INTS 12: The Endocrine Regulation of Metabolism

Question 1

What is metabolism?

Answer 1

• Metabolism refers to the chemical processes occurring within the body of a living organism

Question 2

What is intermediary metabolism?

Answer 2

• refers to the metabolic reactions that occur between the uptake of nutrients, their conversion into cellular components and fuel, and the formation of excretory products
• The citric acid cycle (CAC), which is also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, sits at the heart of intermediary metabolism, allowing different macronutrients (carbohydrates, proteins and fats) to be used as carbon and energy sources
• You have previously discussed a number of aspects of intermediary metabolism, and the way in which different macronutrients are metabolised, in CBI 7.
• Study the figure below (click to enlarge) for a summary of how the body uses macronutrients

Question 3

What do hormones do in regulating intermediary metabolism?

Answer 3

• Hormones have important regulatory effects on intermediary metabolism.
• For example, the endocrine control of blood glucose levels is very tightly related to the regulation of carbohydrate metabolism, but also to protein and fat metabolism

Question 4

What kinds of physiological processes are impaired when glucose levels are too low?

Answer 4

• hunger (the body trying to replenish glucose)
• trembling and sweating (with nervous activation acting to liberate glucose)
• Severe hypoglycaemia can cause confusion as brain function is compromised, and in very severe cases can cause a loss of consciousness.

Question 5

What are the consequences of high glucose levels?

Answer 5

• Temporarily high levels of glucose have little effect
• If they persist, they can result in dehydration, thirst, frequent urination and tiredness
• Extremely high blood glucose can cause serious complications due to fluid loss.
• If insulin levels are very low, a condition called ketoacidosis can result, in which the body breaks down fats into ketone bodies to use as an energy source (as glucose can’t be used as a fuel in the absence of insulin).
• These ketone bodies accumulate and lower the pH of the blood, and, if untreated, can result in coma and death.
• Over the long term, high blood glucose levels can damage nerves and blood vessels, leading to neuropathy and cardiovascular disease.

Question 6

Observe this diagram of the pancreas

Answer 6

Question 7

Give a very brief summary of the action of insulin and glucagon on glucose metabolism

Answer 7

Question 8

Describe the effects of insulin

• is it an anabolic or catabolic hormone?

Answer 8

• Insulin is an anabolic hormone:
• it promotes the synthesis of glycogen from glucose, particularly in liver,
• but also in adipose tissue and muscle, and increases the rate of glucose uptake, particularly in adipose tissue and muscle, storing it as fat.
• Insulin also has anabolic effects on fat and protein metabolism.
• Insulin inhibits the rate of lipolysis in adipose tissue, and stimulates fatty acid and triacylglycerol synthesis in adipose tissue and liver.
• It also increases amino acid transport into muscle, adipose tissue, liver and other cells, and increases the rate of protein synthesis in muscle, adipose tissue, liver and other tissues.

Question 9

Is glucagon an anabolic or catabolic hormone?

Answer 9

• catabolic
• nreaks down glycogen to free glucose for use in the circulation

Question 10

Is the catecholamine (hormone made from adrenal gland) epinephrine an anabolic or catabolic hormone?

Answer 10

• it plays a catabolic role
• contributes to:
• glycogenolysis
• gluconeogenesis
• lipolysis

Question 11

What effects do growth hormone have?

• is it anabolic or catabolic?

Answer 11

• GH counters the effects of insulin on blood glucose
• reducing muscle uptake of glucose
• promoting lipolysis
• However, it has an anabolic effect on protein metabolism, promoting muscle growth.

Question 12

What effects do the stress hormone, cortisol have in glucose and protein metabolism?

Anabolic or catabolic?

Answer 12

• The stress hormone, cortisol, has a catabolic role in glucose and protein metabolism,
• promoting the release of glucose into the blood, and stimulating proteolysis, resulting in the release of amino acids into the blood.
• It also has a complex role in fat metabolism.
• At high levels cortisol can drive the expansion of visceral fat depots, but it can also directly stimulate lipolysis, particularly in subcutaneous fat depots, resulting in high levels of free fatty acids in circulation.
• See below for a diagram that explains the location of different fat depots.

Question 13

Define:

• glycolysis
• gluconeogenesis
• glycogenesis
• glycogenolysis

Answer 13

Question 14

What do alpha, beta. delta cells release?

