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Gastro nutrition > Endo pancreas and insulin > Flashcards

Endo pancreas and insulin Flashcards

1
Q

Endocrine pancreas is what % of pancreatic mass?

A

1-2%

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2
Q

What % of pancreatic blood flow goes to the endocrine pancreas?

A

20%

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3
Q

What is the microstructure anatomy of pancreatic endocrine tissue called? Where are they found?

A

Consists of several million small (50-500 μm) islands of cells (islets of Langerhans), scattered through the pancreatic tissue, clustering near large vessels.

Encapsulated by single layer of fibroblasts
Beta cells form inner core around afferent arteriole and capillaries, other cells more associated with efferent

Efferent blood to acinar cells of exocrine pancreas (local portal system)

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4
Q

How are the cells arranged in Islets of Langerhans

A
  • Vascularised with a tuft of highly fenestrated capillaries and long cluster surround blood vessels
    ◦ 1-2% of total mass receiving 15% of pancreatic blood supply
    ◦ Beta cells form inner core around afferent arteriole and capillaries
    ◦ Other cells form the mantle more associated with efferent vessels
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5
Q

Describe endocrine pancreatic innervation

A
  • Well innervated with autonomic fibres - no specialised synapses instead NT wash over all cells
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6
Q

Pancreatic endocrine cell types 5 and their production

A
  • α-cells, which produce glucagon (30%)
  • β-cells, which produce insulin (60%)
  • γ-cells, which produce pancreatic polypeptide (5%)
  • δ-cells, which produce somatostatin (10%)
  • ε-cells, which produce ghrelin (small fraction)
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7
Q

What % of pancrreatic endocrine cells produce insulin?

A
  • α-cells, which produce glucagon (30%)
  • β-cells, which produce insulin (60%)
  • γ-cells, which produce pancreatic polypeptide (5%)
  • δ-cells, which produce somatostatin (10%)
  • ε-cells, which produce ghrelin (small fraction)h
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8
Q

What % of pancreatic endocrine cells produce glucagon?

A
  • α-cells, which produce glucagon (30%)
  • β-cells, which produce insulin (60%)
  • γ-cells, which produce pancreatic polypeptide (5%)
  • δ-cells, which produce somatostatin (10%)
  • ε-cells, which produce ghrelin (small fraction)
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9
Q

What is glucagon

A
  • Hormone of the fasted state preventing hypoglycaemia
  • 29 amino acid peptide secreted by alpha cells - stored in granules, exocytosed
    ◦ Preproglucagon –> proglucgon –> released
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10
Q

What is the structure of glucagon? Secreted by>

A
  • Hormone of the fasted state preventing hypoglycaemia
  • 29 amino acid peptide secreted by alpha cells - stored in granules, exocytosed
    ◦ Preproglucagon –> proglucgon –> released
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11
Q

What are the hepatic and extrahepatic actions of glucagon

A

◦ Hepatic - responsible for 75% of hepatic glucose release between meals
‣ Hepatic glucose release - glycogenlysis, decreased glycogen synthesis. decreased hepatic glycolysis, increased gluconeogenesis (does not increase substrate availability)
‣ Decreased VLDL synthesis - as beta oxidation is stimulated
‣ Increased beta oxidation of fatty acids leading to ketosis
‣ Also increases urea cycle enzyme activity causing ammonia levels to decrease in spite of increased amino acid metaboism
◦ Extrahepatic
‣ Decreased release of insulin
‣ Decreased appetitie
‣ Increased basal energy expenditure
‣ Increased cardiac contractility and HR

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12
Q

What % of glucose release is due to glucagon between meals?

A

◦ Hepatic - responsible for 75% of hepatic glucose release between meals
‣ Hepatic glucose release - glycogenlysis, decreased glycogen synthesis. decreased hepatic glycolysis, increased gluconeogenesis (does not increase substrate availability)
‣ Decreased VLDL synthesis - as beta oxidation is stimulated
‣ Increased beta oxidation of fatty acids leading to ketosis
‣ Also increases urea cycle enzyme activity causing ammonia levels to decrease in spite of increased amino acid metaboism
◦ Extrahepatic
‣ Decreased release of insulin
‣ Decreased appetitie
‣ Increased basal energy expenditure
‣ Increased cardiac contractility and HR

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13
Q

What effect does glucagon have in the liver?

