Diabetes Flashcards
what are the 2 glands of the pancreas and what are their functions?
- EXOCRINE - secrete digestive enzymes into intestine
- ENDOCRINE - secrete hormones by Islets of Langerhans
what type of cell is important for hormone secretion in the pancreas?
islets of Langerhans
what 3 types of cells make up the islets of langerhans?
- Alpha cells
- Beta cells
- Delta cells
what do alpha cells secrete?
glucagon
what do beta cells secrete?
- insulin
- C-peptide
- amylin
what do delta cells secrete?
somatostatin
who discovered insulin?
Charles Best and Frederick Banting
how did Best and Banting discover insulin?
- tested pancreatic extracts in dogs without pancreas to see if they could reduce blood glucose levels
- found an extract that lowered glucose levels in dogs without pancreas and person with T1D
- the extract contained insulin
how is insulin produced? (4)
- preproinsulin is translated
- in ER, cleaved to proinsulin (containing C peptide, A + B chains)
- In golgi, cleaved to individual C peptide, A chain, and B chain
- A chain and B chain connected by disulfide bridges released as insulin from pancreas by secretory vesicles
describe the structure of insulin
A chain and B chain joined by disulfide bridges
what is the main stimulator of insulin?
glucose
glucose stimulation causes the release of which 3 molecules?
- insulin
- C peptide
- amylin
how does glucose stimulate the release of insulin/C peptide/amyline? (8)
- glucose enters pancreatic cell via GLUT2
- glucose metabolized by pancreatic cell
- increased ATP/ADP ratio
- K+ channel inhibited
- membrane depolarizes
- V-gated Ca2+ channel opens
- Ca2+ influx
- Insulin, C peptide, amyline released
what receptor allows for glucose-induced insulin secretion?
GLP-1
what type of receptor is GLP-1?
GPCR
how does glucose stimulate the transcription of preproinsulin? (10)
- glucose enters pancreatic cell via GLUT2
- glucose metabolized by pancreatic cell
- increased ATP
- GLP-1 activates adenylyl cyclase to use ATP
- makes cAMP
- activates PKA
- activates CREB to increase transcription
- increased preproinsulin transcription
- preproinsulin chopped up in golgi
- increased Ca2+ causes release of insulin, C peptide, and amylin
what is insulin complexed with?
Zn2+
what types of structures does insulin aggregate into?
dimers and hexamers
what is the role of amylin?
slows gastric emptying and promotes satiety to prevent blood glucose control
what is the role of C peptide?
no established biological action, mostly excreted in urine
is insulin, C peptide, or amylin produced in greater quantities?
insulin
where is insulin secreted?
portal blood flow first, then muscle and adipose
what are the 4 main roles of insulin?
- glucose transport
- glycogen synthesis
- lipid synthesis
- protein synthesis
what is the mechanism of insulin?
- binds insulin receptor (tyrosine kinase)
- tyrosine and IRS (scaffolding protein) get phosphorylated
- IRS binds effector proteins
- P13K binds to stimulate PKC and Akt
- increases glucose transport, glycogen synthesis, lipid synthesis, protein synthesis
what type of protein is Akt?
protein kinase B
what are the 2 roles of Akt?
- allows translocation of folded GLUT4 in a vesicle to the cell membrane
- inhibits GSK-3 activity to prevent phosphorylation of glycogen synthase, therefore activating it to store glucose as glycogen
what is the role of G6P?
allosteric activator of glycogen synthase and UDP-glucose –> allows glycogen production
what is the role of G6P?
allosteric activator of glycogen synthase and UDP-glucose –> allows glycogen production
what is the role of G6P?
allosteric activator of glycogen synthase and UDP-glucose –> allows glycogen production
why do we store glucose as glycogen?
insulin allows glycogen production so glucose levels don’t get too high
how do glucose and insulin levels change after a meal?
glucose increases quickly, then insulin increases
this causes glucose to decrease, so insulin also decreases
T1D
- what is it caused by?
- how is insulin affected?
caused by a T-cell mediated immune response that destroys BETA CELLS
irreversible, complete/major insulin deficiency
why does exogenous insulin help with T1D?
T1D only involves an inability to produce insulin, so tissue responsiveness is not affected and exogenous insulin can still work
T2D
- what is it caused by? what does this impact (3)?
caused by genetic and metabolic defects that impact:
1. glucose metabolism
2. insulin secretion
3. insulin action in tissues
T2D
- how is insulin affected?
decreased responsiveness/sensitivity to insulin at the tissue
describe the progression of T2D (4)
progresses from:
1. Impaired glucose tolerance
2. insulin-independent T2D
3. insulin-requiring T2D
4. leads to hyperglycemia and other symptoms
describe glucose and insulin levels in T1D
glucose levels stay high, insulin levels very low
describe glucose and insulin levels in T2D?
glucose levels stay high, insulin secretion delayed
describe glycogen in T1D
not enough glycogen store, body has trouble using glucose
what is common for T1D and T2D? (2)
- glucose accumulates
- increased lipid metabolism
why is increased lipid metabolism bad?
releases ketone bodies, leading to complications
how can you test for diabetes?
look at glycohemoglobin which stays in blood for a long time –> can determine the average level of glucose that was in the blood over the past few months
what is glycohemoglobin?
Hb glycated with lots of glucose
what are 3 types of treatments of T1D?