Answer 14

• They are found within the Islets of Langerhans in the pancreas and secrete insulin when blood glucose levels are high.
• Insulin increases glycogenesis and glycolysis as well as increasing glucose uptake in cells via the GLUT4 transporter.
• It also increases lipogenesisand protein synthesis (by increasing amino acid transport to cells.)
• Delta cells secrete somatostatin which inhibits the secretion of insulin, whereas Alpha cells stimulate the beta-cells in response to the release of glucagon.
• Sympathetic activity inhibits the secretion of insulin as it would require the release of energy rather than its storage, whilst Parasympathetic activity generally stimulates the secretion of insulin.
• GIP and glucagon-like-peptide 1 (incretins) can cause increases in insulin secretion as well.

Question 15

What do alpha-cells in the pancreas?

What inhibits them?

Answer 15

• These are responsible for secreting glucagon in response to a decrease in blood glucose levelsand increase glycogenolysis and gluconeogenesis.
• Gluconeogenesis in the liver is driven by increased lipolysis and transport of amino acids to cells (gluconeogenic amino acids converted to glucose.)
• Beta-cells secreting insulin inhibits the alpha-cell secreting glucagon whilst Delta cells secrete somatostatin which also inhibits glucagon secretion.
• The parasympathetic nervous system is a stimulant of glucagon secretion.

Question 16

Using the diagram, explain the cellular mechanisms of insulin release

Answer 16

1. Once in the cell, an enzyme called glucokinase catalyses the phosphorylation of glucose to glucose-6-phosphate, in the first step of glycolysis. Through this mechanism, glucokinase thus acts as a glucose sensor, triggering insulin release in response to rising levels of glucose.
2. Glucose-6-phosphate then undergoes further conversion to pyruvate via the subsequent steps of glycolysis.
3. Pyruvate undergoes oxidative decarboxylation to enter the citric acid cycle, the products of which then undergo oxidative phosphorylation, resulting in the production of ATP.
4. Increased levels of ATP block the ATP sensitive potassium channels in the cell membrane. Normally, the activity of these potassium channels allows positively charged potassium ions to flow out of the cell, and thus for the Beta cell to maintain a negative resting membrane potential.
5. When the channels are closed in the presence of ATP, potassium ions accumulate within the cell, depolarising the cell membrane.
6. This in turn opens voltage gated calcium channels in the cell membrane, allowing the influx of extracellular calcium to increase intracellular calcium concentations.
7. This increase in intracellular calcium causes the fusion of insulin containing secretory granules with the cell membrane and the release of their cargo into the bloodstream.

Question 17

What is type 1 diabetes mellitus?

• causes
• who it affects

Answer 17

• caused by the autoimmune destruction of the beta cells of the pancreas, leading to extremely low or absent insulin levels.
• There is a genetic component to the disease, but it also requires an environmental trigger to manifest.
• It generally occurs in younger patients, who will need to be treated with synthetic insulin for the rest of their lives.

Question 18

What is type II diabetes mellitus?

Answer 18

• characterised by resistance to the actions of insulin and by the inability of insulin secretion to meet metabolic requirements
• Essentially, as insulin becomes less effective, the pancreas needs to release more to overcome this resistance.
• However, in type II diabetes, the pancreas cannot release sufficient insulin to compensate for the resistance, and so blood glucose concentrations rise, and eventually the Beta cells will ‘burn out’, lowering insulin levels.
• Type II diabetes mellitus generally occurs in older patients, and is associated with obesity.
• It represents approximately 90% of all diabetes, and rates are accelerating globally, driven by the increasing prevalence of obesity.

Question 19

What is the treatment for type I diabetes?

Answer 19

• In type I diabetes, patients are treated by replacing their missing insulin with exogenous (i.e. originating from outside of the body) insulin

Question 20

What are some treatments for type II diabetes

Answer 20

• Patients with type II diabetes can also benefit from treatment with insulin, particularly if their Beta cells have failed following the overproduction required to overcome insulin resistance.
• Those with remaining Beta cell function can be treated by a variety of medications.
• Some medications, including thiazolidinediones and metformin, increase insulin sensitivity, allowing endogenous insulin to act more effectively.
• Other medications increase insulin release from the pancreatic Beta cell.
• Glucagon-like peptide-1 (GLP-1) agonists are synthetic versions of GLP-1, a hormone released from the gastrointestinal tract that we will discuss in subsequent sections.
• They promote insulin release by activating the GLP-1 receptor which causes intracellular signalling changes that block the ATP-sensitive potassium channels on the Beta cell, increase intracellular calcium and further promote insulin release via cyclic AMP.
• Sulfonylureas are anti-diabetic medications that bind to ATP-sensitive potassium channels on the Beta cell.

