Diabetes

Question 1

What two roles does the pancreas have? What does each do?

Answer 1

Exocrine function = secretes digestive enzymes directly into the GI tract

Endocrine function = secretes hormones from the islets of Langerhans
Insulin – from β-cells
Glucagon – from α-cells

Question 2

Describe glucose and insulin homeostasis. (Draw a graph representing it)

Answer 2

Homeostasis maintains a balance of large upswings and downswings of blood sugar due to eating; not a straight line

Insulin release follows a similar pattern, released in response to high BG levels

Question 3

What is insulin’s role in glucose homeostasis?

Answer 3

Released in response to HIGH blood sugar
Promotes the uptake, utilization, and storage of glucose (glycogen) → lowers blood glucose concentration

Question 4

What is glucagons role in glucose homeostasis?

Answer 4

Released in response to LOW blood sugar
Increases the hepatic glucose output → increases blood glucose concentration

Question 5

What is the structure of insulin?

Answer 5

• 51 amino acids (A, B chain connected by 2 disulfide bonds)

Question 6

When is insulin release stimulated?

Answer 6

Elevation of blood glucose (i.e. eating)
Other circulating fuels like amino acids or fatty acids
Hormones: GLP-1, GIP, epinephrine, adrenergic and cholinergic stimulation, and estrogen

Question 7

What antagonizes insulin?

Answer 7

In times of stress, cortisol, glucagon, and growth hormone antagonize insulin

Question 8

Describe how insulin works?

Answer 8

The endocrine hormone that regulates blood sugar
Causes rapid uptake, storage, and use of glucose by insulin sensitive tissues
Muscle, adipose, liver, brain*
*Brain is the only organ that doesn’t need insulin to use glucose this explains hypoglycemic symptom progression later

Serum glucose goes down because it enters cells to be used
Suppresses endogenous glucose
Inhibits glucagon release

Insulin is a “key” for the glucose to get into the cells

Question 9

What cells does glucose enter into in the pancreas? How does it do this?

Answer 9

A human eats food and it is broken down into glucose
Glucose enters the beta cells in the pancreas via GLUT2 transporters

Question 10

How does the pancreas know how much insulin to release?

Answer 10

Each glucose molecule is broken down to ATP (i.e. energy) and it attaches to an ATP-sensitive K channel and CLOSES IT
This causes depolarization – and the amount of depolarization determines how many Ca channels will open to try to balance out the charges
Calcium enters the cell and facilitates exocytosis of the pre-made insulin

Continual process and a proportional amount of insulin is dtermined by the amount of gucose that enters the cell

Question 11

How does insulin allow glucose uptake in cells? (Insulin signal transduction)

Answer 11

Insulin binds to the insulin receptor (a D-R interaction)
Cascade of protein activations and translocation of GLUT4 to the cell membrane
Glucose enters the cell
Cell converts to whatever the cell needs (fat, glycogen, or just energy in the form of ATP to use)

Question 12

What is the basal release rate of insulin? (actual numbers)

Answer 12

Basal release rate of 0.5 – 1.0 unit / hour
Oscillates every 3-6 minutes

Question 13

What is the bolus rate of release of insulin?

Answer 13

Rate of release increases when blood glucose (BG) > 5.5mmol/L (in response to eating - bolus)

Question 14

Define basal release

Answer 14

Beta cells secrete small amounts of insulin
throughout the day.

Question 15

Define bolus release

Answer 15

At mealtime, insulin is rapidly released in response to food.

Question 16

What are the two incretin hormones? What are their role? What enzyme inhibits them?

Answer 16

GLP-1 and GIP: hormones secreted by the GI tract at a baseline level all day (basal) and surges with eating a meal (bolus)
Sent to the pancreas to release insulin

DPP-4 is the enzyme that inactivates them (incretin hormones)

Question 17

How does insulin resistance occur? Explain its correlation to obesity?

Answer 17

Strong correlation between obesity and insulin resistance
Excess nutrition inevitably leads to storage of free fatty acids as triglycerides in adipose tissue – peripherally then viscerally – which causes:

Enhanced sensitivity to counter-regulatory hormones by expressing more 𝛃 receptors and activating more cortisol
Lowers insulin receptor affinity

Question 18

Define diabetes

Answer 18

A metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion, insulin action, or both

Question 19

Define Type-1 Diabetes

Answer 19

Type 1 – due to defective insulin secretion
Caused by an auto-immune disease (beta-cells destroyed by immune system –> mainly in youth, but not exclusive)
Pancreas not making any insulin
Insulin declines quickly and steadily
Trigger of immune response is unknown

Question 20

Define Type-2 Diabetes

Answer 20

Type 2 – due to insulin resistance, eventually leading to defective insulin secretion (no autoimmunity) –> High correlation btwn obesity and type 2 but not causational

• Slower than type 1
• Due to environmental influences (overweating, sedentary lifestyle) on a genetically susceptible individual (COMBINATION OF BOTH)

Question 21

What are the macrovascular complications of diabetes?