- medical nutrition counselling, exercise
- insulin
- drugs to control insulin resistance
what happens if you inject insulin directly into the blood?
insulin in blood rises slowly, and it is difficult to reach baseline –> after injection, must wait some time before a meal
doesn’t allow for good control of insulin levels!
why is it difficult for injected insulin to reach baseline?
insulin is injected in subcu environment as a hexamer and it must dissociate to a monomer in the blood to have an effect
the insulin is not given directly in portal vein like natural insulin
how do some insulin analogs have activity more quickly?
AA are modified to change the dimer/hexamer so it can dissociate into monomer more quickly, i.e. have more activity
describe 4 different types of insulin analogs
- attached to lipid so it can bind albumin and last longer in blood
- precipitates in subcu space
- complexes/multi-hexamers that take a long time to dissociate
- some dissociate very quickly
what is metformin used for?
initial choice for hyperglycemia and T2D
how does metformin treat hyperglycemia? (2)
- inhibits gluconeogenesis to decrease hepatic glucose output
- increases insulin-mediated glucose utilization in periphery
what are 2 additional functions of metformin?
- decreases food intake and body weight
- may affect composition of gut microbiota
what is the mechanism of metformin?
mechanism not completely understood, but it is a small molecule that is likely to have interactions with other proteins –> multiple pathways likely involved
what is an example of an amylin analog?
pramlintide
what are the 4 functions of amylin analogs/pramlintide?
- slows gastric emptying –> promotes satiety
- inhibits glucagon secretion from alpha cells
- reduces liver gluconeogenesis and glycogenolysis
- improves insulin sensitivity in peripheral tissues
how do amylin analogs/pramlintide inhibit glucagon secretion?
via hypothalamic cells
which types of diabetes are amylin analogs/pramlintide used for?
T1D and T2D
how are amylin analogs/pramlintide administered?
subcu injection before major meal
what are incretins?
hormones released from endocrine cells in SI epithelium
what are 2 examples of incretins?
- Glucose-dependent Insulinotropic Polypeptide (GIP)
- Glucagon-Like Peptide (GLP)
where do incretins bind? what are the 4 functions?
incretins bind GPCR in pancreas, adipose, brain
- promotes glucose-dependent INSULIN SECRETION from beta cells
- impairs glucagon secretion from alpha cells
- GLP-1 delays gastric emptying and promotes satiety
- increases thermogenesis and lipolysis in adipose tissue
how does incretin increase thermogenesis and lipolysis in adipose tissue?
by releasing ATRIAL NATRIURETIC PEPTIDE
what is the general function of incretins?
better glucose control and weight loss
what breaks down endogenous incretins?
DIPEPTIDYL PEPTIDASE-IV (DPP-IV)
What is the role of GLP-1 receptor agonists?
to bind the GLP-1 receptor and allow increased insulin transcription
what is the role of insulin secretagogues? what do they depend on?
allow for increased insulin secretion
they depend on functioning pancreatic beta cell
what are 3 examples of insulin secretagogues? 2 examples of incretin analogs?
- incretin analogs
- gliptins
- sulfonylureas meglitinides
INCRETIN ANALOGS
- Exenatide
- Semaglutide
what do gliptins do?
inhibit DPP-IV to increase T1/2 of endogenous incretins
what do sulfonylureas meglitinides do?
mimics the increased ATP/ADP ratio and inhibits the K+ channel
what is the difference btwn the half lives of endogenous GLP-1 and GLP-1 analogs?
endogenous GLP-1 –> T1/2 = a few minutes
GLP-1 analogs –> T1/2 = hours - days
what is Exendin 4/Exenatide?
toxin found in Glia monster saliva
how does Exendin 4/Exenatide differ from GLP-1?
GLP-1 is broken down quickly by DPP-IV
Exendin 4/Exenatide has different AA where DPP-IV acts so it is broken down more slowly
what are 2 types of Semaglutide?
- Ozempic
- Wegovy
what is Semaglutide?
has a different DPP-IV binding site than GLP-1 so it is broken down less quickly
AND has lipid so it can bind albumin and stay longer in bloodstream
how is semaglutide administered?
injected 1x a week
Semaglutide for weight loss
may be effective for:
- obesity w/o diabetes
- overweight w/ weight-related comorbitidy + w/o diabetes
what is a type of Gliflozin?
Canagliflozin
what is the mechanism of gliflozin?
inhibits Na+/glucose cotransporter (SGLT2) in the kidneys
what does SGLT2 do normally?
causes reabsorption of glucose back to circulation so glucose is not lost in urine
what do gliflozins do to glucose, urine volume, and plasma volume?
high glucose in renal tubules induces osmotic diuresis so there is less Na+ reabsorption and more glucose is lost in urine
increases urine volume, decreases plasma volume
what is a risk of gliflozins?
increased UTI and genital infection
what are 2 examples of alpha-glucosidase inhibitors?
- acarbose
- miglitol
what do alpha-glucosidase inhibitors do?
competitively inhibit alpha-glucosidase enzymes that degrade starch into glucose –> therefore less glucose absorbed in GIT after meal
why are alpha-glucosidase inhibitors typically not used alone? (2)
less effective and there are side effects
what are 2 side effects of alpha-glucosidase inhibitors?
- starch goes to colon and gets fermented + degraded by microbiota –> diarrhea, abdominal pain, flatulence
- contraindicated if IBS