exocrine & endocrine a or alpha cells-glucagon (25%) b or beta cells-insulin (60%) d or delta...

EXOCRINE & ENDOCRINE

A or alpha cells-Glucagon (25%)

B or beta cells-Insulin (60%)

D or delta cells-Somatostatin (10%)

PPcells-Pancreatic Polypeptide(5%)

1. Concerned with utilization , and storage of of nutrients pr. in E.C.F.,by the target cells.

2. So, called hormone of abundance.

Timeline

1978 production of Human insulin in Escheria coli bacteria using recombinant DNA technique

1985 Axel Ullrich sequences the human insulin receptor .

1922 Banting ,Best & Collip used bovine pancreatic extract in humans.

Mol. Wt.= 5808.

1. Translated as a straight chain Preprohormone in ribosomes ( 86 A.A.).

2. Has 5 functional components : a.A leader sequence or signal peptide,

(23A.A.) b.A beta chain(21 A.A.) c. Connecting peptide ( C peptide,31 A.A.) d. Junctional peptides ( 2A.A. on each end

of C peptide.) e. An alpha chain ( 30 A.A.)

3. Leader sequence (23 A.A.) removed, Prohormone formed in E.R., transported to G.A.

4. Folded and packaged in G.A. 5. Hormone (51A.A.) formed in

vescicles. 6. Secretion= Hormone + prohormone

+ connecting peptide.

(Through binding with it’s receptors.)

1. Found on many different tissues. 2. Some of them do not increase their

glucose uptake on their activation.

1. Made of two α (Extracellular) and two β ( Transcellular) subunits.

2. α subunits bind Insulin. 3. Intracellular parts of β subunit on activation have

autophospho- rylating activity on tyrosine

residues.

4.Leading to phosphorylation or dephospho- rylation of some cytoplasmic proteins, mostly

on serine and threonine residues. 5. Some of them are Insulin Receptor Substrates

(I.R.S.-1,2,3.) 6. This leads to activation or inactivation or

increased or decreased production of some enzymes, and effects of insulin.

7. After effects, receptors aggregate and are endocytosed,and enter lysosomes.

8. Some of them are broken down and some of them are recycled.

1. Renal tubular epithelial cells—SGLT 1 & 2, GLUT 1,2,3.

2. Small intestinal epithelial cells, SGLT- 1, GLUT 2 . 3.Brain– GLUT 1 & 3.

4.Placenta – GLUT 3. 5. B.B.B.—GLUT 1 . 6. R.B.Cs, Colon,& Placenta, – GLUT 1. 7. Liver,β cells of I.L.,- GLUT-2. 8. Muscles, Adipose tissues– GLUT 4.

9. Jejunum, Sprems– Fructose transport-GLUT- 5.

10. Liver– Glucose 6 phosphate transporter in

endoplasmic reticulum– GLUT-7.

Mechanisms: A. In muscles and adipose tissue : Through GLUT 4 transport proteins by

F.D. Steps : 1. Combination of insulin with it’s receptors. 2. Activation of Phosphoinositide 3 kinase . 3. Movement of vesicles, containing GLUT 4 molecules, to the cell membrane.

4. Insertion of GLUT 4 into cell membrane.

5. Entry of Glucose by F.D.

6. Termination of insulin action.

7. Endocytosis of same vesicles.

8. Their storage in cytoplasm.

On Liver : By increasing the activity of enzyme

glucokinase, it keeps the level of free glucose inside the

cellslow, this facilitates entry of glucose inside.

Maximal decline in plasma glucose occurs after 30 min.

1. Activation of Glycogen synthase and inactivation of phosphorylase increases glycogen content of muscles ( max.2-3%) and liver ( max.5-6%), (About 60% of food CHO.)