Answer 21

Cardiovascular disease (dyslipidemia, hypertension, coronary artery disease, stroke, erectile dysfunction)

Question 22

What are the microvascular complications of diabetes?

Answer 22

• Small blood vessels

Nephropathy  kidney impairment  kidney failure
Retinopathy  blindness
Peripheral neuropathy  infection  amputation

Question 23

Type 1 Diabetes Symptoms

Answer 23

Hyperglycemia – no insulin, so glucose can’t enter cells

Fatigue – cells aren’t getting energy
Polyphagia – cells are starving so they signal for hunger
Weight loss – use up stored energy instead*

Polyuria – kidney tries to help clear the excess glucose
Glucosuria – the pee has more glucose than normal
Polydipsia – we are thirsty because of peeing so much

Question 24

What can undiagnosed type-1 diabetes lead to?

Answer 24

Severe, undiagnosed Type 1 Diabetes usually presents as diabetic ketoacidosis (DKA)
The body breaks down *ketones for energy instead (because it can’t use the glucose)  produce keto acids  coma  death

Question 25

What are the signs of diabetic ketoacidosis?

Answer 25

nausea, vomiting, severe abdominal pain, thirst, excessive urine production, dry mouth, hypotension, tachycardia, deep and laboured breathing (acetone), confusion Can monitor for ketones in urine (will ‘spill over’ into urine when high level in blood) – Ketostix®

Question 26

How is type-1 diabetes treated?

Answer 26

We give patients insulin and do our best to mimic normal pancreatic function with products we have available

Question 27

How is type-1 treated? What is it classfied as? What are the benefits of this?

Answer 27

Our insulin is made within bacterial cells (e. coli) as a biologic, which means: Less allergies and resistance More effective Can be modified to have desired results on blood glucose levels

Question 28

Signs and symptoms of type-2 diabetes?

Answer 28

Entirely depends how far the disease has progressed Can be asymptomatic at diagnosis Possibly any Type 1 signs and symptoms Often overweight or obese but not all (~85%) May have already developed complications at presentation Macro – signs of cardiovascular disease Micro – kidney disease, retinopathy, peripheral neuropathies

Question 29

Where is the problem in Type-1? Where is the problem in Type-2?

Answer 29

Type-1 --> Pancreas --> Insulin sensitive tissues not affected Type 2 --> Begins at the insulin sensitive tissues (pancreas may die out eventually)

Question 30

How is type-2 diabetes treated?

Answer 30

- Lifestyle and healthy diet --> can effectively delay progression - Oral hypoglycemic (or antihyperglycemic) drugs - Patients may eventually need insulin

Question 31

What is the goal of treatment for both type-1 and type-2?

Answer 31

By giving patients insulin or oral medications, we attempt to mimic the normal production and release of insulin by the pancreas as much as possible to accomplish glucose homeostasis In order to do this, we need to recognize the signs and symptoms of both hyperglycemia and hypoglycemia Hypoglycemia is very dangerous as well – we need a balance

Question 32

How can we measure blood glucose>

Answer 32

Fasting Post-prandial Hemoglobin A1C

Question 33

Fasting Glucose Measurement

Answer 33

Fasting (FPG) (mmol/L)= technically no caloric intake for at least 8h This term is sometimes used to indicate a BG reading right before a meal (pre-prandial) - The lowest reading, only a snapshot in time

Question 34

Post-Prandial Glucose Monitoring

Answer 34

Post-Prandial (PPG) (mmol/L) = 2 hours after a meal In someone without diabetes, the glucose has entered the cells by then - Just a snapshot --> No info about past or present

Question 35

Hemoglobin A1C Glucose Measurement

Answer 35

Hemoglobin A1C (%) = measures an average of blood glucose control over the last 3 months Measures the % of hemoglobin that has been glycosylated, which is correlated with blood glucose levels A hemoglobin cell lives ~3 months, and glycosylation is irreversible (i.e. it does not exist in an equilibrium) - Not a snapshot --> gives us a look back over the last 3 months - Does not tell us how high or how low

Question 36

What is the A1C target for most patients?

