Exam 2: Lecture X, Insulin Flashcards
Hallmark of diabetes is…
the absent or decreased insulin production
Diabetes mellitus is characterized by…
hyperglycemia and profound change of protein,carb, and lipid metabolism
Lack of what responsible for Diabetes mellitus?
Lack of insulin, resulting in increased blood glucose level
one of many physiological and biochemical changes
Insulin and Glucagon are released in….
blood
NaHCO3 and Pancreatic enzymes released in…..
Dueodenum
What kind of hormone is Insulin?
Anabolic
Islets of Langerhands
Alpha = glucagon = 20% of islets Beta = insulin/amylin = 75% of islets Delta = somatostain = 3% of islets F or PP = pancreatic polypeptide pp = 1% of islets G cells = gastrin = 1% of islets
Major types of Diabetes Mellitus
Type 1 = 5-10%, insulin dependent
Type 2 = 90-95%, insulin independent
Type 3 = other (pancreatitis, drug therapy)
Type 4 = Gestational diabetes, 7% of pregnancy in USA
Insulin info….
MW 6000
51AA, two highly ordered polypeptide chains, joined by disulfide bonds (Chain A = 21 AA)(Chain B = 30 AA) (C-peptide = connecting, 31 AA gets removed by proteolysis)
only insulin has physiological effect
Human pancreas contains 8 mg of insulin, 200 units
Forms of Insulin
Hexamer ( 3 Dimmers)
Dimmer
Monomer
Hexamer form of insulin stored in….
pancreatic cells, dissociates into monomers
2 Zn molecules of Zn are coordinated in hexameter
Which form of insulin is biologically active?
only monomer
Factors controlling insulin secretion?
All stimulation (+) increases except Sympathetic Stimulation which will (-) decrease
Glucose principle stimulus, causes greater release of insulin than after IV when taken orally.
Mechanism of Insulin secretion?
- Glucose transported via GLUT-2 into the beta cells
- Change of ATP/ADP ratio and ATP increase
- Inhibition of ATP-dependent potassium channels—>depolarization
- Wave of depolarization —–> cause opening of calcium channels
- Calcium moves inside the cell
- Calcium further mobilized from endoplasmic reticulum
- Increased calcium concentration —-> stimulates insulin secretion
More info Mechanism Insulin secretion
2 phases
- Insulin secretion is a tightly regulated process
- Insulin secretion provides stable concentrations during fasting/feeding
- Insulin secretion is biphasic (1 phase/ 2 phase)
- First phase - short lived (1-2 min) - stored hormone
- Second phase - delayed phase - stored hormone + new hormone
- 1/5 of stored insulin in pancreas secreted daily
- Insulin secretion is in pulses every 15-30 minutes
- Insulin is secreted into portal circulation
Insulin Pharmacokinetics
- Insulin circulates in blood and lymph
- Insulin mostly circulates in a free form (2-4 ng/ml portal blood)
- Liver + kidneys + muscles - proteolytic degradation of insulin
- Liver - 40% of insulin degraded
- Kidneys - 40% of insulin degraded
- Insulin 1/2 life: 5-6 min
Insulin actions
- Insulin stimulates synthesis of glycogen, protein, and fat
- Important target: Liver, Muscles, Fat Cells
- Overall effect: Conservation of body fuel supplies
- Cell growth and differentiation
- Most obvious effect: Reduction of blood glucose level (due to increased glucose transport)
Other effects of insulin
- Increased transport into the cells of K+, Ca2+, and phosphate
- Increase/decrease synthesis of key enzymes
- Stimulate cell proliferation in vitro/growth regulation in vivo
- Effects upon DNA and RNA
Insulin Receptors
- Specific receptor - transmembrane glycoprotein
- Receptor consists of - 2alpha and 2 beta subunits (400 000 MW)
- Alpha and beta subunits are linked by disulfide bonds (S-S)
- Alpha subunits - entirely extracellular (ligand-binding site)
- Beta subunits - transmembrane proteins with tyrosine-kinase activity
Resistance to insulin explained by…
**Insulin-receptor complex after some time internalize in vesicles - loss of insulin receptors occurs. (Receptor down regulation).
