MM1 Flashcards
The body keeps blood glucose tightly regulated.
- Why is it important to maintain blood glucose homoeostasis?
- What level is blood glucose maintained at in normal circumstances?
- How is blood glucose maintained in fasting state?
- Certain tissues can only metabolise glucose. These tissues are the brain, kidney and RBCs.
- The level is usually maintained at 4-5.5 mmol/L
- The liver is the primary organ for maintaining blood glucose. It does this via two main pathways:
- Glycogenolysis (breakdown of stored glycogen)
- Gluconeogenesis (synthesis of new glucose)
(1.1)
Identify the correct metabolic effects of glucagon:
- Glycolysis increased/decreased?
- Gluconeogenesis increased/decreased?
- Glycogen synthesis increased/decreased?
- Glycogen breakdown increased/decreased?
- Fatty acid synthesis increased/decreased?
- Fatty acid oxidation increased/decreased?
- DECREASED glycolysis
- INCREASED gluconeogenesis
- DECREASED glycogen synthesis
- INCREASED glycogen breakdown
- DECREASED fatty acid synthesis
- INCREASED fatty acid oxidation
(1.1)
True or False: The liver is the only organ with a complete gluconeogenesis pathway in the body
False. The kidneys also has a complete GNG pathway. However, due to its size, the liver is the body’s primary GNG organ
(1.1)
What is the role of cortisol in gluconeogensis?
Cortisol acts on the GNG pathway to promote glucose synthesis and mobilisation, acting similarly as glucagon, and opposing insulin.
(1.1)
True or False: Acetyl-CoA can be converted to glucose in times of fasting.
False. Whilst pyruvate, lactate and several other substrates can be converted into glucose acetyl-CoA cannot.
(1.2)
What is the rate limiting step of beta-oxidation at the mitochondria?
It is the transport of fatty acids into the mitochondria that is rate-limiting, not any of the enzymatic reactions themselves
(1.2)
True or False: Ketone bodies can only be formed in the liver.
True
1.2
Which of the following is NOT a benefit of producing ketone bodies during fasting?
A) Ketone bodies more easily metabolised than FAs
B) The brain can oxidise ketones but not FAs
C) Ketone bodies provide energy faster than oxidation of glucose or FAs
D) Use of ketone bodies reduces need for GNG and spares protein breakdown
C) Ketone bodies provide energy faster than oxidation of glucose or FAs.
This is not correct, ketone bodies simply keep the TCA cycle spinning, producing energy via the exact same mechanism as glucose or FA oxidation.
The rest of the options are correct.
(1.2)
What is the effect of catecholamines/ adrenaline on lipolysis?
Include the signalling pathway regulating lipolysis.
Catecholamines stimulate lipolysis.
- Catecholamines act on adipose tissue to increase cAMP and thus PKA, which phosphorylates HSL (hormone stimulate lipase) and perilipin A.
- HSL and perilipin A complex together, causing the release of CTG1 (which is normally bound to perilipin A)
- The released CTG1 then goes onto complex with ATGL (Adipose triglyceride lipase) which initiates lipolysis.
- ATGL liberates one fatty acid from TAGs, HSL liberates one fatty acid from DAGs, whilst monoglyceride lipase (MGL) liberates the final fatty acid.
(1.2, Tutorial 3)
Outline the BMI categories.
- BMI: < 20 = underweight
- BMI: 20-25 = healthy weight
- BMI: 25-30 = overweight
- BMI: >30 = obese (class 1)
- BMI: >35 = obese (class 2)
- BMI: >40 = obese (class 3)
(Ranges taken from lecture slides)
(1.3)
In broad terms, outline the contributors to energy expenditure.
- Basal metabolic rate (60-70%)
- Physical activity energy expenditure (10-20%)
- Adaptive thermogenesis (10-20%)
(1.3)
Which of the following sites is NOT a major site of energy balance signalling:
a) Stomach
b) Pancreas
c) Adipose tissue
d) Skeletal muscle
d) Skeletal muscle
The stomach, pancreas and adipose tissue are the major tissues signalling the brain in response to energy balance.
