Endocrine Pancreas (Rogers) Flashcards
1
Q
- major anabolic hormone
- secreted in response to carb and/or protein intake
- glucose is the major stimulatory factor for this hormone’s secretion
A
insulin
2
Q
- condition caused by “insulin resistance”
- 95% of diabetes cases, 8.2% of US adults in 2018
- increasing numbers of children w/ disease
- $300+ billion in health care costs
A
type 2 diabetes mellitus
3
Q
What hormones does the endocrine pancreas cells secrete and what is the function of these hormones?
A
- secrete insulin, glucagon, somatostatin
- large role in regulating lipid, carb, and AA metabolism
4
Q
What is the cell organization of the endocrine pancreas?
A
- cell arranged in clusters: islets of Langerhans
- 1-2% of pancreatic mass
- 2500 cells/islet
- innervated by adrenergic, cholinergic, and peptidergic neurons
5
Q
- cell type in endocrine pancreas
- 60-65% of islet, centrally located
- secrete insulin and C peptide
A
β cells
6
Q
- cell type of endocrine pancreas
- 20% of islet, peripherally located
- secrete glucagon
A
α cells
7
Q
- cell type of endocrine pancreas
- 5% of islet, interspersed between alpha and beta cells
- secrete somatostatin
- neuronal in appearance and send “dendrite-like” processes to beta cells
A
δ cells
8
Q
- cell type of endocrine pancreas
- secrete pancreatic polypeptide
- acts like a satiety signal (neuropeptide Y, peptide YY family)
A
F cells
9
Q
How do cells within pancreatic islets communicate w/ one another?
A
- ion concentration changes signal
- gap junctions: rapid cell to cell communication between alpha-alpha, beta-beta, and alpha-beta
10
Q
What is the blood supply to pancreatic islets cells?
A
- islets receive 10% of pancreatic blood flow
- venous blood from beta-cells carries insulin to alpha and delta-cells
- blood flow is first to center (for insulin)
- flows through periphery (on alpha-cells insulin inhibits glucagon release)
11
Q
What are the precursor molecules to insulin?
A
- peptide hormone: 2 chains linked by disulfide bridges
- preproinsulin > proinsulin > insulin and C peptide
- preproinsulin: signal peptide w/ A and B chains w/ connecting peptide (C peptide), no disulfide bonds
- proinsulin: no signal peptide, C peptide still attached to insulin, packaged into secretory granules, proteases here cleave proinsulin
- C peptide: secreted in equimolar quantities into blood and can be used as marker of endogenous insulin secretion
12
Q
What are the 8 steps of insulin release?
A
- glucose enters β-cell via GLUT-2 transporter
- glucose is phosphorylated to glucose-6-phosphate by glucokinase
- glucose-6-phosphate is oxidized, promoting ATP generation
- ATP closes the ‘inward-rectifying’ K+ channel
- plasma membrane is depolarized
- activation of voltage-gated Ca2+ channels
- Ca2+ enters the cell and levels increase
- this initiates mobilization of insulin (and C peptide) containing vesicles to plasma membrane for exocytosis
13
Q
What are key concepts to remember regarding insulin release?
A
- rises in ATP closes K+ channels (ATP-dependent K+ channels)
- sulfonylurea receptor, a/w ATP-dependent K+ channels, increases insulin secretion: causes membrane depolarization to occur more easily, more Ca2+ entry, used for tx of TIIDM
- C peptide secretion used as tool to measure function of β-cells and endogenous insulin secretion
14
Q
What phase pattern does insulin release follow?
A
- insulin release is biphasic
- initial insulin spike is within minutes (of eating)
- further increase occurs 0.5-1 hr later
- first phase of insulin secretion is lost first in TIIDM
15
Q
What are the intracellular steps of insulin signaling?
A
- insulin binds to receptor
- substrate proteins phosphorylate and activate/inactivate downstream pathways: PI3K/Akt/mTOR and MAP kinases (these mediate metabolic/mitogenic responses)
- translocation of vesicles containing GLUT4 to membrane (muscle and adipose): glucose enters via facilitated diffusion
16
Q
Where does insulin resistance occur specifically in the body?
A
- occurs at peripheral tissues: adipose tissue and skeletal muscle, also liver but this works differently
- occurs very early in disease progression
17
Q
Describe the progression of insulin resistance:
A
- in nml physiological conditions, glucose elicits insulin release from pancreas; insulin release activates adipose tissue, liver, and skeletal muscle to use/store glucose, which in turn reduces glucose level within body
- in insulin resistance, glucose levels are elevated which elicit pancreas to release higher levels of insulin, however adipose tissue, liver, and skeletal muscle are no longer “normally” activated by inslin to use/store glucose, thus glucose levels can be elevated
18
Q
What is the intracellular mechanism for insulin resistance?
