Exam 2: Lecture X, Insulin

Question 1

Hallmark of diabetes is…

Answer 1

the absent or decreased insulin production

Question 2

Diabetes mellitus is characterized by…

Answer 2

hyperglycemia and profound change of protein,carb, and lipid metabolism

Question 3

Lack of what responsible for Diabetes mellitus?

Answer 3

Lack of insulin, resulting in increased blood glucose level

one of many physiological and biochemical changes

Question 4

Insulin and Glucagon are released in….

Answer 4

blood

Question 5

NaHCO3 and Pancreatic enzymes released in…..

Answer 5

Dueodenum

Question 6

What kind of hormone is Insulin?

Answer 6

Anabolic

Question 7

Islets of Langerhands

Answer 7

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

Question 8

Major types of Diabetes Mellitus

Answer 8

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

Question 9

Insulin info….

Answer 9

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

Question 10

Forms of Insulin

Answer 10

Hexamer ( 3 Dimmers)
Dimmer
Monomer

Question 11

Hexamer form of insulin stored in….

Answer 11

pancreatic cells, dissociates into monomers

2 Zn molecules of Zn are coordinated in hexameter

Question 12

Which form of insulin is biologically active?

Answer 12

only monomer

Question 13

Factors controlling insulin secretion?

Answer 13

All stimulation (+) increases except Sympathetic Stimulation which will (-) decrease

Glucose principle stimulus, causes greater release of insulin than after IV when taken orally.

Question 14

Mechanism of Insulin secretion?

Answer 14

1. Glucose transported via GLUT-2 into the beta cells
2. Change of ATP/ADP ratio and ATP increase
3. Inhibition of ATP-dependent potassium channels—>depolarization
4. Wave of depolarization —–> cause opening of calcium channels
5. Calcium moves inside the cell
6. Calcium further mobilized from endoplasmic reticulum
7. Increased calcium concentration —-> stimulates insulin secretion

Question 15

More info Mechanism Insulin secretion

Answer 15

2 phases

1. Insulin secretion is a tightly regulated process
2. Insulin secretion provides stable concentrations during fasting/feeding
3. Insulin secretion is biphasic (1 phase/ 2 phase)
4. First phase - short lived (1-2 min) - stored hormone
5. Second phase - delayed phase - stored hormone + new hormone
6. 1/5 of stored insulin in pancreas secreted daily
7. Insulin secretion is in pulses every 15-30 minutes
8. Insulin is secreted into portal circulation

Question 16

Insulin Pharmacokinetics

Answer 16

1. Insulin circulates in blood and lymph
2. Insulin mostly circulates in a free form (2-4 ng/ml portal blood)
3. Liver + kidneys + muscles - proteolytic degradation of insulin
4. Liver - 40% of insulin degraded
5. Kidneys - 40% of insulin degraded
6. Insulin 1/2 life: 5-6 min

Question 17

Insulin actions

Answer 17

1. Insulin stimulates synthesis of glycogen, protein, and fat
2. Important target: Liver, Muscles, Fat Cells
3. Overall effect: Conservation of body fuel supplies
4. Cell growth and differentiation
5. Most obvious effect: Reduction of blood glucose level (due to increased glucose transport)

Question 18

Other effects of insulin

Answer 18

1. Increased transport into the cells of K+, Ca2+, and phosphate
2. Increase/decrease synthesis of key enzymes
3. Stimulate cell proliferation in vitro/growth regulation in vivo
4. Effects upon DNA and RNA

Question 19

Insulin Receptors

Answer 19

1. Specific receptor - transmembrane glycoprotein
2. Receptor consists of - 2alpha and 2 beta subunits (400 000 MW)
3. Alpha and beta subunits are linked by disulfide bonds (S-S)
4. Alpha subunits - entirely extracellular (ligand-binding site)
5. Beta subunits - transmembrane proteins with tyrosine-kinase activity

Question 20

Resistance to insulin explained by…

Answer 20

**Insulin-receptor complex after some time internalize in vesicles - loss of insulin receptors occurs. (Receptor down regulation).