Answer 36

- Less than or equal to 7% A1C --> 6.5% for some patients A1C 7.1 – 8.5% for some patients

Question 37

When would hyperglycemia occur? What does it look like? What is the numerical value of hyperglycemia?

Answer 37

HYPERglycemia would occur if a patient with diabetes did not have enough insulin It looks like: Polyuria = peeing Polydipsia = thirsty Polyphagia = hungry Glucosuria = glucose in urine Fatigue = very tired FPG > 7.0mmol/L

Question 38

What is hypoglycemia and what doe sit look like?

Answer 38

HYPOglycemia would occur if a patient with diabetes had too much insulin, improper timing of insulin, or skipped a meal FPG < 4mmol/L It looks like: Mild --> moderate --> severe symptoms --> coma/death Autonomic --> neurological changes (periphery --> CNS) Autonomic --> trembling, sweating, nauseau, tingling Neuroglycopenic --> Drunk --> Confusion, weakness, diffucluty speaking concentrating, drowsiness Recurrent episodes of hypoglycemia can impair their ability to sense future episodes – elderly major concern

Question 39

How do insulin preparations vary?

Answer 39

Insulin preparations vary by: Onset of action Time to peak glycemic effect Duration of action Appearance

Question 40

How can insulin be given?

Answer 40

Subcutaneously (most common) – layer of fat Must rotate sites to prevent localized fat deposits (lipodystrophy) With an insulin pump (continuous subcutaneous) IV - **only regular (R or Toronto)** **emergencies**

Question 41

Lipodystrophy

Answer 41

Abnormal distribution of fat (both atrophy and hypertrophy can present H>A) Repeated injections of insulin into the same tissue over and over again causes the tissue to adapt Glucose enters cells here at a higher rate due to proximity Worsened by frequent needle re-use

Question 42

Where should insulin be injected?

Answer 42

Rotate injections systematically within the same anatomical region Rates of absorption remain similar Reduces chances of lipodystrophy effects Underarm, around belly button, thigh, love handles

Question 43

What are the classes of hypoglycemics to treat type-2 diabetes?

Answer 43

Metformin Sulfonylureas (Insulin secretagogues) Repaglinide (Insulin secretagoue) Thiazolidinediones Acarbose Dipeptidyl Dipeptidase 4 (DPP4) inhibitors Glucagon-like peptide 1 (GLP-1) agonists SGLT-2 Inhibitors

Question 44

Metformin

Answer 44

Mechanism is to increase activity of enzyme AMPK that regulates multiple metabolic processes Enhances tissue sensitivity to insulin --> reducing insulin resistance Decreases hepatic gluconeogenesis (amount of glucose the liver us making) Decreases intestinal glucose absorption

Question 45

Sulfonylureas

Answer 45

Enhance insulin secretion from the pancreas (insulin secretagogue) How? inhibiting ATP-sensitive potassium channels to stimulate insulin secretion from functioning beta cells of the pancreas

Question 46

Repaglinide

Answer 46

Same mechanism as sulfonylureas but works much quicker and arguably less effective (insulin secretagogue) Requires presence of glucose to exert action, therefore MUST BE TAKEN BEFORE (within 30 mins) OR WITH A MEAL Skip a meal, skip a dose; add a meal, add a dose

Question 47

Thiazolidinediones

Answer 47

Enhance insulin sensitivity at target tissues similar to metformin How? Agonist for PPAR𝛄 – peroxisome proliferator-activated receptor-gamma which forces the insulin receptor to the cell surface, combating insulin resistance

Question 48

Acarbose

Answer 48

Inhibits α–glucosidase, which reduces the rate of absorption of carbohydrates from the GI tract, preventing hyperglycemia – therefore TAKE WITH MEALS

Question 49

DPP4 Inhibitor

Answer 49

DPP-4 inhibitors inhibit the breakdown of incretins, which increases and prolongs their activity  instructs pancreas to release more insulin for longer

Question 50

GLP-1 Agonists

Answer 50

GLP-1 agonists mimic endogenous GLP-1

Question 51

SGLT-2 Inhibitors

Answer 51

Increases excretion of glucose in the kidney by preventing glucose reabsorption, therefore reducing blood glucose levels

Question 52

Insulin in type 2?

Answer 52

With progression of the disease, eventually β–cells are destroyed and insulin must be started Begin with a long-acting insulin analogue (glargine or detemir), progress to addition of bolus insulin with meals over time