Learning Objectives Flashcards
Draw a histological diagram of cells in the pancreas. Which cells produce glucagon and which produce insulin?
What is the difference between a GLUT and an SGLT transporter? What do they stand for? What number types are there? And where can they be found?
Draw how these Glucose transporters are used in the gut, and in the PCT respectively
How do glucose levels in the blood influence the Beta-cellular production of Insulin in the pancreas?
How is the hormone GLP-1 involved? And how can it be degraded?
How does Insulin facilitate entry of glucose into certain tissues?
Insulin facilitates entry of glucose into muscle, adipose and several other tissues.
In many tissues - eg skeletal muscle - the major family of hexose transporters used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.
GLUT4 glucose transporters are present in cytoplasmic vesicles. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose.
When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.
Some tissues - e.g. Brain and Liver - do not require insulin for efficient uptake of glucose: they use GLUT-2 instead of GLUT-4.
How does Insulin encourage the production of Free Fatty Acids in the liver?
- Insulin promotes synthesis of fatty acids in the liver. As discussed above, insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.
When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are then exported from the liver as lipoproteins (VLDL etc).
The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.
How does Insulin stimulate the accumulation of fat in adipose tissue?
- Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyses triglycerides to release fatty acids.
- Insulin facilitates entry of glucose into adipocytes (through GLUT-4), and within those cells, glucose can be used to synthesize glycerol.
This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte.
From a whole body perspective, insulin drives most cells to preferentially oxidize carbohydrates instead of fatty acids for energy.
Draw the Dwara diagram, but include separate diagrams for what is happening in the Liver, Skeletal muscle and Adipocytes
Give a clinical definition of Diabetes Mellitus
“A state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues, notably the retina, kidney, nerves, and arteries.
It is due to the inadequate production of insulin and/or ‘resistance’ to the glucose lowering and other actions of insulin
It is a significant and growing threat to global health, affecting more than 400 million people worldwide.”
Give an outline of Type 1 Diabetes Mellitus and its cause/pathophysiology
Autoimmune condition - belongs to a family of human leukocyte antigen (HLA)-associated autoimmune
diseases.
Causes a Type IV hypersensitivity (cell-mediated immune response) targeting pancreatic B-cells
(Cytotoxic T-cells ——Cytokines——> Plasma Cells —> Release antibodies)
Autoantibodies directed against pancreatic islets appear in circulation in first few
years of life often well before clinical onset
Susceptibility is polygenic but HLA region is the big player. HLA-DR3 or DR4
in >90% cases
Environmental component poorly understood. Do research for details.
Give an outline of Type 2 Diabetes Mellitus and its cause/pathophysiology
A developed condition.
Suspected genetic component. Twin studies / first-degree relative probability increases.
Risk factors include: Hypertension, Obesity, Smoking etc.
Insulin resistance is a common result of Metabolic Syndrome (see next card)
Pathophysiology
GLUT-4 Insulin receptors on tissue cells become resistant to Insulin
Leads to decreased cellular absorption, leading to hyperglycaemia in the blood.
Pancreas attempts to compensate via hyperplasia and hypertrophy to produce more insulin to make up for the resistance
Eventually the pancreatic cells become dysfunctional, and you see hypotrophy and hypoplasia.
Finally, permanent hyperglycaemia develops.
What are the diagnostic criteria for Metabolic Syndrome?
NB 100mg/dl Glucose = 5.6 mmol/L Glucose
What is the WHO diagnostic criteria for diagnosing Diabetes?
NB:
An HbA1c of 6.5% is recommended as the cut point for diagnosing diabetes.
A value of less than 6.5% does not exclude diabetes diagnosed using glucose tests.
OGTT: Oral Glucose Tolerance Test
Patient fasts 8-14 hours over night (water permitted). Take blood in the morning. Give patient 75g anhydrous glucose in 250-300mL water over five minutes. Patient rests for 2 hours (no smoking!). Take second blood sample after 120 minutes.
