Page 764 - Basic _ Clinical Pharmacology ( PDFDrive )

750 SECTION VII Endocrine Drugs

Vagus

α Insulin Liver
subunits Insulin molecule
+
Receptor
Pancreas
β +
subunits
Substrate
Extracellular
Betacytotropic
hormones Fat

Cytoplasm
Tyrosine
kinase Muscle
domains
P
Intestine
FIGURE 41–4 Insulin promotes synthesis (from circulating nutrients)
P
and storage of glycogen, triglycerides, and protein in its major target tissues: liver,
ATP fat, and muscle. The release of insulin from the pancreas is stimulated by increased
Tyr
blood glucose, incretins, vagal nerve stimulation, and other factors (see text).
IRS

Tyr – P
Glucagon is extensively degraded in the liver and kidney as
ADP well as in plasma and at its tissue receptor sites. Its half-life in
IRS plasma is between 3 and 6 minutes, which is similar to that of
insulin.
+ +
Phosphatidylinositol-3 MAP kinase Pharmacologic Effects of Glucagon
kinase pathway pathway
A. Metabolic Effects
The first six amino acids at the amino terminal of the gluca-
FIGURE 41–3 Schematic diagram of the insulin receptor het- gon molecule bind to specific G protein–coupled receptors on
s
erodimer in the activated state. IRS, insulin receptor substrate; MAP, liver cells. This leads to an increase in cAMP, which facilitates
mitogen-activated protein; P, phosphate; Tyr, tyrosine.
catabolism of stored glycogen and increases gluconeogenesis and
ketogenesis. The immediate pharmacological result of glucagon
29 amino acids, with a molecular weight of 3485. Selective infusion is to raise blood glucose at the expense of stored hepatic
proteolytic cleavage converts a large precursor molecule of glycogen. There is no effect on skeletal muscle glycogen, presum-
approximately 18,000 MW to glucagon. One of the precur- ably because of the lack of glucagon receptors on skeletal muscle.
sor intermediates consists of a 69-amino-acid peptide called Pharmacological amounts of glucagon cause release of insulin
glicentin, which contains the glucagon sequence interposed from normal pancreatic beta cells, catecholamines from pheochro-
between peptide extensions. mocytoma, and calcitonin from medullary carcinoma cells.

TABLE 41–2 Glucose transporters.

Glucose K m
Transporter Tissues (mmol/L) Function
GLUT 1 All tissues, especially red cells, brain 1–2 Basal uptake of glucose; transport across the blood-brain barrier
GLUT 2 Beta cells of pancreas; liver, kidney; gut 15–20 Regulation of insulin release, other aspects of glucose homeostasis
GLUT 3 Brain, placenta <1 Uptake into neurons, other tissues
GLUT 4 Muscle, adipose ~5 Insulin-mediated uptake of glucose
GLUT 5 Gut, kidney 1–2 Absorption of fructose