Tutorial: Diabetes and integrated glucose metbaolism Flashcards
Normal glucose level in body
4-6 mM
normoglycemia
What happens in a well fed state?
aka postprandial state
Ample nutrients (glucose, amino acids, fatty acids)
Insulin is secreted, causing a high insulin/glucagon ratio
Ratio activates pathways to store excess nutrients
Insulin lowers glucose levels in blood and promotes synthesis of glycogen, amino acid uptake, lipogenesis and inhibits lipolysis
What happens after the body has been fasting for more than 8 hours?
Glucagon secretion is increased, insulin is decreased
Ratio of insulin to glucagon activates the generation of energy from stored molecules
Glycogenolysis in liver, protein breakdown, lipid breakdown
Sensitivity of lipase to insulin
Very sensitive!!
Only a small amount is necessary to prevent uncontrolled breakdown of lipids
Prolonged fasting and starvation
Further decrease in insulin/glucagon ratio
Causes changes in energy metabolism to maintain the constant supply of glucose required as an energy source by the brain and RBC
Glycogen supplies become exhausted and glucose must be synthesized from amino acids, glycerol and lactate
Lipolysis increases and ketone bodies are formed. Can be used by the brain to decrease body’s demand for glucose
Major anabolic and catabolic pathways
See figure
Where is insulin synthesized?
As a preprohormone in the beta cells of the islet of langerhans
When is insulin released into blood?
In response to high glucose
In response to high amino acids
Pathway of insulin release
Increased uptake of glucose by pancreatic beta cells leads to increased glucose oxidation
Elevation in ATP/ADP ratio
High ATP inhibits ATP sensitive potassium channel, which depolarizes the cell
This leads to Ca2+ influx and insulin secretion
What route of glucose administration has a greater effect on insulin secretion?
Oral glucose has greater effect than injected glucose
Probably because there is secretion of gut incretin hormones (glucagon-like peptide 1 and gastric inhibitory peptide)
What does glucagon-like peptide 1 do?
GLP-1
Increases insulin secretion only in the presence of elevated plasma glucose levels
Avoids inappropriately high insulin during fasting
On what organs does insulin have its effects?
On tissues that have abundant insulin receptors
Liver
Adipose
Skeletal muscle
What happens when insulin binds insulin receptor?
Autophosphorylation of insulin receptor on several kinase residues
Activates the receptor as a kinase toward downstream binding partners and substrates
Secondary messengers activate most anabolic pathways (except gluconeogenesis)
What are the main counter-regulatory hormones that act in opposition to insulin?
Glucagon
Epinephrine
Cortisol
Growth hormone
Raise glucose level in bloodstream
Glucagon - where is it secreted and why?
Fast acting
Secreted by pancreatic alpha cells
In response to low blood glucose
What does glucagon act on?
Receptors in the liver
Works to increase cAMP and activate protein kinase A
This leads to activation of enzymes that release glucose into blood stream
How does epinephrine increase blood glucose?
Short acting
Activates hepatic glycogenolysis and gluconeogenesis via beta-adrenergic receptors
Action of cortisol and growth hormones
Longer acting
How to glucocorticoids work?
ex: cortisol
Elevate blood glucose by decreasing glucose uptake and stimulating transcription of phosphoenolpyruvate carboxykinase (key enzyme in gluconeogenesis)
How does growth hormone work to increase blood glucose?
Primarily by decreasing glucose uptake in peripheral tissues
How does type 1 diabetes arise?
Destruction of pancreatic beta cells, which synthesize insulin
Often due to production of autoantibodies against beta cells, but initiating event is unclear
Insulin deficiency results. Relative high glucagon levels.
What is type 1 diabetes often referred to as?
Juvenile diabetes
Majority of cases present before 18 years of age
What happens if someone with type 1 diabetes goes untreated?
Catabolic state
High glucose levels due to glycogen breakdown and gluconeogenesis
High ketone levels due to uncontrolled lipolysis
Protein is degraded
Fatty acids are used as source of energy and glucose is not used
Leads to weight loss, hyperglycaemia and ketonuria
What are the symptoms of uncontrolled type 1 diabetes?
