Insulin

INTRODUCTION:
  • Insulin is a peptide hormone, produced by beta cells of the pancreas, and is central to regulating carbohydrate and fat metabolism(Activate lipoprotein lipase) in the body.
  • In fetus the insulin secretion begins by 3rd month
  • Insulin causes cells in the liver,RBC, skeletal muscles, and fat tissue to absorb glucose from the blood.
  • In the liver and skeletal muscles, glucose is stored as glycogen, and in fat cells (adipocytes) it is stored as triglycerides.
  • When control of insulin levels fails, diabetes mellitus can result.
  • Insulin secretion seen in Glucose, Vagal stimulation & Acetylcholine
  • Insulin does not cross placenta
  • As a consequence, insulin is used medically to treat some forms of diabetes mellitus.
  • Newer insulins are neutral
  • Recombinant human insulin is made by CDNA of pancreatic cell
  • Chromium is required for proper effects of Insulin
STRUCTURE OF INSULIN:
  • Human insulin consists of 51aa in two chains connected by 2 disulfide bridges (a single gene product cleaved into 2 chains during post-translational modification).
  • T1/2~5-10 minutes, degraded by glutathione-insulin transhydrogenase (insulinase) which cleaves the disulfide links.
  • Bovine insulin differs by 3aa, pork insulin differs by 1aa.
  • Insulin is stored in a complex with Zn2+ions.
REGULATION OF INSULIN:
  • Insulin secretion is decreased by Somatostatin
  • The endogenous production of insulin is regulated in several steps along the synthesis pathway:
  1. At transcription from the insulin gene
  2. In mRNA stability
  3. At the mRNA translation
  4. In the post translational modifications
ACTION:
Rapid (seconds)
  • Increased transport of glucose, amino acids, and K+ into insulin-sensitive cells
Intermediate (minutes)
  • Stimulation of protein synthesis
  • Inhibition of protein degradation
  • Activation of glycolytic enzymes and glycogen synthase<
  • br> Inhibition of phosphorylase and gluconeogenic enzymes
Delayed (hours)
  • Increase in mRNAs for lipogenic and other enzymes
  • Insulin promotes lipogenesis by
  1. Decreasing intracellular cAMP,
  2. Increasing the transport of glucose into the cell &
  3. Increasing activity of acetyl-CoA carboxylase
EFFECT OF INSULIN ON GLUCOSE UPTAKE AND METABOLISM:
Insulin secretion is normally stimulated by GLP-1
Insulin binds to its receptor

Starts many protein activation cascades

Glycogen synthesis

These include translocation of Glut-4 transporter to the plasma membrane and influx of glucose

Glycolysis

Triglyceride

MECHANISM OF ACTION:
  • Insulin acts on specific receptors located on the cell membrane of practically every cell, but their density depends on the cell type: liver and fat cells are very rich.
  • The insulin receptor is a receptor tyrosine kinase (RTK) which is a heterotetrameric glycoprotein consisting of 2 extracellular α and 2 transmembrane β subunits linked
  • together by disulfide bonds, orienting across the cell membrane as a heterodimer
  • It is oriented across the cell membrane as a heterodimer.
  • The α subunits carry insulin binding sites, while the β subunits have tyrosine kinase activity.


  • Insulin stimulates glucose transport across cell membrane by ATP dependent translocation of glucose transporter GLUT4 to the plasma membrane.
  • The second messenger PIP3 and certain tyrosine phosphorylated guanine nucleotide exchange proteins play crucial roles in the insulin sensitive translocation of GLUT4 from
  • cytosol to the plasma membrane, especially in the skeletal muscles and adipose tissue.
  • Over a period of time insulin also promotes expression of the genes directing synthesis of GLUT4.
  • Increased ratio of insulin to glucagon causes Decreased levels of cyclic AMP
  • Genes for a large number of enzymes and carriers are regulated by insulin through Ras/Raf and MAP-Kinase as well as through the phosphorylation cascade.
DEGRADATION OF INSULIN:
  • The internalized receptor-insulin complex is either degraded intercellularly or returned back to the surface from where the insulin is released extracellularly.
  • The relative preponderance of these two processes differs among different tissues: maximum degradation occurs in liver, least in vascular endothelium.
  • Insulin clearance closely resembles G.F.R
DIFFERENT TYPES OF INSULIN PREPARATIONS:

