Unit 03: Pancreas & diabetes mellitus

Question 1

what type of tissue does the pancreas contain

Answer 1

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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Question 2

what produces insulin and what controls its release

Answer 2

* 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

Question 3

what causes inhibtion of insulin release

Answer 3

inhibition can occur following somatostatin and a-adrenergic stimulation

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Question 4

how does insulin circulate

Answer 4

• as a free monomer and has a short half life of 3-5 min where it is metabolized mainly by the liver

Question 5

describe channels involved in insulin secretion and glucose entering the cell

Answer 5

• 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

Question 6

where are insulin target receptors located

Answer 6

• 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

Question 8

descrieb the strcuture of the insulin receptor

Answer 8

• 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

Question 9

describe activation of the insulin receptor

Answer 9

• 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

Question 11

describe the mechanism of activtion of the insulin receptor

Answer 11

• 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

Question 12

what does insulin do in the liver

Answer 12

promotes glucose uptake and storage as glycogen

-increases fatty acid synthesis from glucose to be transported to adipocytes for storage

Question 13

what does insulin do to skeletal muscle

Answer 13

• 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

Question 14

what is characteristic of diabetes mellitus

Answer 14

• patients exhibit excessive thirst and urination as well as urine containing sugar
• results from heterogenous group of metabolic disorders that have hyperglycemia in common

Question 15

what causes hyperglycemia

Answer 15

• absolute lack of insulin (type 1 diabetes mellitus)
• relative insufficiency of insulin production in the face of insulin resistance (type 2 diabetes mellitus)

Question 16

describe type 1 diabetes

Answer 16

• 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

Question 17

describe type 2 daibeties mellitus

Answer 17

• 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

Question 18

3 main types of isnulin preparations

Answer 18

1. short acting
2. intermediate acting
3. ultralente insulin (slow acting)

Question 19

describe short acting insulin

Answer 19

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

Question 20

describe intermediate acting insulin

Answer 20

• include neutral protamine hagedorn (NPH) and lente

formulated as cloudy suspensions with buffers and since

• also sued to cover basal and prandial hyperglycemia

Question 21

long acting insulin

Answer 21

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

Question 22

what do the basis for duration of action of insulin rely on

Answer 22

• 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

Question 23

what is the goal f insulin therapy

Answer 23

• 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

Question 24

what is hyperglycemia a risk factor for?

Answer 24

• long term problems like blindness, kidney disease, peripheral nerve damage and cardiovascular disease

*prevenitng is important

Question 25

regimen for insulin therapy

Answer 25

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

Question 26

what is the most common complication of insulin therapy

Answer 26

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

Question 27

what is the treatment for hypoglycemia

Answer 27

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.

Question 28

what types of drugs are used to treat diabetes that lower bloog clucose?

Answer 28

• 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.

Question 29

3 main categories of diabetes drugs

Answer 29

1. increase amount of insulin secreted by pancreas
2. increase sensitivity of target organs to insulin
3. decreasing rate of glucose absorption by gastrointestinal tract

Question 30

what are insulin secretagogues

Answer 30

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

Question 31

what are sulfonylureas? give examples

Answer 31

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

Question 32

what are meglitinides give an ex

Answer 32

• 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

Question 33

what are insulin sensitizers

Answer 33

• 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

Question 34

what are thiazolidnediones

Answer 34

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

Question 35

what are alpha-glucosidase inhibitors

Answer 35

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

Question 36

descirbe treatment with glucagon and glucagon-like peptide-1

Answer 36

*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

Question 37

what is exenatide

Answer 37

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