Endocrine Pancreas Flashcards
Describe the organization of the islets of Langerhans in terms of cell types and
hormones secreted.
LO1
Hormones of endocrine cells of pancreas
- insulin
- glucagon
- somatostatin
Fxn: lipid, CHO, and AA metabolism
Clusters= islets of Langerhans
- 1-2% of pancreatic mass
- 2500 cells/islet
- innervated by adrenergic, cholinergic, and peptidergic neurons
B cells of pancreas
- %
- secretion
60-65% of islet
centrally located
secrete insulin and C peptide
A cells of pancreas
- %
- secretion
20% of islet
peripherally located
secrete glucagon
D cells of pancreas
- %
- secretion
5% of islet
secrete somatostatin
neuronal in appearance and send “dendrite-like” processes to B cells
F cells of pancreas
Secrete pancreatic polypeptide
acts like a satiety signal
- neuropeptide Y
- peptide YY family
Describe the paracrine mechanisms of hormones in the pancreatic islets
- how do islets of langerhans communicate with each other? (2)
LO2
Ion concentration changes signal
- Gap junctions
- rapid cell-to-cell communication - Blood supply
- islets receive 10% of pancreatic blood flow
- venous blood from one cell type bathes other cell types
- venous blood from B cells carries insulin to a and b cells- blood flow to center of islet & pick up insulin
- flows through periphery on a cells to inhibit glucagon secretion
*paracrine actions work in reverse of blood flow
Explain the significance of the C
peptide as a diagnostic tool
Lo3
insulin and cleaved C peptide packaged together in secretory vesicles
- secreted in equimolar quantities into blood
**C peptide can be used as marker of endogenous insulin secretion
Insulin
- characteristic
- secreted in response to…
- main stimulator
Major anabolic hormone
secreted in response to carbohydrate and protein meal
glucose is main stimulatory factor of insulin secretion
Insulin synthesis
- components
- pathway
LO3
Peptide hormone- 2 chains linked by disulfide bridges
Preproinsulin-> proinsulin-> insulin and C peptide
Preproinsulin
signal peptide with A & B chains with connecting peptide (C peptide)
- no disulfide bonds
Proinsulin
no signal peptide
- c peptide still attached in insulin
- packaged into secretory granules
- proteases here cleave proinsulin
Explain the glucose-dependent regulation of insulin secretion/release from pancreatic β cells
- 8 steps
LO4
- Glucose enters cells via GLUT2
- Glucose is phosphorylated by glucokinase
- Glucose 6 phosphate is oxidized promoting ATP generation
- ATP closes the “inward-rectifying” K+ channels
- Plasma membrane is depolarized
- Activation of voltage-gated Ca2+ channels
- Ca2+ enter cells
- Initiates mobilization of insulin(and C peptide) containing vesicles to plasma membrane and exocytosis
Explain the glucose-dependent regulation of insulin secretion/release from pancreatic β cells
- key ideas/ concepts (sulfonylurea, c peptide)
- rises in ATP CLOSES the K+ channels ( ATP dependent K channels)
- Sulfonylurea receptor, associated with ATP- dependent K+ channels, increase insulin secretion
- causes membrane depolarization to occur more easily
- more Ca2+ entry
- used for type 2 DM treatment - C peptide secretion used as tool to measure function to b cells and endogenous insulin secretion
- C peptide is typically secreted in urine
Insulin Receptor
- mechanism it undergoes
bound-insulin receptor autophosphorylates itself and phosphorylates other proteins
insulin-receptor complex is internalized by target cell
downregulation of receptor by insulin itself
Intracellular steps leading to insulin
secretion (3)
LO4a
- insulin binding to receptor
- phosphorylation of insulin receptor substrate (IRS) and other proteins - Substrate proteins phosphorylate and activate/inactivate downstream pathways
- PI3k/AKt/ mtor
- MAP kinases
- these mediate metabolic and mitogenic responses - Translocation of vesicles containing GLUT4 to membrane
- Glucose enters via faciliated diffusion
Insulin secretion in relationship to blood glucose
- diabetics
LO4a
insulin secretion is PROPORTIONAL to plasma glucose changes
glucose stimulate insulin secretion in a BIPHASIC manner
- in diabetic individuals: “first phase” or acute insulin response is lost first
Alternative Intracellular Pathways for Glucose Uptake Independent of Insulin
LO4a
activation of AMP-kinase (AMPK) results in GLUT 4 translocation to plasma membrane
muscle contractions stimulate this process
How does GI peptides (CCK, GLP-1, GIP), and local glucagon and somatostatin
modulate insulin release?