Insulin action of receptors
- Insulin binds with extracellular ligand-binding site
- Dimerization of the receptor occurs - Beta subunits act upon themselves (autophosphorylation)
- Beta subunits enhance the action of the kinases on other targets - Typical targets - synthesis of glycogen, lipids, proteins and enzymes
- Translocation of glucose transporters (GLUT-4) also takes place
- GLUT-4 is recruited from Golgi apparatus to plasma membrane
- Glucose facilitated diffusion through the glucose transporter
Glut 1 location
All tissues, Brain RBC
Glut 2 location
B cells pancreas, liver,kidneys,gut
Glut 3 location
Brain, placenta
Glut 4 location
Muscle, adipose tissue
Glut 5 location
Kidney,gut
Insulin effects take place in second/minutes
effects on glucose/ion transporters
Insulin effects take place in few hours
effects on gene transcriptions
Insulin effects take place in days
effects on cell proliferation and differentiation
Glucagon fuel
- Produced in alpha cells of pancreas and in stomach (21 AA)
- Structurally similar to GI hormones (secretin, VIP, gastric inhibitory peptide)
- Aminoacids (especially arginine) - physiological stimuli for the secretion
- Secretion is stimulated by high protein meal
- Secretion is stimulated by low glucose and fatty acids in the plasma
- CNS and circulating epinephrine stimulate glucagon through beta-receptors
Glucagon Actions
- Acts upon specific receptors (similar to beta-receptors)
- Similar to epinephrine in action
- More pronounced metabolic effects, rather than cardiovascular
- Can increase rate/force of contraction (sometimes used to treat cardiac failure)
- Actions are opposite those of insulin
- Increases breakdown of glycogen
- Inhibits glycogen synthesis
- Both 6 and 7 result in elevation of blood glucose (used to treat hypoglycemia)
- Can be administered IM, SC, IV (treatment of hypoglycemia)
Major Symptoms Diabetes
- Hyperglycemia (due to: ↑hepatic output ↓skeletal muscles uptake ↓reduced glycogen synthesis)
- Polyuria
- Polydipsia (thirst and increased drinking)
- Polyphagia
- Ketoacidosis (T1DM) fat breakdown to β-hydroxybutyrate (acidosis) and acetone (ketone)
- Hyperlipidemia
- Muscle wasting
- Electrolyte depletion
Long term Medical problems of diabetes
- Neuropathy
- Nephropathy
- Microangiopathy
- Retinopathy
- Nonretinal visual problems
Insulin Route of Admin
- Subcutaneous (usual)
- Occasionally intramuscularly
- Intravenous - (emergency – Regular insulin)
- Peritoneal infusion
- Intranasal administration
Origin of Insulin
- Early preparations were acidic. Precipitated in tissues. Impurities.
- Bovine (discontinued in 1999)
- Porcine (discontinued in 2006)
- Mixture of bovine and porcine - discontinued
- Semisynthetic (chemical alteration of pork insulin) - discontinued
- Insulin analogue - chemical alterations of human insulin
- “Human” - recombinant DNA
Rapid acting Insulin
very rapid onset and very short action
Insulin Lispro, aspart, Glulisine
Onset: 1/4 hr
Peak: .5-1.5 hr
Duration: 3-4hr
enters circulation twice as fast as regular, suitable immediately before meals
Short acting insulin
rapid onset and short action
Humulin R, Novolin R
Onset: .5-1hr
Peak: 2-3hr
Duration 3-6hr
Subcu, IV in emergency only, admin 1 hr before meal. can be mixed with longer acting insulin
Intermediate acting insulin
intermediate onset and action
Humulin N, Novolin N
Onset: 2-4hr
Peak 6-10hr
Duration, 10-16hr
Given subcu,depot formed and slowly released
Long acting insulin
slow onset and long action
Lantus, Levemir
Onset: 5-10hr
Peak: 10-16hr
Duration, 18- 24hr
Provide relatively constant release for 24hr, forms stable hexameter upon subcu inj
Insulin Conc
100U/ml = all insulins in USA/Canada
500U/ml = rare cases of severe insulin resistance
Type 1 requires….
combo of rapid/intermediate acting insulin
Type 2 requires….
intermediate or long acting insulin
Patients with T1DM require
long-term maintenance treatment with insulin
Many patients with T2DM ultimately require
chronic insulin treatment
Insulin Devices
pump
Nasal spray (Exubera 2006-2007 Discontinued and Afrezza 2014)
Subnlingual (oralin) in Clincial trials canada
Transderaml patch in clinical trials
Transplantation of pancreatic beta cells
Hypoglycemia
Insulin shock !!!
- Anxiety
- Confusion
- Blurred vision
- Cold sweating
- Tachycardia
- Hunger
Most common adverse effect of insulin therapy, 60-170 episodes/100 patients/yr
Hypoglycemia treatment
inject 20g of glucose, ie fruit juice
Glucose iv - 50 ml of 50% glucose for 2 min
Glucagon sc/im - 1 mg of glucagon
Local reactions insulin
Lipodystrophy (older forms)
Hypertrophy of subcu fatty tissue
infections
local allergic reaction
Antigenic response to insulin
(Highest-lowest)
Beef >Pork >Highly purified (“single-peak”) pork >Human insulin
Microvascular complications (due to growth-promoting properties)
Weight gain
Increased cancer risk (?)