A

◦ Hepatic - responsible for 75% of hepatic glucose release between meals
‣ Hepatic glucose release - glycogenlysis, decreased glycogen synthesis. decreased hepatic glycolysis, increased gluconeogenesis (does not increase substrate availability)
‣ Decreased VLDL synthesis - as beta oxidation is stimulated
‣ Increased beta oxidation of fatty acids leading to ketosis
‣ Also increases urea cycle enzyme activity causing ammonia levels to decrease in spite of increased amino acid metaboism
◦ Extrahepatic
‣ Decreased release of insulin
‣ Decreased appetitie
‣ Increased basal energy expenditure
‣ Increased cardiac contractility and HR

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14
Q

What effect does glucagon have extrahepatically? 4

A

◦ Hepatic - responsible for 75% of hepatic glucose release between meals
‣ Hepatic glucose release - glycogenlysis, decreased glycogen synthesis. decreased hepatic glycolysis, increased gluconeogenesis (does not increase substrate availability)
‣ Decreased VLDL synthesis - as beta oxidation is stimulated
‣ Increased beta oxidation of fatty acids leading to ketosis
‣ Also increases urea cycle enzyme activity causing ammonia levels to decrease in spite of increased amino acid metaboism
◦ Extrahepatic
‣ Decreased release of insulin
‣ Decreased appetitie
‣ Increased basal energy expenditure
‣ Increased cardiac contractility and HR

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15
Q

What is the MOA of glucagon?

A

◦ Gs protein GPCR and increased adenylyl cyclase –> increased cAMP therefore bypassing beta blocker effects and CaB effects. Mainly in liver
◦ Gq GPCR activating phospholipase C and IP3

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16
Q

What type of receptor does glucagon act on?

A

◦ Gs protein GPCR and increased adenylyl cyclase –> increased cAMP therefore bypassing beta blocker effects and CaB effects. Mainly in liver
◦ Gq GPCR activating phospholipase C and IP3

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17
Q

What causes the release of glucagon?

A

◦ Sympathetic stimulation
◦ Intrinsic glucose sensing - glucokinase as a sensor similar to Beta cells
◦ Paracrine signal like GIP and somatostatin
◦ Dietary
‣ Fasting
‣ Protein meals
‣ Exercise

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18
Q

What inhibits glucagon release?

A

◦ Somatostatin
◦ INsulin
◦ Zinc
◦ Hyperglycaemia - Glucagon release maximally inhibited at BSL 7-8mmol/L

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19
Q

What is the structure of insulin?

A
  • A 51 maino acid peptide hormone
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20
Q

How many units of insulin are in the body at any one time in storage in the pancreas?

A

200 units

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21
Q

Describe the production of insulin

A

◦ Produced from preproinsulin and proinsulin and stored as a crystallised hexamer with zinc and calcium
‣ C peptide a cleaved portion of proinsulin

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22
Q

How much insulin is generally secreted per hour under normal conditions?

A

0.5-1.5 units per hour

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23
Q

Describe the process triggering insulin release

A

◦ Glucose enters cells through GLUT2 (non insulin dependent) and equilibrates with blood in 60 seconds –> converted rapidly to glucose 6 phosphate by glucokinase (only works if BSL normal or high - starts working at 4-6mmol/L) and is unable to leave the cell
◦ Utilised for energy in the cell –> ATP production and DAG
◦ ATP sensitive potassium channels on the surface –> ATP production CLOSES these channels
◦ Membrane depolarisation caused by K channel closure
◦ Depolarisation prompts L type Ca channel opening
◦ Intracellular calcium rises causing release of insulin

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24
Q

What pattern is there to insulin release during the day

A

Basal insulin in the fasted state - this has fluctuations for an unknown reason
◦ Post prandial insulin - released in biphasic pattern

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25
Q

What stimulates insulin release

A

‣ Glucose - directly sensed
‣ ANS - vagal tone
‣ Growth hormone, prolactin, gonadotropins
‣ Incretin

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26
Q

What inhibits insulin release

A

‣ Somatostatin
‣ Adreanline, SNS, catecholamines
‣ Cortisol acutely (chronically actually promotes release)
‣ Glucagon
‣ PTH
‣ Ghrelin
‣ Leptin
‣ Inflammation

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27
Q

What is an insulin receptor? How does signal transduction occur?

A

◦ Transmembrane receptor with intracellular tyrosine kinase
◦ P13K secnodary messenger pathway - phosphatidyl inositol 3 kinase –> PIP3
◦ Insulin binding to receptors causes exocytosis of vesicles containing GLUT4 glucose transport proteins - required due to hydrophilic nature of glucose
‣ GLUT4 on skeletal, cardiac and adipose tissue
* The brain also has them but additionally primarily has GLUT3 insulin independent

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28
Q

What glucose entry protein does insulin increase?

A

◦ Transmembrane receptor with intracellular tyrosine kinase
◦ P13K secnodary messenger pathway - phosphatidyl inositol 3 kinase –> PIP3
◦ Insulin binding to receptors causes exocytosis of vesicles containing GLUT4 glucose transport proteins - required due to hydrophilic nature of glucose
‣ GLUT4 on skeletal, cardiac and adipose tissue
* The brain also has them but additionally primarily has GLUT3 insulin independent

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29
Q

What glucose entry protein is on the brain? How is this different to muscle?

A

◦ Transmembrane receptor with intracellular tyrosine kinase
◦ P13K secnodary messenger pathway - phosphatidyl inositol 3 kinase –> PIP3
◦ Insulin binding to receptors causes exocytosis of vesicles containing GLUT4 glucose transport proteins - required due to hydrophilic nature of glucose
‣ GLUT4 on skeletal, cardiac and adipose tissue
* The brain also has them but additionally primarily has GLUT3 insulin independent

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30
Q

How does insulin affect macronutritient metabolism?