What are the normal ranges for Glucose and HbA1c in the blood?
NB:
HbA1c reflects average blood glucose over period of 2-3 months.
What are IFT and IGT?
Both impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are pre-diabetic states.
IGT:
Normal fasting plasma glucose (< 6.1 mmol/l)
Abnormal OGTT plasma glucose
(>7.8 mmol/l)
IFG:
Normal OGTT plasma glucose (<7.8 mmol/l)
Abnormal fasting plasma glucose (>6.1 mmol/l)
What can a urine dip tell you about diabetes?
Ketonuria – DKA.
Glycosuria – less diagnostically useful (see below)
“Glycosuria depends on the renal threshold for glucose reabsorption and its presence does not necessarily indicate hyperglycaemia; conversely, glucose may be absent from the urine in diabetic subjects who also have a high renal threshold. However, abnormal results with any of these tests suggest diabetes and indicate the need for formal blood glucose screening”
How does Insulin deficiency lead to Diabetic Keto Acidosis?
Fat in adipose tissue –> Free Fatty Acids
In the absence of insulin there is uncontrolled hepatic ketogenesis,
i.e.
FFAs-> ketone bodies
Accumulation of these ketone bodies causes a metabolic acidosis
Ketones are excreted in uria and exhaled in breath
Vomiting leads to loss of fluid and electrolytes
Why do potassium levels fluctuate severely during the treatment of DKA?
Lower blood pH induces exchange of H+ and K+, and K+ is shifted in large quantities from ICF to ECF
In a healthy individual, Insulin decreases potassium levels in the blood by redistributing it into cells via increased sodium-potassium pump activity.
Obviously an insulin deficiency will impair this process. Additionally, during a DKA much of the K+ will be lost in urine because of osmotic diuresis.
Kumar and Clark: “Patients have a total body K+ deficiency at admission although plasma K+ measurements may not be low”
Hypokalemia (low blood potassium concentration) often follows treatment.
Therefore, continuous observation of the heart rate is recommended, as well as repeated measurement of the potassium levels and addition of potassium to the intravenous fluids once levels fall below 5.3 mmol/l.
If potassium levels fall below 3.3 mmol/l, insulin administration may need to be interrupted to allow correction of the hypokalemia
Give a definition of:
Polyphagia
Polydipsia
Glycosuria
Polyuria
What are the three main types of Diabetic Neuropathy?
NB: Follows a typical Glove and Stocking Pattern
Draw a rough description of the pathophys of vascular damage as result of diabetes
- Increased blood glucose leads to increase uptake of Glucose into cells
- Cells generate lots of ATP and ROS, stimulating PKC
- PKC encourages growth factors, vascular permeability, LDLs and Macrophages invade and form foam cells
- Leads to atherosclerosis, damage and blocking of blood vessels
What are the main 3 microvascular complications of Diabetes?
Retinopathy
Neuropathy
Nephropathy
What are the three main categories of macrovascular complications of diabetes? And what conditions do they entail?
What is the pathophys of microvascular damage to the nervous system?
NB: Axonal dieback is a process in which axons in spinal tracts retract away from the initial site of injury.
Draw a diagram showing areas of the body that can be affected by diabetic neuropathy:
What infections are diabetics prone to? And why?
Infectious diseases are more frequent and/or serious in patients with diabetes mellitus.
The greater frequency of infections in diabetic patients is caused by the hyperglycemic environment that favors immune dysfunction. These include:
Damage to neutrophil function
Depression of the antioxidant system (and humoral immunity)
Micro and macro-angiopathies
Neuropathy
Decrease in the antibacterial activity of urine
Gastrointestinal and urinary dysmotility
The effect of a greater number of medical interventions in these patients.
⤓
Genetics / Risk Factors
⤓
Insulin Resistance
⤓
Beta-cell failure
⤓
Insulin Deficiency
⤓
(see image)
What is the normal plasma concentration of Glucose? And what is the cutoff for a diagnosis of Hypoglycemia?
