Insulin, Glucoregulatory Molecules & Diabetes Flashcards
What is the “glucose sensor” in the body?
The beta cells of the pancreas (islets of Langerhans)
In response to increased blood glucose, beta cells of the pancreas secrete…
insulin, which stimulates glucose uptake into cells
Type I vs Type II diabetes
Type I: The body develops autoimmunity against beta cells and destroys them. You thereby do not produce insulin and blood glucose increases. Defect in insulin secretion.
Type II: The cells become resistant (do not respond as easily) to insulin (it takes more insulin secretion to stimulate glucose uptake).
Over time, beta cells become less efficient at making enough insulin to overcome the resistance. Both a defect in insulin secretion and insulin action.
*Something about the liver
Where are alpha vs beta cells located on the islets of Langerhans (in mice)? what does this imply?
Beta cells: occupy the core of the islets
Alpha: occupy the rim of the islets
This implies that beta cell secretions may regulate alpha cells.
In humans the alpha and beta cells are more mixed, but they still cross-talk.
How does glucose stimulate insulin secretion?
Glucose gets taken up by beta cells via GLUT2 channels and metabolised to ATP. The increase in ATP inhibits the potassium channel, preventing the K to leak out of cells. The cell depolarizes and leads to calcium inflow. This stimulates the exocytosis of insulin.
Review
Why is the beta-cell uniquely able to sense glucose?
Because the GLUT2 transporters on its plasma membrane have a very high Km for glucose. Thus, when blood glucose concentration increases, the rate of glucose uptake rises significantly.
ATP sensitive K+ channel
The nucleotide binding domains (NDBs) bind ATP, which shuts down the Kir6 channels, preventing K+ leakage from the beta cells.
Drugs (sulfonylureas) that mimic the effects of ATP in beta-cells (2)? How do they work? What is their risk
Glyburide and glicazide (sulfonylureas)
They stimulate insulin release, independent of blood glucose level (risk of developing hypoglycemia and can promote weight gain).
How do glitinide drugs work? Name some common examples?
Repaglinide, meglitinide, nateglinide
Short-acting compare to sulfonylureas
Which drug can be used in renal failure:
a) sulfonylureas
b) glitinides
a) glitinides (because they are metabolized by the liver rather than the kidneys)
Name non-glucose regulators of insulin secretion (3 that increase, 3 that decrease)
Increase insulin secretion:
* Amino acids
* Fatty acids
* Estrogens (pregnancy)
Decrease insulin secretion:
* Leptin
* Melatonin
* IGF-1
Most potent combination of amino acids to increase insulin secretion
Leucine and glutamate
Amino acids have a minor effect on insulin, and are mostly potent as combinations
Giving glucose orally stimulates more insulin secretion than intravenous glucose. Why?
Due to peptides released by the gut when food enters the mouth (GIP and GLP-1). These hormones are called incretins and promote insulin release in response to oral glucose intake.
True or false: Cells only respond to GIP and GLP-1 when blood glucose is high.
True: What is the advantage? I did not understand
GIP and GLP-1 and diabtes?
??
Why is GLP-1difficult to target by drugs?
Because it has a very short half-life in circulation and gets inactivated within minutes by proteases (dipeptidypeptidase IV)
Effects of GLP-1
- Stimulates insulin release in a glucose-dependent manner
- Decreased gut motility
- Decreased glucagon secretion
- At large pharmacological doses, promotes weight loss
How do we develop a drug that increases GLP-1 action?
By increasing levels of GLP-1:
- Increase production
- Decrease degradation
What is exenatide?
A drug that stimulates the GLP-1 receptor, but not very practical (needs to be administered multiple times per day). It is no longer used anymore because there are better drugs.
What is liraglutide?
A drug that stimulates the GLP-1 receptor that is fused to a long-chain fatty acid, allowing the peptide to bind to albumin. This prevents it from being rapidly degraded by proteases.
Ozempic is a more potent form of liraglutide
Vitagliptin, sitagliptin, saxagliptin…
raise GLP-1 levels in the blood but… ???
Mechanism of GLP-1
Acts via G-protein coupled receptor
???
Tirzepatide
Tirzepatide is a dual GLP1 and GIP agonist, because its sequence has enough similarity to both GLP1 and GIP that it can bind both receptors.
It also has the helpful effect of inducing weight loss.
Additional benefits of semaglutide GLP1 agonist (Ozempic)
Weight loss
Cardioprotection
Renal protection
Improved fatty liver disease
How must we treat type I diabetes?
Since they cannot produce their own insulin, we must administer insulin!
Describe the structure of insulin
C-peptide cleaved by proconvertases in beta cells of the pancreas.
Something about it remaining ends to hang together via 2 cysteine residues.
There are different variants of insulin we can administer to patients.
