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Translational Medical Sciences > Insulin Secretion > Flashcards

Insulin Secretion Flashcards

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USMLE® Step 1 flashcards
1
Q

What are the characteristics of T1 diabetes

A
  • destruction of insulin secreting B cells in the pancreas

- lowered insulin levels

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2
Q

Describe the insulin signalling pathway

A
  • Activation of insulin receptor, a tyrosine kinase receptor, by insulin causes autophosphorylation
  • IRS1 binds to phosphotyrosine residue through a PTB domain, the activated kinase in the receptor’s cytosolic domain phosphorylates IRS1
  • One subunit of PI3K binds to receptor bound IRS1 via its SH2 domain, and the other subunit phosphorylates PIP2 to PIP3
  • PIP3 binds PH domain of AKT, recruiting it to the plasma membrane
    Akt (also called PKB) helps in translocation of GLUT4 storage vesicles to plasma membrane by a series of events leading to activation of Rab protein (promotes glucose uptake)
  • As GLUT4 vesicles fuse with plasma membrane, number of receptors increase and hence glucose uptake increases
  • Akt catalyses phosphorylation of GSK3, converting it from its active to inactive form. As a result, GSK-mediated inhibition of glycogen synthase is relieved, promoting glycogen synthesis in skeletal muscle and liver
  • PKB increases lipogenesis and inhibition of gluconeogenesis in liver
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3
Q

Illustrate the process of the breakdown of glucose in the liver

A
  • Draw flowchart for glucose -> energy

- Flowchart for glucose -> glycogen

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4
Q

How and where does glucagon act

A
  • Acts on liver via glucagon recepyors (GPCRs) to increase cAMP and PKA
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5
Q

What are the downstream actions of glucagon

A
  • Inhibition of glycolysis and glycogenesis (decrereases glycogen production)
  • Promotes gluconeogenesis and glycogenolysis (increases glucose production)
  • important counter regulatory hormone to prevent hypoglycaemia
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6
Q

What can change blood sugar levels

A
  • exercise
  • illness
  • stress
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7
Q

Where is insulin stored

A
  • in granules in cytoplasm of beta-cells
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8
Q

Characterise the insulin response to glucose

A
  • First phase: initial peak, up to 15 minutes, rapid transient burst of insulin, probably due to release of insulin by granules that were docked to the membrane and ready to release insulin
  • Second phase: if glucose levels remain high there is a sustained release of insulin, newly synthesised and stored insulin is released
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9
Q

Describe how increase in glucose leads to insulin secretion

A
  • Increase of glucose in blood detected by beta cells
  • Glucose is taken up by GLUT2 (in the liver)
    Glucose enters cell and is metabolized by Krebs cycle into pyruvate and then ATP (Glucose -> Glucose-6-phosphate -> Pyruvate + NADPH)
  • K channels are sensitive to ATP (increase of ATP:ADP ration will close these channels)
    -Closure of potassium channels leads to depolarization of the membrane leading to opening of Ca channels and an influx of Ca into cell
  • Increase in intracellular Ca stimulates insulin release from the granules
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10
Q

Describe amplifying pathways independent of glucose which can affect how much insulin is secreted

A
  • Fatty acids can be taken up and metabolized into energy
  • Fatty acids can also activate GPR40 and then activate intracellular pathways which lead to increase in intracellular Ca levels
  • GLP1 comes from incretins (produced in gut after eating), and acts on Beta cells and increases levels of cAMP and PKA and promote the amount of insulin secreted
  • Amino acids can directly be metabolised to produce ATP and hence increase insulin production
  • Some amino acids can also depolarize the cell and lead to opening of Ca channels to increase insulin secretion
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11
Q

Describe the incretin affect

A
  • Much more insulin produced when glucose is ingested orally as the gut releases GLP1 as well
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12
Q

Describe how neuronal stimulation can affect insulin secretion

A
  • Parasympathetic: : acetylcholine increases DAG and PKC levels and hence increases insulin secretion, lowering blood sugar levels
  • Sympathetic: fight or flight response, lowers cAMP levels and hence inhibits insulin secretion, so there’s more sugar in blood for higher energy
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13
Q

How are beta-cells specialised to allow glucose regulated insulin secretion to occur?