A

◦ Cabohydrate metabolism
‣ Increased glucose uptake by skeletal muscle (80%), myocardium, adipose tissue, and liver –> 1 unit of insulin drops BSL by 2mmol/.L (10-15g of carbohydrate)
‣ Decreased glycogenolysis and decreased gluconeogenesis
‣ Increased deposition of muscle and hepatocyte glycogen
◦ Lipid metabolism
‣ Decreased free fatty acid mobilisation by adipose tissue (decreased activity of hormone-sensitive lipase)
‣ Increased triglyceride synthesis in liver and adipose tissue
‣ Increased synthesis of VLDLs and increased activity of lipoprotein lipase peripherally to break down circulating triglycerides for absorption in fat. Additionally increased uptake of TG and FFA into adipose tissue (clearance)
◦ Protein metabolism
‣ Decreased protein catabolism, increased protein synthesis
‣ Decreased gluconeogenesis from amino acids, and thus decreased urea production

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31
Q

What are the effects of insulin on carbohydrate metabolism

A

◦ Cabohydrate metabolism
‣ Increased glucose uptake by skeletal muscle (80%), myocardium, adipose tissue, and liver –> 1 unit of insulin drops BSL by 2mmol/.L (10-15g of carbohydrate)
‣ Decreased glycogenolysis and decreased gluconeogenesis
‣ Increased deposition of muscle and hepatocyte glycogen
◦ Lipid metabolism
‣ Decreased free fatty acid mobilisation by adipose tissue (decreased activity of hormone-sensitive lipase)
‣ Increased triglyceride synthesis in liver and adipose tissue
‣ Increased synthesis of VLDLs and increased activity of lipoprotein lipase peripherally to break down circulating triglycerides for absorption in fat. Additionally increased uptake of TG and FFA into adipose tissue (clearance)
◦ Protein metabolism
‣ Decreased protein catabolism, increased protein synthesis
‣ Decreased gluconeogenesis from amino acids, and thus decreased urea production

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32
Q

What are the effects of insulin on lipid metabolism

A

◦ Cabohydrate metabolism
‣ Increased glucose uptake by skeletal muscle (80%), myocardium, adipose tissue, and liver –> 1 unit of insulin drops BSL by 2mmol/.L (10-15g of carbohydrate)
‣ Decreased glycogenolysis and decreased gluconeogenesis
‣ Increased deposition of muscle and hepatocyte glycogen
◦ Lipid metabolism
‣ Decreased free fatty acid mobilisation by adipose tissue (decreased activity of hormone-sensitive lipase)
‣ Increased triglyceride synthesis in liver and adipose tissue
‣ Increased synthesis of VLDLs and increased activity of lipoprotein lipase peripherally to break down circulating triglycerides for absorption in fat. Additionally increased uptake of TG and FFA into adipose tissue (clearance)
◦ Protein metabolism
‣ Decreased protein catabolism, increased protein synthesis
‣ Decreased gluconeogenesis from amino acids, and thus decreased urea production

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33
Q

What are the effects of insulin on protein metabolism?

A

◦ Cabohydrate metabolism
‣ Increased glucose uptake by skeletal muscle (80%), myocardium, adipose tissue, and liver –> 1 unit of insulin drops BSL by 2mmol/.L (10-15g of carbohydrate)
‣ Decreased glycogenolysis and decreased gluconeogenesis
‣ Increased deposition of muscle and hepatocyte glycogen
◦ Lipid metabolism
‣ Decreased free fatty acid mobilisation by adipose tissue (decreased activity of hormone-sensitive lipase)
‣ Increased triglyceride synthesis in liver and adipose tissue
‣ Increased synthesis of VLDLs and increased activity of lipoprotein lipase peripherally to break down circulating triglycerides for absorption in fat. Additionally increased uptake of TG and FFA into adipose tissue (clearance)
◦ Protein metabolism
‣ Decreased protein catabolism, increased protein synthesis
‣ Decreased gluconeogenesis from amino acids, and thus decreased urea production

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34
Q

What are the effects of insulin

A

Macronutrient metabolism
- Carbs
- Lipids
- Protein
Electrolytes
Inodilator
On the release of glucagon

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35
Q

How does insulin effect potassium

A

‣ Intracellular shift of potassium and phosphate
* why you see DKA patients get hypophosphataemic
* Hypokalaemia due to –> increased Na/H+ exchange and Na entry into cells, subsequent Na/K ATPase action and inhibited K efflux from cells

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36
Q

How does insulin effect electrolytes

A

‣ Intracellular shift of potassium and phosphate
* why you see DKA patients get hypophosphataemic
* Hypokalaemia due to –> increased Na/H+ exchange and Na entry into cells, subsequent Na/K ATPase action and inhibited K efflux from cells

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37
Q

Why does insulin work in hyperkalaemia?