Question 21

Use the diagram to understand the effects of anti-diabetic drugs on pancreatic Beta cells

Answer 21

• Glucagon-like peptide 1 (GLP1) analogues bind to GLP-1 receptors on Beta cells, stimulating intracellular signalling pathways
• in particular, intracellular cAMP is raised resulting in signalling cascades which close KATP channels and promote the influx of extracellular calcium and the release of calcium from intracellular stores, thus promoting insulin release
• Sulfonylureas bind to the ATP-sensitive potassium (KATP) channels on pancreatic beta cells, causing them to close, and thus promoting insulin release.
• Meglitinides have a similar effect
• Potential therapies targeting other GPCRs besides the GLP-1R are currently under development.
• Therapies targeting glucokinase are currently being investigated as treatments for type II diabetes, but have not reached the clinic.

Question 22

Does glucagon stimulate insulin release?

Answer 22

Question 23

What is the diffuse endocrine system?

Answer 23

• collectively to the many endocrine cells that are found scattered through tissues and organs that are not predominantly endocrine in function
• Diffuse endocrine cells are most widespread in the gastrointestinal tract, which is home to a number of endocrine cell types and releases a number of different hormones, but are also found, for example, in the heart.

Question 24

Observe the diagram for some hormones released from different regions of the gastrointestinal tract and their function

Answer 24

Question 25

What are incretins?

How were they discovered?

Answer 25

• Incretins are hormones released after food intake which augment insulin secretion.
• Their existence was first inferred when it was noted that people given the same amount of glucose orally or intravenously released more insulin following oral administration.
• That is because detection of glucose within the gastrointestinal tract stimulates the release of incretins from the intestine, and these incretins travel in the circulation to the Beta cells of the pancreas, where they help to stimulate further insulin release, in addition to the direct effects of glucose on the Beta cell.

Question 26

What are the two major incretins?

Answer 26

• glucose-dependent insulinotropic peptide (GIP)
• glucagon-like peptide-1 (GLP-1)

Question 27

Why is the GLP-1 system the basis of a major class of anti-diabetic drugs?

Answer 27

• One of the advantages of these drugs is that they only augment glucose-stimulated insulin release;
• in the absence of raised blood glucose, they should have minimal effect, thus avoiding unwanted hypoglycaemia.

Question 28

In the figure, why do you think the obese subjects have higher insulin and glucose levels following glucose administration?

Answer 28

• Obesity is associated with insulin resistance, and therefore the obese subjects need to release more insulin to suppress their circulating glucose levels.
• Even with this extra insulin release, they will tend to suppress glucose less effectively and less quickly than healthy weight individuals, hence the higher glucose.

Question 29

What do you think happens to the release of incretins following a meal?

Answer 29

Question 30

What is energy homeostasis?

Answer 30

• refers to the process by which the regulation of food intake (energy inflow) and energy expenditure (energy outflow) is coordinated to regulate body weight

Question 31

Which areas of the body regulate energy homeostasis?

Answer 31

• it is regulated by a complex series of neuronal circuits in the brain
• major brain regions involved:
• the hypothalamus
• the brain stem:
• The brain stem receives neural input from the gastrointestinal tract via the vagus nerve (one of the cranial nerves),
• and also receives direct signalling from specific hormones that regulate appetite.
• Brainstem neurons then signal to the hypothalamus, which integrates this information with other inputs, including direct hormonal signalling to the hypothalamus, and signalling from other brain regions.

Question 32

What are some responses to changes in homeostasis?

Answer 32

• In response to changes in energy homeostasis, such as fasting, food intake, exercise, or altered fat mass, the hypothalamic circuitry coordinates a response to restore homeostasis.
• This can include:
• the modulation of pituitary hormone release (for example, thyroid hormones regulate metabolic rate),
• the autonomic nervous system (signalling to peripheral tissues to, for example, promote lipolysis),
• signalling to higher brain centres to regulate behaviour (for example, promoting or inhibiting food intake).

