INSULIN -1

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

Pancreas

Exocrine, enzymatic Acinar cells�Endocrine, hormonal-ISLET OF LANGERHANS Alpha cells- Glucagon Beta cells -Insulin, proinsulin, amylin� Delta cells -Somatostatin, � F cells- pancreatic polypeptide

Endocrine functions of the pancreas

Regulation of storage and use of carbohydrates, �fats and protein within liver, muscle and adipose tissue

Facilitation of cellular storage of nutrients �following a meal

Release of metabolic substrates during fasting�

ISLET OF LANGERHANS-paracrine regulation

Insulin-Synthesis and metabolism

Synthesized as a preproinsulin� After cleavage of � signal sequence proinsulin folds and forms S-S bonds In proinsulin A and B chains are � connected by a C peptide Cleavage of C peptide forms� final product Species differences: biologic activities� overlap but antigenic activities don’t

Synthesis of insulin

Chromosome no-11 Involves all steps of protein synthesis.The signal sequence attaches mRNA to REM. Endopeptidase breaks down the prepro-Ipro-II Secretory vesicles- Insulin+c peptide+ endopeptidase+Zn.

Release of insulin

GLUT-2 present on ß cells,liver, intestine, kidney-facilitated transportation.(B CELL LIKES GLUT2)

GlucoseG -6-Po4glycolysis pathwaypyruvic acid TCA cycleATP synthesis.

Release of Insulin

ATP decreases ADP levelsclosing of ATP dependent K channels K inside cell-60mvolts -50mvactivation of voltage dependent Ca channels intracellular Cavesicles move towards membranerelease of insulin.

Meglitinides

Insulin

Polypeptide consisting of an A and B chain of 21 and 30 aa Two chains are linked by a pair of S-S bonds� An intrachain S-S bond connects 6th and 11th aa �

within A chain Forms a dimer with 2 Zn ions� Hexameric form

Mechanism of insulin

Pharmacological actions

RAPID EFFECT

Promotes the uptake & storage of glucose,fats, & protein-effects on liver,muscles and adipose tissue

Carbohydrate Metb lipid metabolism

Protein metabolism

LONG TERM EFFECT

Gene transcription Cell proliferation

and differenciation Protein synthesis Growth regulation

Effect on Carbohydrate Metabolism

Promotes Muscle Glucose Uptake and Metabolism Storage of Glycogen in Muscle Promotes Liver Uptake, Storage and Use of Glucose

Mechanisms: inactivates liver phosphorylase causes enhanced uptake of glucose from the blood

by the liver cells -by increasing the activity of the enzyme glucokinase

Effect on Fat Metabolism

Insulin promotes Fat Synthesis and Storage

Synthesis- Insulin promotes glucose transport through the cell membrane into the fat cells

Storage -Adipose Cells-Insulin inhibits the action of hormone-sensitive lipase

Insulin deficiency causes increase metabolic use of fat causing lipolysis of storage fat and release of free fatty acids increase plasma cholesterol and phospholipid excess usage of fats during insulin lack causes ketosis and acidosis

Effect on Protein Metabolism

insulin promotes protein synthesis and storage stimulates transport of amino acids into the cells

(valine, leucine, isoleucine, tyrosine, phenylalanine) increases the translation of messenger RNA, forming

new proteins increases the rate of transcription of DNA genetic

sequences in cell nuclei inhibits catabolism of proteins depresses the rate of gluconeogenesis

Type 1 Diabetes:

Impaired or absent ß cell function: insulin secretion

The insulin deficiency results in unacceptable blood glucose control

Type 2 Diabetes:

Impaired ß cell function: insulin secretion

Impaired insulin action: insulin resistance

Results in unacceptable blood glucose control

Type 1 & 2 Diabetes:

Minimizing the complications of diabetes requires: Early diagnosis and treatment of diabetes Maintaining HbA1C level < 7%

Achieving HbA1C < 7% requires control of post-prandial and fasting hyperglycemia

Type 3 DM

Chronic pancreatitis Chronic drug therapy- glucocorticoids,

thiazides, protease inhibitors

Type 4 DM

Gestational diabetes mellitus Last trimester of pregnancy

Glycosylated haemoglobin

Integrated measure of glycaemic control

Non-enzymatic glycosylation of proteins

Rate of glycosylation is directly proportional to glucose concentration

Insulins use and charecteristics

Beef insulin Pork insulin Insulin by recombinant DNA

technology Human insulin

Insulin

Proinsulin and insulin High molecular weight polypeptide Metabolism Degraded within the liver and kidneys� 80% metabolized in the liver-H.insulinase� Half-life of about 5 minutes� Degraded by hepatic glutathione insulin �

dehydrogenase Enzyme disrupts S-S bonds�

u

Ultra short acting insulin

Insulin lispro Insuin aspart Insulin glulisine-CSII Rapid absorption from subcutaneous

tissue

Short acting insulin

Regular insulin Prompt insulin-Zn suspension recombinant DNA tech NPH or isophane insulin

Intermediate acting insulin NPH or isophane insulin Rapid absorption and sustained

action

Long acting insulin- not given IV

INSULIN GARGINE

Long acting insulin analogue

Soluble at pH 4

INSULIN DETRIMER

Has fatty acid side chain Slow and sustained release

Therapeutic uses

Type 1 DM Diabetic keto acidosis Non-ketotic hyperglycemia

Adverse effects

Hypoglyceminia Lipodystrophy Allergic manifestations Insulin resistance >100 units/day

THANK YOU