Unit 03: Pancreas & diabetes mellitus Flashcards
what type of tissue does the pancreas contain
both exocrine and endocrine
exocrine: 99% of pancreatic mass - secretes bicarbonate and digestive enzymes in the gastrointestinal tract
* has almost 1 millon small islands of endocrine tissue that secrete hormones directly into blood
tiny endocrine glands have several diff cell types that secrete diff hormones
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what produces insulin and what controls its release
* release of most hormones discussed is contorled by pituitary gland- not insulin
- insulin is produced by B-cells of islets of langerhans
- released priamrily in response to glucose, however vagal and B2-adrenergic stimulation and leucine, arginine and various gastrointestinal hormones also cause its release
what causes inhibtion of insulin release
inhibition can occur following somatostatin and a-adrenergic stimulation
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how does insulin circulate
- as a free monomer and has a short half life of 3-5 min where it is metabolized mainly by the liver
describe channels involved in insulin secretion and glucose entering the cell
- in Basal state and K+/ATP channel is open less insulin is released - when channel is closed more insulin is released
- in basal state, the PM of B cells is hyperpolarized and rate of insulin secretion from cell is low
- when glucose is available it enters via GLUT2 transporters in PM and is metabolized to generate ATP
- ATP then binds and inhibits the plasma membrane K+/ATP channel to decrease K+ conductance
*resulting depolarization of membrnae activates voltage gated Ca2+ channels to sitmlate influx of Ca2+
*Ca2+ mediates fusion of insulin containing secretory vesiles with the PM leading to insluin secretion
where are insulin target receptors located
- insulin bidns to receptors on target cells = virtually all tissues expres insulin receptors
- energy storing tissues (liver, muscle and adipose) expres higher levels of the receptor so are the main target tissues
descrieb the strcuture of the insulin receptor
- its a glycoprotein consisting of 4 disulfide linked subunits (heterotetramer)
- 2 extracellular α subunits (entirely extracellular) and two β subunits (have extracellular, transmembrane and nitracellular domains).
- each of the β subunits is composed of a short extracellular domain, transmembrane domain and an intracellular tail that contains a tyrosine kinase domain
*binging to extracellular portion of the receptor activates tyrosine kinase domains in the intracellular regions of the β subunits
describe activation of the insulin receptor
- insulin bidns to the extracellular portion
- activates the intracellular tyrosine kinase resulting in autophosphorylation of tyrosine on the nearby β subunit and the phosphorylation of intracellular substrate proteins (IRS)
- Tryosine phosphorylates IRS proteins recruit second messenger proteins that are important for many asepcts of insulins action
describe the mechanism of activtion of the insulin receptor
- insulin binds to the extracellular portion of the receptor activates tyrosine kinase domains in the intracellular regions of the β subunits.
- tyrosine kinase domains mediate “autophosphorylation” of the receptor and tyrosine phosphorylation of cytoplasmic substrate proteins like Shc and isulin receptor substrate (IRS) proteins
- phosphorylated Shc promotes mitogenesis
- phosphorylated IRD protines interact with other signalling proteins (Grb-2, SHp-2, p85 and p110 to effect changes in cellular function
what does insulin do in the liver
promotes glucose uptake and storage as glycogen
-increases fatty acid synthesis from glucose to be transported to adipocytes for storage
what does insulin do to skeletal muscle
- promotes protein synthesis from amino acid uptake and increases glucose uptake and storage as glycogen
- insulin increases triglyceride synthesis and storage from fatty acid and glycerol
what is characteristic of diabetes mellitus
- patients exhibit excessive thirst and urination as well as urine containing sugar
- results from heterogenous group of metabolic disorders that have hyperglycemia in common
what causes hyperglycemia
- absolute lack of insulin (type 1 diabetes mellitus)
- relative insufficiency of insulin production in the face of insulin resistance (type 2 diabetes mellitus)
describe type 1 diabetes
- lack of insulin
- marked by an autoimmune β-cell destruction with severe to absolute insulin deficiency
- presentation is usually sudden and often occurs during chilhood or adolescence and cause can be unknonw or idiopathic
- cinical signs = persistent hyperglycemia, polyuria, polydipsia and weight loss
- ketoacidosis might also result in severe cases
- those with type 1 require insulin therapy
describe type 2 daibeties mellitus
- most comon
- marked by tissue resistance to the action of insulin combined with a relative decrease in insulin secretion
- those diagnosed with type 2 are typically older and obesity is often present
- similar clinal signs to type 1 is disorder is less severe
- may not require insulin but could benefit from it
- may become type 1 diabetics therefore lifestyle changes and oral hypoglycemic agents are mainstay of treatment
3 main types of isnulin preparations
- short acting
- intermediate acting
- ultralente insulin (slow acting)
describe short acting insulin
include lispro (lily) and aspart (Novo-Nordisk)
- have very fast onset and short duration
- formulated as solutions that contain zinc but no added protein and have pH 7.2-7.4
- would be applied to over prandial (mealtime) hyperglycemia and emergency situations
- dissociate into monomers very quickly
describe intermediate acting insulin
- include neutral protamine hagedorn (NPH) and lente
formulated as cloudy suspensions with buffers and since
- also sued to cover basal and prandial hyperglycemia
long acting insulin
ultralente and gargine insulin
- usually 2 hour coverage
- ultralente is clound and buffered while glargine is clear with no bugger
- both ahve high zinc concentrations which forms aggregates
- glargine is eyr slow acting and does not peak therefore its used to proide basal insulin coverage over the day
what do the basis for duration of action of insulin rely on
- the structure of the insulin preparation
- lente and ultralente (intermediate) are suspensions of zinc aggregaes in acetate buffer so the insulin monomer is slowly released
- NPH (also intermediate) is complexed with basic protein (protamine) which modulates its release
- Glargine insulin has one asparagine in the A chain replaced by glycine and two argininges added to C term of the B chain *results in very slow release into blood and once a day inj sufficient
what is the goal f insulin therapy
- normalize blood glucose and metabolism
- fasting blood glucose often range from 90-120 mg/dL compared to post prandial blood glucose levels that can be up to 150 mg/dL
- biabetics often have blood glucose in excess of 200 mg/dL
what is hyperglycemia a risk factor for?