A
  • presence of glucokinase
  • high vascularised
  • Glut2 receptors in beta-cells have low affinity for glucose
  • number of beta cells is tightly controlled
  • beta cells are highly differentiated and have a number of unique transcription factors
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14
Q

What is the role of glucokinase

A
  • phosphorylates glucose into Glucose-6-phosphate
  • member of hexokinase family
  • present only in pancreas and some of the liver
  • sets threshold for glucose stimulated insulin secretion
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15
Q

What makes glucokinase different from hexokinase

A
  • Lower affinity for glucose (only phosphorylates it when the glucose levels are high enough)
  • Lack of inhibition by substrate (accumulation of substrate in enzymes often leads to inhibition of the reaction. doesn’t happen in glucokinase making it specialised for longer period of high blood glucose levels)
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16
Q

What are the consequences of diabetes

A
  • decreases life expectancy

- major contributor to renal disease, retinopathy, cardiovascular disease

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17
Q

Define diabetes mellitus

A
  • hyperglycaemia due to insufficient insulin secretion

- fasting blood glucose over 7mmol/L

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18
Q

Describe monogenic forms of diabetes

A
  • single gene of beta-cells that cause diabetes
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19
Q

What are the most common mutations of neonatal diabetes

A

KCNJ11 and ABCC8 (form subunits of ATP controlled potassium channel)

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20
Q

Name the genes identified as responsible for mature onset diabetes of the young

A
  • Glucokinase
  • HNF1A
  • HNF1B
  • HNF4A
  • IPF1 (PDX-1)
  • NEUROD1
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21
Q

Name the ratio of diabetes types

A

10%: T1

90%: T2

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22
Q

People with T2 diabetes usually have high levels of insulin secretion at diagnosis:
True or False

A

true

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23
Q

Describe the characteristics of T2 diabetes

A
  • Insulin resistance in combination with beta-cell defects

- can have very high levels of insulin secretion but due to insulin resistance glucose levels remain high

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24
Q

What are the defects in regulation of blood glucose in T2 diabetes

A
  • diagnosis of T2 diabetes is made when insulin is unable to act on muscle, adipose and liver due to insulin resistance
  • It is hence unable to lower blood sugar levels
  • When beta cells are also unable to make sufficient insulin to stabilise blood glucose, diabetes is diagnosed
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25
Q

What is the presentation of T2 diabetes

A
  • long duration (months or years)
  • older at diagnosis (50s-60s)
  • Tiredness, sleepiness, change of behaviour
  • thirst, hunger, polyuria (symptoms of high glucose)
  • Oral/vaginal thrush, periodontal disease
  • strong family history
  • obese/overweight
  • diabetes defining complications
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26
Q

What are the treatment options of T2 diabetes

A
  • Diet/exercise
  • Drugs to promote insulin secretion (GLP-1 agonists, sulphonylureas)
  • Drugs to improve insulin sensitivity (metformin, pioglitazone)
  • Drugs to increase glucose excretion from kidneys (glifozins)
  • insulin injections
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27
Q

Name drugs that improve insulin sensitivity

A

Metformin, pioglitazone

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28
Q

Name drugs that promote insulin secretion

A

GLP1 agonists, suphonylureas

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29
Q

Name drugs that increase glucose excretion in the kidneys

A

Glifozins

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30
Q

What are the characteristics of T1 diabetes

A
  • autoimmune destruction of B cells of pancreas
  • presence of autoantibodies or autoreactive Tcells directed against islet cells or their antigenic constituents (eg. insulin, GAD64, IA-2)
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31
Q

What are the defects in regulation of blood glucose in T2 diabetes

A
  • pancreas is unable to produce insulin which can act on tissues
  • exogenous insulin injections required
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32
Q

What is the presentation of Type 1 diabetes

A
  • Having to use the toilet frequently
  • Thinner
  • Tired
  • Thirsty
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33
Q

