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BIOM3015 2024 > Metabolism and diabetes Lecture 1 > Flashcards

Metabolism and diabetes Lecture 1 Flashcards

1
Q

explain how insulin and glucagon regulate glucose homeostasis

A
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2
Q

outline the pathophysiology of type II diabetes

A
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3
Q

In the Major Metabolic Pathways, What is the function of Stage 1: GI tract

A

Digestion of micronutrients, then the micronutrients are absorbed by the small intestine into blood and transported

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4
Q

In the Major Metabolic Pathways, What is the function of Stage 2: Target tissue cells

A

Anabolism or catabolism of nutrients.
Glycolysis is the major catholic pathway (glucose -> pyruvate)

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5
Q

In the Major Metabolic Pathways, What is the function of Stage 3: Mitochondria

A
  • Oxidative (oxygen required) breakdown of micronutrients
  • Citric acid cycle and oxidative phosphorylation are the major pathways
  • Results in generation of ATP and release of CO2 and water
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6
Q

What is Glucose and its functions

A
  • Glucose is a simple sugar or hexose monosaccharide
  • Glucose is an important short term energy source for all cells (oxidised to generate ATP)
  • Glucose is converted to glycogen and stored in the liver or muscle for energy or fat
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7
Q

What is a normal Blood Glucose Level (BGL) and how is it regulated

A
  • Normal BGL is 4.5 - 5.5 mmol/L
  • BGL is principally regulated by pancreatic endocrine peptide hormones insulin and glucagon
  • Other stress hormones can also regulate BGL such as Epinephrine, Growth Hormone, and Cortisol
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8
Q

Explain the Glucose and Neurons relationship

A
  • Glucose is the major energy source for neurons
  • Neurons cannot store glycogen (although glial cells nearby can)
  • adequate blood glucose is essential for normal CNS function
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9
Q

Explain the anatomy and physiology of the pancreas

A
  • Mixed gland comprising both endocrine and exocrine gland cells
  • Comprises of mostly acinar exocrine cells
  • contains 1 million tiny islets that produce endocrine hormones
  • alpha-islet cells secrete glucagon (hyperglycemic hormone)
  • beta-islet cells secrete insulin (hypoglycemic hormone)
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10
Q

What do alpha and beta cells secrete

A
  • alpha-islet cells secrete glucagon (hyperglycemic hormone)
  • beta-islet cells secrete insulin (hypoglycemic hormone)
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11
Q

What is insulin

A

Insulin is a Hypoglycemic 51 aa peptide hormone that lowers blood glucose levels

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12
Q

Explain insulin production in the Pancreas

A
  • Produced in the beta-islet cells
  • Initially produced as a larger pro-insulin form that undergoes proteolytic maturation to form “mature insulin”. This process removes 31 aa C-peptide
  • ## Mature insulin comprises 2 disulphide linked A and B peptide chains
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13
Q

Where is insulin stored in the pancreas

A

Insulin is stored in the beta-islet cell granules in complex with zinc

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14
Q

Explin the actions of Glucose

A
  • Facilitating glucose entry into cells (particularly in muscle/fat) via glucose transports (GLUT)
  • Enhancing glucose oxidation (glycolysis)
  • Stimulating conversion of glucose to glycogen (glycogenesis) in the liver and muscle
  • Enhancing fat synthesis (lipogenesis) and inhibiting fat breakdown (lipolysis) in adipose tissue
  • Promoting amino acid uptake and protein synthesis in muscles
  • Inhibiting manufacture (gluconeogenesis) and liberation of
    glucose (glycogenolysis) in the liver
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15
Q

What is the glucose transport process

A

Glucose enters target cells by facilitated diffusion via GLUT transporter proteins
1. Glucose binds to GLUT transporter resulting in
conformational change
2. Conformation change allows glucose to enter
interior of GLUT transporter and cytosol of the cell
3. Release of glucose from GLUT causes GLUT
protein to return to its glucose receptive state

