pre-pro-PTH with an additional 31 amino acids and a pro-PTH with an additional
6 amino acids only. Parathyroid hormone increases the serum Ca^2 +content and decreases
the inorganic phosphate content of the body by inhibiting renal phosphate absorption
and mobilizing Ca^2 +from bone. It therefore has an action opposite to that of calcitonin.
Both hormones act through the production of cAMP, but at different receptors in dif-
ferent zones of the bones and kidneys. Teriparatide acetate is a synthetic polypeptide
constructed from the N-terminal 34 amino acid residues of PTH; this peptide possesses
the full structural complement necessary for bioactivity. It is used as a diagnostic tool
during the clinical evaluation of patients with hypocalcemia due to hypoparathyroidism.
5.20 PEPTIDE HORMONES OF THE PANCREAS:
INSULIN AND GLUCAGON
The homeostatic regulation of nutrient levels is a basic biochemical task that is currently
not well understood. Three peptide hormones occupy a central role in this regulation of
carbohydrate, lipid, and amino acid metabolism: insulin, glucagon, and somatostatin. A
lack of insulin leads to diabetes mellitus,characterized by high blood glucose levels,
excretion of glucose in the urine (hence mellitus: “honeyed”), and failure to utilize car-
bohydrates and lipids. The disease is invariably fatal if untreated. Recently, hypotheses
of immunological and viral origin of diabetes are being examined.
Whereas insulin causes hypoglycemia, the other pancreatic hormone, glucagon,
mobilizes glucose from its stores and causes hyperglycemia. Somatostatin, originally
discovered as a hypothalamic hormone that inhibits growth-hormone release, is also
found in the pancreas, where it inhibits the secretion of both insulin and glucagon. The
interrelationship of these three hormones may ultimately be central to long-term treat-
ment strategies for diabetes.
5.20.1 Insulin5.20.1.1 Insulin: Structure, Metabolism, and Receptors
Structure. In 1916, Schafer discovered that the βcells of the “islets of Langerhans”
in the pancreas secrete an antidiabetic substance, which he named insulin (“of an
islet”). This was followed by the isolation of the peptide by Banting and Best in 1922,
its sequencing by Sanger in 1955, and its total synthesis by several groups in the early
1970s. The cloning of the human insulin gene and its transfer into bacteria has been
achieved, and human insulin is now produced by fermentation technology.
Insulin is synthesized by the pancreatic βcells in the form of proinsulin (5.113), in
which a connecting “C-peptide” consisting of amino acids 31–60 joins the A chain at
A^1 through an Arg–Lys, to connect with B^30 through an Arg–Arg fragment. In this way
364 MEDICINAL CHEMISTRY