Insulin, Glucagon and Diabetes mellitus Flashcards
Two major tissue types of the pancreas
Acini
Islets of langerhans
Hormone commonly secreted together with insulin
amylin
Distribution of the different types of cells in islets of langerhans and their secretions
Beta cells
- 60% of the cells
- found mostly in the middle of islets
- secrete insulin and amylin
Alpha cells
- 25% of the cells
- secrete glucagon
Delta cells
- 10%
- secrete somatostatin (Growth hormone inhibitory hormone)
PP cells
- 5%
- pancreatic polypeptide
insulin is inhibited by
amylin and somatostatin
5 functions of insulin
- energy storage; promoting glucose uptake
- conversion of excess carbohydrates into lipids to be stored in adipocytes
- promotes uptake of amino acids
- promotes conversion of amino acids into protein
- prevents protein breakdown
why is C peptide secreted in same amounts as insulin?
Because during cleavage of pre-insulin, insulin and the resulting C peptide are released as products of the cleavage and packaged together in the same secretory vesicles
Connecting (C) peptide binds to
sodium potassium ATPase
nitric oxide synthase
Low levels of C peptide is an indication of which condition?
type 1 diabetes as it indicates patients not able to produce insulin
Insulin is cleaved by
insulinase
Explain structure of insulin receptor
Made of four subunits held together by disulfide bonds
2 alpha subunits lie outside cell membrane facing ECM while 2 beta subunits connected to alpha subunits penetrate through membrane to protrude on cytoplasmic side
Insulin receptor is what type of receptor
enzyme-linked
Mechanism of insulin binding to insulin receptor
Insulin binds to alpha subunits
Autophosphorylation of beta subunits
Activation of tyrosine kinase
Activation of IRS = activation of proteins involved in glucose transport, protein synthesis, fat, glycogen synthesis and gene expression
End effects of insulin binding to its receptor
- Increased glucose uptake due to release of glucose transporters to cell membrane
- Increase cell permeability to amino acids, potassium, and phosphate ions
- Phosphorylation of intacellular enzymes changes their activity levels deactivating some and further increasing others
- Change in DNA transcription and mRNA translation (slowest effect) = formation of new proteins to exert insulin effects
Insulin greatest effect is on which tissues?
Muscles
Adipose
Liver
During resting, what is muscle’s main energy source? Why?
It’s fatty acids because during resting membrane potential, muscle cells less permeable to glucose so don’t have much glucose entering
True or false: In between meals under normal conditions, insulin causes increase in glucose uptake, resulting in glucose instead of fatty acids being used by muscles
False: In normal conditions, amount of insulin secreted is too small to cause significant glucose uptake by muscles for them to switch to using glucose
When does muscle cell use glucose for energy?
Right after a meal when insulin secreted is high enough to cause significant glucose uptake, but only if the muscle is exercised. If it’s not exercised most of the glucose goes into glycogen storage.
During exercise (this effect is not insulin mediate), when contraction causes increased translocation of GLUT4 to membranes
Concentration limit of glycogen storage in muscles
2-3%
Effect of insulin on liver
Increase glycogen storage
Mechanism of insulin effect on liver
To increase glycogen storage
- Deactivation of glycogen phosphorylase which causes inhibition of glycogenolysis
- Activation of glycogen synthase
- Activation of glucokinase = trapping of glucose to increase glucose available for glycogenesis
Rate by which insulin increase glucose transport into a resting muscle
15-fold
At which glucose level does hypoglycemic shock develop?
20 to 50 mg/100 mL plasma
How does insulin promote fat deposition of TAGs?
by increasing glucose uptake, it provides glycerol backbone for TAGs
Amino acids most strongly transported due to insulin effect
Valine Leucine Isoleucine Tyrosine Phenylalanine
How do GH and insulin work synergistically?
They each promote uptake of their respective different amino acids to have complementary effect and provide cells with ALL the amino acids needed for synthesis of proteins
When pancreas stops secreting insulin, how do levels of blood glucose, free fatty acids, and acetoacetic acid change?
Fatty acids increase by the greatest rate and then remain constant, but lower than glucose levels. Glucose increases by a lower rate, but over a longer period of time and does not reach a plateau but continues increasing far above that of fatty acids.