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16
Q

Which cells does GLUT 1 transport in, their uptake and are they insulin dependent

A

Many cells, blood brain barrier & erythrocytes
basal G uptake
insulin-independent

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17
Q

Which cells does GLUT 2 transport in, their uptake and are they insulin dependent

A

Liver hepatocytes and Pancreatic beta cells
G uptake
insulin-independent

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18
Q

Which cells does GLUT 3 transport in, their uptake and are they insulin dependent

A

Most cells Impt central nervous system (neurons)
basal G uptake
insulin-independent

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19
Q

Which cells does GLUT 4 transport in, their uptake and are they insulin dependent

A

Muscle myocytes and Fat adipocytes
G uptake
insulin-dependent
Insulin promotes glucose uptake into muscle (skeletal and cardiac) and fat cells via GLUT4

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20
Q

Which cells does GLUT 5 transport in, their uptake and are they insulin dependent

A

Intestinal epithelial cells (luminal side)
Fructose transport
insulin-independent

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21
Q

Explain the process of GLUT4 Insulin dependent glucose transporter under Low insulin

A

Under conditions of LOW insulin:
Dormant GLUT4 is sequestered in
cytoplasmic vesicles.

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22
Q

Explain the process of GLUT4 Insulin dependent glucose transporter under High insulin

A

Under conditions of HIGH insulin:
Insulin binds to its receptors on the cell membrane which initiates a cell signalling cascade (IRS-PI3K-PKB cascade) that promotes the exocytosis of GLUT4 containing vesicles to the cell surface. Glucose can then enter the cells via GLUT4

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23
Q

Explain the roles of GLUT2 in pancreatic beta-cells

A
  • GLUT2 is the main modulator of glucose uptake in beta-cells
  • Also present in tissues with high glucose concentrations (intestine, liver, kidney, nervous system)
  • GLUT2 facilitates K+-ATP-dependant insulin secretion
    (ATP liberated via glucose metabolism)
24
Q

Explain the roles of GLUT2 in pancreatic beta-cells in the fed state

A

In the fed state, GLUT2 transports glucose into cells and interacts with glucokinase (GCK) as a glucose sensor → regulates glucose concentrations on both sides of the
cell membrane

25
Q

Explain the roles of GLUT2 in pancreatic beta-cells in the fasted state

A

In the fasted state, intracellular glucose-6-phosphatase hydrolyzes glucose-6-phosphate to glucose and
phosphates → glucose transported out of cells by GLUT2

26
Q

Explain Glucagon Production

A
  • Hyperglycemic 29 aa peptide hormone – raises blood glucose levels
  • Produced by alpha-islet cells of pancreas
  • Initially synthesised as larger
    preproglucagon that undergoes proteolytic maturation to form “mature glucagon”
  • Preproglucagon also produced in the brain and intestines, but glucagon not liberated in these tissues (as they lack enzyme Psck2)
  • Several biproducts of glucagon synthesis are also involved in glucose homeostasis (and basis of drug targets)
27
Q

How does Glucagon increase blood glucose

A

Glucagon increases blood glucose by:
- stimulating liver hepatocytes to produce glucose via
glycogenolysis AND gluconeogenesis
- stimulates adipocytes to produce fatty acids

28
Q

What is the mode of action by glucagon

A

Glucagon:
- Acts via G-protein coupled receptor (GPCR) on hepatocytes
- Glucagon binding to GPCR activates adenylate cyclase
- Results in cAMP increase which activates PKA pathway to:
- drive glycogen breakdown (glycogenolysis)
- promote gluconeogenesis
- block glycolysis

29
Q

Explain Glucagon-like peptide 1 (GLP-1)

A
  • Byproduct of preproglucagon liberated in the gut (after eating)
  • Binds also to GPCRs (GLP-1R) on beta-cells to promote insulin release (via cAMP/PKA pathway)
  • Also inhibits release of glucagon
  • Short half-life of ∼2–3 min
  • GLP1 system major therapeutic target for the treatment of type 2 diabetes
30
Q

What are the treatments for type 2 diabetes and why they work?

