Endocrinology of Insulin Flashcards
What cells are in the Islets of Langerhans (in the pancreas) and what do they produce?
they produce hormones
beta cells - produce insulin
alpha cells - produce glucagon
delta cells - produce somatostatin
F cells - produce pancreatic polypeptide
What is the role of insulin?
increases glucose uptake into cells
= via increased number of GLUT4 transporters in the cell membrane
increases glucose use, breakdown (glycolysis) and storage
= via increasing transcription of genes regulating enzymes needed for metabolism of glucose
increases glycogen synthesis (glycogenesis)
increases protein synthesis
increases fat synthesis
increases uptake of ions into cells - potassium, phosphate
inhibits lipolysis - cause of weight loss in diabetes
inhibits ketogenesis
inhibits proteolysis
What is the mechanism of insulin release from beta cells?
glucose enters the cell via GLUT1 and GLUT2
glucose is phosphorylated into glucokinase then broken down via glycolysis or respiration to release ATP
ATP binds to potassium channels causing it to close and blocking potassium efflux
depolarisation occurs due to positive membrane potential
this causes voltage dependent Ca channels to open and Ca influx
Ca influx triggers insulin release via exocytosis
How is insulin release controlled?
autonomic nervous system
- parasympathetic and sympathetic
glucocorticoids
glucagon
incretins
somatostatin
How does the autonomic nervous system regulate insulin release?
beta adrenergic stimulation INCREASES insulin release
parasympathetic stimulation via the vagus nerve INCREASES insulin release
alpha adrenergic stimulation DECREASES insulin release
- prevents hypoglycaemia during exercise
= exercise increases absorption of glucose by tissues leading to excessive depletion if insulin is also released
How do glucocorticoids regulate insulin release?
INCREASES blood glucose
- treats hypoglycaemia
in the muscle
- promotes breakdown of proteins to amino acids which are then available for glucose synthesis
in the liver
- increases synthesis of gluconeogenic enzymes to utilise circulating amino acids and produce glucose
How does glucagon regulate insulin release?
increases blood glucose
at HIGH glucose levels, GLUT1 is fully saturated
glycolysis occurs releasing ATP
ATP binds to potassium channels causing them to close blocking potassium efflux
increased potassium levels cause EXCESSIVE depolarisation resulting in VDCC closing
low Ca levels cause VDNC to close thereby reducing Na levels/influx
blocks glucagon exocytosis
at LOW glucose levels
- increased potassium levels cause MODERATE depolarisation
- VDCC open causing Ca influx which opens VDNC resulting in Na influx
- Ca dependent glucagon exocytosis occurs
What are the types of incretins? How do incretins regulate insulin release?
glucagon-like intestinal peptide 1 (GLP-1) in the L cells of the gut
cholecystokinin (CCK) in the I cells of the duodenum/jejenum
gastric inhibitory peptide (GIP) in the K cells of the duodenum/jejenum
all are released by gut tissues in response to feeding causing enhanced insulin release
- via priming of beta cells
= need the GIT for priming so must be given orally
How does somatostatin regulate insulin release?
somatostatin regulates glucagon and insulin release
- inhibits both via Gi coupled protein receptors
bind to receptors coupled to Gi protein which prevents cAMP formation and PKA activation
- blocks insulin exocytosis
What are the types of diabetes?
T1DM insulin dependent diabetes mellitus (IDDM)
- cells that produce insulin are destroyed
T2DM non-insulin dependent diabetes mellitus (NIDDM)
- lack of insulin production
- insufficient insulin action leading to eventual beta cell failure
gestational diabetes
maturity onset diabetes of the young (MODY)
secondary diabetes
- as a result of another condition
What are the types of Sulphonylureas? How do they work?
1st Gen - tolbutamide, chlorpropamide (‘AMIDE’)
2nd Gen - glipizide, glicizide (‘IZIDE’)
3rd Gen - glimepiride (‘IRIDE’)
work by blocking ATP sensitive potassium channels in pancreatic beta cells causing insulin release via exocytosis
- do not bind at the same site as ATP
What are the types of Biguanides? How do they work?
Metformin
increases insulin sensitivity by
- increasing peripheral glucose uptake and utilisation via skeletal muscles
activates AMPK (adenosine monophosphate kinase)
- increases glucose uptake and glycogen synthesis
- reduces gluconeogenesis
What are the types of thiazolidinediones? How do they work?
Pioglitazone (TZD’s)
increases insulin sensitivity especially in fat cells (adipose)
- action depends on peroxisome proliferator activated receptor (PPAR)
PPAR activation by ligand TZD causes the PPAR/TZD complex to bind to a specific region of DNA which regulates transcription of genes involved in glucose and fatty acid metabolism
What are the types of alpha-glycosidase inhibitors? How do they work?
Acarbose
block intestinal glucosidase causing reduced carbohydrate digestion and thereby reduced glucose absorption
- slows absorption of glucose
What are the types of meglitinides? How do they work?
Repaglinide
work by blocking ATP sensitive potassium channels in pancreatic beta cells causing insulin release via exocytosis
- do not bind at the same site as ATP or Sulphonylureas
