Physiology of Pancreas Flashcards
Which hormones are released during the fasting state?
- Glucagon
- Catecholamines
- Cortisol (supplementary if the first two don’t get the job done)
- Growth hormone (supplementary if the first two don’t get the job done)
What are the sources of control of the synthesis and secretion of islet hormones?
-
Humoral communication
- Blood supply of the islet course otuward from the center toward the periphery, carrying glucose and other secretagogues
-
Cell-cell communication
- Cells within an islet connect with one another and communicate through gap junctions
-
Neural communication
- Islets are innervated by the sympathetic and parasympathetic divisions of the ANS
Products of alpha cells
- Glucagon (20% of islet cells located near periphery)
Products of beta cells
- Insulin-60-75% of islet cells located mainly in the center
- Amylin
Products of delta cells
- Somatostatin- 5% of islet cells interspersed between the alpha and beta cells
Products of F cells
Pancreatic polypeptide
Insulin is encoded by a single gene on Chromosome ___.
11
Insulin synthesis and secretion is stimulated when islets are exposed to glucose. What are the components of the secretory granules that secrete insulin?
Insulin, C peptide and a small amount of proinsulin
NOTE: The half-life of insulin is approximately 5 mins
What are the mechanism by which insulin beinds to it’s cell receptors?
- Insulin binds to specific receptor tyrosine kinase on the plasma membrane
- Insulin recept can phosphorylate both itself and other intracellular substrate at tyrosine kinase residues
- insulin is able to transmit its signal across the plasma membrane of insulin target tissues
Approximately 60% of insulin that enters into the portal vein is removed by the _____.
Liver
NOTE: C-peptide is not extracted by the liver, but is excreted by the kidneys. This is important diagnostically. C-peptide is not harmed by the liver, so it makes it out of circulation in the exact amount that the beta cells synthesized it.
High C-peptide levels are diagnostic of __________.
DM II
When is glucose response to insulin maximal?
When only approximately 5% of the receptors are occupied
What effect does insulin have at the liver?
Glycolysis
Glycogen synthesis
Liogenesis
Protein Metabolism
The biggest issue with diabetes is the inability of ______ to take up glucose.
Skeletal muscle
Function of insulin at skeletal muscle
- Increases GLUT4 translocation
- Increases glycogen synthesis
- Increase glycolysis
- Increases protein synthesis and slows protein degradation
- Increases triglycerides
Function of insulin at adipocytes
- Increase GLUT4 transporters
- Increase glycolysis
- Increase in a-glycerol phosphate
- Increase in acteyl CoA
- Increase in FA synthesis
- Increase triglycerides
- Increase LPL
- Inhibits hormone sensitive lipase
How does glucose stimulate the release of insulin?
- Glucose enters the β-cells through the glucose transporters, GLUT2.
- The glucose that enters the β-cell is phosphorylated to glucose-6-phosphate by glucokinase
- Glucose-6-phosphate enters glycolytic pathway, leading to a rise in the ATP:ADP ratio within the cell.
- An increased intracellular ATP:ADP ratio closes the ATP-sensitive potassium channel.
- Upon depolarization, voltage-gated calcium ion (Ca2+) channels open, allowing calcium ions to move into the cell by facilitated diffusion.
- The significantly increased amount of calcium ions in the cells’ cytoplasm causes the release into the blood of previously synthesized insulin, which has been stored in intracellular secretory vesicles.
Aside from glucose, what other factors stimulate the release of insulin?
- FFAs
- Amino acids
- Sulfonyurea drugs
- Epinephrine and norepinephrine
*
A healthy person will have a spike of insulin within ____ minutes of eating.
60
*There’s a drop and then another slight increase of insulin within 120 minutes of eating. This 2nd peak is caused by reload of beta cells, which are synthesizing more insulin
What is the one time in which glucagon and insulin work together?