A

Semaglutide (Ozempic , Rybelsus , Wegovy )

GLP1 receptor agonists - mimic GLP1 peptide

Improves glycaemic control in T2D:
- Works as adjunct with diet and exercise to support weight loss in obese individuals
- Reduces risk of cardiovascular associated death and stroke in overweight/obese adults with
cardiovascular disease

31
Q

What are some of the contraindications of treatments used for T2D

A
  • Can cause hypoglycaemia, gastrointestinal upset (nausea, vomiting, diarrhea), indigestion,
    abdominal discomfort
  • Indications that some formulations promote thyroid C-cell tumours (rodents)
  • Also been shown to promote marked muscle loss
32
Q

What are some of the other factors that can influence glucose homeostasis

A
  • Carbohydrate intake
  • Intestinal absorption
  • Glucose utilisation in cells
  • Renal elimination of glucose
33
Q

What are the 3 types of diagnostic tools for diabetes

A
  1. Random or Fasting Blood Glucose concentration
  2. Oral Glucose Tolerance Test (OGTT)
  3. Glycosylated Haemoglobin (Haemoglobin A1c) Concentration
34
Q

Explain Random or Fasting Blood Glucose concentration test

A

Indicative of current blood glucose levels - quick look/see.
Need to account for time since last meal if non-fasting.

35
Q

Explain Oral Glucose Tolerance Test (OGTT)

A

Following fasting, glucose administrated orally, and then blood sampled over a period of hours to measure glucose concentration and glucose clearance.

36
Q

Explain Glycosylated Haemoglobin (Haemoglobin A1c) Concentration test

A

Measures haemoglobin with bound glucose (glycated haemoglobin) – found in red blood cells.
Can persist in blood for 3+ months, so can be used to track BGL over months.

37
Q

Explain type 1 diabetes

A
  • accounts for 10% cases
  • insulin hyposecretion
  • deficiency in insulin secretion from pancreatic beta-islet cells
  • elevated blood glucose
38
Q

Explain Type 2 diabetes

A
  • accounts for 90% cases
  • insulin hypoactivity
  • deficiency in insulin activity and therefore, glucose uptake into
    muscle and fat
  • elevated blood glucose
39
Q

Explain Diet induced type 2 diabetes

A
  • Represents 85 to 90% of all cases of diabetes
  • Pathophysiology characterised by insulin resistance (cells not responding to insulin) and initial hyperinsulinemia (elevated insulin production), followed by progressive decline in insulin production from beta-islet cells
  • By diagnosis 40-80% of beta-cell function is typically lost, but with good glycaemic control this can be restored
  • Almost 60 per cent of all cases of type 2 diabetes can be delayed or prevented with changes to diet and lifestyle
40
Q

What are the risk factors for developing type 2 diabetes

A
  • family history of type 2 diabetes
  • being overweight or obese, especially abdominal fat accumulation
  • a low level of physical activity
  • poor diet
  • being over 55 years of age
  • for women — having had gestational diabetes
  • for women — having polycystic ovarian syndrome
  • for women — having had a baby weighing over 4.5kg
41
Q

Explain insulin resistance

A
  • insulin actions on targets cells – cells/tissues “resistant” or “insensitive” to insulin
  • Pancreas produces ↑ more insulin to compensate
  • Excess insulin helps to drive glucose uptake and keep BGL in healthy range
42
Q

Explain prediabetes

A
  • Estimated as many as 1 in 3 adults are prediabetic

↑ BGL but not high enough to be diagnosed as diabetic

  • Occurs often with insulin resistance OR as consequence of defective insulin -production in pancreatic beta-cells
  • In absence of sufficient insulin, glucose uptake is impaired and BGLs are elevated (but not to diabetic levels), HbA1c < 6.4% (46 mmol/mol)
43
Q

