component of the endocrine system and play a crucial role in regulating blood glucose levels in the body

> beta cells (65-85%): insulin
alpha cells (15-20%): glucagon
delta cells (3-10%): somatostatin
gamma cells (3-5%): pancreatic polypeptide
epsilon cells (<1%): ghrelin

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6
Q

What are some of the multiple fate selections that allow the development of the pancreatic islet lineages?

A

> Sox17 (endodermal cell)
Sox9 (can split into hepatocytes and liver duct cells, or duodenum epithelial cells and endocrine cells)

> > Pdx1 (pancreatic progenitor cells)
can split into acinar cells or duct cells
Ngn3 (islet progenitor)
beta and alpha cells

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7
Q

What is insulin?

A
  • Peptide hormone that decreases blood glucose levels
  • Encoded by INS gene on chromosome 11
  • Initially translated as a single polypeptide chain: it consists of A chain and a B chain
  • Proinsulin is cleaved to form insulin + C-peptide
  • Insulin is produced and stored as a hexamer coordinated around zinc ions , monomeric form is not stable, thus stored as a hexomer, stable while inside the beta cell waiting for stimulus to be degranulated
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8
Q

How does glucose trigger insulin secretion from beta cells?

A

1) Increase in BGL
2) Uptake of glucose into Beta cells via GLUT 1/2/3 Transporters

3) Glycolysis in beta cells > produce ATP and NADH
>Increased ATP:ADP ratio

4) ATP blocks K+/ATP channels
>increased K+ in cell makes cell more positively charged
>depolarisation of cell membrane
>opens up voltage-dependent Ca2+ channels

5) Influx of Ca2+ into cell
>stimulates exocytosis of insulin granules

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9
Q

What are other amplification factors which promote insulin secretion?

A

o Hormones: glucagon, GIP and GLP-1
o All 3 can act on beta cells to amplify glucose-stimulated insulin secretion
o Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretin hormones
o Also replenishes insulin by inducing insulin transcription
o Increased fatty acid or amino acids in the blood

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10
Q

What are inhibitory factors for insulin secretion?

A

o Norepinephrine/noradrenaline:
 Sympathetic nervous system
 Activated during stressful situations – therefore glucose is needed
o Somatostatin:
 Inhibitory hormone – produced by delta cells
 Inhibits excessive release of pancreatic hormones

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11
Q

What is the insulin synthesis pathway?

A

1) Chr11 INS gene

2) Pre-pro-insulin
>signal sequence (directs PPI to ER) + Beta chain + C-peptide + Alpha chain

3)Endoplasmic reticulum (ER) processing
>cleave signal sequence
>formation of B-A disulphide bonds
>Pro-insulin

4) Shuttle to Golgi Apparatus
>C-peptide cleaved by pro-hormone convertase
>always 1:1 ratio of c-peptide to active insulin

5) Mature biological active insulin stored in insulin granules, secreted by exocytosis

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12
Q

What is insulin’s effects on target cells?

A

Insulin
>anabolic hormone
>promotes conversion of small energy molecules (glucose, fatty acids, amino acids) into large storage molecules

> > binds to cellular receptors (2 alpha 2 beta subunits-RTK) on target cells, and signals upregulation of GLUT4 transporters

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13
Q

What does insulin promote?

A

Insulin promotes *glycogenesis
>Liver
»glucose > glycogen

> > once glycogen storage in liver is full
glycolysis of glucose into pyruvate (+acetyl-coa in adipose tissue)
form fatty acids to store as fat

> Skeletal muscle
stimulates uptake of glucose and amino acids
promotes protein production and muscle growth

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14
Q

What does insulin inhibit?

A

Insulin inhibits *gluconeogenesis
>Liver
»prevent formation of glucose from lactic acid and non-carbohydrate molecules

Insulin inhibits *lipolysis
>adipose tissue
»prevent breakdown of fatty acids

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15
Q

What is glucagon?

A

Encoded by GCG gene on long arm of Chr2
>Peptide hormone that increases BGL

> stored in granules in the alpha cell where it waits to be released (monomer form)

> Preproglucagon
(leader signal peptide moves it into ER and golgi)
proglucagon
glucagon

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16
Q

What are the stimulatory and inhibitory factors of glucagon secretion?