Question 21

Insulin action of receptors

Answer 21

1. Insulin binds with extracellular ligand-binding site
   - Dimerization of the receptor occurs
2. Beta subunits act upon themselves (autophosphorylation)
   - Beta subunits enhance the action of the kinases on other targets
3. Typical targets - synthesis of glycogen, lipids, proteins and enzymes
4. Translocation of glucose transporters (GLUT-4) also takes place
   
   • GLUT-4 is recruited from Golgi apparatus to plasma membrane
5. Glucose facilitated diffusion through the glucose transporter

Question 22

Glut 1 location

Answer 22

All tissues, Brain RBC

Question 23

Glut 2 location

Answer 23

B cells pancreas, liver,kidneys,gut

Question 24

Glut 3 location

Answer 24

Brain, placenta

Question 25

Glut 4 location

Answer 25

Muscle, adipose tissue

Question 26

Glut 5 location

Answer 26

Kidney,gut

Question 27

Insulin effects take place in second/minutes

Answer 27

effects on glucose/ion transporters

Question 28

Insulin effects take place in few hours

Answer 28

effects on gene transcriptions

Question 29

Insulin effects take place in days

Answer 29

effects on cell proliferation and differentiation

Question 30

Glucagon fuel

Answer 30

1. Produced in alpha cells of pancreas and in stomach (21 AA) 2. Structurally similar to GI hormones (secretin, VIP, gastric inhibitory peptide) 3. Aminoacids (especially arginine) - physiological stimuli for the secretion 4. Secretion is stimulated by high protein meal 5. Secretion is stimulated by low glucose and fatty acids in the plasma 6. CNS and circulating epinephrine stimulate glucagon through beta-receptors

Question 31

Glucagon Actions

Answer 31

1. Acts upon specific receptors (similar to beta-receptors) 2. Similar to epinephrine in action 3. More pronounced metabolic effects, rather than cardiovascular 4. Can increase rate/force of contraction (sometimes used to treat cardiac failure) 5. Actions are opposite those of insulin 6. Increases breakdown of glycogen 7. Inhibits glycogen synthesis 8. Both 6 and 7 result in elevation of blood glucose (used to treat hypoglycemia) 9. Can be administered IM, SC, IV (treatment of hypoglycemia)

Question 32

Major Symptoms Diabetes

Answer 32

1. Hyperglycemia (due to: ↑hepatic output ↓skeletal muscles uptake ↓reduced glycogen synthesis) 2. Polyuria 3. Polydipsia (thirst and increased drinking) 4. Polyphagia 5. Ketoacidosis (T1DM) fat breakdown to β-hydroxybutyrate (acidosis) and acetone (ketone) 6. Hyperlipidemia 7. Muscle wasting 8. Electrolyte depletion

Question 33

Long term Medical problems of diabetes

Answer 33

1. Neuropathy 2. Nephropathy 3. Microangiopathy 4. Retinopathy 5. Nonretinal visual problems

Question 34

Insulin Route of Admin

Answer 34

1. Subcutaneous (usual) 2. Occasionally intramuscularly 3. Intravenous - (emergency – Regular insulin) 4. Peritoneal infusion 5. Intranasal administration

Question 35

Origin of Insulin

Answer 35

1. Early preparations were acidic. Precipitated in tissues. Impurities. 2. Bovine (discontinued in 1999) 3. Porcine (discontinued in 2006) 4. Mixture of bovine and porcine - discontinued 5. Semisynthetic (chemical alteration of pork insulin) - discontinued 6. Insulin analogue - chemical alterations of human insulin 7. "Human" - recombinant DNA

Question 36

Rapid acting Insulin

Answer 36

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

Question 37

Short acting insulin

Answer 37

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

Question 38

Intermediate acting insulin

Answer 38

intermediate onset and action Humulin N, Novolin N Onset: 2-4hr Peak 6-10hr Duration, 10-16hr Given subcu,depot formed and slowly released

Question 39

Long acting insulin

Answer 39

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

Question 40

Insulin Conc

Answer 40

100U/ml = all insulins in USA/Canada 500U/ml = rare cases of severe insulin resistance

Question 41

Type 1 requires....

Answer 41

combo of rapid/intermediate acting insulin

Question 42

Type 2 requires....

Answer 42

intermediate or long acting insulin

Question 43

Patients with T1DM require

Answer 43

long-term maintenance treatment with insulin

Question 44

Many patients with T2DM ultimately require

Answer 44

chronic insulin treatment

Question 45

Insulin Devices

Answer 45

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

Question 46

Hypoglycemia

Answer 46

Insulin shock !!! - Anxiety - Confusion - Blurred vision - Cold sweating - Tachycardia - Hunger Most common adverse effect of insulin therapy, 60-170 episodes/100 patients/yr

Question 47

Hypoglycemia treatment

Answer 47

inject 20g of glucose, ie fruit juice Glucose iv - 50 ml of 50% glucose for 2 min Glucagon sc/im - 1 mg of glucagon

Question 48

Local reactions insulin

Answer 48

Lipodystrophy (older forms) Hypertrophy of subcu fatty tissue infections local allergic reaction

Question 49

Antigenic response to insulin

Answer 49

(Highest-lowest) Beef >Pork >Highly purified ("single-peak") pork >Human insulin Microvascular complications (due to growth-promoting properties) Weight gain Increased cancer risk (?)