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:
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.
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