A

‣ Intracellular shift of potassium and phosphate
* why you see DKA patients get hypophosphataemic
* Hypokalaemia due to –> increased Na/H+ exchange and Na entry into cells, subsequent Na/K ATPase action and inhibited K efflux from cells

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38
Q

How does insulin effect the heart?

A

‣ Increased cardiac contractility - increases catecholamine release, increased myocyte calcium concentration and increased myocardial carbohydrate metabolism
‣ Increased coronary blood flow
‣ Decreased afterload due to decreased peripheral vascular resistance at skeletal muscle - increased endothelial nitric oxide and hyperpolarises smooth muscle membranes (Na/K ATPase stimulated)
‣ Increased sympathetic nervous system activity

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39
Q

How does insulin effect the liver?

A
  • Specifically on the liver - glucose enters by GLUT2 (insulin insensitive)
    ◦ Reduces the rate of gluconeogenesis
    ◦ Reduces the rate of glycogenolysis
    ◦ Increases the rate of glycogen synthesis
    ◦ Reduces the rate of free fatty acid oxidation (and therefore ketone production)
    ◦ Increases the rate of synthesis of VLDLs
    ◦ Decreases the rate of hepatic urea synthesis (mainly by decreasing amino acid deamination for gluconeogenesis)
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40
Q

How does insulin effect skeletal muscle?

A

◦ Increased glucose uptake –> glycogen synthesis
◦ Increased protein synthesis with decreased metabolism

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41
Q

How does insulin effect adipose tissue

A

◦ Increased glucose uptake
◦ Increased synthesis of TG and decreased lipolysis
◦ Increased lipoprotein lipase activity
◦ Increased uptake of FFA

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42
Q

What is pancreatic polypeptide?

A
  • Pancreatic polypeptide, which inhibits gastrointestinal secretions
    ◦ 36 amino acid polypeptide
    ◦ 6 minute half life
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43
Q

What causes release of pancreatic polypeptide?

A

‣ Gut contents - protein > fat > glucose
‣ Vagal stimulation

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44
Q

What causes inhibition of pancreatic polypeptide release

A

‣ Ghrelin
‣ Somatostatin
‣ Atropine

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45
Q

What does pancreatic polypeptide do?

A

‣ Inhibits pancreatic exocrine and endocrine secreiton
‣ Inhibits gallbladder contraction
‣ Decreased motility
‣ Inhibition of aptetiie

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46
Q

Somatostatin sturcturally?

A

◦ 2 cyclic peptides - 14 amino acid, 28 amino acid variant

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47
Q

Where is somatostatin produced?

A

‣ 65% in intestine
‣ 25% brain
‣ 5% in pancreatic islet delta cells

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48
Q

How long does somatostatin last?

A

◦ Half life 2 minutes

49
Q

What stimulates somatostatin release?

A

‣ Gut lumen content (fat esp)
‣ CCK, insulin, glucagon, gastrin, GIP
‣ Increased BSL
‣ Acidic pH in duodenum - most potent stimulus
‣ Sympathetic stimulation and Beta agonists

50
Q

What inhibits somatostatin release?

A

‣ Starvation
‣ Muscurinic agonists and vagal tone
‣ Adrenergic antagonists (alpha)

51
Q

What is the MOA of somatostatin?

A

Gi protein coupled receptors inhibiting adenylyl cyclase and reducing cAMP

52
Q

What is the action of somatostatin?

A

‣ Inhibition of all endocrine hormones - pancreatic, pituitary, endocrine pancreas, thyroid, renal
‣ Inhibits all exocrine secretions - intestinal secretions, bile pancreas
‣ Inhibits splanchnic flow
‣ Inhibits motility inc gall bladder contraction, peristalsis
‣ Increased intestinal absorption of carbohydrates, amino acids, TG, calcium, water and electrolytes
‣ Inhibits mucosal cell prolifation, inhibits immune cell activation, promotes apoptosis

53
Q

What effect does a lack of insulin have?

A

Decreased insulin availability leads to:
* Decreased glucose uptake into skeletal muscle
* Increased reliance on glycogenolysis and gluconeogenesis in liver and muscle
* Increased hormone-sensitive lipase activity, leading to an increased release of free fatty acids from adipose tissue
* Lack of insulin regulation in the liver leads to increased fatty acid oxidation
* Increased availability of acetyl CoA liberated through fatty acid oxidation causes increased ketone synthesis because of excess acetyl CoA being metabolised into acetoacetyl-CoA and ultimately into the ketones acetoacetate and β-hydroxybutyrate
The consequences of this are:
* Hyperglycaemia
◦ Thus:
‣ osmotic diuresis
‣ volume depletion
‣ compensatory cardiovascular changes in response to volume loss (eg. tachycardia)
◦ With volume loss, electrolytes are also lost, leading to a total body potassium and phosphate deficit
* Metabolic acidosis
◦ Thus, increased respiratory rate to compensate by lowering systemic CO2
◦ Increased anion gap (ketones are unmeasured anions)

54
Q

what is normal blood glucose concentration?

