Insulin & Glucagon Flashcards
What are the endocrine products of the following pancreatic cells:
- Alpha
- Beta
- Delta
- F
- Glucagon
- Insulin, c-peptide, proinsulin, amylin
- somatostatin
- pancreatic polypeptide
Blood supply to the pancreas comes from what sources?
Celiac trunk (splenic artery and anterior/posterior superior pancreaticoduodenal artery)
SMA (anterior/posterior inferior pancreaticoduodenal artery)
Where does blood leaving the pancreas drain into?
What are the implications of this?
Portal vein
Goes to liver and there is first pass effect where pancreatic hormones can be metabolized / inactivated
Discuss how blood enters the islets of langerhans.
Enters centrally –> insulin is delivered to alpha and delta cells –> can impact their function
True/false: somatostatin can regulate function of other cells within the islet of langerhans via gap and tight junctions.
True
What are the neural inputs to the pancreas?
SNS –> stimulate or inhibit
PSNS –> augment insulin secretion
Thought to mediate effects / response to sight/smell of food
Discuss the process of insulin production, processing and secretion.
Translated as preproinsulin –> goes to golgi –> cleaved into proinsulin –> secreted in vesicles –> cleaved to insulin + cpeptide in insulin granules
Which chromosome contains insulin gene?
Short arm of 11
True/false: more insulin is secreted than c-peptide.
False - equimolar amounts
What factors increase insulin secretion?
- High blood glu
- FFAs and AAs
- GIP, GLP-1, CCK, secretin, other incretins
- PSNS stimulation via Ach
- SNS stimulation via Beta adrenergic receptors
- Sulfonylureas
What factors have the opposite effect of insulin?
Glucagon, GH, cortisol
What factors decrease insulin secretion?
- Decreased blood glu
- Fasting
- Somatostatin
- Leptin
- SNS alpha adrenergic receptor activation
- Beta blockers
- Thiazide diuretics
Describe the process of how pancreatic beta cells sense glucose levels in the blood and then secrete insulin in response.
Pancreatic beta cells have GLUT2 transporters in their membranes, which are glucose leak channels. They are glucose independent, meaning these cells express constant levels of GLUT2 in their membranes regardless of glucose levels in the blood. The glucose enters the cell, undergoes glycolysis, TCA and OxPhos resulting in an increase in intracellular ATP. Increased intracellular ATP stimulates an ATP sensitive K+ channel which leads to closing of the channel and retention of K+ which depolarizes the cell. Cell membrane depolarization causes voltage dependent Ca++ channels to open, leading to an influx of Ca++, which is used to:
- promote transcription of genes related to insulin secretion
- promote insulin granule vesicle trafficking to the membrane for exocytosis and release
What part of the insulin secretion pathway do sulfonylureas act on?
They stimulate the ATP sensitive K+ channel causing the channel to remain closed and causing increased depolarization of the cell and increased insulin secretion
Discuss the structure and physiological role of proinsulin.
- Has very minor insulin-like activity, only really becomes an issue when a person has insulinoma b/c it can be produced in excess and trigger enough of a response that could result in hypoglycemia.
- Can complex with insulin –> again only really issue when hypersecreted
- Structure as shown in image
True/false: insulin’s quaternary structure consists of only 1 peptide
False - insulin has both an alpha and a beta chain that complex together into a quaternary structure
Insulin is released into portal blood in association with what ion?
Zinc
What happens to insulin once it binds to its receptor?
Internalized in vesicle, fused with endosome, proteolytically degraded
True/false: insulin has a very long half life.
False - half life is 5 mins
If you want to know what someone’s insulin levels are, what do you measure and how?
60% of insulin sent into portal vein is removed by first pass metabolism in liver. However, c-peptide leaves liver unchanged and is secreted in 1:1 ratio with insulin. Thus, you must measure c-peptide, not insulin, b/c insulin levels will underestimate insulin secretion while c-peptide will accurately reflect insulin secretion. C-peptide is excreted in urine, so you can measure urinary levels and it will reflect last 24 hours of insulin secretion.
Discuss how levels of insulin change over time following glucose infusion.
What is one of the earliest metabolic defects seen in T2D?
