Endocrine Pancreas Flashcards
What are the cells located in the Islets of Langerhans and what all do these cells secrete?
B cells:
- 60-65% of islet centrally located
- secrete insulin and C peptide
A cells:
- 20% of islet, peripherally located
- secrete glucagon
Delta cells:
- 5% of islet; interspread between alpha and beta cells
- secrete somatostatin
- Neuronal in apperance and send dendrite-like processes to B-cells
F Cells:
- Secrete Pancreatic Polypeptide
- Acts like satiety signal (neuropeptide Y, peptide YY family)
how do the cells in the islets communicate with each other?
gap junctions - rapid cell to cell communication
-between a-a and a-b
What is the blood supply for the cells of Islets of Langerhans?
-Recieve 10 percent of pacreatic blood flow
-Venous blood from one cell type bathes other cell types
-Venous blood from B-cells carries insulin to alpha and delta cells
(blood flow first to center for insulin then through periphery to inhibit release of glucagon from alpha cells)
what are the precursors and components to Insulin?
Insulin is a Peptide hormone that are 2 chains linked by disulfide bridges
Preproinsulin: Proinsulin: Insulin and C peptide
Preproindulin: signal peptide with A and 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
C-Peptide:
- packaged together with insulin in secretory vesicles
- secreted in equimolar quantities into blood
- can be used as a marker of endogenous insulin secretion
What are the 8 steps to insulin release?
1) glucose enters cell via GLUT-2
2) Glucose is phosphorylated by glucokinase
3) Glucose-6-phosphate is oxidized promoting ATP generation
4) ATP closes the inward rectifing K channel
5) PLasma membrane is depolarized
6) Activation of Voltage gated Ca channels
7) Ca enters the cell and
8) initiates mobilization of insulin (and C peptide) containing vesicles to plasma membrane and exocytosis
what are some key concepts with Insulin release?
-Rises in ATP closes the K+ channel (ATP dependent K+ channel)
Sulfonylurea receptor, associated with ATP dependant K+ channels increase insulin secretion
- causes membrane depolarization to occur more easily
- More Ca entry
- used for treatment of type 2 DM
how is the insulin response?
Biphasic
First phase insulin secretion is lost in diabetic individuals
what are the characteristics of the Insulin receptor?
Insulin = insulin receptor
- bound insulin receptor will autophosphorylates itsself and phosphorylates other proteins
- insulin receptor complex is internalized by target cell
- downregulation of receptor by insulin itself
what does insulin do when it binds to its receptor
Phosphorylation of insulin receptor substrate (IRS) and other proteins
Leads to downstream activation of pathways like:
- PI3K/Akt/mTOR
- MAP kinases
- THese mediate metabolic and mitogenic responses
this all leads to translocation of vesicles containing GLUT4 to membrane
-GLucose enters via facilitate diffusion
what is the alternative intracellular pathway for glucose Uptake independant of insulin?
Activation of AMPK results in GLUT4 translocation to plasma membrane
Muscle contractions stimulate this process
Stimulatory factors of Insulin secretion?
- Increased glucose concentration
- increased amino acid concentration
- increased fatty acid and ketoacid concentration
- GLucagon
- cortisol
- Glucose dependant insulinotropic peptide (GIP)
- Potassium
- Vagal stimulation; acetylcholine
- sulfonylurea dugs
- Obesity
Inhibitory factors of insulin secretion
-Decreased blood glucose
-Fasting
-Exercise
-Somatostatin
-a adrenergic agonists; norepinephrine
Diazoxide (smooth muscle vasodilater to treat hypoglycemia)
how does ACh, CCK, and GLP-1 modulate insulin release?
activates and increases insulin release
how does somatostatin and glucagon affect insulin release
inhibits insulin release
glucagon is inhibited by insulin release but helps modulate insulin release
How does insulin affect the skeletal muscle?