LO5
GI peptides
- via GPCR signaling/ adenlyl cyclase/ camp
- via GPCR signaling/ IP3/DAG/PKC
glucagon
- via GPCR signaling
- adenlyl cyclase
Somatostatin
via GPCR signaling
- andenylyl cylase
Stimulatory Factors for insulin secretion
LO8
- increase glucose concentration
- increase AA concentration
- increase FA and ketoacid concentration
- glucagon
- cortisol
- glucose-dependent insulinotropic peptide (GIP)
- potassium
- vagal stimulation (ACH)
- Sulfonylurea drugs
Inhibitory Factors for insulin secretion
LO8
- decreased blood glucose
- fasting
- exercise
- somatostatin
- alpha adrenergic agonist; NE
- diazoxide
Describe the main effects of insulin on carbohydrate, protein, and fat metabolism
- on Skeletal muscles (5)
LO6
- increased glucose uptake
- increase GLUT4 and better translocation - increase glycogen synthesis
- increase hexokinase/glucokinase
- activates glycogen synthase - Increase glycolysis and CHO oxidation
- increase glycolysis- hexokinase, PFK, PDH - increased protein synthesis
- decreased protein breakdown
Describe the main effects of insulin on carbohydrate, protein, and fat metabolism
- on liver (7)
LO6
- promote glycogen synthesis
- glucokinase and glycogen synthase - increases glycolysis and CHO oxidation
- glucokinase, PFK, pyruvate kinase - decreases gluconeogenesis
- inhibit PEPCK, fructose 1,6 biphosphate, and G6P phosphatase - increase hexose monphosphate shunt
- increase pyruvate oxidation
- increase lipid storage and decrease lipid oxidation
- increases protein synthesis and decrease protein breakdown
Describe the main effects of insulin on carbohydrate, protein, and fat metabolism
- on adipose tissue (4)
LO6
- increased glucose uptake
- increased GLUT4 and better translocation - increased glycolysis
- more production of a-glycerol phosphate for esterification and lipogenesis - decreased lipolysis
- inhibit HSL - promotes uptake of fatty acids
- LPL (lipoprotein lipase) activity/ synthesis
Coordinated Actions of Insulin
LO8
*** MEMORIZE
- increase glucose uptake into cells
- decrease glucose in blood levels - increased glycogen formation
- decreased glycogenolysis
- decrease gluconeogenesis
- increase protein synthesis
- decrease amino acids - increased fat deposition
- decreased fatty acids - decrease lipolysis
- decrease keto acids - increased K+ uptake into cells
- decreased K+
Type 1 DM
- general effects
- conditions
LO10
Juvenile Onset diabetes
inadequate insulin secretion
destruction of B cells
- often from autoimmune disease
- increased blood glucose
- fatty acids
- ketoacids
- increased conversion of fatty acids to ketoacids
decreased utilization of ketoacids results in diabetic ketoacidosis (DKA)
Type 1 diabetes
- effects on macromolecules (3)
- increase blood [glucose]
- decrease uptake of glucose
- decrease glucose utilization
- increase gluconeogenesis - increase blood [FA} and [ketoacid]
- decrease FA synthesis
- decrease TG synthesis
- increase TG breakdown
- increase level of circulating free FA
- increased conversion of FA to ketoacids
- decreased ketoacid utilization by tissues
* results: Diabetic ketoacidosis= metabolic acidosis - increase amino acid concentation
- increase protein breakdown
- decrease protein synthesis
- increase catabolism of aa- loss of lean body mass (catabolic state)
- increase ureagenesis
- loss of lean body mass (catabolic state)
Type 1 Diabetes Mellitus
- effects on ions and nutrients (2)
LO10
- hyperkalemia- shift of K+ out of cells
- intracellular concentration is thus low
- lack of insulin effect on Na/K Atpase
- plasma levels may be normal, total K+ is usually low due to polyuria and dehydration - Osmotic diuresis/ Glucosuria
- increased blood glucose increases filtered load of glucose, exceeds reabsorptive capacity of proximal tubule
- water & electrolyte reabsorption also blunter
- Polyuria-increases excretion of Na and K even though urine concentration of electrolytes if low
- thirst (polydipsia)
Treatment of Type 1 DM insulin replacement
- goal
- drawbacks (5)
LO11
goal: recreate normal physiology (basal and bolus insulin)
- insulin injections right before meals
Drawbacks
- painful and time consumin
- lag between glucose measurement and insulin dosing
- delayed absorption of insulin following sc injections