A
  • Normal BSL is on average 5 mmol/L during the fasting state.
  • 4-7.8 a reasonable normal range
  • It increases to no more than 9-10 mmol/L following a meal
  • There is a balance between tissue utilisation, release from stores, and production from dietary carbohydrates and gluconeogenesis
55
Q

Where does glucose come from between meals?

A
  • Release from storage: 50%
    ◦ glycogen and fat in the liver,
    ◦ glycogen in skeletal muscle
    ◦ fat in adipose tissue
  • De novo synthesis: 50%
    ◦ Gluconeogenesis by the liver (80%) and kidney (20%)
    ‣ Kidney up to 50% in prolonged starvation. Release from PCT
  • Total glucose supply = ~42mmol/hr or 0.7mmol/min in a 70kg patient
    ◦ 50% consumed by the brain
    ◦ 20% skeletal muscle
    ◦ 10% each by kidney and splanchnic organs
56
Q

What is the demand for glucose per hour? Where does this glucose go? What %

A
  • Release from storage: 50%
    ◦ glycogen and fat in the liver,
    ◦ glycogen in skeletal muscle
    ◦ fat in adipose tissue
  • De novo synthesis: 50%
    ◦ Gluconeogenesis by the liver (80%) and kidney (20%)
    ‣ Kidney up to 50% in prolonged starvation. Release from PCT
  • Total glucose supply = ~42mmol/hr or 0.7mmol/min in a 70kg patient
    ◦ 50% consumed by the brain
    ◦ 20% skeletal muscle
    ◦ 10% each by kidney and splanchnic organs
57
Q

Where is gluconeogenesis between meals done?

A
  • Release from storage: 50%
    ◦ glycogen and fat in the liver,
    ◦ glycogen in skeletal muscle
    ◦ fat in adipose tissue
  • De novo synthesis: 50%
    ◦ Gluconeogenesis by the liver (80%) and kidney (20%)
    ‣ Kidney up to 50% in prolonged starvation. Release from PCT
  • Total glucose supply = ~42mmol/hr or 0.7mmol/min in a 70kg patient
    ◦ 50% consumed by the brain
    ◦ 20% skeletal muscle
    ◦ 10% each by kidney and splanchnic organs
58
Q

Where is glucose sensed? How?

A
  • Mainly by pancreatic islet β-cells and α-cells
  • The molecular mechanism involves glucokinase, which has an affinity for glucose concentrations higher than 3-4 mmol/L
  • Glucokinase activity leads to the production of ATP and DAG
  • ATP inhibits ATP-sensitive potassium channels, depolarising the β-cell membrane and producing insulin release ( or suppressing glucagon release)
  • Minor role is played by hypothalamus and midbrain, which regulate satiety and the autonomic responses to hyper and hypoglycaemia
59
Q

What is the response to increased BSL

A
  • Glucagon release is suppressed
  • Insulin release is directly stimulated (biphasic pattern)
  • Insulin produces effects which promote the storage, and inhibit the release, of glucose:
    ◦ Reduced gluconeogenesis, glycogenolysis, free fatty acid oxidation and ketone production by the liver
    ◦ Increased glycogen synthesis and increased VLDL synthesis
    ◦ Increased glucose uptake by insulin-sensitive tissues which express GLUT4 glucose transport channels (skeletal muscle and adipose tissue)
60
Q

What is the effect of hypoglycaemia?

A
  • Insulin release is suppressed, and glucagon release is stimulated
  • Glucagon stimulates glucose mobilisation:
    ◦ Hepatic glycogenolysis increases, liberating stored glucose
    ◦ Hepatic and renal gluconeogenesis is stimulated - mainly by the breakdown of amino acids (although the rate-limiting step here is the supply of suitable amino acids, which is not something glucagon can control). At the same time it appears to increase the activity of urea cycle enzymes, which means that ammonia levels actually decrease in spite of increased amino acid metabolism.
  • Glucagon inhibits the transfer of glucose into storage forms:
    ◦ Glucagon inhibits glycolysis and hepatic glycogen synthesis
    ◦ Glucagon also inhibits the synthesis of VLDLs and triglycerides, and stimulates the beta-oxidation of fatty acids in the liver, which promotes ketogenesis.
61
Q

What is in 50% dextrose solution?

A
  • 50ml of 50% dextrose is 25g of dextrose in 50ml
    ◦ Osmolality 2780mosm/kg
    ◦ 25g of dextrose i 138mmol
62
Q

If you gave someone 50% glucose 50mls what happens to its distribution and absorption?

How does it effect osmolality? Blood volume? Blood volume?