Loss of 1st phase of insulin response to glucose infusion
Insulin Receptor
- Type of receptor?
- Function of alpha and beta subunits?
- What happens when ligand binds?
- Tyrosine kinase
- Alpha = ligand binding, beta = auto-phosphorylation
- Catalytic subunits are activated, auto-phosphorylation and then docking / recruitment of other proteins/enzymes for intracellular signaling pathways
- Ras pathway –> general gene expression, cell growth, differentiation
- PI3K pathway –> cell growth, differentiation, glucose metabolism, glycogen/lipid/protein synthesis, specific gene expression, responsible for increasing transcription of GLUT4
GLUT1
- Where is it found?
- What is its function?
- Brain, erythrocyte, fetal tissue
- Transport glucose (high affinity) and galactose
GLUT2
- Where is it found?
- What is its function?
- Liver, pancreatic beta cells, small intestine, kidney
- Transport glu, gala, fru, low affinity but high capacity
GLUT3
- Where is it found?
- What is its function?
- Brain, testes, placenta
- Transport glu (high affinity), gala, *primary glu transporter for neurons*
GLUT4
- Where is it found?
- What is its function?
- Skeletal muscle, adipose tissue, cardiac muscle
- Insulin responsive glucose transport, high affinity
GLUT5
- Where is it found?
- What is its function?
- Small intestine, sperm, brain, kidney, adipocytes
- Transport fructose
SGLT1
- Where is it found?
- What is its function?
- Small intestines
- Abs glu
SGLT2
- Where is it found?
- What is its function?
- Renal tubule
- Abs glu
What cellular processes does insulin inhibit?
What cellular processes does it stimulate?
What effects does insulin have on the:
- Liver
- Adipose tissue
- Skeletal muscle
What are the short term, intermediate, and long term effects of insulin?
What is the relationship between insulin and K+?
Insulin entry into cells promotes entry of K+ into cells by stimulating Na+/K+ ATPase pumps –> high dose of insulin can lead to hypokalemia –> can be deadly (arrythmias)
Children who develop T1D early in life may be […] unless caught and treated early.
Short –> failure to grow
Glucacon is a […] family protein that is transcribed as […] and then cleaved to glucagon in […] cells
Secretin
preproglucacon
alpha
What signaling pathway is utlized by glucagon?
GPCR –> Gas –> increase cAMP –> increase PKA activity –> enzyme phosphorylation –> gene transcription and protein synthesis
Most glucagon acts on the […] with lesser effects in […]
Liver
adipose tissue
What factors stimulate glucagon secretion?
What factors inhibit its secretion?
Stimulate
- Decrease blood glu
- Exercise
- Catacholamines
- Cortisol
- Stress
- AAs
- GIP
Inhibit
- High blood glu
- Ketones
- FFAs
- Secretin
- Somatostatin
- Insulin and amylin
- GLP-1
What are the effects of glucagon on the liver?
Promote glucose production:
- (+) glycogenolysis
- (+) gluconeogenesis
- (+) ketogenesis
- (-) glycolysis
- (-) glycogenesis
- (-) FFA synthesis
What are the effects of glucagon on adipose tissue?
When are these effects most physiologically relevant?
- (+) adipose cell lipase –> FFAs available for energy production
- (-) hepatic TG storage
- Most physiologically relevant when [glucagon] very high (not seen in normal human function)
What are the effects of somatostatin on:
- Pancreas
- GI tract
- Hypothalamus / anterior pituitary
- (-) secretion insulin and glucagon
- (-) motility, secretion and absorption
- (-) releasing hormones and those from ant. pit.
- All this is done to extend the time over which nutrinents are assimilated into blood to decrease tissue utilization of nutrients preventing rapid exhaustion of food
What function does pancreatic polypeptide have?
- Released from F cells after meals, exercise and Vagal stimulation
- Reduced pancreatic secretions and GB contraction
- Modulate gastric acid secretion and GI motility
What is the function of amylin?
- Stored in beta granules with insulin and c peptide, binds to GPCR and acts to modulate [glu] in blood.
- Reduces postprandial glucagon
- Delay gastric emptying
- Reduce muscle glycogenesis and increase glycolysis and glycogenolysis
Which hormones (other than glucagon) have anti-insulin effects?