- poor blood glucose control -prolonged periods of hyperglycemia
- insulin pumps have advantages
Type 2 Diabetes Mellitus
- describe
LO12
insulin resistance
- progressive exhaustion of active B-cells due to environmental factors (amongst others)
- includes sedentary lifestyle, malnutrition, obesity
- pt produce insulin, but often ned more and more
95% of diabetes cases
Type 2 DM
- associations
- progression of insulin resistance (3)
LO12
reactive hyperinsulinemia followed by relative hypoinsulinemia
obesity-induced insulin resistance
- decreased GLUT 4- uptake of glucose in response to insulin (classical skeletal muscle impairment)
- Decreased ability of insulin to repress hepatic glucose production
- inability of insulin to repress adipose tissue uptake (via LPL) and lipolysis (via HSL)
Type 2 DM pathophysiology
- effects and mechanism
- insulin resistance mechanism still not well understood
- post-receptor signaling- ultimately results in decreased glucose transport number and mobilization - increased hepatic glucose productions
- non-alchoholic fatty liver disease/ hepatic steatosis
- hyperglucagonemia
- not as prone to ketoacidosis as T1DM
non-obese patients T2DM can occur due to decreased insulin release by pancreas independent of peripheral insulin resistance
Treatment of Type 2 DM
LO12
- Caloric restriction, weight reduction, physical activity/exercise
- insulin secretagogues
- sulfonylurea drugs
- incretin analog of GLP-1 (exanatide);injection needed - slow absorption of CHO
- a-glucosidase inhibitors (acarbose, migitol)
- amylin analogs (pramintide) - Insulin sensitizers
- biguanide drugs (metformin)- better insulin receptor trafficking - bariatric surgery
Glucose Tolerance Test
if insulin slowly rises, no biphasic first phase=> diabetics
Incretin Hormones
- types
- characteristics
intestine derived hormones
- GLP-1, GIP (secreted in response to GI glucose and fat)
short half life
stimulate insulin secretion (glucose dependent)
inhibit glucagon secretion
slow gastric emptying
Type 1 DM Summary
- age of onset
- ketosis on onset
- family history
- pathophysiology
- associated conditions
LO13
age of onset
- peak in early childhood and adolescence
ketosis on onset
- common
family history
- 10-20%
pathophysiology
- autoimmune disease
associated conditions
- autoimmune thyroid disease
- Celiac Disease
- Addison’s Disease
Type 2 DM Summary
- age of onset
- ketosis on onset
- family history
- pathophysiology
- associated conditions
LO13
age of onset
- post-pubertal
ketosis on onset
- uncommon
family history
- >50%
pathophysiology
- insulin resistance
associated conditions
- obesity
- lipid abnormalities
- PCOS
- NAFLD
Glucagon
- characteristics & structure
- synthesis
- storage
single straight-chain polypeptide with 29AA
member of same peptide family as secretin and GIP
synthesized as preproglucagon
stored in dense granules of a-cells
Secretion of Glucagon - stimulated by... (6) - blood glucose - insulin - inhibitory factors LO15
stimulated by
- **decrease blood glucose\
- increased AA
- fasting
- CCK
- b adrenergic agonists
- Ach
Blood glucose reflects balance between hypoglycemic actions of insulin and hyperglycemic actions of anti-insulin hormones
insulin inhibits glucagon production and secretion
other inhibitory factors include:
- somatostatin, FA, ketoacids
Actions of Glucagon on liver
LO14
Glucagon increases blood glucose
- substrates are directed toward glucose formation
- increases gluconeogenesis (reduced productions of Fructose 2,6 biphosphate)
- increased glucogenolysis
- inhibit glycogen synthesis
Glucagon actions on other organs
Stimulates lipolysis- both adipose tissue and skeletal muscle
ketoacids produced from fatty acids
Stimulatory factors affecting glucagon secretion (7)
- fasting
- decrease glucose conc
- increase aa concentration
- increase FA and ketoacid concentration
- CCK
- B adrenergic agonist
- ACh
inhibitory factors affecting glucagon secretion (3)
- insulin
- somatostatin
- Increase FA and ketoacid concentration
Glucagon actions and effects of blood levels (4)
- increase glycogenolysis
- increase blood glucose concentration - increae gluconeogenesis
- increase lipolysis
- increase blood FA concentration - increase ketoacid formation
- increase blood ketoacid concentration