A

Absorption and distribution
* Distributed within intravascular space and interstitial fluid rapidly
* Uptake into cells is mediated by insulin and tissue blood flow to brain/liver where insulin independent glucose uptake occurs
* 95% equilibrates across all compartments within 30 minutes

Effect on osmolality
* Transient increase –> 280mosm/kg by adding 138mosm you increase the serum osmolality to 307mosm/kg but rapid redistribution prevents osmoreceptor activation

Blood volume
* Movement of water transiently out of cells before rapid movement back into cells

63
Q

WHat effect would giving 50% dextrose 50mls have on BSL?

A
  • Rise in BSL diffusing into pancreatic Beta and alpha cells via GLUT2 transporters –> glucokinase transformation to glucose 6 phosphate –> ATP
  • Increased ATP –> inhibition of ATP dependent K efflux pumps depolarising the Beta cell membrane
    ◦ Release of insulin in a biphasic manner
  • Inhibition of alpha cell release of glucagon
64
Q

Dexscribe the actions of insulin?

A
  • Hepatic
    ◦ Reduced gluconeogenesis
    ◦ Reduced glycogenlysis
    ◦ Increased glycogen synthesis
    ◦ Increased VLDL packaging
    ◦ Reduced Beta oxidation and ketone production
  • Peripherally
    ◦ Increased glucose uptake via GLUT4 in skeletal and cardiac muscle in particular lowering glucose concentration
    ◦ Reduced activity of hormone sensitive lipase preventing peripheral lipolysis
    ◦ Increased lipoprotein lipase action causing peripheral fatty acid and TG breakdown and absorption into adipose tissue
    ◦ Increased TG synthesis
    ◦ Increased protein syntheiss and decreased protein catabolism in skeletal muscle
    ◦ Skeletal muscle glycogen synthesis
65
Q

Insulin structurally is?

A

◦ 51-amino-acid peptide, with several variants modified to adjust self-association behaviour
‣ Synthetic polypeptides

66
Q

In a concentrated solution what do insulin molecules do?

A

◦ In concentrated solution, associates into hexamers, and only soluble at a pH of 2-3
‣ pKa 5.4
‣ Excipients - phosphate and glucerol to enhance solubility

67
Q

What si the pKa of insulin?

A

◦ In concentrated solution, associates into hexamers, and only soluble at a pH of 2-3
‣ pKa 5.4
‣ Excipients - phosphate and glucerol to enhance solubility

68
Q

What is used to increase solubility of insulin?

A

◦ In concentrated solution, associates into hexamers, and only soluble at a pH of 2-3
‣ pKa 5.4
‣ Excipients - phosphate and glucerol to enhance solubility

69
Q

1 unit of insulin designates

A

◦ 1 unit - 38.5 microgof dry insulin crystals and corresponds to making a 2kig rabbit hypoglycaemic and develop seizures

70
Q

What is the oral bioavailability of insulin

A

0%

71
Q

Describe the determinants of absorption from SC depot of insulin 3

A

◦ Absorption from subcutaneous depot depends on
‣ Microcirculation to the region injected
‣ Concentration - the more insulin the more likely insulin will associate into oligmoers and slow absorption, the opposite to what you would expect due to a concentration gradient developing
‣ rate of dissociation from oligomers -
◦ Rapid acting insulins (eg. insulin aspart, Novorapid) have weak self-association and absorb more rapidly, whereas long-acting insulins remain in hexameric form for longer

72
Q

How does the concentration of insulin effect SC absorption profile?

A

◦ Absorption from subcutaneous depot depends on
‣ Microcirculation to the region injected
‣ Concentration - the more insulin the more likely insulin will associate into oligmoers and slow absorption, the opposite to what you would expect due to a concentration gradient developing
‣ rate of dissociation from oligomers -
◦ Rapid acting insulins (eg. insulin aspart, Novorapid) have weak self-association and absorb more rapidly, whereas long-acting insulins remain in hexameric form for longer

73
Q

How are rapid acting insulins different from slow acting insulins

A

◦ Absorption from subcutaneous depot depends on
‣ Microcirculation to the region injected
‣ Concentration - the more insulin the more likely insulin will associate into oligmoers and slow absorption, the opposite to what you would expect due to a concentration gradient developing
‣ rate of dissociation from oligomers -
◦ Rapid acting insulins (eg. insulin aspart, Novorapid) have weak self-association and absorb more rapidly, whereas long-acting insulins remain in hexameric form for longer

74
Q

Describe the distribution of insulin and protein binding

A

◦ Distributed to extracellular fluid; apart from detemir, most species are minimally protein bound; VOD is between 0.1 and 0.44 L/kg
◦ Half-life of IV insulin is 2-5 minutes mainly because of this distribution
◦ Distribution of insulin via injection is quite different to pancreatic release into portal circulation –> as this directly proceees to the liver, however SC insulin leads to delayed onset of action at absorbing glucose and depositing glycogen in skeletal muscle and slow to stop this function when glucose is gone –> higher risk hypoglycaemia

75
Q

Describe how insulin distribution is different between endogenous adn exogenous insulin

A

◦ Distributed to extracellular fluid; apart from detemir, most species are minimally protein bound; VOD is between 0.1 and 0.44 L/kg
◦ Half-life of IV insulin is 2-5 minutes mainly because of this distribution
◦ Distribution of insulin via injection is quite different to pancreatic release into portal circulation –> as this directly proceees to the liver, however SC insulin leads to delayed onset of action at absorbing glucose and depositing glycogen in skeletal muscle and slow to stop this function when glucose is gone –> higher risk hypoglycaemia

76
Q

what is the half life of IV insulin?

