Top 4 basic functions of insulin which every medico should know

Insulin does the following things in carbohydrates metabolism:

1. promote glucose uptake in skeletal muscle, cardiac muscle, and adipose tissue.
2. Stimulate glycogen formation in skeletal muscle and liver
3. Inhibit Glycogen degradation in skeletal muscle and liver
4. Promote liver uptake, storage, and use of glucose
5. Stimulate Conversion of excess glucose into fatty acid and inhibits gluconeogenesis in the liver

 

In fat metabolism

1. Promotes fat synthesis and storage
2. Inhibit lipolysis in adipose tissue
3. Decreases the cholesterol and phospholipid concentration

In protein metabolism

 

 

Promotes protein synthesis via

• Transport of amino acid into the cell
• Increase the transcription rate
• Increase the translation rate
• Inhibit protein catabolism
• Suppression of gluconeogenesis

Insulin and growth hormone interact synergistically to promote growth.

mechanism of action of insulin

Insulin Receptor is a member of the receptor tyrosine kinase gene family. Most of the insulin's action on metabolism involves activation of protein kinase Akt, which has clear pleiotropic action on cell metabolism. The insulin receptor is expressed on the cell membrane as homeo dimers, with each monomer containing the tyrosine kinase domain on the cytosolic side. Binding of insulin to the receptor induces cross phosphorylation of subunits. The insulin receptor substrate protein then bounds these phosphotyrosine residues.The insulin receptor phosphorylates the insulin receptor substrate protein on specific tyrosine residue, which then recruits phosphoinositide 3 kinases to the insulin receptor substrate protein bound to the insulin receptor.Phosphoinositide 3-kinase converts Phosphoinositol 4 5 bisphosphates to phosphoinositide 3, 4,5 -trisphosphate.PIP3 then recruits proteins to the membrane.In this pathway, PIP3 recruits proteins Akt protein kinase to the cell membrane, where it becomes activated. this pleiotropic Akt protein kinase signaling orchestrates the numerous metabolic actions of insulin on hepatocyte, muscles, and adipose tissue.

 

 

Translocation of glut4  glucose Transporter to the cell membrane so that glucose can enter skeletal and adipose tissue

 Protein phosphatases which in turn regulate the activity of multiple metabolic enzymes in all insulin and target cells

Activation of protein Complex mechanistic  target of rapamycin complex Type 1 which promotes protein synthesis and inhibit protein degradation via proteasomes

Activation of transcription factor sterol response element-binding protein Type 1

sterol response element-binding protein Type 1 is important for insulin action on the liver where it orchestrates glycolysis  and de novo lipogenesis for the production of phospholipids, fatty acids, and triacylglycerol from excessive ingested glucose and fructose

Activation of transcription factor FOXO Type 1. Akt mediated phosphorylation of fox Type 1 promotes the nuclear explosion of FOXO 1. In the absence of insulin signaling, fox Type 1 induces expression of genes encoding gluconeogenic enzymes and proteins involved in hepatic, very-low-density lipoprotein assembly, and export.

 

 

metabolism and half-life of insulin

Insulin has a short Half-Life of about 5 minutes and is cleared rapidly from the circulation. It is degraded by an insulin-degrading enzyme, also called insulinase, produced by the liver-kidney and other peripheral tissues. Because insulin is secreted into the pathetic portal vein, it is exposed to liver insulin-degrading enzyme, also called insulinase, before it and enters the peripheral circulation. About half of the insulin is degraded before leaving the liver; hence peripheral tissues are exposed to significantly less serum concentration than the liver. The Recombinant human insulin and insulin analogs promote the insulin action very quickly because they are exposed to peripheral tissues much more than normal concentration.

 

 

factors /conditions that control the insulin secretion

Factors that increase insulin secretion

1. The increased blood glucose level
2. increased blood free fatty acid level
3. increased blood amino acid level
4. GIT hormones like gastrin cholecystokinin secretingastric inhibitory peptide
5. glucagon growth hormone cortisol
6. parasympathetic stimulation like acetylcholine
7. beta-adrenergic stimulation like epinephrine
8. insulin resistance like obesity
9. sulphonylurea drugs like glyburide and tolbutamide

 

 

Fctors that decrease insulin secretion

1. Decrease blood glucose level
2. decrease blood amino acid level
3. decrease blood free fatty acid level
4. fasting
5. somatostatin
6. alpha-adrenergic activity
7. leptin

 

Control of insulin secretion by blood glucose level and others

1)Increased blood glucose concentration is the primary controller of insulin secretion. The Beta cells have many glucose Transporters that permit glucose influx that is proportional to blood glucose concentration in the physiological range. Once inside the cells, glucose is phosphorylated to glucose 6 phosphate by glucokinase. This phosphorylation is the rate-limiting step .the glucose 6 phosphates are oxidized to form adenosine triphosphate ATP, inhibiting the ATP sensitive potassium channels.Closure of potassium channels depolarizer cell membrane so that voltage-gated Calcium channel can open which are sensitive to changes in membrane voltage so that calcium can enter the cell and it stimulates the fusion of docked insulin-containing bicycle with the cell membrane and secretion of insulin into an extracellular fluid by exocytosis

2)other nutrients like a minus amino acid, specifically arginine lysine, are also metabolized by Beta cells of the pancreas to increase the intracellular concentration of ATP; this ATP inhibits the ATP sensitive potassium channel so that insulin can be secreted by exocytosis

3)some hormones just like glucagon, growth hormone,glucose-dependent insulinotropic peptide also called a gastric inhibitory peptide, and acetylcholine raises the intracellular concentration of calcium through another signaling pathway, but glucose is the major and the primary stimulus for secretion of insulin by Beta cells of the pancreas

4) the other hormones, including somatostatin, norepinephrine activate Alpha-adrenergic receptors that secretion of insulin is inhibited. This is because pancreas tissues like islets of Langerhans are richly innervated with the sympathetic and parasympathetic nervous system. The stimulation of the parasympathetic nerve to the pancreas can increase insulin secretion during the hyperglycemic condition; on the other hand, sympathetic stimulation to the pancreas can increase glucagon secretion and decrease insulin secretion hypoglycemia. The glucose concentrations are detected by specialized neurons of the hypothalamus and brainstem as well as glucose-sensing cells in peripheral location, for example, liver

5)sulphonylurea drugs like glyburide tolbutamide stimulate insulin secretion by binding to the ATP sensitive potassium channels. So, beta cells of the pancreas will be depolarised easily,y and insulin will be secreted. These drugs are used in the treatment of diabetes mellitus type 2.