What are the characteristics of Type 1 Diabetes

A
  • young and rapid onset (under 5s - puberty)
  • thin at diagnosis
  • immune (auto-antibodies and Tcells)
  • genetic problems within the immune system
  • weak family history (most cases are spontaneous)
  • need insulin to live
34
Q

What are the treatment options of T1 Diabetes

A
  • insulin replacement injections/pumps
  • regular blood glucose monitoring
  • carb counting/exercise
  • transplantation - islet/pancreas
35
Q

Name some triggers suggested for T1 diabetes

A
  • Viral infections
  • Lack of vitamin D
  • Cow’s milk
  • Environmental toxins
  • Obesity
  • Gut microbiota
36
Q

What impact does glycagon have on glycolysis

A

inhibits

37
Q

What is the name of the transported that allows glucose entry into muscle

A

Glut2

38
Q

Insulin receptors is a GPCR: True or false

A

false

39
Q

What component in beta cell sets the threshold for glucose stimulated insulin secretion

A

glucokinase

40
Q

Glucokinase has a low affinity for glucose: true or false

A

True (along with a lack of inhibition by substrate)

41
Q

What action does increased ATP levels have on the K+ATP channel in beta-cells

A

closes the channels

42
Q

Glucose is the only molecule that can moderate insulin secretion: True or false

A

False, can be done by fatty acids, amino acids, incretins, acetylcholine, epinephrine/neuroepinephrine

43
Q

Which second messenger does GLP-1 increase in beta-cells to promote insulin secretion?

A

cAMP

44
Q

How do fatty acids stimulate insulin secretion?

A
  • direct metabolisation into ATP
  • increasing DAG
  • binding to GPR40
45
Q

Which second messenger does GRP-40 increase in beta-cells to promote insulin secretion?

A

DAG, cAMP

46
Q

Name a transcription factor not present in adult beta-cells

A

HNF1b

47
Q

When might you suspect a diagnosis of Type 1 diabetes in children might not be correct?

A
  • diagnosis under the age of 6 months
  • family history of diabetes in parent of the affected child
  • evidence of endogenous insulin production outside of the honeymoon period (after 3 years of diabetes) along with detectable levels of c peptide when glucose >8mMol/L
  • pancreatic islet autoantibodies are absent, especially if measured at diagnosis
48
Q

What are T2 diabetes defining complication

A

Microvascular disease: retinopathy, neuropathy, nephropathy or foot ulcers
Macrovascular disease: myocardial infarction, stroke, peripheral gangrene

49
Q

When might you suspect a diagnosis of Type 2 diabetes in adults might not be correct?

A
  • Not markedly obese or diabetic family members who are normal weight
  • No acanthosis nigrosis detected
  • ethnic background from a low prevalence T2 diabetes race
  • no evidence of insulin resistance with fasting c peptide within the normal range
50
Q

Give an overview of Embryonic Stem cell based generation of insulin producing cells

A
  1. Sperm and egg join
  2. Embryo develops for 5-7 days
  3. Removal of inner cell mass from balstocyst
  4. These cells are grown in vitro
  5. Change culture conditions to stimulate cells to differentiate into a variety of cell types
51
Q

How can ES cell be differentiated

A
  • They can be differentiated by altering gene expression via chemicals than can be introduced by viruses
  • The stage of transformation the cell is in can be determined by using transcriptional factors present in the in-vitro cell as biomarkers
52
Q

What are the potential challenges of using ES stem cells for treating diabetes?

A
  • heterogeneity of ES cell progeny is unacceptable in a clinical setting (tricky to differentiate and not very feasible as you start with many cells and don’t end up with a lot of Beta cells)
  • Use of viruses, transgenes and genetic modifications increases the risk of ccancer in the recipient
  • Risk of immune attack
  • Ethical issues around source of ES cells
  • Often hard to generate fully functioning insulin-producing cells comparable with in-vivo mature beta cells (don’t respond to glucose to produce insulin)
  • full maturation can be achieved by growing the stem-cell progeny in an animal model
53
Q

Explain a recent study which includes the generation of functional human beta cells in vitro

A
  • Human/iPS cell converted into B-cell by soluble inductive signals like small molecules and proteins
  • Scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro
  • Stem-cell-derived β cells (SC-β) express markers found in mature β-cells
  • Flux Ca(2+) in response to glucose,
  • Package insulin into secretory granules,
  • Secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro.
  • Similar (but not identical) transcription profile
  • Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner
  • Transplantation of these cells ameliorates hyperglycemia in diabetic mice.
54
Q

Name some setbacks of the in-vivo study

A

Debate over kind of diabetic model used

55
Q

How do iPS cells differ from embryonic stem cells?