A
  • Alpha cells are sensitive to low glucose concentrations in the blood
  • Other stimulatory factors:
    o Adrenaline
     Sympathetic nervous system
     Activated by stress
    o Cholecystokinin
     Produced by intestinal cells
     Also aids digestion: stimulates digestion and absorption
  • Inhibitory factor:
    o Insulin
    o Somatostatin:
     Inhibitory hormone produced by delta cells
     Inhibits excessive release of pancreatic hormones
17
Q

What is the effect of glucagon on target cells ?

A

Glucagon
>catabolic hormone
>promotes breakdown of large storage molecules

> binds to receptors on target cells (7TM receptor)
signals cell to breakdown glycogen and fat

Glucagon promotes
>glycogenolysis (breakdown of glycogen into glucose)
>gluconeogenesis (synth of glucose from non-carbohydrate carbon sources)
>*lipolysis
»>causes blood glucose levels to rise
»>breakdown of fatty acids converted into ketone bodies in liver (might lead to diabetic ketoacidosis)

18
Q

What is the interplay between insulin and glucagon to maintain blood glucose levels?

A

> Increase in blood glucose concentration (e.g. after a meal)
Increase insulin secretion by pancreatic beta cells
»glucose uptake by liver (adipose tissue, muscle)
»increase in glycogenesis (also lipogenesis)
Decreased in glycogenolysis, gluconeogenesis

«Decrease in blood glucose concentration (e.g. fasting, sleeping, exercise)
Increase in glucagon secretion by pancreatic alpha cells
»Breakdown of glycogen by liver
»increase in glycogenolysis, glyconeogenesis (also lipolysis in adipose tissue)
Decrease in glycogenesis

19
Q

What is the pancreas interplay with brain, liver, gut, adipose and muscle tissues?

A

Brain-islet axis
Liver-islet axis
Gut-islet axis
Adipose/muscle tissue

20
Q

How is blood glucose levels monitored?

A
  • Electrode used instead of oxygen. The electrons produce an electronic current proportional to glucose concentration in the blood
  • Some variation is normal – depends on when it is measured
  • Measurement of blood glucose for diagnosing diabetes needs to be done by a certified laboratory

Hyperglycaemia = BGL > 7.8mmol
Hypoglycaemia = BGL < 3.3mmol

21
Q

How is glucose measured for diagnostic purposes?

A

Random venous plasma glucose measurement:
1. A blood sample is taken randomly (intravenous collection done in the clinic)
2. Plasma/serum glucose concentrations measured by a certified laboratory
a. Requires centrifugation to remove red blood cells
**>11.1 mmol/L = diabetes mellitus

22
Q

How is insulin and C-peptide measured?

A

Detecting insulin:
* Detects insulinomas (e.g., insulin-secreting tumour)
* Limited utility for diabetes  does not reliably identify patients who require insulin therapy
C-peptide: typically used in research studies to determine beta cell function
* Identify individuals at-risk for developing T1D
* Determine residual beta cell function in long-standing T1D patients
* Measures beta cell function in patients after pancreas/islet transplantation

23
Q

Why can’t a diagnosis of T1D be made based on this value of random venous blood glucose >11.1mmol/L alone?

A

A diagnosis of Type 1 Diabetes (T1D) cannot be made based on a single value of random venous blood glucose alone. The diagnosis of T1D is based on a combination of factors including symptoms, medical history, physical examination, and laboratory tests.

24
Q

What can be determined from a radioimmunoassay?

A

Radioimmunoassay:
* Combines the use of a radiolabelling and specific antibodies to measure the concentrations of hormones and peptides in the blood

25
Q

What are the pancreatic and islet abnormalities in T1D?

A

Endocrine compartment:
Variable distribution and severity of infiltrating immune cells
Loss of beta cells and insulin expression

Exocrine compartment:
Loss of pancreatic volume
Exocrine tissue atrophy

26
Q

What is diabetic ketoacidosis?

A
  1. Lack of insulin
  2. Increased glucagon: insulin
  3. Release of free fatty acids from adipose tissue (lipolysis)
  4. Converted by the liver into ketone bodies (beta oxidation)
  5. Ketone bodies have a low pKa - very acidic
  6. Decreased blood pH + acetone (fruity breath)
27
Q

Compare T1D and T2D

A

T1D: autoimmune mediated destruction of insulin-producing beta cells
>5-10% oif cases
Loss of insulin production

T2D: body cells become resistant to insulin, body has to produce more and more insulin to keep up
>insulin resistance, insulin deficiency
>90-95% of cases
Pancreatic beta cells compensate by producing more insulin leads to excessive blood insulin levels (Hyperinsulinemia)
Pancreatic beta cell failure
Preventable by lifestyle modification