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CHAPTER 41 Pancreatic Hormones & Antidiabetic Drugs 749

K channel Sulfonylurea drugs
+
– (block, depolarize)

(Closes channel, K +
depolarizes cell)

Glucose
transporter ATP
Ca channel
2+
GLUT2
(depolarization
Glucose Metabolism – + opens channel)
Ca 2+ Ca 2+
Insulin

Exocytosis

Insulin
FIGURE 41–2 One model of control of insulin release from the pancreatic beta cell by glucose and by sulfonylurea drugs. In the resting
cell with normal (low) ATP levels, potassium diffuses down its concentration gradient through ATP-gated potassium channels, maintaining the
intracellular potential at a fully polarized, negative level. Insulin release is minimal. If glucose concentration rises, ATP production increases,
potassium channels close, and depolarization of the cell results. As in muscle and nerve, voltage-gated calcium channels open in response to
depolarization, allowing more calcium to enter the cell. Increased intracellular calcium results in increased insulin secretion. Insulin secreta-
gogues close the ATP-dependent potassium channel, thereby depolarizing the membrane and causing increased insulin release by the same
mechanism.

and adipose tissue. The receptors bind insulin with high specificity message and results in multiple effects, including translocation of
and affinity in the picomolar range. The full insulin receptor con- glucose transporters (especially GLUT 4, Table 41–2) to the cell
sists of two covalently linked heterodimers, each containing an α membrane with a resultant increase in glucose uptake; increased
subunit, which is entirely extracellular and constitutes the recogni- glycogen synthase activity and increased glycogen formation; mul-
tion site, and a β subunit that spans the membrane (Figure 41–3). tiple effects on protein synthesis, lipolysis, and lipogenesis; and
The β subunit contains a tyrosine kinase. The binding of an activation of transcription factors that enhance DNA synthesis
insulin molecule to the α subunits at the outside surface of the and cell growth and division.
cell activates the receptor and through a conformational change Various hormonal agents (eg, glucocorticoids) lower the affin-
brings the catalytic loops of the opposing cytoplasmic β subunits ity of insulin receptors for insulin; growth hormone in excess
into closer proximity. This facilitates mutual phosphorylation of increases this affinity slightly. Aberrant serine and threonine
tyrosine residues on the β subunits and tyrosine kinase activity phosphorylation of the insulin receptor β subunits or IRS mol-
directed at cytoplasmic proteins. ecules may result in insulin resistance and functional receptor
The first proteins to be phosphorylated by the activated recep- down-regulation.
tor tyrosine kinases are the docking proteins: insulin receptor
substrates (IRS). After tyrosine phosphorylation at several critical Effects of Insulin on Its Targets
sites, the IRS molecules bind to and activate other kinases subserv-
ing energy metabolism—most significantly phosphatidylinositol- Insulin promotes the storage of fat as well as glucose (both sources
3-kinase—which produce further phosphorylations. Alternatively, of energy) within specialized target cells (Figure 41–4) and influ-
they may stimulate a mitogenic pathway and bind to an adaptor ences cell growth and the metabolic functions of a wide variety of
protein such as growth factor receptor–binding protein 2, which tissues (Table 41–3).
translates the insulin signal to a guanine nucleotide-releasing
factor that ultimately activates the GTP binding protein, Ras, ■ GLUCAGON
and the mitogen-activated protein kinase (MAPK) system. The
particular IRS-phosphorylated tyrosine kinases have binding
specificity with downstream molecules based on their surround- Chemistry & Metabolism
ing 4–5 amino acid sequences or motifs that recognize specific Src Glucagon is synthesized in the alpha cells of the pancreatic
homology 2 (SH2) domains on the other protein. This network islets of Langerhans (Table 41–1). Glucagon is a peptide—
of phosphorylations within the cell represents insulin’s second identical in all mammals—consisting of a single chain of