Endocrine Pancreas Flashcards
Describe insulin
Major historical discovery and major anabolic hormone
Secrete in response to o CHO and/or protein digestion
What is the major stimulatory factor of insulin secretion?
Glucose
What are the precursors to insulin?
Pre-proinsulin —> proinsulin —> insulin and C peptide
What is pre-proinsulin?
Signal peptide with A and B chains with connecting peptide (C peptide) and no disulfide bonds
What is proinsulin?
No signal peptide
Still attached in insulin
Package into secretory granules
Proteases here cleave proinsulin
What are the steps of insulin release?
Glucose enters cell via GLUT2 and is phosphorylated by glucokinase
G6P is oxidized promoting ATP generation
ATP closes the inward rectifying K channel
Plasma membrane is depolarized
Activation of voltage gated Ca channels
Ca enters the cell and initiates mobilization of insulin (and C peptide)
A rise in ATP levels will close what?
K channels (ATP dependent K channels)
Describe sulfonylurea receptors
Associated with ATP dependent K channels
Increase insulin secretion
Causes membrane depolarization to occur more easily
More Ca entry
Used for treatment of T2DM
Describe the biphasic release of insulin
Initial spikes within minutes
Further increase in half hour to an hour later
First phase of insulin secretion is lost first in T2DM
Where does insulin resistance primarily occur?
In adipose tissue and skeletal muscle
Occurs very early in disease progression
What are the intracellular steps of insulin signaling?
Insulin binding to receptor
Substrate proteins phosphorylate and activate/inactivate downstream pathways P13/Akt/mTOR and MAP kinases (these mediate metabolic and mitogenic responses)
Translocation of vesicles containing GLUT4 to membrane (muscle and adipose)
Glucose enters via facilitated diffusion
What are the stimulatory factors for insulin secretion?
ACh, CCK, GIP, GLP Glucagon (inhibited by insulin but modulates insulin action) Cortisol K+ Obesity Sulfonylurea drugs
What are some inhibitory factors for insulin secretion?
Fasting, exercise
Somatostatin
NE
What are the actions of insulin on skeletal muscle?
increased glucose uptake, glycogen synthesis, glycolysis and CHO oxidation, protein synthesis and decreased protein breakdown
What are the actions of insulin on the liver?
promotes glycogen synthesis, glycolysis and CHO oxidation, decreases gluconeogenesis, increases hexose monophosphate shunt, increase pyruvate oxidation, increases lipid storage and decreases lipid oxidation, increases protein synthesis and decrease protein breakdown
What are the actions of insulin on adipose tissue?
increased glucose uptake, glycolysis and uptake of FAs; decreased lipolysis
Which ion does insulin effect the concentrations of?
Increases uptake of K into cells —> decreased K in blood
Describe the effects of blood sugar and insulin
Muscle contraction stimulates glucose uptake independent of insulin (activation of AMP kinase (AMPK) results in GLUT4 translocation to plasma membrane)
Blood sugar usually roughly normal (except for long distance aerobics)
Insulin may decrease
Eating too close to exercise can disrupt glucose homeostasis
Describe beta cells
60-65% of the islets of langerhans
Centrally located
Secrete insulin and C peptide
Describe alpha cells
20% of islet
Peripherally located
Secrete glucagon
Describe delta Ellis
5% of islet
Interspersed between alpha and beta cells
Secrete somatostatin
Neuronal appearance and send dendrite like processes to beta cells
Describe F cells (PP cells)
Secrete pancreatic polypeptide
Acts like a satiety signal (neuropeptide Y of the peptide YY family)
How do cells of islets communicate with each other?
Ion concentrations changes signal
Gap junctions allow for rapid cell to cell communication between alpha-alpha, beta-beta and alpha-beta cells
Describe the blood supply to the islets of langerhans
Islets receive 10% of pancreatic blood flow
Venous blood from beta cells carries insulin to alpha and delta cells
Blood flows first to the center (for insulin)
Flows through periphery (on alpha cells inhibits glucagon release)
Blood glucose reflects balance between what?
