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9780521704632c24 CUFX213A/Peck 9780521618168 December 29, 2007 15:7
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Drugs used in DiabetesInsulin
Sulphonylureas
Biguanides
Other antidiabeticsInsulin
Physiology
Human insulin is a polypeptide of 51 amino acids and is formed by the removal of a
connecting or ‘C’ peptide (34 amino acids) from pro-insulin. It has A and B chains,
which are joined by two disulphide bridges. A third disulphide bridge connects two
regions of the A chain.
Glucose forms the most potent stimulus for insulin release. It enters theβ-cells of
the islets of Langerhans in the pancreas, resulting in an increase in ATP, which closes
K+channels. This causes depolarization and Ca^2 +influx through voltage-sensitive
Ca^2 +channels, which triggers insulin release. By way of negative feedback the K+
channels are re-opened. In health there is a continuous basal insulin release, which
is supplemented by bursts when plasma glucose levels rise. Following its release it
is carried in the portal circulation to the liver (its main target organ) where about
one-half is extracted and broken down, as glucose is converted to glycogen.
Insulin binds to theαsubunit of the insulin receptor, which consist of twoαand
twoβsubunits that span the cell membrane. Once bound, the whole complex is
internalized. The mechanism by which this complex produces its effects is unclear
but the tyrosine kinase activity of theβsubunit appears important.
Insulin affects carbohydrate, fat and protein metabolism. It promotes hepatic (and
extrahepatic) uptake of glucose and subsequently facilitates the actions of enzymes
required to convert glucose into glycogen. Glycogenolysis is inhibited. Fat deposition
is also increased by the promotion of hepatic fatty acid synthesis and subsequent
storage as triglycerides. Lipolysis is inhibited. The storage of amino acids as proteins
(anabolism) is promoted and catabolism inhibited.Preparations
Insulin used to be extracted from porcine or beef pancreas but now is almost entirely
produced by recombinant DNA technology usingE.coli.Preparations are classified