Type Appearance Onset (hr) Peak (hr) Duration (hr)
RAPID ACTING
Insulin lispro Clear 0.2-0.3 1-1.5 3-5
Insulin aspart Clear 0.2-0.3 1-1.5 3-5
Insulin glulisine Clear 0.2-0.4 1-2 3-5
SHORT ACTING
Regular (soluble) insulin(I.V.) Clear 0.5-1 2-3 6-8
INTERMEDIATE ACTING
Insulin zinc suspension or Lente Cloudy 1-2 8-10 20-24
NPH or isophane Insulin Cloudy 1-2 8-10 20-24
LONG ACTING
Insulin glargineand Insulin detemir Clear Glargine: 2-4Detemir: 1-4 _ _ Glargine:24 (never mixed)
Detemir:20-24
USES:
  • Infusion of insulin + glucose fastest way to reduce the hyperkalemia
  • DIABETES MELLITUS:
  1. Insulin is effective in all forms of diabetes mellitus and is a must for type 1 cases, as well as for post pancreatectomy diabetes and gestational diabetes.
  2. Many type 2 cases can be controlled.
  3. Insulin therapy is generally started with regular insulin given s.c. before each major meal.
  4. The requirement is assessed by testing urine or blood glucose levels .
  5. Basal insulin in bolus basal regimen in children is 25-50%
  • DIABETIC KETOACIDOSIS (DIABETIC COMA)
  1. Regular insulin is used to rapidly correct the metabolic abnormalities.
  2. Usually within 4-6 hours blood glucose reaches 300 mg/dl. Then the rate of infusion is reduced to 2-3 U/hr
  3. The drug of choice in a 50 year old patient presenting with hyperglycemia and ketoacidosis is Regular Insulin HYPEROSMOLAR (NONKINETIC HYPERGLYCAEMIC COMA)
  4. This usually occurs in elderly type 2 cases. The cause is obscure.
  5. The general principles of treatment are the same as for ketoacidotic coma, except that faster fluid replacement is to be instituted as alkali is usually not required. 
ADVERSE EFFECT:
  • Hypoglycemia
  • Local reactions: Swelling erythema, stinging, injection site lipodystrophy.
  • Allergy: Urticaria, angioedema and anaphylaxis.
  • Edema
  • Rapid infusion of insulin causes Hypokalemia
Exam Question
  • Insulin performs Glycogen synthesis,Glycolysis & Lipogenesis
  • Insulin clearance closely resembles G.F.R
  • Human insulin differs from beef insulin by 1 amino acid residue
  • Rapid infusion of insulin causes Hypokalemia
  • Insulin is Required for transport of glucose, aminoacid, K+ & Na
  • In fetus the insulin secretion begins by 3rd month
  • Increased ratio of insulin to glucagon causes Decreased levels of cyclic AMP
  • Insulin promotes lipogenesis by Decreasing intracellular cAMP, Increasing the transport of glucose into the cell & Increasing activity of acetyl-CoA carboxylase Insulin secretion seen in Glucose, Vagal stimulation & Acetylcholine
  • Insulin activate lipoprotein lipase to aid fat metabolism
  • Insulin facilitate glucose uptake in Liver,RBC & Kidney
  • Insulin acts on glucose metabolism by permeability across cell membrane against glucose gradient
  • Sulfonylurea is shifted to insulin in pregnant lady because Insulin does not cross placenta
  • Newer insulins are neutral
  • Regular insulin can be give through IV
  • Lispro,Aspart & Glulisine short and rapid acting insulin
  • Long acting insulin is Insulin glargine
  • NPH insulin is an intermediate acting insulin
  • Glargine is never mixed with other insulins
  • Edema, Hypoglycemia & Lipodystrophy are side effects of insulin
  • Fetal growth is maximally affected by Insulin
  • Caudal regression in a newborn is specific for maternal insulin dependent diabetes mellitus
  • Percentage of dose given as basal insulin in bolus basal regimen in children is 25-50%
  • Infusion of insulin + glucose fastest way to reduce the hyperkalemia
  • The drug of choice in a 50 year old patient presenting with hyperglycemia and ketoacidosis is Regular Insulin
  • Recombinant human insulin is made by CDNA of pancreatic cell
  • Chromium is required for proper effects of Insulin
  • Plasma half life of insulin is 10 minutes
  • Glucose-6-phosphatase is increased in low insulin/glucagon level
  • Insulin secretion is normally stimulated by GLP-1
  • Insulin secretion is decreased by Somatostatin
  • Crystallization and storage of insulin requires Zn++
Don't Forget to Solve all the previous Year Question asked on Insulin