A
  • Adult stem cells, skin cells from an adult can be turned into Beta cells
  • less ethical issues
  • Lowered risk of rejection
56
Q

How are iPS cells produced?

A
  1. Isolate cells (skin or fibroblasts), grow in a dish
  2. Apply reprogramming factors like Oct4, Sox2, Klf4 and c-Myc
  3. Wait a few weeks
  4. Pluripotent stem cells
  5. Change culture conditions to stimulate cells to differentiate into a variety of cell types
57
Q

Name the medical applications of iPS cells

A
  • Disease/mutation specific research of beta cells
  • Personalised treatment
  • Replacement therapies
  • Circumvention of the need for immuno-suppressants
  • Correction of genetic defects
58
Q

What are the challenges of using iPS cell-based insulin producing cells

A
  • Producing a clinically relevant number of mature Beta cells
  • Time/cost: as a last ditch effort for patients not responding to other treatments?
  • Use of viruses causing random integration of pluripotency factors resulting in potential mutagenesis
  • Presence of pluripotent cells which can form teratomas
59
Q

Name a potential device that shows a safe way to use pluripotent cells

A
  • Theracyte: a device with an impermeable membrane with secretory cells on the inside which release therapeutic product. the impermeable membrane keeps the cells safe from outside immune cells and also potential uncontrolled teratoma formation
60
Q

Name some genes which can transform liver cells into beta cells

A

PDX1, Ngn3, Mafa

61
Q

Describe transdifferentiation

A

Transdifferentiation is defined as the process of the transformation of one mature somatic cell to another mature somatic cell

62
Q

Outline a study which highlights the transdifferentiation of liver cells to Beta cells

A
  • Adenovirus used to deliver Ngn3, Mafa, PDX1 to diabetic mice
  • Pancreas islet cells are usually exocrine in nature and are sparse across pancreatic tissue
  • A month after infection, insulin positive cells were seen in the pancreas
63
Q

Why is transdifferentiation preferred over stem cells

A

Liver is an easier organ to deliver to as compare to the pancreas

64
Q

Outline the two ways by which transdifferentiation can be used to create Beta cells

A
  • Transdifferentiation of liver cells to pancreatic islet cells
    Adenovirus used to deliver Ngn3, Mafa, PDX1 to diabetic mice
  • Pancreas islet cells are usually exocrine in nature and are sparse across pancreatic tissue
  • A month after infection, insulin positive cells were seen in the pancreas
  • Transdifferentiation of alpha cells to beta cells by changing expression of Pax4
65
Q

How might this research into transdifferentiation be translated into a treatment for type 1 diabetes in humans?

A
  • Long-term application of GABA an induce the conversion of rat alpha cells into beta cells
  • GABA also induces alpha cell mediated beta like cell neogenesis in vivo
66
Q

What evidence is there to suggest that beta-cell regeneration might be possible in patients with type 1 diabetes?

A
  • some patients with type 1 diabetes can have detectable c-peptide levels for over 50 years
  • there is an increased proliferation of beta cells upon the recent onset of T1 diabetes
  • Several signals can increase beta-cell proliferation. E.g. hepatocyte growth factor, insulin-like growth factor I, exendin-4 placental lactogen and adenosine
  • Fasting mimicking diet promotes Ngn3 driven beta-cell regeneration
67
Q

How does an islet transplantation work?

A
  • Pancreatic islet cells are isolated from donor
  • Isolated cells are injected into the recipient’s liver (portal vein)
  • Beta cell function is restored
68
Q

What are the advantages of islet transplantation for the treatment of type 1 diabetes?