(1.3)
In broad terms:
- what is the physiological effect of Neuropeptide Y (NPY) and Agouti-related protein (AGRP) on food intake?
- what is the physiological effect of Cocaine- and amphetamine- regulated transcript (CART) and Pro-opiomelanocortin (POMC) on food intake?
- NPY/AGRP = increase food intake (Orexigenic peptides)
- CART/POMC = decrease food intake (Anorexigenic peptides)
(1. 3)
Leptin:
- Where is leptin produced?
- What stimulates it release? What inhibits its release?
- Where are leptin receptors located?
- What is the effect of leptin binding to its receptor?
- Leptin is produced by white adipose tissue in concentrations proportional to the amount of adipose tissue in the body.
- Leptin release is stimulated by insulin and glucocorticoids. Leptin release is inhibited by beta-adrenergic stimulation.
- Leptin receptors are found in the hypothalamus and brainstem.
- Leptin receptor activation leads to reduced appetite and increased energy expenditure. Leptin also has effects on glucose homeostasis, bone remodelling and reproduction.
(1. 3)
Regarding the hormone Ghrelin select the correct answer:
- Ghrelin is released BEFORE/AFTER a meal to STIMULATE/INHIBIT food intake
- Ghrelin responds to NUTRIENTS/GASTRIC VOLUME
- Ghrelin activates NPY/POMC neurons in the arcuate nucleus of the hypothalamus
- Ghrelin is released BEFORE a meal to STIMULATE food intake.
- Ghrelin responds to NUTRIENTS
- Ghrelin activates NPY neurons in the arcuate nucleus of the hypothalamus
(1.3)
In the following list identify the satiety signals:
- Ghrelin
- Cholecystokinin
- PYY
- GLP-1
- Insulin
- Glucagon
- Amylin
The satiety signals listed where:
- Cholecystokinin
- PYY
- GLP-1
- Insulin
- Amylin
Ghrelin and glucagon are not satiety signals.
(1.3)
Can muscle produce free glucose through GNG?
No- due to lack of glucose-6-phosphotase, which is only present in liver and kidney.
(1.1)
What key enzyme does Glucagon act on to increase Glycogenolysis?
Glycogen phosphorylase
- Glucagon signals via secondary messenger cAMP to activate protein kinase A (PKA) that activates Glycogen phosphorylase.
(1.1)
What is the sole source of glucose during fasting >2days?
Gluconeogenesis
1.1
What are the 3 irreversible steps of glycolysis that are bypassed by Gluconeogenesis?
- Pyruvate kinase
- Phosphofructokinase
- Glucokinase/hexokinase
- note that glucagon regulates the Gluconeogenic enzymes at these three steps.
(1. 1)
What are the substrates for Gluconeogenesis?
- Glycerol (from TAG hydrolysis)
- Alanine (from muscle breakdown)
- Other glucogenic amino acids (major carbon source for GNG when glucose levels are low)
- Lactate (from working muscle- not major substrate during fasting state)
(1.1)
Describe insulin resistance, insulin production and blood glucose levels over time during the natural progression of type 2 diabetes mellitus .
- Insulin resistance increases progressively for a period of time before until reaching a plateau point. It does not decrease.
- Insulin production initially increases as the beta cells of the pancreas attempt to produce enough to overcome the developing insulin resistance. However eventually beta cell dysfunction occurs, leading to insulin production levels to fall away.
- Blood glucose levels remain constant for much of the progression until beta cell dysfunction occurs. At this point, as insulin level begin to decrease, blood glucose begins to rise. Blood glucose will continue to increase as insulin production falls.
(1.4)
Describe the clinical features of a presentation of T2DM and the diagnostic test used to confirm the diagnosis
- Typically T2DM presents later with mild, gradually increasing symptoms. These include polyuria, polydipsia, fatigue, weakness and blurred vision.
