Lecture 7: Endocrine Pancreas Flashcards
What cells are found in the Islets of Langerhans; where are they located and what do they secrete?
β cells: secrete insulin and C-peptide; located in central core
α cells: secrete glucagon; located near the periphery
D cells: secrete somatostatin, interspersed between α and β cells
How do the cells of the islets of Langerhans communicate w/ eachother?
Gap junctions:
- Rapid cell-to-cell communication
- β-β; α-α; and α-β
What is the blood supply like to the Islets of Langerhans; how does this relate to the paracrine mechanism of the hormones within the endocrine pancreas?
- Receive 10% of the total pancreatic blood flow
- Venous blood from one cells type bathes the other cells types
- Venous blood from the β carries insulin to the α and D cells
- Blood flows first to center (for insulin), then:
- Flows through periphery acting on α-cells inhibiting glucagon release.
What is the main stimulatory factor for insulin secretion?
Glucose
What are the components of preproinsulin vs. proinsulin vs. insulin?
Preproinsulin: signal peptide, A and B chains and C peptide
Proinsulin: no signal peptide, C peptide still attached
Insulin: is packaged w/ C peptide, but only consists of the A and B chains whilst inside secretory vesicles
Why is C peptide significant?
- Is released in equimolar amounts into the blood w/ insulin and excreted unchanged in urine
- Can be used as a long-term marker of endogenous insulin secretion, specifically endogenous B cell function
What are Sulfonylurea drugs (i.e., tolbutamide, glyburide) and what are they used for?
Promote the closing of the ATP-dependent K+ (inward-rectifier K+ channel); increasing insulin secretion; used in the treatment of Type II DM
Describe the 6 steps upon glucose binding pancreatic B-cell to insulin release
1) Glucose enters cell via GLUT-2
2) Phosphorylated by Glucokinase
3) G-6-P is oxidized promoting ATP generation
4) ATP closes the ‘inward-rectifying’ K+ channel; membrane depolarization
5) Activation of voltage-gated Ca2+ channels; Ca2+ enters cell
6) Vesicles of insulin mobilized to plasma membran and exocytosis
What is the proportionality of insulin secretion in relation to blood glucose?
Insulin secretion is basically proportional to plasma glucose changes
What does biphasic secretion of insulin refer to; which phase is lost first in diabetic patients?
First phase: rapid and transient release
Second phase: delayed/longer chronic phase of release
*First phase is the first thing to dissapear in diabetic individuals*
What are the other modulators of insulin secretion?
- GI peptides, glucagon, somatostatin, and ACh
- Different intracellular pathways
How is GLUT-4 translocated to the plasma membrane; what else stimulates this process and why is this significant?
- Activation of AMP-kinase (AMPK) upon insulin binding its receptor
- Muscle contractions stimulate this process, highlighting the importance of exercise in the management of insulin resistance and/or diabetes
How is glucose taken up by peripheal cells?
Facilitated diffusion
Insulin is important for glucose uptake into what tissues?
Adipose tissue, resting skeletal muscle, and liver
What are the major effects of insulin on skeleal muscle?
- Increased glucose uptake and GLUT 4 transporter
- Activates glycogen synthase = increased glycogen synthesis
- Increased glycolysis and CHO oxidation (hexokinase, PFK, PDH)
- Increased protein synthesis and decreased breakdown
What are the major effects of insulin on the liver?
- Promotes glycogen synthesis (glucokinase and glycogen synthase)
- Increased glycolysis and CHO oxidation
- Decreases gluconeogenesis
- Increases hexose monophosphate shunt
- Increase pyruvate oxidation
- Increase lipid storage and decrease lipid oxidation
- Increase protein synthesis and decrease breakdown
What are insulins actions on Adipose Tissue?
- Increases glucose uptake (GLUT 4 trasnlocation)
- Increases glycolysis (increased production of α-glycerol phosphate for esterification and lipogenesis)
- Decreased lipolysis (inhibits HSL)
- Promotes uptake of FA’s (LPL activity/synthesis), favoring the formation of TAG’s
What is the effect of insulin on the blood levels of K+, glucose, FA’s, ketoacids, and AA’s?
Decreases them all!
What is one of the common treatments for hyperkalemia?
The administration of some insulin w/ small amount of glucose.
What are some of the stimulatory factors for the secretion of insulin?
- Increased [Glucose]
- Increased [AA]
- Increased [FA] and [Ketoacid]
- Glucagon
- GIP (glucose-dependent insulinotropic peptide)
- Vagal stimulation; ACh
- K+
- Sulfonylurea rugs
- Obesity
What are some of the inhibitory factors for the secretion of insulin?
- Decreased blood glucose
- Fasting
- Exercise
- Somatostatin
- α-adrenergic agonists
- Diazoxide (K+ channel activator)
How is the signal for insulin shut down?
Lysosomes will internalize the receptor from the plasma membrane, shutting down the signal
What is Type I DM; symptoms seen when and what metabolic problems occur?
- Inadequate insulin secretion
- Destruction of β cell, often the result of autoimmune disease
- Symptoms do not become evident until > 80% of β cells are destroyed
- Increased blood glucose, fatty acids, ketoacids, amino acids, increased conversion of fatty acids to ketoacids
- Results in diabetic ketoacidosis (DKA): metabolic acidosis
How does hyperkalemia develop in Type I DM patients; what are the total body K+ levels like?
- Shift of K+ out of the cell
- Intracellular concentration is low
- Lack of insulin effect on Na+/K+ ATPase
- Even though plasma levels may be able normal, total body K+ is usually below normal due to the polyuria and dehydration