What are the major effects of Insulin?
What are the four main counter-regulatory hormones for Glucose? And what are their main effects?
What is meant by
Lipolysis
Lipogenesis
B-Oxidation
Esterification
Lipolysis
- TGs are broken down by Adrenalie/Noradrenaline to FFA + Glycerol
- FFAs undergo B-oxidation to become Acetal-CoA and take part in ATP production or Ketogenesis
Lipogenesis
- Acetal-CoA is converted to FFA
- FFA + Glycerol undergo esterification to become TGs to be stored in adipose tissue
How is fat stored in adipose tissue, and how is it broken down, and how is insulin involved? Create a diagram
How does a chronic lack of insulin cause DKA in type 1 DM?
Under normal conditions, insulin allows free fatty acids, as triglycerides, to be stored in adipose tissue. As a result of the reduced insulin levels and the concomitantly elevated levels of glucose counter-regulatory hormones, there is excessive production of free fatty acids from the breakdown of triglycerides.
In the liver oxaloacetate is wholly or partially diverted into the gluconeogenic pathway during in uncontrolled type 1 diabetes mellitus.
Under these circumstances oxaloacetate is hydrogenated to malate which is then removed from the mitochondrion to be converted into glucose in the cytoplasm of the liver cells, from where the glucose is released into the blood.[1]
In the liver, therefore, oxaloacetate is unavailable for condensation with acetyl-CoA when significant gluconeogenesis has been stimulated by low (or absent) insulin and high glucagon concentrations in the blood.
Under these circumstances, acetyl-CoA is diverted to the formation of acetoacetate and beta-hydroxybutyrate.[1]
Acetoacetate, beta-hydroxybutyrate, and their spontaneous breakdown product, acetone,[5] are known as ketone bodies.
Draw a flow chart of the metabolic disturbances caused by a lack of insulin
Draw a diagram of how the body tries to compensate for a state of hypoglycemia
Which endogenous factors stimulate and which inhibit insulin release?
Which endogenous factors stimulate and which inhibit Glucagon release?
How does Glucagon function (put simply)
- Counter-regulatory hormones act principally (not exclusively) through activity of PKA, which phosphorylates key enzymes in metabolic pathways
- Insulin action leads to dephosphorylation of these same enzymes
How does Insulin work (put simply)
Give an outline of the basal-bolus regime of managing insulin therapy in T1 DM
What is lipohypertrophy and can one avoid it?
Lipohypertrophy is when lumps of fat or scar tissue form under your skin. It is caused by repeat injections or infusions in the same area of the body and is more common in people with diabetes
What are some common signs and symptoms of hypoglycemia?
How do you treat a hypoglycemic episode?
- Give glucose 15 – 20 g
- Recheck CBG 10 – 15 minutes later
- If still below 4 mmol/L – give glucose again
- Recheck CBG and document
- Give slow acting carbohydrate e.g. a sandwich, banana, crackers
- Analyse cause of hypo and review treatment.
- Refer to Diabetes Specialist Nurse
Draw a diagram of the typical stepwise management of type 2 DM
What are the 6 main treatments used to manage type 2 DM?
Draw a diagram to outline their effects
- Biguanides - Metformin
- Sulphonylureas
- GLP-1 analogues (Subcutaneous)
- DPP-IV inhibitors
- SGLT2 inhibitors
- Glitazones
- Insulin
Give an overview of the action of Metformin
Give an overview of the action of Sulfuroneas
- Stimulate insulin secretion
- Potent
- Act on beta-cells
- Closes ATP dependent K+ channels
- Results in Ca2+ influx and release of insulin storage granules
Give an overview of the role and action of Incretins (e.g. GLP-1)
GLP-1 Analogues include:
Exenatide
Liraglutide
Lixisenatide
Exenatide is particularly useful as it is resistant to DPP-IV inactivation
What are the main side effects of each diabetes drug?
SAME QUESTION, NEW TABLE
Give a management strategy for Drug treatment of type 2 diabetes
