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