Question 33

Describe the central role of the hypothalamus in the regulation of energy homeostasis

Answer 33

• the hypothalamus acts as the main controller, integating many different signals in order to change our food intake
• it takes behavioural effects (culture, memory) and signals from gut and adipose
• leptin is released and signalled to the brain
• other hormones from the gastrointestinal tract also signal
• usually directly to the brainstem or hypothalamus ot even via the vagus nerve
• it adjust metabolism and behaviour through different pathways
• e.g. signalling to the pituitary
• regulsting the thyroid axis
• signal via the autonomic nervous system
• signal to higher brain centres e.g. cerebral cortex for behavioural changes

Question 34

How is appetite regulated?

Answer 34

• Appetite regulation occurs from the hypothalamus and brainstem of the brain.
• The brainstem receives signals through the vagus nerve from the Gastrointestinal tract, adipose tissue, or appetite-regulating hormones and passes this on to the hypothalamus.
• Adipose tissue releases Leptin which signals about the body’s energy stores and regulates food intake.
• The hypothalamus integrates this signal with information from other regions of the body/brain and responds to restore homeostasis.
• The hypothalamus’ nucleus for appetite regulation is the arcuate nucleus.
• Within this there are populations of neurons that produce neuropeptide Y (NPY) and agouti-related peptides (AgRP) which signal for hunger and POMC, which forms a-MSH, that signals satiety.
• Dysfunction of a-MSH production leads to obesity as satiety-signalling pathways do not function correctly.
• Signals from the arcuate nucleus is then sent to the paraventricular nucleus which produces an appropriate response.
• This includes signalling to the pituitary gland to stimulate the thyroid etc.

Question 35

What is the gut-brain axis?

Answer 35

• The gut-brain axis is the bidirectional biochemical signalling that occurs between the gastrointestinal tract and the central nervous system.

Question 36

Describe the gut to brain signalling of the gut-brain axis

Answer 36

• Hormones from GI tract can communicate to the brain by directly binding to receptors on neurons, or through the vagus nerve(receptors on nerve).
• Ghrelin increases with fasting and drives the increased feeling of hunger.
• GLP-1 and PYY3-36 are released after a meal from the enteroendocrine L cells and suppress food intake.
• Cholecystokinin also suppresses food intake when at high concentrations.
• These hormones regulate short term appetite and prevent the digestive system becoming overwhelmed when digestion is occurring.
• There are suggestions that fasted patients feel satiated when administered satiety hormones without food.

Question 37

Study these images showing the effect of GLP-1 and PYY3-36 alone and in combination on human brain activity, as measured using blood-oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) in different brain regions, comparing the changes when the subjects are looking at food and non-food images

Answer 37

Question 38

Observe this micrograph of an L cell and describe what it is showing

Answer 38

Question 39

Describe the brain to gut signalling in the gut-brain axis

Answer 39

• The brain regulates gut-motility, digestive process and GI hormone release.
• For example, GLP-1 and PYY3-36 reduces Ghrelin secretion through the modulation of neuronal signals in the brain.
• Hormones increasing hunger are orexigenic and those that suppress hunger are anorexigenic.

Question 40

What does orexigenic mean?

Answer 40

• an appetite-stimulating hormone

Question 41

What does anorexigenic mean?

Answer 41

• an appetite-reducing hormone

Question 42

Study this graph

Is it an orexigenic or anorexigenic hormone?

Answer 42

• This circulating profile is reflective of an orexigenic hormone, because levels increase before a meal (driving hunger) and then fall following a meal.
• In fact, this figure shows the levels of circulating ghrelin.

Question 43

Study this graph

Is it an orexigenic or anorexigenic hormone?

Answer 43

• This circulating profile is reflective of an anorexigenic hormone, because levels are low before a meal (when you do not want to drive satiety) and then increase following a meal (when you do want to feel sated).
• In fact, this figure shows the levels of circulating cholecystokinin.

Question 44

What are the roles of adipose tissue?

Answer 44

• a major energy store in the body
• an endocrine function:
• releasing homrones that act on heart, vasculature, liver, muscle, CNS
• adipose tissue contains immune cells which release a variety of cytokines

Question 45

What are hormones released from the adipocytes called?

Answer 45

• adipokines

Question 46

Give some hormones that adipose tissue release

Answer 46

Question 47

How do adipokines and cytokines affect the immune system?

Answer 47

• Adipokines and cytokines can have important effects on immunity and inflammation.
• Obesity, when excess adipose tissue has a negative effect on health, is a pro-inflammatory state.
• Hormones such as, for example, interleukin-6 (IL-6) can drive the population expansion and activation of T cells, B cell differentiation, and can regulate the acute-phase response that you will learn about in other INTS sessions.
• Pro-inflammatory signalling also promotes insulin resistance, providing a functional link between increased adipose tissue and insulin resistance.