When amino acids levels are high
________ mg/dL of glucose is the “magic mark” where glucagon is shut down and insulin begins to rise.
80
When do growth hormone and cortisol come into play with regard to hypoglycemia?
When fasting for 2 or more days
NOTE: The kidneys can also produce glucose by gluconeogenesis in cases of prolonged fasting.
REMEBER: Glucagon and epinephrine are the first hormones to kick in when blood glucose is low. Cortisol and GH supplement them
Type I DM
- Diabetes B- cell destruction
- Immmune-mediated
- Idiopathic
NOTE: Autoantibodies are formed against islet cell cell autoantibodies, insulin, and GAD65
Type II DM
- Progressive insulin secretory defect
- Gestational diabetes mellitus (3rd trimester of preganancy)
- MODY
- Disease of the exocrine pancreas (cystic fibrosis)
- Drug or chemical induced diabetes
What are the general signs and symptoms of DM?
- Polyrua, nocturia, polydipsia
- Weight loss, sometimes with polyphagia
- Blurred vision
- Impairment of growth
- Susceptibility to certain infections
- Hyperglygemia with keto acidosis
- Hyperglycemic Hyperosmolar syndrome
NOTE: Ketoacidosis is generally associated with Type I. Type II is associated with hyperosmolar hyperglycemic syndrome (HHS).
________ cell loss to a certain degree triggers Type I DM.
Beta
NOTE: Immunologic trigger can lead to diabetes in people with genetic predisposition to it. When an immunologic trigger you can see beta cell numbers steadily dropping.
What are the metabolic consequences of insulin deficiency?
- Increased blood glucose concentration
- Increased blood FFA and ketoacid concentration- fat depletion
- Increased blood amino acid concentration- protein depletion
What are the consquences of DM Type I on fluids and electrolytes?
- Metabolic acidosis
- Glycosuria and osmotic diuresis
- Increased plasma osmolality
- Hyperphagia
- Polydipsia
- Hypovolemia and hypotension
- Coma and death
MODY
Refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production.
NOTE: Genes affected are HNF-4a, HNF-1a, IPF-1, HNF-1B, NeuroD1
Contrast MODY from DM II
MODY
- Nonobese
- Monogenic
- Metabolic syndrome absent
DM II
- Obese
- Polygenic
- Metabolic syndrome present
How does exercise affect GLUT4 transporters?
Exercise activates GLUT4 so that it is translocated to the plasma membrane of skeletal muscle cells, allowing glucose to enter
What are the secondary causes of diabetes mellitus?
- Acromegaly
- Cushing’s syndrome
- Glucagonoma
- Pheochromocytoma
- Hyperthyroidism
- Somatostatinoma
- Aldosteronoma
_________ is the first line of treatment for Type II DM.
Metformin
NOTE: It is controversial and is thought to reduce gluconeogenesis in the liver
Aside from metformin, which drugs are most oftern prescribed to treat DM Type II?
Biguanides
Sulfonylureas
Hyperglycemic Hyperosmolar syndrome (HHS) symptoms
- Altered level of consciousness
- Neurologic signs including: blurred vision, headaches, focal seizures, myoclonic jerking, reversible paralysis
- Motor abnormalities including flaccidity, depressed reflexes, tremors or fasiciculations
- Hyperviscosity and increased risk of blood clot formation
- Dehydration
- Weight loss
- Nausea, vomiting, and abdominal pain
- Weakness
- Low blood pressure with standing
Diagnostic criteria for HHS
- Plasma glucose level >30 mmol/L (>600 mg/dL)
- Serum osmolality >320 mOsm/kg
- Profound dehydration, up to an average of 9L (and therefore substantial thirst (polydipsia))
- Serum pH >7.30
- Bicarbonate >15 mEq/L
- Small ketonuria (~+ on dipstick) and absent-to-low ketonemia (<3 mmol/L)
- Some alteration in consciousness
- BUN > 30 md/dL (increased)
- Creatinine > 1.5 mg/dL (increased)