Acetic acid increases at higher rate than glucose but lower than free fatty acids, but very briefly, then slowly rises, and may be higher than free fatty acids depending on how long the patient doesn’t have insulin
Mechanism of insulin release by Beta cells
Beta cells have glucose transporters and are very permeable to glucose so that the concentration of glucose that enters is proportional to that in the bloodstream
- Glucose is converted to Glucose-6phosphate
- Formation of ATP increases as glycolysis proceeds
- ATP blocks potassium channels
- Results in depolarization
- Voltage gated calcium channels then open
- Calcium influx into cell
- Insulin vesicles dock on cell membrane
- Release of insulin by exocytosis
Other hormones that cause increase in intracellular calcium to cause insulin release
Glucagon
Gastric inhibitory peptide
Acetylcholine
Gastric inhibitory peptide is also called
glucose-dependent insulinotropic peptide
Factors that inhibit insulin secretion
Somatostatin
Norepinephrine
Sulfonylurca drugs
stimulate secretion of insulin via blocking potassium channels
What kind of receptors do sulfonylurca drugs bind to
Beta adrenergic
Normal fasting levels of glucose
80-90mg/100ml
Enumerate the two stages by which insulin secretion increases when glucose concentration above normal fasting levels
- First phase is fast. Sudden increase in insulin caused by dumping of preformed insulin by beta cells. Eventually secretion decreases as the stores of insulin are depleted
- Before the rate falls completely, insulin exerts its genomic effects of causing increased DNA transcription and mRNA translation and phosphorylation of certain proteins to increase enzyme formation of insulin. This time glucose levels rise even though not at as fast a rate as in the first stage and continue to reach a higher plateau
Glucagon is secreted by
alpha cells of islets of langerhans
An injection of 1 microgram per kilogram can elevate blood glucose by
25%
20mg/100 ml
Glucagon also called the
Hyperglycemic hormone
Glucagon’s greatest effect is on which aspect of metabolism
Enhanced glycogenolysis in the liver
Mechanism of glucagon in increasing glycogenolysis
- Binds to its receptors on hepatic membrane
- Activation adenylyl cyclase
- cAMP formation
- Activation of protein kinase regulator
- Activation of protein kinase
- Activation of phosphorylase b kinase
- Conversion of phosphorylase b to phosphorylase a
- Glycogen degradation = Glucose release
How can some a small amount of glycogen cause such a great increase in glucose?
via its cAMP amplification effect, at every stage, more product is produced than the preceding product
Why does glucagon continue causing hyperglycemia even when liver glycogen stores are depleted?
because it also enhances gluconeogenesis and amino acid uptake for those amino acids to be converted into glucose
at what pH does acidotic coma occur?
below
Why is acetone breath not detected in the initial stages of type 2 diabetes?
Because the insulin is still being produced enough to prevent severe hyperglycemia. But later on when insulin stops completely, the fatty acid levels increase severely as well as acetoacetate
Treatment of type 2 diabetes versus treatment of type 1.
Type 2 in the initial stages can be treated without giving insulin injections by exercise and caloric restriction, administration of drugs that increase insulin sensitivity, and suppress gluconeogenesis. But in its late stages, it’s treated the same way as diabetes 1 by administration of insulin injections
Name a drug that increases insulin sensitivity
Thiazolidinedione
Function of metformin drug
suppresses gluconeogensis so used in treatment of diabetes type 2 in its early stages
Incretins. Their role
Incretins refer to Glucagon like peptide (GLP 1 and 2) release from GIT.
They enhance insulin release so drugs that mimic them used to treat diabetes 2 early stages
Why is blocking the dipeptidyl peptidase 4 (DPP-4) a therapeutic way of managing diabetes 2?
DPP-4 deactivates incretins. By inactivating it, the effects of incretins of insulin release are prolonged
Sulfonylurea drugs
Cause increase in insulin. used for type 2 diabetes
Compare and contrast treatment and symptoms of diabetes 1 and 2
Diabetes 1
- high levels of glucagon which can be suppressed
- acetone breath develops early
- low levels of insulin in blood
- significant weight loss
- insulin sensitivity of cells normal
- usually starts below 20 years
- management is by insulin injections
Diabetes 2
- initial low levels of glucagon, but increase to point where it can’t be suppressed in late stages
- acetone breath develops later
- high levels of insulin in blood in early stages
- weight gain around abdominal area
- cells have decreased insulin sensitivity
- usually beings above 30 years
- management is by diet restriction, exercise, weight management, thiazolidinedioles, metformin, sulfonylurea, and later on insulin
Diagnosis of diabetes
- Concentrations of glucose in urine
(normal people have undetectable levels of glucose, but those with diabetes have high levels of glucose in urine) - Fasting Glucose and Insulin levels
(normal people’s fasting glucose levels are 80-90mg/100ml plasma with almost undetectable amounts of insulin, but those with diabetes have fasting glucose concentrations higher than 110mg/100ml and high levels of insulin) - Glucose tolerance curve
(After a meal, a normal person’s glucose levels rise above 90mg/100 ml, but after around 2 hours drop back down to the normal 80-90mg/100 ml. In a diabetic patient, after a meal, their glucose levels rise very high and after a longer period of 4-6 hours, drop, but they never drop back to the level they were, remaining at a higher level than before the meal) - Acetone breath indicates high levels of acetoacetic acid in the body. Mostly useful in type 1 diabetics because it can only be used in the late stages of type 2 diabetes.
Difference between ‘regular’ insulin and other forms of insulin.
Regular insulin has a prolonged effect of 3-8 hours, but other forms of insulin last 10-48 hours
Why are lipid-lowering drugs given in addition to insulin in management of diabetes?
Because of associated effects of increased fatty acid release like atherosclerosis. So to prevent these disturbances, such drugs are given.
At which glucose level does the CNS become excitable? results in hypoglycemic coma?
50-70 mg/100 ml causes CNS excitability
20 mg and below/100 ml =hypoglycemic coma
Differentiate hopoglycemic from diabetic coma.
In hypoglycemic coma, patient has no acetone breath and does not breath rapidly and deeply
Proper treatment of hypoglycemic shock
Immediate large intravenous administration of glucose
Administration of glucagon and epinephrine to cause glycogenolysis = increase in glucose