Explain insulin resistance pathophysiology in muscle

A

In muscle, insulin resistance is associated with impaired GLUT4 translocation (via disrupted IRS1/PI3K/Akt signalling)

44
Q

Explain insulin resistance pathophysiology in fat

A

In fat, insulin resistance is related to heightened lipolysis (fatty acid flux) and a reduction in adipogenesis, which has indirect consequences for nutrient delivery to the liver and muscle

45
Q

Explain insulin resistance pathophysiology in the liver

A

In the liver, insulin resistance influences multiple arms of hepatic signalling, resulting in increased gluconeogenesis and
lipogenesis

46
Q

Explain pancreatic beta-cell failure in diabetes

A
  • T2D ultimately occurs when progressive loss of beta-cell function results in an inability to compensate for insulin resistance
  • Reduced pancreatic production of insulin owing to ↓ beta -cell numbers, beta-cell exhaustion, and beta-cell differentiation into other cell types
  • beta-cell mass typically lower (up to 60%) in T2D
  • Mediators of beta-cell dysfunction include hyperglycaemic-induced cell death, oxidative stress (owing to altered glucose metabolism), and de/transdifferentiation of beta-cells into other cell types
  • beta-cell dysfunction sufficient to cause hyperglycaemia, but ↓ beta-cell numbers may not (as other beta-cells may overcompensate)
47
Q

Explain how glucagon is dysregulated in diabetes

A
  • Glucagon secretion is flawed in T2D patients
  • ↑ glucagon in fasted state and defective postprandial glucagon suppression that leads to ↑ glucagon concentrations in the presence of hyperglycaemia
  • ↑ glucagon levels drive gluconeogenesis in the liver to increase hepatic glucose output
  • Mechanisms by which this occurs not fully understood, but evidence supports that in T2D pancreatic alpha-cells are resistant to the glucagon-suppressive effects of glucose and insulin
  • Gut likely to play a role as glucose ingestion in T2D patients results in more pronounced hyperglucagonemia relative to IV glucose delivery
48
Q

In type 2 diabetes what pathophysiology occurs in the pancreas

A
  • ↓ insulin secretion
  • ↓ beta-cell mass
  • ↑ beta-cell apoptosis
  • Hyperglucagonemia
49
Q

In type 2 diabetes what pathophysiology occurs in the Adipocytes

A
  • ↑ circulating fatty acids
  • Hyperlipidemia
50
Q

In type 2 diabetes what pathophysiology occurs in the Liver

A
  • ↑ hepatic glucose output
  • insulin resistance
51
Q

In type 2 diabetes what pathophysiology occurs in the Gut

A
  • Impaired incretin effect
52
Q

In type 2 diabetes what pathophysiology occurs in the Muscle

A
  • Insulin resistance
53
Q

What is the first line of oral therapy for Type 2 Diabetes

A

Metformin first line oral therapy for T2D; lowers hepatic glucose production, increases insulin sensitivity, and reduces appetite (via growth and differentiation factor 15, GDF15)

54
Q

What regulates glucose homeostasis

A
  • Glucose homeostasis is regulated by pancreatic hormones, insulin and glucagon.
55
Q

What is insulin and what does it promote

A
  • Insulin is a hypoglycemic hormone that promotes glucose conversion and cellular uptake in muscle
56
Q

What is Glucagon

A
  • Glucagon is a hyperglycemic hormone that helps to liberate glucose from stores in the liver and fat
57
Q

Explain in a summary type 2 diabetes

A
  • Type II diabetes is associated characterised by insulin resistance followed by progressive decline in
    insulin production from beta-islet cells
  • Type II diabetes involves dysfunction across multiple systems: impaired pancreatic beta-cell numbers/function, reduced glucose uptake by the muscles, increased hepatic production of glucose, and elevated lipolysis in fat

BIOM3015 2024 (14 decks)

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