DYOSISISTAH NOTES: DR.

ROXAS

Physiology of Insulin Secretion & Action:

1. Secreted in the Islets of Langerhans ( endococrine portion of the pancreas) : Beta

cells
2. Beta cell: Produce/synthesize insulin production + secretes insulin only if in the
presence of glucose in the body: 80 – 130 mg/dl of glucose in the blood stream.
3. Beta cell also secretes insulin in the presence of amino acid or protein:
tryptophan.
4. In sympathetic response or in the presence of epinephrine: Insulin secretion in
the beta cell will be inhibited via sympathetic nerve, alpha cell is favored by
secreting glucagon.
5. During well fed state (parasympathetic response) as glucose rises in the blood
stream (not GI TRACT) insulin secretion in the beta cells is favored.
6. Produced in the beta cell:
Preproinsulin ( higher MW)  Proinsulin  Insulin (lower MW) ( favored by the
removal of C-polypeptide chains.)

Diagnostic Exam: C-polypeptide chain assay determination = (+)  DM type 2

(-)  DM type 1
 Secretion of Insulin in the Beta Cell: (Pancreas)

1. Presence of glucose in the surface of the cell membrane of the beta cell 80-
130mg/dl.
2. Glucose enters in the GLUT 2 receptor of the surface of the beta cell
3. Entry glucose in the beta cell initiates the formation of Pyruvate  gluconeogenesis
in the mitochondria  ATP production
4. ATP production  inhibit the opening of the ATP dependent K channel  that
inhibits the release of the K ions in the cytoplasm.
5. Accumulation of K+ in the cytoplasm causes + ions and makes depolarized
membrane of the beta cell.
6. If the membraine is depolarized by the K ions  that will enhance the Calcium
voltage gated channel to open  allowing Calcium entry from the extracellular 
cytoplasm
7. In the presence of Calcium inside the beta cell  enhaces the secretion of vacuoles
containing insulin via exocytosis = Enhance secretion
The Acceptance of Insulin in the Insulin Receptor:

Function of Insulin (regulating the glucose)

1. Insulin  binds in the binding site insulin receptor (any form of cell = muscles
and other organs)
2. Conformational change in the insulin receptor  opens  allow the entry of
Insulin in the cytoplasm.
3. Insulin cytoplasm  IRS  formation GLUT 4 receptors
4. GLUT 4 receptor will travel from the cytoplasm (translocation) surface of the
cell membrane  will allow the entry of glucose in the cell  decrease glucose
in the blood.
Function of Insulin: Cellular Growth and Regeneration

1. Insulin in the cytoplasm  bind in the IRS  Protooncogens (C- jun & K-ras) 
activate MITOGENESIS ( it will initiate DNA Synthesis) in the nucleus of the cell

Insulin Function: Inhibit Cell Death by inhibiting Pro-apoptotic genes ( bcl2, bax,
bad)

1. It prevents the death cell by avoiding program cell death (apoptosis) by enhancing
the anti-apoptotic genes (p53).
2. In the mitochondria will inhibit the release of cytochrome c  prevents the release
and conversion of capsases to induce apoptotic blebing & immune response
recognition by the Antigen Presenting Cells.
Indices of Poor wound healing in DM:

(Immunosupression)

1. The antigen presenting cells reduces (macrophages) its lymphocytic activity

(Rolling and Transmigration)

Rolling: P selectin (Cell Adhesion molecules)

Transmigration: (ICAM/ VCAM)

CAM = found on the endothelial cells. Are responsible for the binding of the
receptors of the macrophages through attachment.

DM = Increase in concentration gradient  accumulation of glucose in the

blood  increase to resistance to flow  VISCOSITY
 Viscosity: that cause damage to the CAM  Friction, move through and
resistance flow and high pressures.

2. Stress (DM)  Cortisol release in the adrenal gland  Inhibition of

Phospholipase A2  Inhibition of Leukotrine pathway  LTD’d inhibition.
 Inhibition of leukocytic activity.