Question 48

Describe the role of adipose tissue hormone, adiponectin

Answer 48

• the more fat mass you have, the less adiponectin you release
• it might be a signal that adipocytes are empty and perhaps working well
• its main role is an insulin sensitiser: increasing sensitvity to the action of insulin, to reduce gluconeogenesis etc
• via two receptors:
• travels to muscle to act via the adipoR1 receptor
• travels to liver to act via adipoR2 receptor
• it also signals into the hypothalamus to play some role in regulating food intake

Question 49

Describe the role of adipose tissue hormone, leptin

Answer 49

• one receptor is important to note: Ob-Rb receptor in the hypothalamus
• a long receptor
• main role: regulating fat mass
• with more body fat, so adipocytes storing more fat, leptin increases and the leptin signalling increases in the hypothalamus
• this reduces food intake
• opposiute effect after weight loss
• this system does not work perfectly

Question 50

Does this mouse on the right have too much or too little leptin?

Answer 50

• too little

Question 51

Why is calcium metabolism important?

Answer 51

• it is vital for a number of physiological processes including neuromuscular excitability and muscle contraction, and blood coagulation,
• it is necessary to provide strength in bones, and acts intracellularly as a second messenger and as a co-enzyme.
• Within neurons and endocrine cells, increases in intracellular calcium are critical to stimulating neurotransmitter or hormone release.

Question 52

What are the effects of high or low calcium levels in the blood stream?

Answer 52

• Low levels of calcium in the bloodstream will result in the effects of calcium being compromised.
• see previous flashcard
• The effects of hypercalcemia (i.e. high calcium) are dependent on the severity of the increase and the rate of change of the circulating calcium levels, with rapid changes causing more problems such as cognitive dysfunction, lethargy and kidney problems.

Question 53

How are circulating calcium levels regulated?

Answer 53

• Calcium levels are primarily regulated by a peptide hormone called parathyroid hormone,
• which is released from the parathyroid glands.

Question 54

What is the main function of the parathyroid hormone?

Answer 54

• to increase circulating calcium levels.
• Calcium sensing receptors on the parathyroid glands detect that circulating levels of calcium are low and in response the parathyroid gland releases parathyroid hormone.
• As the diagram below illustrates, to increase circulating calcium levels, parathyroid hormone promotes the resorption of bone, liberating calcium, drives calcium reabsorption in the kidney, and increases vitamin D activity.
• Vitamin D then acts to promote the efficient absorption of calcium from the gastrointestinal tract.

Question 55

How does the parathyroaid hormone regulate calcium levels?

Through the bone, kidmey and gastrointestinal tract

Answer 55

• The regulation of Ca2+ levels is done by the parathyroid gland, which has Ca2+sensing receptors.
• If the Ca2+level is low, PTH (parathyroid hormone) is released and acts on bone, liver, kidneys and intestines to increase the circulating Ca2+levels:
• Bone:
• Osteoblasts have PTH receptors which signal for the decrease of osteoblast (bone building) activity.
• Through intracellular signalling factors the increase of osteoclast (bone breakdown) activity is signalled for, and Ca2+is liberated.
• Kidney:
• PTH promotes the reabsorption of Ca2+from the urine
• Vitamin D3:
• Vitamin D3(cholecalciferol) is activated by two hydroxylation steps that can be promoted by PTH.
• The first hydroxylation is in the liver to form 25-hydroxycholecalciferol, and the second is in the kidney to form the active form 1,25-dihydroxycholecalciferol.
• This acts on the GI tract to drive Ca2+ into enterocytes and pumped into the bloodstream.

Question 56

What are the three types of parathyroidism?

Answer 56

• Primary:

• Secretion of PTH remains high even if Ca2+levels are high
• Insensitivity to negative feedback mechanisms can be a cause of adenomas in the parathyroid.

• Secondary:

• Target organs of PTH unable to effectively respond, so Ca2+levels are low even though PTH is high.
• This can arise from kidney failure etc.

• Tertiary:

• If Ca2+ levels have been persistently low despite high PTH for some time, Ca2+ becomes unable to suppress PTH, disrupting the negative feedback mechanism.
• This can be the result of Vitamin D deficiency.