Pancreatic hormones, Insulin and glucagon Flashcards
Endocrine pancreas
Islets of Langerhans, made up of 5 different cell types; each produces insulin, glucagon, somatostatin, pancreatic polypeptide, or ghrelin (all are peptide hormones)
Islets
• Islets: richly vascularized (5-10X blood flow compared to exocrine tissue); innervated by sympathetic, parasympathetic, and sensory neurons, and surrounded by astroglial cells
Blood glucose levels: …
• Blood glucose levels: precisely controlled
within a narrow range
High blood glucose
(hyperglycemia) – affects osmotic
balance of blood, and causes long-term damage to
organs and tissues
Main pancreatic hormones controlling blood glucose:
Insulin
• Insulin (lowers blood glucose levels)
Main pancreatic hormones controlling blood glucose:
glucagon
• Glucagon (raises blood glucose levels)
• Antagonistic hormone pairing:
one hormone activates a process, the other inactivates it;
provides rapid, fine-tuned control
Insulin
INS gene
INS gene expressed due to
unique set of transcription
factors in β cells
Insulin
Preproinsulin
Preproinsulin: Signal peptide is cleaved almost immediately after translation in ER, producing proinsulin (folded, disulphide bonds)
: 110-a.a.,
biologically inactive.
In ER.
Insulin
Proinsulin
Proinsulin: transported to Golgi apparatus (further post -translational modifications); packaged into secretory granules
86-a.a., biologically inactive. • In ER: folding, disulphide bonds • In Golgi apparatus: further modifications (glycosylation)
Insulin
Maturation..
Maturation” of secretory granules (proinsulin cleavage and changes to pH & contents that cause insulin crystallization )
Insulin
___ stimulated exocytosis
___
Ca2+
-stimulated exocytosis
(subset of granule pool)
Insulin
51-a.a.,
biologically active as monomer.
In secretory granules.
small amount of
__ escapes cleavage
and is secreted intact
small amount of
proinsulin escapes cleavage
and is secreted intact
Basal insulin secretion
(without exogenous
stimuli) takes place in the fasted state
Food ingestion
Food ingestion: leads to rise in insulin levels
within 8-10 minutes (2 phases/peaks of insulin
if stimulus persists); decline to basal levels by
90-120 minutes after meal
Primary stimulus for insulin secretion….
rise in blood glucose
Insulin secretion
step 1
β cell senses glucose levels via its
metabolism. Glucose enters β cell
transported by GLUT glucose transporters
Insulin secretion
step 2
Glycolysis and oxidative phosphorylation:
increases ATP:ADP ratio in β cell
Insulin secretion
step 3
ATP-dependent K+ channels close
Insulin secretion
step 4
β cell depolarizes
Insulin secretion
step 5
This activates voltage-gated Ca2+ channels,
allowing an influx of Ca2+ that stimulates
exocytosis of insulin-containing granules)
Primary stimulus for insulin secretion:
rise in blood glucose; but other factors also have
effects…..
Primary stimulus for insulin secretion:
rise in blood glucose; but other factors also have
effects – e.g., GLP-1 & other gastrointestinal
hormones; some amino acids, neural inputs, etc.