A

◦ Distributed to extracellular fluid; apart from detemir, most species are minimally protein bound; VOD is between 0.1 and 0.44 L/kg
◦ Half-life of IV insulin is 2-5 minutes mainly because of this distribution
◦ Distribution of insulin via injection is quite different to pancreatic release into portal circulation –> as this directly proceees to the liver, however SC insulin leads to delayed onset of action at absorbing glucose and depositing glycogen in skeletal muscle and slow to stop this function when glucose is gone –> higher risk hypoglycaemia

77
Q

What is the Vd of insulin

A

◦ Distributed to extracellular fluid; apart from detemir, most species are minimally protein bound; VOD is between 0.1 and 0.44 L/kg
◦ Half-life of IV insulin is 2-5 minutes mainly because of this distribution
◦ Distribution of insulin via injection is quite different to pancreatic release into portal circulation –> as this directly proceees to the liver, however SC insulin leads to delayed onset of action at absorbing glucose and depositing glycogen in skeletal muscle and slow to stop this function when glucose is gone –> higher risk hypoglycaemia

78
Q

How is insulin metabolised?

A

◦ Receptor/ligand complex is endocytosed and degraded, preserving the receptor which is recycled

79
Q

Where is insulin metabolised?

A

◦ This happens in most insulin-sensitive tissues, but mainly in the liver (50%) and kidney (30%)
‣ The liver like skeletal muscle, cardiac muscle and adipose tissue endocytoses and degrades the insulin in an acidic vesicle
‣ Insulin is filtered at the glomerulus, ends up being reabsorbed by the proximal tubule cells, and undergoes degradation in lysosomes. Only about 1% is eliminated as unchanged drug.

80
Q

What % of insulin is eliminated unchanged

A

1%

81
Q

What is the elimination half life of insulin

A

50-120 minutes

82
Q

Describe the duration of action of short acting insulins? Describe onset, time until peak effect and duration of action

A

◦ Short-acting: 1-3 hrs (aspart, lispro, glulisine)
‣ Aspart - novorapid - onset, 10-20 mins, 1-3 hours til peak, 3-5 hour duration
‣ Lispro (Humalog) - onset 15-30 minutes, peak 0.5 - 2.5 hours, duration 3 - 6.5 hours
‣ Glulisine (apidra) - 10 - 15 minute onset, peak 1 - 1.5 hours, duration 3-5 hours

83
Q

What are the short acting insulins

A

◦ Short-acting: 1-3 hrs (aspart, lispro, glulisine)
‣ Aspart - novorapid - onset, 10-20 mins, 1-3 hours til peak, 3-5 hour duration
‣ Lispro (Humalog) - onset 15-30 minutes, peak 0.5 - 2.5 hours, duration 3 - 6.5 hours
‣ Glulisine (apidra) - 10 - 15 minute onset, peak 1 - 1.5 hours, duration 3-5 hours

84
Q

What are the key performance characteristics of short acting insulins - how do they differ

A

◦ Short-acting: 1-3 hrs (aspart, lispro, glulisine)
‣ Aspart - novorapid - onset, 10-20 mins, 1-3 hours til peak, 3-5 hour duration
‣ Lispro (Humalog) - onset 15-30 minutes, peak 0.5 - 2.5 hours, duration 3 - 6.5 hours
‣ Glulisine (apidra) - 10 - 15 minute onset, peak 1 - 1.5 hours, duration 3-5 hours

85
Q

Descibre intermediate acting insulins - onset, time to peak effect and duration

A

◦ Intermediate-acting: 6-12 hrs (isophane), 6-10 hrs (regular human insulin)
‣ Regular human insulin = actrapid - Onset 30-60 minutes, peak 2-3 hours, duration 6-10 hours
‣ Isophane or NPH/protophane - Onset 1.5 - 4 hours, peak 6-14 hours, duration 16- 24 hours

86
Q

Regular human insulin is otherwise known synthetically as? Onset? Peak? Duration?

A

◦ Intermediate-acting: 6-12 hrs (isophane), 6-10 hrs (regular human insulin)
‣ Regular human insulin = actrapid - Onset 30-60 minutes, peak 2-3 hours, duration 6-10 hours
‣ Isophane or NPH/protophane - Onset 1.5 - 4 hours, peak 6-14 hours, duration 16- 24 hours

87
Q

Long acting insulin examples? Onset? time to peak? duration?