- Increases glucose uptake
- Increased glycogen synthesis
- Increased glycolysis and CHO oxidation
- Increased protein synthesis
- Decreased protein breakdown
How does insulin affect the liver?
- Promotes glycogen synthesis
- increases glycolysis and CHO oxidation
- Decreases gluconeogenesis
- Increases hexose monophosphate shunt
- Increase pyruvate oxidation
- Increase lipid storage and decreases lipid oxidation
- Increases protein synthesis and decreases protein breakdown
How does insulin affect Adipose tissues?
- Increased glucose uptake
- increased glycolysis
- decreased lipolysis
- promotes uptake of fatty acids
what are the effects insulin has on blood level metabolites?
- decreases glucose
- decreases amino acids
- decreases fatty acids
- decreases keto acids
- decreases K+
Characteristics of glucagon and where is it made and stored?
- Single straight-chain polypeptide with 29 AA
- Membrane of same peptide family as secretin and GIP
- Synthesized as preproglucagon
- stored in dense granules of A cells
what stimulates the secretion of GLucagon?
Stimulated by major decreased blood
also by:
- increased AA (arginine and alanine)
- Fasting
- CCK
- B adrenergic agonists
- ACh
what inhibits the secretion of glucagon?
Insulin inhibits glucagon production and secretion
other inhibitory factors
- Somatostatin
- Fatty acids
- Keto acids
what are major actions of glucagon on the liver?
Glucagon increases blood glucose
- substrates are directed toward glucose formation
- increases gluconeogenesis (reduced productions of fructose 2,6-bisphosphate)
- increased glucogenolysis
- inhibits glycogen synthesis
Glucagon actions throughout the body?
Stimulates lipolysis, both adipose tissue and skeletal muscle
Ketoacids produced from fatty acids
what is the underlying cause of Type 1 diabetes mellitus? and some of the symptoms that come with it?
Inadequate insulin secretion:
- destruction of B cells often from autoimmune disease
- symptoms dont show until >80 percent b cells destroyed
- increased glood glucose, fatty acids, ketoacids, and amino acids
- decreased utilization of ketoacids results in diabetic ketoacidosis
Hyperkalemia: shift of K+ out of cells
- intracellular concentration is thuus low
- lack of insulin effect on Na+/K+ ATPase
- plasma levels may be normal, total K+ 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 and electrolyte reabsorption also blunted
- Polyuria
- polydipsia
Treatment for Type 1 DM?
insulin replacement drawbacks: -painful and time consuming -lag between glucose measurements and insulin dosing -delayed absorption -poor blood glucose control
Transplantation of B cells
underlying cause of type 2 diabetes mellitus
Insulin resistance
-progressive exhaustion of active B cells due to environmental factors
Pathophysiology of the progression of insulin resistance and type 2 DM
Reactive hyperinsulinemia
Obesity induced insulin resistance:
- decreased GLUT4 uptake of glucose in response in insulin
- decreased abillity of insulin to repress hepatic glucose production
- inabillity of insulin to repress adipose tissue uptake and lipolysis
- ultimately results in decreased glucose transporter number and mobilization of GLUT4
how does T2DM appear in non-obese patients
decreased insulin release by pancreas independant of peripheral insulin resistance, however both can and often do occur
what are incretin hormones?
Intestine derived hormones
- GLP-1, GIP
- SHort half life
- Secreted in response to GI glucose and fat
Stimulates insulin secretion
inhibits glucagon secretion
slow gastric emptying
What is the Treatment of Type 2 DM?
Caloric restriction, weight reduction, physical activity/exercise
Insulin secretagogues
- sulfonylurea drugs
- incretin analog of GLP-1 (exenatide)
Slow absorption of CHO
- alpha glucosidase inhibitors (acarbose, miglitol)
- amylin analogs (pramlintide)
Insulin sensitizers
-Biguanide drugs (metformin) - better insulin receptor trafficking
Bariatric surgery