A
  • Improve glucose control
  • Reduced hypoglycaemic events
  • Reduced exogenous insulin dependancy
  • improved hypoglycaemic awareness
69
Q

What are the disadvantages of islet transplantation for the treatment of type 1 diabetes?

A
  • high levels of cell death occur
  • multiple donors required to achieve insulin independence
  • insulin independence doesn’t last very long
  • immunotherapy is required so no rejection takes place
  • possible problems at the site of injection
70
Q

How might the current islet transplant protocol be changed to overcome these problems?

A
  • whole pancreas transplantation
  • animal sources of islets
  • alternative sites of injection
  • improved culture of islets before injection
71
Q

What methods can be used to measure blood glucose levels?

A 
Invasive
- Finger prick test
- Hba1c test (checks for glycated haemoglobin, can't be used for people with kidney problems
Non-invasive
- Flash glucose monitoring
- Continuous glucose monitoring
72
Q

What are the disadvantages of non-direct methods of glucose monitoring?

A
  • more expensive
  • less accurate as they measure interstitial fluid instead of blood glucose
  • can be affected by temperature
73
Q

Describe the normal processing of insulin

A
  • Preproinsulin is produced in the ribosomes of the rough ER
  • Preproinsulin is cleaved to proinsulin and is then transported to the golgi apparatus and is transported close to the membrane in secretory granules
  • Proinsulin is then cleaved into equimolar amounts of insulin and peptide c within these granules
74
Q

How are insulin analogues modified to alter their properties (and why is this useful)?

A

Rapid acting insulin analogues: Aspart, Glulisine, Lispro
- normally human insulin forms hexomers around zinc ions, slowing down it’s absoprtion
- Rapid acting: changes in amino acid sequence to disrupt dimer formation: faster absorption and rapid onset of action
Long acting insulin analogues: glargine and determir
- Glargine: two additional arginine residues and glycine replacing an asparagine shifts isoelectric point – reduced solubility at physiological pH – slow release
- Determir: promotes self association and binding to albumin

75
Q

Name some alternative methods to deliver insulin

A
  • insulin pumps
  • inhaled insulin (not used much, problems around variable absorption of insulin and local irritation)
  • insulin patches
76
Q

Name some advantages of inhaled insulin

A
  • Exubera was too big and inconvenient to carry around
  • Afrezza administered dry-powder insulin before meals
  • Rapid absorption of insulin
  • Cleared up quickly in the blood
  • causes rapid drop in glucose level which return to normal in a much shorter time than after subcutaneous administration
77
Q

How do microneedle array patches work

A
  • Patches have microneeedles piercing into the skin
  • Needles have nanoparticles that consist of the following:
    • insulin
    • glucose oxidase
    • polymer that dissociates in hypoxic conditions
  • when glucose levels rise, hydrogen peroxide levels go up and dissolve the polymer and releases insulin
78
Q

How can SMART insulins be manipulated?

A
  • Glucose sensors attached to albumin
  • Modulating insulin molecule itself
  • Modulating the release of insulin
79
Q

What are the components of an artificial pancreas?

A
  • insulin pump
  • continuous glucose monitor
  • algorithm
80
Q

Why is it hard to write an algorithm for an artificial pancreas

A
  • complicated system
  • various factors that regulate glucose levels like food consumed and exercise done
  • loads of feedback mechanisms also involved
81
Q

Describe the hybrid closed loop system recently approved by the FDA

A
  • adjust insulin levels with little to no input from the user
  • measures blood glucose levels every 5 minutes and automatically administers or withholds insulin
  • predicts when a person’s blood glucose levels are rising or falling and corrects them
  • a hybrid as users have to signal before they eat and estimate carbohydrate count of food
  • insulin is deposited just under the skin and takes a long time before working
82
Q

What properties would a ‘SMART insulin’ need to be effective?

A
  • must improve disease control
  • limit potential for excessively low levels of blood glucose
  • must respond rapidly to high glucose levels
  • cost-effective

Translational Medical Sciences (8 decks)

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