2. Stimulatuion of glycolytic enzymes increases glycolysis in liver :

a. Phosphofructokinase (Fructose 6 phosphate Fructose1,6 diphosphate)

b. Pyruvate kinase :( Phosphoenol pyruvate

Pyruvate ) c. Pyruvate dehydrogenase.( Pyruvate

Acetyl Co A. )

3. Decreased output of glucose from liver due to : a. Decreased neoglucogenesis in liver, by

inhibiting the enzymes concerned with it :

1.Glucose 6 phosphatase.(Glucose 6 phosphate

Glucose ) 2. Phosphoenolpyruvate carboxykinase, ( Oxaloacetate Phosphoenol pyruvate)

3. Fructose 1: 6 diphosphatase ( Fructose 1,6

di phosphate Fructose 6 phosphate.)

4. Pyruvate carboxylase ( Pyruvate Oxaloacetate.)

b. Decreasing plasma A.A. levels.

1. Decreased use of lipids for energy release, ( Lipid sparing effect).2. Increased synthesis of fatty acids, and T.G. ( Increased lipogenesis,due to stimulation of Acetyl-CoA carboxylase due to accumulation

of citrates and isocitrates which helps conversion of A-CoA to Malonyl Co A.)

3. It inhibits hormone sensitive lipase. 4. Decreases blood F.F.A. and ,T.G..

7. Stimulates lipoprotein lipase. 8. Decreased ketogenesis, ( Acetyl Co A conversion to Malonyl Co A,& Carnitine transport into mitochondria aCoA. 9. Decreased plasma cholesterol due to

decreased plasma levels of VLDL& LDL. Due to : a.Decreased hepatic production of VLDL. b.Increased removal of VLDL and LDL from plasma.

1. Increased glucose supply leads to decreased use of intracellular proteins for energy liberation( Protein sparing effect). 2. Increased protein synthesis : due to : a. Increased A.A. uptake by muscles. b. Increased protein translation. c. Increased transcription. 3. Inhibits protein breakdown. 4. Decreased plasma A.A. levels.

. 5. Decreased neoglucogenesis in liver. 6. Net effect is increased protein content

of cells

1. Tissues : Muscles and Adipose. 2. Causes fall in plasma K+. 3. Cause : ? Stimulation of Na K pump.

Adipose tissue    Increased glucose entry   Increased fatty acid synthesis   Increased glycerol phosphate

synthesis   Increased triglyceride deposition   Activation of lipoprotein lipase   Inhibition of hormone-sensitive lipase   Increased K+ uptake

Muscles :   Increased glucose entry   Increased glycogen synthesis   Increased amino acid uptake   Increased protein synthesis   Decreased protein catabolism   Decreased release of gluconeogenic amino

acids   Increased ketone uptake   Increased K+ uptake

Liver   Decreased ketogenesis  Increased protein synthesis   Increased lipid synthesis. Decreased glucose output due to

decreased gluconeogenesis, increased glycogen

synthesis, and increased glycolysis

General : Increased cell growth.

Rapid (seconds- Due to changes in cell membrane)   Increased transport of glucose, amino acids, and K+ into insulin-

sensitive cells 

Intermediate (minutes- Due to Phosphorylation of enzymes)    Stimulation of protein synthesis   Inhibition of protein degradation   Activation of glycolytic enzymes and glycogen synthase   Inhibition of phosphorylase and gluconeogenic enzymes Delayed (hours or days ) Changes in genes.   Increase in mRNAs for lipogenic and other enzymes

1. Plasma glucose levels : The most important. At 80-90 mg.% minimum. X 2-3. Occurs in two phases : a. Rapid and short lived 3-5min. X10-20 b. Slow and prolonged 15-120min.( higher.) 2. Mechanisms : a. For rapid release : a.Glucose into β cells through GLUT 2 proteins. b. Metabolism produces ATPs. c. ATPs close K+ channels.

e.Depolarisation of cells. f. Ca++ entry through voltage gated Calcium

channels. g. Exocytosis. b. For slow increase : 1. Metabolism through citric acid cycle. 2. Formation of Glutamate. 3. Decreased pH in some secretory

granules. 4. Maturation of vesicles. 5. Release of a second gr. of vesicles.