Describe regular insulin
Short acting (duration ~6h)
Peak at 2-4 hours
Describe rapid-acting insulin
Lispro, aspart, glulisine
Duration~4 hours
Peak 1-2 hours
Can be injected right before eating.
Describe intermediate-acting insulin
Insulin is complexed with protamine, which slows the absorption of insulin.
Duration~18h
Peak 8-12 hours
Describe long-acting insulin
Detemir, glargine
Duration ~24h
Minimal peak
Describe very long-acting insulin
Degludec
Duration ~40hours
?
True or false: Insulin is only released when we eat.
False! There is a basal insulin production even in fasting states!
I did not understand how we can combine different insulin types to mimic natural insulin production. Rewatch pls
Effects of glucagon (liver) (4)
Stimulates glycogenolysis
Stimulates gluconeogenesis
Stimulates fatty acid oxidatio to ketones
Stimulates protein degradation
Effects of glucagon (adipose tissue)
?
True or false: Unlike insulin, glucagon has no direct effect of skeletal muscle
True!
When does the pancreas release glucagon?
Low blood glucose (this prevents hypoglycemia)
Which pancreatic cells release glucagon?
Alpha cells of the islets of Langerhans
Mechanisms by which low glucose stimulates glucagon secretion (3)
- Direct effect of low glucose on alpha cells
- Cross talk between beta-cells and alpha cells (decreased release of insulin and other factors by beta cells stimulates alpha cells)
- CNS detection of hypoglycemia and activates the SNS. The SNS releases catecholamines to stimulate glucagon release by alpha cells.
How come amino acids stimulate insulin release, but also glucagon secretion?
In case you eat protein without carbohydrates…
Name (and explain) some stimulators of glucagon secretion
- Amino acids
- Exercise
Describe glucose tolerance in obese pre-diabetic patients
Obese patients must produce much more insulin than healthy individuals to maintain the same blood glucose.
Why are obese patients insulin resistant (and pre-diabetic)?
Normally, insulin binds to a ?? receptor. This receptor then phosphorylates tyrosine residues on itself. This helps recruit other proteins that bind the insulin receptor (insulin receptor substrate proteins). The IRS proteins also et phosphorylated and recruit signalling molecules. One of these molecules, PI3K is a kinase that phosphorylates lipids and activates a kinase called Akt.
Ultimately, Akt stimulates transport of glucose into muscle cells (by inserting glucose transporters into the membrane).
In obese/prediabetic patients/type II diabetics, there is a disruption in this signaling pathway such that fewer glucose transporters are inserted in the membrane (?)
Mechanism of insulin resistance - obesity
PI3K is inhibited by…??
How do glucocorticoids affect insulin pathways?
Glucocorticoids decrease PI3 kinase activity by increasing the expression of the p58 regulatory subunit.
Drugs (or other methods) that improve insulin sensitivity
Exercise!!!
- Weight loss
- Exercise stimulates glucose transporter insertion (?)
Metformin
PPARy agonists
First line medication for insulin resistance/type II diabetes?
Metformin
Why is metformin the first line medication for insulin resistance/type II diabetes
- Does not cause hypoglycemia
- Can promote weight loss
- Reduces cardiovascular events
When is metformin contraindicated
- Renal failure
- Liver failure
Severe heart failure - Severe respiratory insufficiency
i.e. in conditions that have a high risk of lactic acidosis
Unpleasant side effect of metformin
GI upset
Why is metformin contraindicated in conditions that have a high risk of lactic acidosis?
What is the mechanism of metformin?
Inhibits ???
Glycerol-3-phosphate accumulates and backs up in cytoplasm, which causes the accumulation of NADH
This starts blocking gluconeogenesis?
What are the effects of PPARy agonists (glitazones)?
They bind a nuclear receptor called PPAR gamma (inside the cell). This receptor can turn on various genes in the nucleus of adipocytes.
Increase sensitivity to insulin
When are PPARy agonists contraindicated?
- Heart failure
- Kidney failure
- Liver failure (since they are metabolized by the liver)
What is acarbose (drug)?
It is a drug that inhibits alpha-glucosidase. This prevents the breakdown of disaccharides to monosaccharides in the small intestine, which slows the absorption of glucose in the gut.
What are the side effects of acarbose (drug)?
It can cause flatulence (more glucose will reach the colon and bacteria will metabolize it, causing gas and bloating).
How do sodium glucose co-transporter 2 inhibitors lower blood glucose?
They inhibit reabsorption of glucose from the proximal tubule for the kidney (increase glucose excretion in urine).
What are the side effects of Na-Glucose co-transporter 2 inhibitors?
Increased risk of genital infections
Other than decreased blood glucose levels, what are other positive effects of SGLT2 inhibitors?
- Decreased risk of kidney and cardiac complications of diabetes
- Decreased intraglomerular pressure (constriction of afferent arteriole)
- Decreased risk of CHF