Insulin receptor
• Insulin receptor: a receptor tyrosine kinase
Leads to a signal transduction cascade; one effect is
phosphorylation of the ____ glucose transporter
Leads to a signal transduction cascade; one effect is
phosphorylation of the GLUT4 glucose transporter
• GLUT4 translocates to the cell surface to facilitate
___ into that cell
• GLUT4 translocates to the cell surface to facilitate
glucose uptake into that cell
PI3K (phosphatidylinositol
3-kinase)-Akt/PKB Pathway:
PI3K
generates 2nd
messenger
PI(3,4,5)P3
PI3K (phosphatidylinositol
3-kinase)-Akt/PKB Pathway:
This eventually leads to recruitment & activation of \_\_\_, an important effector that \_\_\_\_ many cellular proteins, including \_\_\_\_ (not shown here)
In general: ____
uptake; __, ___ and ___
synthesis/storage;
gene expression
This eventually leads to recruitment & activation of Akt, an important effector that phosphorylates many cellular proteins, including transcription factors (not shown here)
In general: glucose uptake; glycogen, protein, & lipid synthesis/storage; gene expression
MAPK (mitogen-activated
protein kinase) Pathways:
Active ____ leads to
____
cascade
Active Ras-GTP leads to
phosphorylation
cascade
MAPK (mitogen-activated
protein kinase) Pathways:
• MAPK is \_\_\_\_ activated in the cascade; it is an important effector that \_\_\_\_ many cellular proteins, and also\_\_\_\_ to the nucleus where it \_\_\_\_ transcription factors
In general: effects on \_\_\_\_ & \_\_\_ , and gene expression (also cross-talk with other pathways)
• MAPK is kinase activated in the cascade; it is an important effector that phosphorylates many cellular proteins, and also translocates to the nucleus where it phosphorylates transcription factors
In general: effects on cell growth & differentiation, and gene expression (also cross-talk with other pathways)
• Insulin: promotes ….
• Insulin: promotes nutrient uptake & storage
Insulin effects
Liver
Liver: promotes glucose storage
(as glycogen);
while inhibiting synthesis/release of glucose
Insulin effects
Skeletal muscle
promotes glucose uptake
& storage, as well as protein synthesis
Insulin effects
White adipose tissue:
: promotes glucose
uptake and facilitates fatty acid uptake
(together, promoting storage of nutrients as
triglycerides);
while inhibiting mobilization of stored lipids
____ is processed in a ____ manner, depending on the
dominant PC in ____
Proglucagon is processed in a tissuespecific manner, depending on the
dominant PC in secretory vesicles
Glucagon
Glucagon: 29-a.a. polypeptide, stored
in vesicles in ⍺ cells
Glucagon : Secreted when blood glucose is ___; also in response to prolonged ___, ___, and protein-rich meals
Glucagon Secreted when blood glucose is low;
also in response to prolonged fasting,
exercise, and protein-rich meals
Glucagon Mechananism not clear. Partly due to
___-intrinsic glucose sensing
when glucose is ___; also, both ___ (from β cells) and
___ (from δ cells) inhibit glucagon secretion when their levels are ___ (___ glucose); also
affected by other hormones &
neural inputs
Mechanism not clear. Partly due to α-cell-intrinsic glucose sensing when glucose is low; also, both insulin (from β cells) and somatostatin (from δ cells) inhibit glucagon secretion when their levels are high (high glucose); also affected by other hormones & neural inputs
Glucagon receptor:___
Glucagon receptor: a GPCR of Gαs class
Glucagon receptor
Activates _____: produces
____ second messenger, activating ____
• Activates adenylate cyclase: produces
cAMP second messenger, activating PKA
Glucagon receptor
PKA phosphorylates many key cellular proteins, including ___ regulating ____ _____
• Glucagon receptor signaling also modifies activity of cAMP-responsive transcriptional regulators (___)
PKA phosphorylates many key cellular proteins, including enzymes regulating nutrient metabolism
• Glucagon receptor signaling also modifies activity of cAMP-responsive transcriptional regulators (effects on gene expression)
Glucagon: promotes delivery of energy from the liver to the other tissues between meals
Glucagon: promotes delivery of energy
from the liver to the other tissues
between meals
Glucagon effects
Liver:
Liver: major target organ for glucagon, where it stimulates breakdown of glycogen (stored glucose), and
production of glucose & ketone bodies
Exercise
__ GH (also testosterone) ____ cortisol (glucocorticoid) and epinephrine & norepinephrine (catecholamines)
…cortisol & epinephrine are key regulators of the
stress response, causing ____ blood glucose (also: ___ insulin, ____ glucagon)
Increased GH (also testosterone)
• Increased cortisol (glucocorticoid) and
epinephrine & norepinephrine (catecholamines)
…cortisol & epinephrine are key regulators of the
stress response, causing ↑ blood glucose
(also: decreased insulin, increased glucagon)