Extreme thirst (polydipsia)
High urine output (polyuria)
During the early stages when there is still a small amount of insulin produced, the individual may have high blood glucose level without ketones because only a small amount of insulin is required to inhibit lipolysis
Symptoms of later stages of uncontrolled type 1 diabetes
Complete insulin deficiency
Hyperglycemia and ketonuria will lead to hyper osmotic ketoacidosis and eventually death
Inflammtory response can lead to increase in counter regulatory hormones
What are most cases of diabetic ketoacidosis caused by?
Non compliance
Infection
Other names for type 2 diabetes
Non-insulin dependent
Adult onset
Causes of type 2 diabetes
Multifactorial
Genetic and environmental contributions
Characterization of type 2 diabetes
Elevated circulating insulin but a resistance to insulin, leading to hyperglycaemia
Why is hyper osmotic ketoacidosis infrequent in type 2 diabetes?
Levels of insulin are often still adequate to prevent uncontrolled breakdown of lipid
Short term consequences of hyperglycemia
Blurred vision
Frequent urination
Thirst
Longterm consequences of hyperglycaemia
Damage to vessels that leads to retinopathy, nephropathy, cardiovascular disease, neurological dysfunction
How can long term control of glucose be monitored?
Hemoglobin A1C
Signs of hypoglycemia
Sweating, pallot, shaking, confusion
If untreated, can lead to seizures, unconsciousness and death
How to treat modest hypoglycaemia?
Fast acting carbohydrate
How to treat severe hypoglycaemia?
Administration of glucagon
How is type 1 diabetes managed?
Providing basal insulin
Supplemented with insulin boluses (around meal time)) to match carbohydrate consumption and exercise
How is insulin administered
Recombinant human insulin
Subcutaneous injection
Subcutaneous catheter connected to an insulin pump
How are synthetic forms of insulin differentiated from endogenous insulin?
Synthetic forms do not contain internal C-peptide that must be removed by processing
Onset and duration of rapid acting insulin
Very fast onset
Short duration (3-5 hrs)
Formulation of rapid acting insulin
monomers or molecules that quickly dissociate into monomers
Can be rapidly absorbed from the site of injection
Useful for prandial insulin replacement
Which form of insulin has the lowest variability of absorption?
Rapid acting (<5% variability of absorption)
Onset of short acting insulin
Rapid onset (30 min)
5-8 hour duration
When is short acting insulin injected?
Injected 30-45 minutes before meal to more closely match insulin levels with glucose levels
What is regular insulin?
Short acting
How does short acting insulin behave after administration
Can form dimers that stabilize around zinc ions to form hexameters.
Slow dilution of the insulin depot by interstitial fluids allows hexameters to break down into dimers and then monomers (3 absorption rates)
Intermediate acting insulin name
NPH = neutral protamine hagendom
How is intermediate insulin prepared?
Mix protamine : insulin (1:10 by mass)
After injection, tissue proteases degrade the protamine, which allows absorption of insulin
Onset of intermediate acting insulin? Peak effect? duration?
Onset: 2 hours
Peak effect: 4-8 hours
Duration: 12-24 hours
Onset, peak effect and duration of long acting insulin
Onset: 4 hours
Peak effect: 8-24 hours
Duration: 24-36
How does long acting insulin work?
Crystalline insulin analog
Precipitates at neutral body pH after subcutaneous injection
Insulin monomers slowly dissolve from crystal
Management of type II diabetes
Sometimes diet and exercise changes can help manage
However, in many cases, insulin secretagogues and/or insulin sensitizing agents are needed
What is Glyburide?
A sulfonylurea
Stimulates endogenous insulin secretion by closing K+ channels on pancreatic beta cells causing depolarization
What is metformin?
Synthetic analogue of guanidine
Activates the AMP-activated protein kinase (AMPK)
Does not increase in secretion of insulin
Effective as mono therapy
How is metformin effective as a monotherapy?
Reduces HbA1C levels
Decreases hepatic and renal gluconeogenesis
Reduces intestinal absorption of glucose
Increases peripheral glucose uptake and utilization (increase glucose transporters in skeletal muscle/adipose tissue)
Reduction of plasma glucagon levels
Why do insulin injections carry a risk for hypoglycaemia?
One may inject more insulin than necessary, and counter regulatory hormones may not be able to response quickly or adequately to avoid hypoglycaemia