(Obstruction)

3. In advent of damage in the endothelial cell wall of blood vessel  There will be
initiation of the platelet plug formation by collagen & vWF  Clotting process 
Obstruction or narrowing of the blood vessel  Turbulent flow & decrease flow or
resistance to flow  partial obstruction

4. Atherosclerosis: Free fatty acids is present in the blood  used up for energy this
could slip through the endothelial surface.

Regeneration inhibition & Apoptosis enhancement:

5. Absence of Insulin or Insulin resistance: If the Insulin fails to stimulate the Insulin
receptor binding site  Inhibition of the following:

a. GLUT 4 receptor will not go the surface of the cell membrane  Glucose
will not enter in the cell  No pyruvate for gluconeogenesis  Reduce
ATP
b. There will be inhibition of the signalling pathway that stimulates your c-jun
protoncogene and k-ras protooncogene for MITOGENESIS  Cellular
regeneration will be inhibited no DNA synthesis.
c. The cell that is being damaged will actually prevent the formation Anti-
apoptotic gens ( p53 & bcl2) responsible for the Apoptosis ( bcl-xs). 
cellular death & immune response surveillance kill the cell.

DM type 1:

a. Absence of insulin in the synthesis (absence of c polypeptide chains)

DM type 2:

a. Minute secretion of Insulin (Insulin fatigue)

b. Normal secretion but mutated chemical structure insulin
c. Insulin Resistance
Classification DM Drugs:

1. Insulin
a. Utrarapid/short-acting ( 20 minutes to act, peak for 3-4 hours)
- (CLEAR) Lispro, Regular Insulin
- used for EMERGENCY of Hyperglycemia & DKA

b. Intermediate
- (CLOUDY) Semilente, NPH
- Maintainance
c. Long Acting
- Zn preparation (Protamine)
- Ultralente

2. Oral Hypoglycemics

a. Oral-Insulin Secretogogues (Sulfonylureas)

- Beta cell by the drug inhibits the opening of the ATP dependent K
ion channels  accumulation of K+ in the cytoplasm 
Depolarization of the cell membrane initiates the opening of the
calcium voltage ion channel  calcium entry  enhanced insulin
binding the cell membrane  secretion via exocytosis with
calcium.
b. Biguanides (Metformin)

- Prevents the gluconeogenesis in the liver by activating AMPK

(activated protein kinase) will:

1. In the cell : Translocation of GLUT 4 enhancement  Insulin

dependent glucose uptake  SE: ( Hypoglycemia)
2. Intestine: Inhibits the glucose absorption  SE: GI upset/
osmotic diarrheal
3. Liver: Enhances Lactic acid synthesis as it opposes the
pyruvate to undergo gluconeogenesis. SE: CTZ zone: H+ 
nausea/Vomit (Electrolyte loss)
4. Muscle: Increase glucose uptake, lactic acid formation SE:
Muscle pain/ spasms, Tachypnea: chemoreceptor reflex,
Damage in the muscle ( decrease pH  increase cell
membrane permeability)
5. Fats: Increase utilization of fats adipose tissue and use FFA
as a source of energy  Weight loss.
6. Weight loss  Increase signalling pathway for insulin 
decreasing insulin resistance.

c. Alpha-Glucosidase Inbitors (Acarbose)

- Ectoenzymes ( lactase, galactase) found in brush boarder in the

mucosal layer of intestine for making complex sugar  simple sugars
( glucose,fructose,lactose)

- Inhibits the alpha glucosidase  inhibition to convert complex

starch and disaccharides  glucose simple compnents 
inhibition of absorption via SGLT 1.  decarese glucose in the
blood. SE: Osmotic Diarrhea, Gasses  Flatulence: Increase
concentration gradient in the intra-luminal wall of the intestine.

d. Thiazolidinedione(Piogliazone)