- A fasting blood glucose of greater than 7 mM on two separate occasions is generally considered diagnostic. The diagnosis can be confirmed with a glucose tolerance test.
(1. 4)
Outline how measuring HbA1C is used in the context of T2DM.
- A measure of long term glucose control (3 months)
- Exposure of Hb to glucose results in a non-enzymatic glycosylation of terminal amino groups in the alpha- and beta- chains
- Amount of HbA1c is proportional to the concentration of glucose
(1.4)
Name three other hormonal regulators of lipolysis (besides Catecholamine)
- Thyroid Hormone
- Cortisol
- TNF-a
(1.2)
During fasting, what two options does the liver have for the metabolism of fatty acids?
- Packaging (with glycerol) into VLDL for redistribution to tissues that need it
- Beta oxidation to produce ketone bodies (note that this is during fasting state)
(1.2)
How does energy balance in the hepatocyte regulate FA oxidation by AMPK?
- AMPK is activated by low energy levels within the hepatocyte
- Through inactivation of the key enzyme, ACC, there is upregulation of the transport protein for fatty acid transport into mitochondria (CPT-1)
- Results in increased fatty acid transport into the mitochondria and increased lipid oxidation.
(1.2)
TorF: energy yield (ATP) from fatty acid (palmitate) oxidation is greater than glucose oxidation
T: ~130 ATP from oxidation of palmitate vs 36 ATP from oxidation of glucose
(1.2)
What (4) factors stimulate synthesis of the rate-limiting enzyme of ketogenesis, HMGCoA synthase?
- Fasting
- Dietary fat
- Fatty acids
- Insulin deficiency
overall act to increase ketogenesis.
(1.2)
Explain what effect impaired insulin action has on:
- muscle
- adipose tissue
- liver
Muscle:
- defective GLUT 4 translocation = decreased glucose uptake
Adipose tissue:
- impaired suppression of lipolysis, resulting in elevated FFAs. This contributes to increased ectopic fat accumulation, contributing to hallmark state of hyperlipidemia.
- defective GLUT4 translocation
Liver:
- impaired inhibition of GNG/GGL elevated hepatic glucose output leading to hyperglycaemia.
(1.4)
Metformin is the 1st line treatment for T2DM
- Describe the actions of metformin
- Side effects
- contraindications
- Actions
1. Acts primarily on the liver to decrease hepatic glucose output (by reducing glycogenolysis).
2. Increases glucose uptake
3. Decreases intestinal glucose absorption
4. Increases insulin sensitivity - Side effects
GI irritation, anorexia, lactic acidosis. Note, metformin doesn’t cause weight gain or hypoglycaemia. - C’indications
Liver or renal impairment
(1.4)
How do Sulfonylureas act?
- act on pancreatic B-cells to increase insulin secretion.
- Stimulates sulfonylurea receptors on B-cells that close potation channels leading to chain events that cause insulin release.
- Note recent evidence suggest they can accelerate B-cel failure and can cause hypoglycaemia.
(1. 4)
TorF
1. GLP-1 agonists mimic GLP-1 to both stimulate insulin secretion and inhibit glucagon secretion
- GLP-1 agonists cause hypoglycaemia
- T
- F
(1.4)
TorF
1. DPP4 inhibitors inhibit the enzyme that breaks down GLP-1
- SGLT-2 inhibitors act on the liver
- T
- F- acts on kidney to decrease glucose reabsorption
(1.4)
What is meant by “T1DM is a disease of fasting”?
T1DM is a state of insulin deficiency while there is a state of hyperglycaemia. The metabolic profile is similar to that of starvation:
- while there is hyperglycaemia, the lack of insulin impairs tissue uptake of nutrients
- adipose tissue: excessive lipolysis (no insulin-mediated suppression)
- Liver: no suppression of hepatic glucose output; high GNG, glycogenolysis and B-oxidation
(1.5)
TorF
Clinical presentation of T1DM is similar to that of T2DM but onset is gradual and later in T1DM
F- onset is acute and juvenile, on average at ages 10-14. But symptoms are similar- polydipsia, polyuria, blurred vision and fatigue.