2. A.A.—Arginine, Leucine. 3.Ketone bodies. Both of them act like glucose.

1. Basal secretion : 1U/ hr. 2. Post prandial : x 5 to 10 3. Concentration range : 0 to 70 µU/ml. or 0 to 502 pmol/L 4. Average secreted/ day : 40 U.( 287

nmol.)

1. Half life in circulation = 5to 6 min.

3. Destroyed mainly in liver, also in muscles kidneys.

TYPES

TYPES A. Juvenile,Type-1,Insulin dependent (IDDM) a.< 40 yrs. b. Not obese. c. Ketosis. d.

Acidosis. e. Aetiology : Autoimmune, Genetic. B. Adult onset,Type-2, Insulin independent (NIDDM) a.Insulin resistance. b. High plasma insulin

levels. c. Impaired secretion. c.Obese. d.>40yrs. e. Insidious

onset.f.Genetic.

1. Pituitary. 2. Thyroid. 3. Adrenal. a. Cortical. b. Medullary. 4. Chronic pancreatitis. 5. Pancretectomy.

A. 220 millions world wide. B. 90%-- Type-2.

Decreased eficiency of Insulin due to : a. Absolute reduction of secretion ( Type-1 ) b.Insufficient secretion compared to the demand ( Type-2 ). c. Presence of anti insulin antibodies ( Type-

1) d. Reduced binding to receptors ( Type-2) e. Reduced eficiency of intracellular

mediators ( Type- 2)

1. Polyurea.

2. Polydypsia.

3. Weight loss.

4. Polyphagia.

5. Coma.

1.Reduced entry of glucose into some cells.

2. Increased release of glucose from liver.

3. NET RESULT : a. Extra cellular glucose excess, and

intracellular deficiency in some cells. b. Referred as “Starvation in the midst of

plenty.”

1. Urine sugar, ketone bodies, pH. 2. Blood sugar (a.Fasting b.Post prandial.) 3. Glucose tolerance test.(G.T.T.) 4. HbA1c. Estimation ( Glucose levels,4-6

wks.) 5. Anti insulin antibodies.

1. Fasting blood sample (Normal= <115mg.%)

2. 75 gms. Of glucose in 300 ml. of water. 3. Blood samples every ½ hr. x 4 . 4. 2 hr. value is < 140mg.%. ( Normals). 5. No value > 200mg. % ( Normals) 6. D.M.- If 2 hr. value and one more value

> 200mg.%. 7. Pre diabetic if between Normal & D.M.

1. Acidosis. 2. Coma ( Hyperglycemia in E.C.F. ) 3. Vascular and neuropathic : Hyperglycemia( ICF) Aldose reductase

Sorbitol Na,K pump, Amadori products Advanced glycosilation end products Damaged proteins.

Leucocyte response to infections. Microvascular : Retinopathy, Nephropathy. Macrovascular : Atherosclerosis Stroke, M.I.

1. Microvascular– Retinipathy,Nephropathy. 2. Macrovascular--Atherosclerosis Stroke,

M.I. . 3. Neuropathy : Involve Peripheral nerves, A.N.S.

1. Reduced pain perception. 2. Circulatory insufficiency. 3. Reduced leucocyte response. Ulceration, and gangrene, particularly in

feet.

Type II 1. Weight reduction. 2. Exercise. 3.Oral hypoglycemics :

a. Sulphonylurea derivatives : Increasing insulin secretion.

b. Biguanides : Decreasing glucose output from liver. c. Thiazolidinediones : Increasing glucose uptake in response to insulin. 4. Insulin.

B. Type I-- INSULIN.

Hypoglycemia initially causes A.N.S. stimulation, causing :

1. Palpitation. 2. Sweating. 3. Nervousness. At lower levels it causes neuroglycopenia which causes : 1. Hunger. 2. Confusion. 3. Cognitive abnormalities.

At still lower levels : 1. Lethargy. 2. Coma. 3. Convulsions. 4. Death.