A
- in nml conditions, AKT activates translocation of GLUT4 transporter to cell membrane
- in hyperinsulinemia, mitochondria become overloaded due to the increase of insulin signaling pathways and, in turn, increased production of ATP
- mito begin releasing fatty acyl carnitines, ceramides, and DAGs
- these cause activation of stress kinases which activate pathways that inhibit insulin signaling pathways
- also, ceramide inhibits AKT pathway, therefore inhibiting GLUT4 transporter translocation
- all of these effects inhibit insulin signaling pathways and glucose entry into the cell, which causes increase in plasma insulin and glucose
19
Q
What are the important modulators of insulin secretion?
A
- GI peptides, glucagon, somatostatin, ACh
- ACh, CCK, GIP, and GLP-1 activate insulin secretion (phospholipase C receptor)
- somatostatin inhibits insulin secretion (Gi adenylyl cyclase receptor)
- use different intracellular pathways
- glucagon release is inhibited by insulin, but modulates insulin action (glucagon stimulates insulin release)
20
Q
What is the effect of incretin in nml and TIIDM conditions?
A
(incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels)
- incretin effect is abolished in TIIDM
23
Q
What are insulin actions on skeletal muscle?
A
- increased glucose uptake
- increased glycogen synthesis
- increased glycolysis and CHO oxidation
- increase protein synthesis
- decreased protein breakdown
24
Q
What are actions of insulin in the liver?
A
- promotes glycogen synthesis
- increase glycolysis and CHO oxidation
- decreases gluconeogenesis
- increases hexose monophosphate shunt
- increases pyruvate oxidation
- increases lipid storage and decreases lipid oxidation
- increases protein synthesis and decreases protein breakdown
25
Q
What are the actions of insulin on adipose tissue?
A
- increased glucose uptake
- increased glycolysis
- decreased lipolysis
- promotes uptake of FAs
27
Q
How does exercise effect blood sugar and insulin levels?
A
- muscle contraction (exercise) stimulates glucose uptake independent of insulin: activation of AMP-kinase (AMPK) results in GLUT4 translocation to membrane
- blood sugar usually roughly nml (except for long distance aerobics)
- insulin may decrease during exercise
- eating too close to exercise can disrupt glucose homeostasis
28
Q
What is the metabolic role of glucagon?
A
- blood glucose reflects balance between hypoglycemic actions of insulin and hyperglycemic actions of anti-insulin hormones
- glucagon increases blood glucose: substrates are directed toward glucose formation; increases gluconeogenesis, lipolysis, glycogenolysis, and inhibits glycogen synthesis
31
Q
What environmental factors increase risk of developing TIIDM?
A
- excessive calroic intake
- sedentary lifestyle
- maternal disease and nutrition
- rapid postnatal growth
- poor sleeping habits
- other endocrine disruptions
- chronic inflammation
32
Q
What is the role of adipose tissue dysfunction and chronic inflammation in development of TIIDM?
A
- when adipose tissue is inflamed, M1 macrophages are recruited
- adipose tissue then releases more inflammatory markers which causes disruption of adipokines (i.e. adiponectin and leptin), leading to release of FAs
- IL-6 and other pro-inflammatory cytokines (i.e. TNFα, IFN-γ, CRP) are the major molecules leading to chronic inflammation
33
Q
How does insulin resistance progress to TIIDM?
A
- systemic insulin resistance
- reactive hyperinsulinemia: postprandial glucose levels are nml but more insulin is req to do the job
- postprandial hyperglycemia
- disrupted response to oral glucose tolerance test
- blunted incretin release
- chronic elevated insulin levels
- mild-moderate chronically elevated glucose levels
- frank hypergylcemia
(time of development 5-30 years)
35
Q
What is the underlying mechanism of disease for type 1 diabetes mellitus?
A
- formely known as juvenile onset diabetes
- caused by inadequate insulin secretion
- T-cell mediated destruction of β-cells: often from autoimmune dz (no insulin or C-peptide produced)
- sx do not become evident until > 80% of β-cells are destroyed
- increased blood glucose, FAs, ketoacids, AAs, and increased conversion of FAs to ketoacids
- decreased utilization of ketoacids results in diabetic ketoacidosis (DKA)
38
Q
What genetic/biologic factors increase the likelihood of developing TIDM?
A
- mother: 2-3% lifetime risk
- father: 5-6% lifetime risk
- both: 30% lifetime risk
- sibling: 6%
- general public: 0.4%
- monozygotic twins: 30-50%
- dizygotic twins: 10%
- HLA class II alleles: encodes MHC class II protein complex
- DQ2/DQ8 (haplotypes DR3DQ2 or DR4DQ8) found in more than 90% of individuals w/ TIDM
- heterogenous genotypes DR3/DR4 are most common in children dx prior to age 5 (50%)
- HLA class II that lack Asp57 of the β-chain a
- number of other genes involved in autoimmunity (e.g. CTLA-4)
40
Q
What is the general treatment for TIDM?
A
- insulin replacement
- goal is to recreate nml physiology (basal and bolus insulin)
- timing insulin dose to meal consumption to mimic physiological response
- graph is nml physiological response
41
Q
Compare and contract TIDM vs TIIDM:
A