- long term problems like blindness, kidney disease, peripheral nerve damage and cardiovascular disease
*prevenitng is important
regimen for insulin therapy
Basal-bolus most popular: invovled basal administration of intermediate or long acting agents before breakfast or bed. Prandial injections of short acting insulin like inspro or aspart can also be applied
split mixed regimen: short acting and intermediate acting insulins are administered pre breakfast and pre supper
what is the most common complication of insulin therapy
hypoglycemia
- can result from inadequate food intake, increased exertion, too large of insulin dose or other diseases
- glucagon and epinephrine are released by body in response to increase blood glucose levels reverses the effects of insulin
- individuals suffering from complications present with symptoms of increased autonomic activity like tachycardia, sweating, tremors, hunger and nausea.
*other complicaiton from insulin therapy is immunopathology
- partial insulin resistance can develop from IgG anti-insulin antibodies in most dibetics *rarely a clinical problem with human insulin therapes
what is the treatment for hypoglycemia
oral or IV administration of glucose in mild and severe cases, respectively.
imp to treat hypoglycemia side effect because complications can progress to coma and death.
what types of drugs are used to treat diabetes that lower bloog clucose?
- act to lower blodo glucose levels and can be admin orally
- *oral hypoglycemics
- use depends on type of diabetes
type 1 which is caused by the lack of insulin require an injection of insulin. type 2 disease is characterized by insulin resistance and oral preparations of insulin can be used.
3 main categories of diabetes drugs
- increase amount of insulin secreted by pancreas
- increase sensitivity of target organs to insulin
- decreasing rate of glucose absorption by gastrointestinal tract
what are insulin secretagogues
bind and inhibit β-cell ATP-sensitive-K+ channels which lead to cell depolarization and insulin release
- used in type 2 patients where diet changes alone insufficient
- general caution for hypoglycemia esp in elderly and those with liver or kidney disease/failure
what are sulfonylureas? give examples
ex: glyburide and glipizide
- 2nd gen compounds that prevail over earlier designed agents
- longer acting agents only requiring once daily dosing and fewer adverse effects
*increasing the amount of insulin secreted by the pancreas
what are meglitinides give an ex
- other class of drugs used to treat type 2 diabetes
- ex = repaglinide a rapidly absorbed and short half life allowing for multiple pre-prandial uses
- can also be used in combo with longer acting agents and complications like hypoglycemia are not as common as with sulfonylureas
what are insulin sensitizers
- require insulin but do not promote its release
- biguanides like metformin reduce hepatic gluconeogenesis and increase insulin utilization by peripheral target cells such as muscle and adipose
- can be used alone or in combo with the secretagogues and are also used with insulin therapy
**increases the sensitivity of target organs to insulin
what are thiazolidnediones
ex = pioglitazone
- decrease peripheral insulin resistance
- ligands at the peroxisome proliferator-activated receptor-gamma (PPAR-γ) and they regulate genes for lipid and glucose metabolism including glucose transporters
- due to the fact that the actions of thiazolidnediones invovle gene transcription they have a slow onset
- similar to other oral hypoglycemics they can be used alone or in combination with other agents and insulin
* increasing the sensitivity of target organs to insulin
what are alpha-glucosidase inhibitors
ex: acarbose
- inhibit intestinal alpha glucosidases and post prandial digestion and absorption of starches and disaccharides
- used alone or in combination with sufonylureas or insulin and side effects include abdominal pain, flatulence and diarrhea
descirbe treatment with glucagon and glucagon-like peptide-1
*pancreatic hormone/agent used f=to treat diabetes
- glucagon is an endogenous hormone produced by the alpha cells of the pancreas and its used in emergency treatment of hypoglycemia in type 1 patients
- individuals who require glucagon are usually unconscious and previous administration of IV glucose was ineffective
what is exenatide
belongs to calss of incretins and is approved for use of ype 2 diabetes with other hypoglyceic agents like metformin
- srug augments glucose dependent insulin secretion which is thought to be due to an increase in beta cell mass
- exenatide is injected subcutaneous and may cause nausea, vomiting and diarrhea