A

◦ Long-acting: 24-26 hours (glargine, detemir, degludec)
‣ Glargine - onst 1-3 hours, duration 24 hours
‣ Levemir the same
‣ Degludec - ONset 30-90 minutes, duration 24 - 36 hours (Tresiba

88
Q

Describe the MOA of insulin

A

◦ Binds to transmembrane receptors with intracellular tyrosine kinase domain
◦ Activates mechanisms to translocate GLUT4 glucose transporter proteins to the cell membrane, to increase cellular glucose uptake

89
Q

WHat effect does insulin have on carbohydrates

A
  • decreased hepatic glycogenolysis and gluconeogenesis
    * increased hepatic glycogen synthesis, and muscle glycogen
    * Increased glucose uptake by skeletal muscle, myocardium, adipose and liver
90
Q

What effect does insulin have on fat metabolism

A
  • decreased free fatty acid mobilisation by fatty tissue - hormone sensitive lipase
    * increased lipoprotein lipase activity
    * VLDL synthesis and release
    * Increased TG syntheiss in liver and adipose
91
Q

What effect does insulin have on protein metabolism

A
  • decreased protein catabolism and increased synthesis
    * Decreased amino acid glyconeogenesis –> reduced urea production
92
Q

What non mcaronutrient metabolic functions does insulin have 3

A

‣ Electrolytes - intracellular shift if phosphate and potassium
‣ positive inotropic effects
‣ decreased release of glucagon

93
Q

Glucagon chemistry

A

Peptide hormone
29 amino acids

94
Q

What is the absorption of glucagon

A

Zero oral bioavailability
Absorbed well from SC depotO

95
Q

What is the onset of SC glucagon

A

20 minutes

96
Q

pKa of glucagon

A

7.1

97
Q

Describe solubility of glucagon

A

Poor water solubility at high concentrations as autoassociates into trimer

98
Q

Vd of gluacgon

A

0.25L/kg

99
Q

What is the protein binding of glucagon

A

minimal

100
Q

Target receptor for glucagon

A

GPCR - Gs and Gq
Increasing cAMP

101
Q

Metabolism of glucagon

A

30% in liver
30% kidney
The rest by reticuloendothelial system
Minimal free drug eliminated in urineH

102
Q

Half life for glucagon

A

20-30 minutes

103
Q

MOA of biguanides

A

Disabling mitochrondrail respiratory chain decreasing ATP supply to hepatocytes which activates AMPK regulating balance of anabolic and catabolic activity

Activates fatty acid oxidation and deactivation of glycogenolysis ad gluconeogenesis

Systemic glucose delivery from the liver is decreased

104
Q

Adverse effects of biguanides

A

lactic acidosis
Diarrhoea, abdominal discomfort, anorexia
Taste disturbance metallic

105
Q

Sulfonylurea MOA

A

Binding ATP sensitive K channel act like ATP causing closure of the channel, depolarisation of the membrane by stopping K efflux, leading to insulin release

106
Q

Sulfonylurea SE

A

Hypoglucaemia as insulin secretion independent of BSL
Hypokalaemia
Secondary failure of therapy with pancreatic burn out
Weight gain

Erythema multiforme
Exfoliative dermatitis
Photosensitivity

107
Q

Alpah glucosidase inhibitors e/g.

A

acarbose

108
Q

MOA of acarbose

A

Alpha glucosidase inhibitor

Acting as a pseudo-carbohydrate substitude themselves as a substrate of alpha-glucosidase instead of sucrase, maltase etc. causing reduced intestinal sborption of complex carbhydrates

109
Q

Meglitinide MOA

A

Same as sulfonylureas

Binding ATP sensitive K channel act like ATP causing closure of the channel, depolarisation of the membrane by stopping K efflux, leading to insulin release

===

110
Q

Meglitinides SE

A

Severe hypoglycaemia but less likely than sulfonylureas as short acting
Respiratory tract infections
Headache

111
Q

Thiazolidinidiones MOA

A

PPAR gamma receptor activation leading to increased synthesis of cellular proteins involved in glucose uptake and processing resulting in increased effect from insulin binding in insulin sensitive tissues especially adipocytes increasing insulin sensitivity

112
Q

THiazolidinidiones SE

A

Weight gain - adipose tissue increasingly insulin sensitive
Increased bone fractures
Fluid retention and oedema
Cardiac ischaemia in rosiglitazone
Unlikely to cause hypoglycaemia

113
Q

Gliptan MOA

A

DPP4 inhibitors decreasing degredation of GLP1 therefore producing insulin secretion

Increased cAMP and increased Ca for exocytosis

114
Q

Gliptan SE

A

Headache
Weight neutral
Nasopharyngitis

115
Q

GLP1 agonists

A

Increased cAMP on pancreatic Beta cells driving insulin exocytosis

116
Q

GLP1 SE

A

Pancreatitis
Weight loss
Nausea/vomiting

117
Q

SGLT2 inhibitors

A

Inhibit PCT reabsorption increasing glucose loss in urine - 30-50% of filtered glucsoe lost (50-90g) resulting in reduced hyperglycaemiaS

118
Q
A

Gastro nutrition (7 decks)

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