Hypoglycemic actions of insulin and hyperglycemic actions of anti-insulin hormones
Describe glucagon
Increases blood glucose
Substrates are directed toward glucose formation
Increases gluconeogenesis, lipolysis and glycogenolysis
Inhibits glycogen synthesis
Describe the secretion of glucagon
Release stimulated by decreased blood glucose (major
Also stimulated by increasing AA (arginine and alanine), fasting, CCK, beta adrenergic agonists and ACh
What inhibits the secretion of glucagon?
Insulin and high blood glucose levels
Somatostatin, FAs and keto acids
What is the incretin effect?
Incretins are a group of metabolic hormones that stimulate a decrease in glucose levels
The incretin effect is abolished in T2DM
Which factors contribute to the development of T2DM?
Multiple genes coupled with environment, environmental exposures, adipose tissue dysfunction and chronic systemic inflammation
Which ethnicities are at a greater risk for T2DM?
African American, Hispanic and Native American
Which environmental exposures are involved in the development of T2DM?
Caloric intake excessive, sedentary behavior, maternal disease and nutrition, rapid postnatal growth, sleep debt, other endocrine disruptions, chronic inflammation
Describe adipose tissue dysfunction involved with development of T2DM
Adipose tissue is inflamed and recruits M1 macrophages causing release of more inflammatory markers
Disposition of adipokines (i.e. adiponectin and leptin)
Release of FAs
IL-6 and other pro inflammatory cytokines (i.e. TNF-alpha, IFN-gamma and CRP)
Describe the progression of insulin resistance to T2DM
- Systemic insulin resistance
- Reactive hyperinsulinemia: postprandial glucose levels are normal but more insulin is required to do the job (reactive hyperinsulinemia)
- Postprandial hyperglycemia
- Disrupted response to oral glucose tolerance test
- Blunted incretin release (don’t need to known within this timeline)
- Chronic elevated insulin levels
- Mild-moderate chronically elevated glucose levels
- Frank hyperglycemia
Timeline of development can be 5-30 years
What are some treatment options for T2DM?
Caloric restriction, weight reduction and physical activity/exercise
Insulin sensitizers and secretagogues
Slow absorption of CHO
Bariatric surgery
Describe type 1 DM
Inadequate insulin secretion
T cell mediated destruction of beta cells often from autoimmune disease (no insulin or C peptide produced)
Sx do not become evident until >80% of beta cells are destroyed
Increase blood glucose, FAs, keto acids, amino acids, increased conversion of FA to keto acids
Decreased utilization of ketoacids results in DKA
Hyperkalemia and osmotic diuresis/glucosuria can occur
Describe the hyperkalemia that occurs during T1DM
Shift of K out of cells (intracellular concentration is low)
Lack of insulin effect on Na/K ATPase
Plasma levels may be normal but total K is usually low due to polyuria and dehydration
Describe the osmotic diuresis/glucosuria that can occur during T1DM
Increased blood glucose increases filtered load of glucose, exceeds reabsorptive capacity of proximal tubule
Water and electrolyte reabsorption also blunted
Polyuria - increases excretion of Na and K even though urine concentration of electrolytes is low
Thirst (polydipsia)
What are some environmental factors that contribute to the development of T1DM?
Breast feeding - early exposure to cow’s milk may predispose
Vitamin D deficiency
Wheat gluten (increased risk in celiac disease pts)
Few childhood infections
Obesity
Viral infections (mumps, rubella, enterovirsues, retroviruses, CMV)
What is the treatment for T1DM?
Goal is to recreate normal physiology (basal and bolus insulin)
Timing insulin dose to meal consumption to mimic physiologic response
T2DM causes increased risk for what other diseases?
CVD/ischemic heart disease, ischemic vascular disease (i.e. stroke), non-alcohol fatty liver disease and steatohepatitis, kidney failure, blindness, skin ulcers and amputations, peripheral neuropathy
Reduced wound healing