(1.5)
TorF
C-peptide is low or absent in T1DM
T
1.5
TorF
Insulin is orally bioactive
F- it must be injected
1.5
How are fatty acids stored in adipose tissue?
Fatty acids are taken up by adipocytes and esterified with glycerol to form triglycerides (the storage form of energy in adipose tissue.
(1.3, Tutorial 3)
What metabolic pathways do adipocytes principally use to metabolise glucose?
After being taken up glucose enters glycolysis and is converted to pyruvate before being oxidised to acetyl-CoA and entering the TCA cycle. I
- if it is not required for ATP production, the TCA cycle intermediate citrate will be exported from the mitochondria via citrate transporter. In the cytosol citrate is reconverted to acetylCoA before undergoing fatty acid synthesis (lipogenesis).
- intermediates of glycolysis can also exit this pathway and enter the pentose phosphate pathway (PPP) and also exit to form glycerol (for TAG production)
(1.2, Tutorial 3)
What hormone promotes the storage of nutrients in adipocytes?
How does it do this?
Insulin- controls uptake of nutrients into adipocytes.
- increase GLUT4 translocation to membrane to increase glucose uptake.
- Promotes glycolysis and fatty acid synthesis to assist with storage
- insulin also increases fatty acid uptake by up regulating FATP.
(1.2, Tutorial 3)
Under what physiological conditions are fatty acids released from adipose tissue?
- During fasting
- During exercise
(1.2, Tutorial 3)
How are fatty acids liberated from lipoproteins and where does this occur?
Fatty acids contained within TAGs in lipoproteins released by liver can be liberated through Lipoprotein Lipases (LPL)
- found in the endothelium around peripheral tissues such as heart and skeletal muscle and adipose tissue.
(1.2, Tutorial 3)
What are ketone bodies?
Acetoacetate, B-hydroxybutyrate, Acetone.
Tutorial 1
How and in what tissues are ketone bodies formed?
- Occurs in liver mitochondria
- Ketone bodies are forming during beta-oxidation of lipids
- Ketone bodies are also formed during amino acid oxidation in the liver (in extreme starvation)
- Keton bodies are formed when acetylCoA generation exceeds the capacity for oxidation by the TCA cycle.
(Tutorial 1)
What is the rate limiting enzyme of Ketogenesis?
HMG CoA synthase (catalyses acetoacetyl CoA to HMG CoA
tutorial 1
What is the rate limiting enzyme of ketolysis?
Acetoacetyl succinyl CoA transferase- activity is the highest in heart and kidney.
(Tutorial 1)
In what physiological situations are ketone bodies important?
- during fasting (for glucose and protein sparing)
- formed from acetyl CoA generated by B-oxidation of lipids, which is enhanced in fasting.
- Kbs are exported from the liver into circulation and transported to other tissue
- after overnight fast, ketone bodies supply 2-6% of body’s energy requirements.
(Tutorial 1)
How do tissues use ketone bodies?
Tissues cover the acetoacetate and B-hydroxybutyrate back into acetyl CoA which then enters the TCA cycle to generate ATP
(Tutorial 1)
How the liver, the tissue that forms ketone bodies maintain ATP production?
- TCA cycle is still producing ATP at the same time as ketogenesis
- Process of B-oxidation that generates the acetylCoA required for ketogenesis provides FADH2 and NADH for respiratory chain.
(Tutorial 1)
What compensatory mechanisms are employed during metabolic acidosis?
- increased respiration to decrease pco2
- kidneys excrete free H+ via NH4+ and increase HCO3- generation
(tutorial 1)
How can uncontrolled Type I Diabetes result in a ketoacidotic state?
Insulin deficiency due to autoimmune destruction of b-cells means tissues no longer have stimulus to take up glucose and therefore low glucose available as substrate, but have free fatty acids available for oxidation.
- leads to increased formation of ketone bodies in the liver
- excessive production reduces pH leading to acidosis
(tutorial 1)
