Actions of Insulin

ACTIONS OF INSULIN

The overall effects of insulin are to favour storage of fuel. The actions of insulin and the results of its deficiency can be summarized as:

1. Insulin facilitates glucose transport across cell membrane; skeletal muscle and fat are highly sensitive. The availability of glucose intracellularly is the limiting factor for its utilization in these and some other tissues. However, glucose entry in liver, brain, RBC, WBC and renal medullary cells is largely independent of insulin. Ketoacidosis interferes with glucose utilization by brain → diabetic coma. Muscular activity induces glucose entry in muscle cells without the need for insulin. As such, exercise has insulin sparing effect.

The intracellular pool of vesicles containing glucose transporter glycoproteins GLUT4 (insulin activated) and GLUT1 is in dynamic equilibrium with the GLUT vesicles inserted into the membrane. This equilibrium is regulated by insulin to favour translocation to the membrane. Moreover, on a longterm basis, synthesis of GLUT4 is upregulated by insulin.

2. The first step in intracellular utilization of glucose is its phosphorylation to form glucose6phosphate. This is enhanced by insulin through increased production of glucokinase. Insulin facilitates glycogen synthesis from glucose in liver, muscle and fat by stimulating the enzyme glycogen synthase. It also inhibits phosphorylase → decreased glycogenolysis in liver.

3. Insulin inhibits gluconeogenesis (from protein, FFA and glycerol) in liver by gene mediated decreased synthesis of phosphoenol pyruvate carboxykinase. In insulin deficiency, proteins and amino acids are funneled from peripheral tissues to liver where these are converted to carbohydrate and urea. Thus, in diabetes there is underutilization and over production of glucose → hyperglycaemia → glycosuria.

4. Insulin inhibits lipolysis in adipose tissue and favours triglyceride synthesis. In diabetes increased amount of fat is broken down due to unchecked action of lipolytic hormones (glucagon, Adr, thyroxine, etc.) → increased FFA and glycerol in blood → taken up by liver to produce acetylCoA. Normally acetylCoA is resynthesized to fatty acids and triglycerides, but this process is reduced in diabetics and acetyl CoA is diverted to produce ketone bodies (acetone, acetoacetate, βhydroxybutyrate). The ketone bodies are released in blood—partly used up by muscle and heart as energy source, but when their capacity is exceeded, ketonaemia and ketonuria result.

5. Insulin enhances transcription of vascular endothelial lipoprotein lipase and thus increases clearance of VLDL and chylomicrons.

6. Insulin facilitates AA entry and their synthesis into proteins, as well as inhibits protein breakdown in muscle and most other cells. Insulin deficiency leads to protein breakdown → AAs are released in blood → taken up by liver and converted to pyruvate, glucose and urea. The excess urea produced is excreted in urine resulting in negative nitrogen balance. Thus, catabolism takes the upper hand over anabolism in the diabetic state.

Most of the above metabolic actions of insulin are exerted within seconds or minutes and are called the rapid actions. Others involving DNA mediated synthesis of glucose transporter and some enzymes of amino acid metabolism have a latency of few hours—the intermediate actions. In addition insulin exerts major longterm effects on multiplication and differentiation of cells.